JP4187462B2 - Pharmaceutical use of N-carbamoylazole derivatives - Google Patents
Pharmaceutical use of N-carbamoylazole derivatives Download PDFInfo
- Publication number
- JP4187462B2 JP4187462B2 JP2002135555A JP2002135555A JP4187462B2 JP 4187462 B2 JP4187462 B2 JP 4187462B2 JP 2002135555 A JP2002135555 A JP 2002135555A JP 2002135555 A JP2002135555 A JP 2002135555A JP 4187462 B2 JP4187462 B2 JP 4187462B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- triazole
- dimethylcarbamoyl
- derivative
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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Description
【0001】
【発明の属する技術分野】
本発明は、1−カルバモイルアゾール誘導体のDPPIV阻害作用に基づく医薬としての用途、およびそれを有効成分とする医薬組成物に関する。
【0002】
【従来の技術】
ジペプチジルペプチダーゼIV(Dipeptidyl peptidase-IV:DPPIV)は、ポリペプチド鎖の遊離N末端からX−Proのジペプチドを特異的に加水分解するセリンプロテアーゼの1種である。
食後に腸管より分泌されるグルコース依存的インスリン分泌刺激ホルモン、つまり、インクレチン(GLP−1;Glucagon-Like Peptide-1 and GIP;Glucose-dependent Insulinotropic Polypeptide)は、DPPIVによって、速やかに分解、不活性化される。このDPPIVによる分解を抑制することで、インクレチン(GLP−1及びGIP)による作用は増強され、グルコース刺激による膵β細胞からのインスリン分泌は亢進する。その結果、経口糖負荷試験後の高血糖を改善することが明らかにされている。(Diabetologia 1999 Nov;42(11):1324-31)。また、GLP−1が食欲、摂食量抑制効果への関与、またGLP−1の膵β細胞の分化、増殖促進作用にもとづくβ細胞保護作用も明らかにされている。
【0003】
これらのことよりDPPIV阻害剤が、肥満、糖尿病などのGLP−1、GIPが関与する疾患に対する有用な治療剤、予防剤となりうることが期待できる。
【0004】
さらに、以下に記す様々な疾患とジペプチジルペプチダーゼIVの関連性が報告されており、これらのことからもDPPIV阻害がそれらの治療剤となりうることが期待できる。
(1)AIDSの予防、治療剤(Science, 262, 2045-2050, 1993.)
(2)骨粗鬆症の予防、治療剤(Clinical chemistry, 34, 2499-2501, 1988.)
(3)消化管障害(intestinal disorder)の予防、治療剤(Endcrinology, 141, 4013-4020, 2000.)
(4)糖尿病、肥満、高脂血症の予防、治療剤(Diabetes, 47, 1663-1670, 1998, Life Sci;66(2):91-103, 2000)
(5)血管新生の予防、治療剤(Agents and actions, 32, 125-127, 1991.)
(6)不妊症の予防、治療剤(WO00/56296)
(7)炎症性疾患、自己免疫疾患、慢性関節リウマチの予防、治療剤(2001, 166, 2041-2048, The Journal of Immunology.)
(8)ガンの予防、治療剤(Br J Cancer 1999 Mar;79(7-8):1042-8, J Androl 2000 Mar-Apr;21(2):220-6)
【0005】
米国特許5510320号、米国特許5338720号、米国特許5258361号、米国特許3308131号、米国特許5424279号、特開平5−255318号公報、特開平9−143181号公報、特開平11−80137号公報に示されるように、1ーカルバモイルアゾール誘導体等は除草剤としての有用性が知られているが、DPPIV阻害作用については報告はない。
【0006】
DPPIV阻害剤としては、米国特許6303661号、米国特許6,011,155号、米国特許2001020006号、米国特許5543396号、WO00/34241等に開示があるが、構造的に本発明とは明らかに異なっている。
【0007】
【発明が解決しようとする課題】
上記のごとく、医薬として有用なDPPIV阻害化合物の提供が切望されている。しかしながら、優れたDPPIV阻害作用を示し、かつ、医薬としても有用性が高く臨床で有効に作用する化合物は未だ見出されていない。すなわち、本発明の目的は、糖尿病疾患などの治療・予防・改善剤として有用なDPPIV阻害化合物を探索し、見出すことにある。
【課題を解決するための手段】
本発明者らは上記事情に鑑みて鋭意研究を行った結果、N−カルバモイルアゾール誘導体にDPPIV阻害作用を有すること見出した。すなわち本発明の特徴は、
<1>一般式
【化5】
[式中、R1aは、C1-6アルキル基、C3-8シクロアルキル基、5ないし10員芳香族複素環式基、C6-10芳香族炭化水素環式基、4ないし10員複素環式基またはC4-13ポリシクロアルキル基を意味する;nは0〜2の整数を意味する;Wは、単結合、C1-6アルキレン基または式
【化6】
(式中、W2は窒素原子またはメチン基を意味し、mは0〜3の整数を意味し、R1bはC1-6アルキル基、C3-8シクロアルキル基、5ないし10員芳香族複素環式基、C6-10芳香族炭化水素環式基、4ないし10員複素環式基またはC4-13ポリシクロアルキル基を意味する。)で表わされる基を意味する;X1およびX2は、それぞれ独立して窒素原子またはメチン基を意味する;Zは、式
【化7】
(式中、R2aおよびR2bは、それぞれ独立してC1-6アルキル基、C2-6アルケニル基またはフェニル基を意味し、Z2は硫黄原子またはメチレン基を意味する。)で表わされる基を意味する。ただし、R1aおよびR1bは、▲1▼ハロゲン原子、▲2▼水酸基、▲3▼C2-6アルケニル基、▲4▼C2-6アルキニル基、▲5▼フェニル基、▲6▼シアノ基、▲7▼1〜3個のハロゲン原子またはC1-6アルコキシ基で置換されていてもよいC1-6アルコキシ基および▲8▼1〜3個のハロゲン原子またはC1-6アルコキシ基で置換されていてもよいC1-6アルキル基からなる群から選ばれる1から3個の置換基で置換されていてもよい。]で表わされる化合物を含有してなるジペプチジルペプチターゼIV阻害剤;
<2>Zが式
【化8】
(式中、R2bは、C1-6アルキル基、C2-6アルケニル基またはフェニル基を意味する。)で表わされる基である前記<1>記載のジペプチジルペプチターゼIV阻害剤;
<3>R1aがフェニル基または4−ピラゾリル基である前記<1>または<2>記載のジペプチジルペプチターゼIV阻害剤;
<4>X1が窒素原子であり、X2がメチン基である前記<1>から<3>いずれか1記載のジペプチジルペプチターゼIV阻害剤;
<5>X1およびX2がメチン基である前記<1>から<3>いずれか1記載のジペプチジルペプチターゼIV阻害剤;
<6>nが1または2である前記<1>から<5>いずれか1記載のジペプチジルペプチターゼIV阻害剤;
<7>糖尿病疾患の治療・予防剤である前記<1>記載のジペプチジルペプチターゼIV阻害剤;
<8>肥満の治療・予防剤である前記<1>記載のジペプチジルペプチターゼIV阻害剤;
<9>高脂血症治療剤、AIDS治療剤、骨粗鬆症治療剤、消化管障害治療剤、血管新生治療剤、不妊症治療剤、抗炎症剤、抗アレルギー剤、免疫調整剤、ホルモン調節剤、抗リウマチ剤、ガン治療剤である前記<1>記載のジペプチジルペプチターゼIV阻害剤、などに関する。
【0008】
以下に、本願明細書において記載する用語、記号等の意義を説明し、本発明を詳細に説明する。
【0009】
なお、本願明細書中においては、化合物の構造式が便宜上一定の異性体を表すことがあるが、本発明には化合物の構造上生ずる総ての幾何異性体、不斉炭素に基づく光学異性体、立体異性体、互変異性体等の異性体および異性体混合物を含み、便宜上の式の記載に限定されるものではなく、いずれか一方の異性体でも混合物でもよい。従って、分子内に不斉炭素原子を有し光学活性体およびラセミ体が存在することがあり得るが、本発明においては特に限定されず、いずれの場合も含まれる。さらに結晶多形が存在することもあるが同様に限定されず、いずれかの結晶形単一または混合物であってもよく、また、無水物であっても水和物であってもどちらでもよい。
【0010】
本明細書中において表される「C1-6アルキル基」とは、炭素数1ないし6個の直鎖状または分枝鎖状のアルキル基を意味し、具体的には例えばメチル基、エチル基、n−プロピル基、i−プロピル基、n−ブチル基、i−ブチル基、t−ブチル基、n−ペンチル基、i−ペンチル基、ネオペンチル基、n−ヘキシル基、1−メチルプロピル基、1,2−ジメチルプロピル基、2−エチルプロピル基、1−メチル−2−エチルプロピル基、1−エチル−2−メチルプロピル基、1,1,2−トリメチルプロピル基、1−メチルブチル基、2−メチルブチル基、1,1−ジメチルブチル基、2,2−ジメチルブチル基、2−エチルブチル基、1,3−ジメチルブチル基、2−メチルペンチル基、3−メチルペンチル基等があげられる。
【0011】
本明細書中において表される「C2-6アルケニル基」とは、炭素数2ないし6個の直鎖状または分枝鎖状のアルケニル基を意味し、具体的には例えばビニル基、アリル基、1−プロペニル基、イソプロペニル基、1−ブテン−1−イル基、1−ブテン−2−イル基、1−ブテン−3−イル基、2−ブテン−1−イル基、2−ブテン−2−イル基等があげられ、好ましくはアリル基である。
【0012】
本明細書中において表される「C2-6アルキニル基」とは、炭素数2ないし6個の直鎖状または分枝鎖状のアルキニル基を意味し、具体的には例えば、エチニル基、1−プロピニル基、2−プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基等があげられる。
【0013】
本明細書中において表される「C3-8シクロアルキル基」とは、炭素数3ないし8個の環状の脂肪族炭化水素基を意味し、具体的には例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基、シクロヘプテニル基などが挙げられる。
【0014】
本明細書中において表わされる「C1-6アルキレン基」とは前記定義「C1-6アルキル基」からさらに水素原子を1個除いて誘導される二価の基を意味し、具体的には例えば、メチレン基、1,2−エチレン基、1,3−プロピレン基などが挙げられ、好ましくはメチレン基である。
【0015】
本明細書中において表わされる「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を意味し、好ましくはフッ素原子、塩素原子である。
本明細書中において表される「C1-6アルコキシ基」とは、前記定義「C1-6アルキル基」が結合したオキシ基を意味し、具体的には例えばメトキシ基、エトキシ基、n−プロポキシ基、i−プロポキシ基、n−ブトキシ基、i−ブトキシ基、t−ブトキシ基、n−ペンチルオキシ基、i−ペンチルオキシ基、ネオペンチルオキシ基、n−ヘキシルオキシ基、1−メチルプロポキシ基、1,2−ジメチルプロポキシ基、2−エチルプロポキシ基、1−メチル−2−エチルプロポキシ基、1−エチル−2−メチルプロポキシ基、1,1,2−トリメチルプロポキシ基、1−メチルブトキシ基、2−メチルブトキシ基、1,1−ジメチルブトキシ基、2,2−ジメチルブトキシ基、2−エチルブトキシ基、1,3−ジメチルブトキシル基、2−メチルペンチルオキシ基、3−メチルペンチルオキシ基等があげられる。
【0016】
本明細書中において表される「C6-10芳香族炭化水素環式基」とは、炭素数6ないし10の芳香族である炭化水素環基をいい、具体的には例えばフェニル基、1−ナフチル基、2−ナフチル基などが挙げられ、好ましくはフェニル基である。
【0017】
本明細書中において表される「ヘテロ原子」とは、硫黄原子、酸素原子または窒素原子を意味する。
【0018】
本明細書中において表される「5ないし10員芳香族複素環式基」とは、環式基の環を構成する原子の数が5ないし10であり、環式基の環を構成する原子中に1から複数個のヘテロ原子を含有する芳香族性の環式基を意味する。この「5ないし10員芳香族複素環式基」における「5ないし10員芳香族複素環」とは具体的には例えば、ピリジン環、チオフェン環、フラン環、ピロール環、オキサゾール環、イソキサゾール環、チアゾール環、イソチアゾール環、イミダゾール環、トリアゾール環、ピラゾール環、フラザン環、チアジアゾール環、オキサジアゾール環、ピリダジン環、ピリミジン環、ピラジン環、インドール環、イソインドール環、インダゾール環、クロメン環、キノリン環、イソキノリン環、シンノリン環、キナゾリン環、キノキサリン環、ナフチリジン環、フタラジン環、プリン環、プテリジン環、チエノフラン環、イミダゾチアゾール環、ベンゾフラン環、ベンゾチオフェン環、ベンズオキサゾール環、ベンズチアゾール環、ベンズチアジアゾール環、ベンズイミダゾール環、イミダゾ[1、2−a]ピリジン環、ピロロピリジン環、ピロロピリミジン環、ピリドピリミジン環などが挙げられ、好ましくはピリジン環、チオフェン環、フラン環、ピロール環、オキサゾール環、イソキサゾール環、チアゾール環、イソチアゾール環、イミダゾール環、トリアゾール環、ピラゾール環、チアジアゾール環、オキサジアゾール環、ピリダジン環、ピリミジン環、ピラジン環などがあげられ、より好ましくは、ピリジン環、イソキサゾール環、チアゾール環、イソチアゾール環、イミダゾール環、トリアゾール環、ピラゾール環、ピリダジン環、ピリミジン環、ピラジン環などがあげられ、さらに好ましくは、ピリジン環、イミダゾール環、トリアゾール環、ピラゾール環、ピリダジン環、ピリミジン環、ピラジン環などがあげられる。
【0019】
「C4−13多環式脂肪族炭化水素」とは炭素数4ないし13個を有する、2以上の環からなる脂肪族炭化水素を意味する。具体的には例えば、ビシクロ[1,1,0]ブタン、スピロ[2,2]ペンタン、ビシクロ[2,1,0]ペンタン、ビシクロ[3,1,0]ヘキサン、ビシクロ[4,1,0]ヘプタン、ノルボルナン、ノルトリシクラン、クアドリシクラン、ビシクロ[3,3,0]オクタン、ビシクロ[2,2,2]オクタン、ビシクロ[4,3,0]ノナン、ビシクロ[3,3,1]ノナン、ビシクロ[4,4,0]デカン、スピロ[5,4]デカン、パーヒドロキナセン、アダマンタン、ビシクロ[3,3,3]ウンデカン、パーヒドロアントラセンなどが挙げられる。
【0020】
本明細書中において表わされる「C4-13ポリシクロアルキル基」とは、炭素数4ないし13個の2以上の環からなる環状の脂肪族炭化水素基を意味する。具体的には、前記「C4−13多環式脂肪族炭化水素」から任意の位置の水素原子を1個除いて誘導される一価の基を意味し、具体的には、endo-ノルボルナン-2-イル基または1-アダマンチル基などを意味する。
【0021】
本明細書中において表わされる「4ないし10員複素環式基」とは、環式基の環を構成する原子の数が4ないし10であり、環式基の環を構成する原子中に1から複数個のヘテロ原子を含有する環式基を意味する。ただし前記「5ないし10員芳香族複素環式基」に含まれるものは除く。この「4ないし10員複素環式基」における「4ないし10員複素環」とは具体的には例えば、アジリジン、アゼチジン、オキセタン、ピロリジン、ピペリジン、テトラヒドロフラン、テトラヒドロピラン、モルホリン、チオモルホリン、ピペラジン、チアゾリジン、アゼピン、ジオキサン、ジオキソラン、イミダゾリン、チアゾリン、テトラヒドロキノリン、テトラヒドロイソキノリン、ジヒドロベンゾピラン、ジヒドロベンゾフラン、クロマン、ジヒドロインドール、8−アザビシクロ[3,2,1]オクタンなどが挙げられる。
【0022】
本発明化合物である一般式(I)中のnとは、0〜2の整数を意味するが、このnは好ましくは1または2を意味し、より好ましくは2を意味する
【0023】
本発明化合物である一般式(I)中のmとは、0〜3の整数を意味するが、このmは好ましくは0または1を意味し、より好ましくは0を意味する。
【0024】
本発明化合物である一般式(I)中のWとは、単結合、C1-6アルキレン基または式
【化9】
(式中、W2は窒素原子またはメチン基を意味し、mは0〜3の整数を意味し、R1bはC1-6アルキル基、C3-8シクロアルキル基、5−10員芳香族複素環式基、C6-10芳香族炭化水素環式基、C4-10複素環式基またはC4-13ポリシクロアルキル基を意味する。)で表わされる基を意味するが、このWは好ましくは単結合またはC1-6アルキレン基であり、より好ましくは単結合である。
【0025】
本発明化合物である一般式(I)中のZとは、式
【化10】
(式中、R2aおよびR2bは、それぞれ独立してC1-6アルキル基、C2-6アルケニル基またはフェニル基を意味し、Z2は硫黄原子またはメチレン基を意味する。)で表わされる基を意味するが、このZは好ましくは、式
【化11】
(式中、R2bは、それぞれ独立してC1-6アルキル基、C2-6アルケニル基またはフェニル基を意味する。)で表わされる基である。
【0026】
本発明における「塩」とは薬理学的に許容される塩を示し、本発明化合物と付加塩を形成したものであれば特に限定されないが、好ましい例としては、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩などのハロゲン化水素酸塩;硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩などの無機酸塩;酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩などの有機カルボン酸塩;メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩などの有機スルホン酸塩;アスパラギン酸塩、グルタミン酸塩などのアミノ酸塩;トリメチルアミン塩、トリエチルアミン塩、プロカイン塩、ピリジン塩、フェネチルベンジルアミン塩などのアミンとの塩;ナトリウム塩、カリウム塩などのアルカリ金属塩;マグネシウム塩、カルシウム塩などのアルカリ土類金属塩等があげられる。
【0027】
【一般的合成法】
本発明にかかる前記式(I)で表わされる化合物の代表的な製造方法について以下に示す。
[製造方法A]
アゾール誘導体(a-1)からカルバモイルアゾール誘導体(a-3)の製造方法
【化12】
(式中、n、W、X1、X2、R1a、Zは前述定義と同意義を意味する。Xはハロゲン原子などの脱離基を意味する。)
【0028】
工程A−1 ((a-1)から(a-3))
アゾール誘導体(a-1)とカルバモイル化試薬(a-2)とを反応させ、カルバモイルアゾール誘導体(a-3)を得ることができる。反応は通常塩基存在下におこなわれるが、塩基としては例えば無水炭酸カリウム、炭酸水素ナトリウム、水素化ナトリウムなどの無機塩基、ブチルリチウムなどの有機金属塩基、トリエチルアミンなどの有機塩基が用いられる。反応溶媒は、通常ジクロロメタンなどのハロゲン化炭化水素系溶媒、酢酸エチルなどのエステル系溶媒、テトラヒドロフランなどのエーテル系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒およびピリジンなどの塩基性溶媒が用いられる。反応温度は通常-78〜100℃、好ましくは-20〜50℃でおこなわれる。
【0029】
工程A−2 ((a-1)から(b-2))
アゾール誘導体(a-1)から活性カルボニルアゾール誘導体(b-2)への変換の工程である。
アゾール誘導体(a-1)とカルボニル化剤(b-1)とを反応させ、活性カルボニルアゾール誘導体(b-2)を得ることができる。ただし活性カルボニルアゾール誘導体(b-2)は単離することもできるが、通常単離せずに次の工程に用いられる。反応は通常塩基存在下におこなわれるが、塩基としては無水炭酸カリウム、炭酸水素ナトリウム、水素化ナトリウムなどの無機塩基、トリエチルアミン、ピリジンなどの有機塩基が用いられる。カルボニル化剤としてはホスゲン、ホスゲンダイマー、トリホスゲン、カルボニルジイミダゾールなどが用いられる。反応溶媒は、通常酢酸エチルなどのエステル系溶媒、テトラヒドロフランなどのエーテル系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒およびピリジンなどの塩基性溶媒が用いられる。反応温度は通常-78〜100℃、好ましくは-20〜25℃でおこなわれる。
【0030】
工程A−3 ((b-2)から(a-3))
活性カルボニルアゾール誘導体(b-2)からカルバモイルアゾール誘導体(a-3)への変換の工程である。活性カルボニルアゾール誘導体(b-2)と有機アミン化合物(b-3)とを反応させ、カルバモイルアゾール誘導体(a-3)を得ることができる。反応は通常塩基存在下におこなわれるが、塩基としては無水炭酸カリウム、炭酸水素ナトリウム、水素化ナトリウムなどの無機塩基、トリエチルアミン、ピリジンなどの有機塩基が用いられる。反応溶媒は、通常酢酸エチルなどのエステル系溶媒、テトラヒドロフランなどのエーテル系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒およびピリジンなどの塩基性溶媒が用いられる。反応温度は通常-78〜100℃、好ましくは-20〜50℃でおこなわれる。
【0031】
[製造方法C]
スルホキシドあるいはスルホン誘導体である化合物(b-4)の製造方法
【化13】
(式中、nは1または2、W、X1、X2、R1a、Zは前述定義と同意義を意味する。)スルフィド誘導体(c-1)を適当な酸化剤と反応させ、スルホキシド、あるいはスルホン誘導体(b-4)を得ることができる。酸化剤としては、m-クロロ過安息香酸、過酸化水素、過硫酸塩、過炭酸塩などが用いられ、タングステンなどの金属塩が触媒として用いられることもある。反応溶媒としては、通常酢酸エチルなどのエステル系溶媒、ジクロロメタンなどのハロゲン化炭化水素系溶媒、エタノールなどのアルコール系溶媒、アセトニトリルなどのニトリル系溶媒、水およびこれらの混合溶媒系が用いられる。反応温度は通常-20〜100℃、好ましくは0〜60℃が用いられる。なお酸化剤の当量や反応条件の調節によってスルホキシド、スルホンを選択的に得ることができる。
【0032】
[製造方法D]
アミノスルホニルアゾール誘導体(d-3)の製造方法
【化14】
(式中、m、X1、X2、R1a、R1b、Zは前述定義と同意義を意味する。 Xはハロゲン原子などの脱離基を意味する。)
活性スルホニルアゾール誘導体(d-1)と有機アミン誘導体(d-2)とを反応させ、アミノスルホニルアゾール誘導体(d-3)を得ることができる。反応は通常塩基存在下でおこなわれ、塩基としては、ピリジン、トリエチルアミンなどの有機塩基、又は炭酸ナトリウム、炭酸カリウム、水酸化ナトリウムなどの無機塩基が用いられる。反応溶媒としては、通常酢酸エチルなどのエステル系溶媒、テトラヒドロフランなどのエーテル系溶媒、ジクロロメタンなどのハロゲン化炭化水素系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒が用いられる。反応温度は-20〜50℃、好ましくは0〜30℃でおこなわれる。
【0033】
工程Aで用いるアゾール誘導体(a-1)には、先行技術である除草剤の合成に用いられる中間体が含まれており、これらの中間体はこれらの特許に合成法が開示されている。ここでは参考までにその一部を以下に示すが、この例に限定されるものではなく、カルバモイルアゾール系除草剤の合成中間体(アゾール誘導体)は一般に工程Aで用いることができる。
【0034】
[製造方法E]
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(e-3)、さらにスルフィニルアゾール誘導体あるいはスルホニルアゾール誘導体(e-4)への変換の工程
【化15】
(式中、nは1または2を意味し、W、X1、X2、R1aは前述定義と同意義を意味する。Xaは、ハロゲン原子、メタンスルホニルオキシ基またはパラトルエンスルホニルオキシ基などの脱離基を意味する。W10は単結合、C1-6アルキレン基または式
【化16】
(式中、mおよびR1bは前記定義と同意義を意味する。)で表わされる基を意味する。)
【0035】
工程 E-1 ((e-1)から(e-3))
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(e-3)への変換の工程である。
メルカプトアゾール誘導体(e-1)と求電子化合物(e-2)とを反応させてチオアゾール誘導体(e-3)を得ることができる。
反応は塩基を加えて行ってもよい。塩基としては例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水素化ナトリウムなどの無機塩基、ナトリウムメトキシド、カリウム t-ブトキシドなどの金属アルコキシド類が用いられる。反応溶媒はメタノール、エタノールなどのアルコール系溶媒、テトラヒドロフランなどのエーテル系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒、アセトニトリルなどのニトリル系溶媒、ジメチルスルホキシドなどのスルホキシド系溶媒、ピリジンなどの塩基性溶媒、又は水、あるいはこれらの混合系溶媒系が用いられる。反応温度は-20〜180℃、好ましくは0〜150℃でおこなわれる。
【0036】
工程 E-2 ((e-3)から(e-4))
チオアゾール誘導体(e-3)からスルフィニル誘導体あるいはスルホニル誘導体(e-4)への変換の工程である。チオアゾール誘導体(e-3)と適当な酸化剤とを反応させてスルフィニル誘導体あるいはスルホニル誘導体(e-4)を得ることができる。反応条件は前記製造方法Cと同様である。
【0037】
[製造方法F]
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(f-2)、さらにスルフィニルアゾール誘導体あるいはスルホニルアゾール誘導体(f-3)への変換の工程。
【化17】
(式中、 、nは1または2、X1、X2は前述定義と同意義を意味する。 X4a-は酸を構成する陰イオン(塩素イオン、硫酸イオンなど)を表し、Araは芳香族炭化水素環式基又は芳香族複素環式基を意味する。)
工程 F-1
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(f-2)への変換の工程である。
メルカプトアゾール誘導体(e-1)と、芳香族アミン(Ara-NH2)から調整されるジアゾニウム塩(f-1)とを反応させて、チオアゾール誘導体(f-2)を得ることができる。芳香族アミンからジアゾニウム塩を調整するには一般的な方法が使用できるが、通常芳香族アミンに対して二当量の酸を加えた水溶液又は水とアルコール系溶媒の混合溶媒中、5℃以下の反応温度で、亜硝酸塩一当量の水溶液を滴下することによって調整することができる。このように調整したジアゾニウム塩の溶液又は懸濁液を、メルカプトアゾール誘導体と二当量の塩基の、水又はアルコール系溶媒あるいはこれらの混合溶媒に溶解した中に、反応温度5℃以下で加えることによりおこなうことができる。酸としては通常塩酸、硫酸、臭化水素酸などの無機酸が用いられ、塩基としては通常水酸化ナトリウム、水酸化カリウムなどの無機塩基が用いられる。反応温度は-20〜20℃でおこなわれる。
【0038】
工程 F-2
チオアゾール誘導体(f-2)からスルフィニル誘導体あるいはスルホニル誘導体(f-3)への変換の工程である。チオアゾール誘導体と(f-2)適当な酸化剤とを反応させてスルフィニル誘導体あるいはスルホニル誘導体(f-3)を得ることができる。反応条件は前記製造方法Cと同様である。
【0039】
[製造方法G]
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(g-4)への変換の工程。
【化18】
(式中、 X1、 X2は前述定義と同意義を意味する。 Xはハロゲン原子などの脱離基を、YはOまたはRe-Nを表す。Rc、Rd、Reは前述の置換されていてもよいC1-6アルキル基、置換されていてもよいC2-6アルケニル基、置換されていてもよいC2-6アルキニル基、置換されていてもよいC6-14芳香族炭化水素環式基、置換されていてもよい4ないし10員複素環式基、置換されていてもよい5ないし14員芳香族複素環式基、置換されていてもよいC3-8シクロアルキル基を意味する。)
【0040】
工程 G-1
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(g-2)への変換の工程である。
メルカプトアゾール誘導体(e-1)と、1,3-ジカルボニル誘導体(g-1)を反応させてチオアゾール誘導体(g-2)を得ることができる。反応は通常塩基存在下でおこなわれ、塩基としては例えば炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水素化ナトリウムなどの無機塩基、ナトリウムメトキシド、カリウム t-ブトキシドなどの金属アルコキシドなどが用いられる。反応溶媒としては、メタノール、エタノールなどのアルコール系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒、ジメチルスルホキシドなどのスルホキシド系溶媒、テトラヒドロフランなどのエーテル系溶媒又は水、あるいはこれらの混合溶媒が用いられる。反応温度は-20〜100℃、好ましくは0〜60℃でおこなわれる。
【0041】
工程 G-2
チオアゾール誘導体(g-2)からチオアゾール誘導体(g-4)への変換の工程である。チオアゾール誘導体(g-2)とアミン化合物(g-3)とを反応させてチオアゾール誘導体(g-4)を得ることができる。反応は塩基を用いても用いなくてもよいが、アミン化合物が塩の場合はこれを中和するに十分な量の塩基を用いる。塩基としては、炭酸水素ナトリウム、炭酸カリウムなどの無機塩基、トリエチルアミンなどの有機塩基が用いられる。反応溶媒としては、メタノール、エタノールなどのアルコール系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒、ジメチルスルホキシドなどのスルホキシド系溶媒、テトラヒドロフランなどのエーテル系溶媒又は水、あるいはこれらの混合溶媒が用いられる。反応温度は0〜120℃、好ましくは20〜100℃でおこなわれる。
【0042】
[製造方法H]
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(h-3)、さらにスルフィニル誘導体又はスルホニル誘導体(h-4)への変換の工程。
【化19】
(式中、nは1または2を、 X1、 X2は前述定義と同意義を意味する。 Arbは電子密度の高い芳香族性炭化水素環式基または芳香族性複素環式基を表し、 Arb Hがこの水素原子とハロゲン化やニトロ化などのいわゆる親電子置換反応を起こすものを意味する。)
【0043】
工程 H-1
メルカプトアゾール誘導体(e-1)からチオアゾール誘導体(h-3)への変換の工程である。
メルカプトアゾール誘導体をハロゲン化剤(h-1)と反応させ、ついで芳香族化合物(h-2)と反応させてチオアゾール誘導体(h-3)を得ることができる。反応は通常塩基存在下でおこなわれ、塩基としては例えば、水素化ナトリウムなどの水素化金属類、ナトリウムメトキシド、ナトリウムエトキシド、カリウム t-ブトキシドなどの金属アルコキシド類などが用いられる。ハロゲン化剤としては塩素、臭素などの単体のハロゲン類、N-クロロコハク酸イミド、N-ブロモコハク酸イミドなどのN-ハロイミド類などが用いられる。反応溶媒としてはメタノール、エタノールなどのアルコール系溶媒、N,N-ジメチルホルムアミドなどのアミド系溶媒が好ましく用いられる。反応温度は-80〜150℃、好ましくは-70〜120℃でおこなわれる。
【0044】
工程 H-2
チオアゾール誘導体(h-3)からスルフィニルアゾール誘導体又はスルホニルアゾール誘導体(h-4)への変換の工程である。チオアゾール誘導体(h-3)と適当な酸化剤とを反応させてスルフィニル誘導体あるいはスルホニル誘導体(h-4)を得ることができる。反応条件は前記製造方法Cと同様である。
【0045】
[製造方法I]
N-スルホニルアゾール誘導体(i−1)からC-スルホニルアゾール誘導体(i−3)または(i−4)への変換の工程
【化20】
(式中、W、X1、X2、R1aは前述定義と同意義を意味する。)
N-スルホニルアゾール誘導体(i-1)とリチウム化試薬(i-2)を反応させて、適当な温度で処理することによって転位が起こり、C-スルホニルアゾール誘導体(i-3)を得ることができる。(i-4)は(i-3)の互変異性体である。リチウム化試薬としては、n-ブチルリチウム、sec-ブチルリチウム、t-ブチルリチウムなどのアルキルリチウム、リチウムジイソプロピルアミドなどのリチウムアミドなどが用いられる。反応溶媒としては、テトラヒドロフランなどのエーテル系溶媒が好ましく用いられる。反応温度は、-100〜100℃、好ましくは-78〜80℃でおこなわれる。
【0046】
[製造方法J]
ベンジルチオアゾール誘導体からクロロスルホニルアゾール誘導体への変換の工程。
【化21】
(式中、 X1、X2、Zは前述定義と同意義を意味する。 )
ベンジルチオアゾール誘導体(j-1)と、塩素を反応させてクロロスルホニルアゾール誘導体(j-2)を得ることができる。反応は通常酢酸、または水、あるいはこれらの混合溶媒中でおこなわれ、3当量から6当量の塩素ガスを通じることによって達成される。反応温度は通常-10〜15℃でおこなわれる。
【0047】
[製造方法K]
二級アミン化合物(b-3)からカルバモイルクロライド(k-2)への変換の工程。
【化22】
(式中、Zは前述定義と同意義を意味する。)
二級アミン化合物(b-3)と、クロロカルボニル化剤(k-1)を反応させてカルバモイルクロライド(k-2)を得ることができる。クロロカルボニル化剤としては、ホスゲン、ホスゲンダイマー、トリホスゲンなどが用いられる。塩基としては通常ピリジン、トリエチルアミンなどの有機塩基、無水炭酸カリウムなどの無機塩基が用いられる。
【0048】
本発明にかかる前記式(I)で表わされる化合物について得られる種々の異性体は、通常の分離手段(例えば再結晶、クロマトグラフィー等)を用いることにより精製し、単離することができる。
【0049】
本発明にかかる化合物もしくはその塩またはそれらの水和物は、慣用されている方法により錠剤、散剤、細粒剤、顆粒剤、被覆錠剤、カプセル剤、シロップ剤、トローチ剤、吸入剤、坐剤、注射剤、軟膏剤、眼軟膏剤、点眼剤、点鼻剤、点耳剤、パップ剤、ローション剤等として製剤化することができる。製剤化には通常用いられる製剤化助剤(例えば賦形剤、結合剤、滑沢剤、着色剤、矯味矯臭剤や、および必要により安定化剤、乳化剤、吸収促進剤、界面活性剤、pH調製剤、防腐剤、抗酸化剤など)を使用することができ、一般に医薬品製剤の原料として用いられる成分を配合して常法により製剤化される。例えば経口製剤を製造するには、本発明にかかる化合物またはその薬理学的に許容される塩と賦形剤、さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤などを加えた後、常法により散剤、細粒剤、顆粒剤、錠剤、被覆錠剤、カプセル剤等とする。これらの成分としては例えば、大豆油、牛脂、合成グリセライド等の動植物油;流動パラフィン、スクワラン、固形パラフィン等の炭化水素;ミリスチン酸オクチルドデシル、ミリスチン酸イソプロピル等のエステル油;セトステアリルアルコール、ベヘニルアルコール等の高級アルコール;シリコン樹脂;シリコン油;ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレンブロックコポリマー等の界面活性剤;ヒドロキシエチルセルロース、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、ポリビニルピロリドン、メチルセルロースなどの水溶性高分子;エタノール、イソプロパノールなどの低級アルコール;グリセリン、プロピレングリコール、ジプロピレングリコール、ソルビトールなどの多価アルコール;グルコース、ショ糖などの糖;無水ケイ酸、ケイ酸アルミニウムマグネシウム、ケイ酸アルミニウムなどの無機粉体、精製水などがあげられる。賦形剤としては、例えば乳糖、コーンスターチ、白糖、ブドウ糖、マンニトール、ソルビット、結晶セルロース、二酸化ケイ素などが、結合剤としては、例えばポリビニルアルコール、ポリビニルエーテル、メチルセルロース、エチルセルロース、アラビアゴム、トラガント、ゼラチン、シェラック、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリプロピレングリコール・ポリオキシエチレン・ブロックポリマー、メグルミンなどが、崩壊剤としては、例えば澱粉、寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、クエン酸カルシウム、デキストリン、ペクチン、カルボキシメチルセルロース・カルシウム等が、滑沢剤としては、例えばステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ、硬化植物油等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、ココア末、ハッカ脳、芳香散、ハッカ油、竜脳、桂皮末等が用いられる。これらの錠剤・顆粒剤には糖衣、その他必要により適宜コーティングすることはもちろん差支えない。また、シロップ剤や注射用製剤等の液剤を製造する際には、本発明にかかる化合物またはその薬理学的に許容される塩にpH調整剤、溶解剤、等張化剤などと、必要に応じて溶解補助剤、安定化剤などを加えて、常法により製剤化する。外用剤を製造する際の方法は限定されず、常法により製造することができる。すなわち製剤化にあたり使用する基剤原料としては、医薬品、医薬部外品、化粧品等に通常使用される各種原料を用いることが可能である。使用する基剤原料として具体的には、例えば動植物油、鉱物油、エステル油、ワックス類、高級アルコール類、脂肪酸類、シリコン油、界面活性剤、リン脂質類、アルコール類、多価アルコール類、水溶性高分子類、粘土鉱物類、精製水などの原料が挙げられ、さらに必要に応じ、pH調整剤、抗酸化剤、キレート剤、防腐防黴剤、着色料、香料などを添加することができるが、本発明にかかる外用剤の基剤原料はこれらに限定されない。また必要に応じて分化誘導作用を有する成分、血流促進剤、殺菌剤、消炎剤、細胞賦活剤、ビタミン類、アミノ酸、保湿剤、角質溶解剤等の成分を配合することもできる。なお上記基剤原料の添加量は、通常外用剤の製造にあたり設定される濃度になる量である。
【0050】
本発明にかかる化合物もしくはその塩またはそれらの水和物を投与する場合、その形態は特に限定されず、通常用いられる方法により経口投与でも非経口投与でもよい。例えば錠剤、散剤、顆粒剤、カプセル剤、シロップ剤、トローチ剤、吸入剤、坐剤、注射剤、軟膏剤、眼軟膏剤、点眼剤、点鼻剤、点耳剤、パップ剤、ローション剤などの剤として製剤化し、投与することができる。本発明にかかる医薬の投与量は、症状の程度、年齢、性別、体重、投与形態・塩の種類、疾患の具体的な種類等に応じて適宜選ぶことができる。
【0051】
本発明にかかる DPPIV阻害剤の投与量は患者の、疾患の種類、症状の程度、患者の年齢、性差、薬剤に対する感受性差などにより著しく異なるが、通常成人として1日あたり、約0.03−1000mg、好ましくは0.1−500mg、さらに好ましくは0.1−100mgを1日1−数回、または数日に1−数回に分けて投与する。注射剤の場合は、通常約1μg/kg−3000μg/kgであり、好ましくは約3μg/kg−1000μg/kgである。
【0052】
本発明にかかる化合物は、例えば以下の実施例に記載した方法により製造することができる。ただし、これらは例示的なものであって、本発明にかかる化合物は如何なる場合も以下の具体例に制限されるものではない。
【0053】
【実施例】
実施例1
3- ベンジルチオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化23】
a) 3-ベンジルチオ-1H-1,2,4-トリアゾール
3-メルカプト-1H-1,2,4-トリアゾール100mgとベンジルブロミド118μlのジメチルホルムアミド溶液2mlを室温下で23時間攪拌した。反応混合物に室温で酢酸エチルと飽和炭酸水素ナトリウム水を加え、得られた混合物を酢酸エチルで1回抽出した。有機層を水で3回および飽和食塩水で1回順次洗浄した後、無水硫酸ナトリウムで乾燥した。残渣を濾過して、得られた濾液から溶媒を減圧留去し白色固形物として標記化合物172mgを得た。
1H-NMR(d6-DMSO) δ=4.35 (2H, s), 7.22-7.31 (3H, m), 7.35-7.38 (2H, m), 8.43 (1H, s)
【0054】
b) 3-ベンジルチオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-ベンジルチオ-1H-1,2,4-トリアゾール172mg、ジメチルカルバモイルクロリド248μlと無水炭酸カリウム621mgのジメチルホルムアミド4ml懸濁液を室温で1時間20分間攪拌した。反応混合物に水を加え、この混合物を酢酸エチルで抽出した。有機層を水で3回、飽和食塩水で1回順次洗浄し、硫酸ナトリウムで乾燥した。濾過した後、残渣から溶媒を減圧留去して透明油状物を得た。得られた油状物をカラムクロマトグラフィー(酢酸エチル/ヘキサン=1/5)にて精製して透明油状物として標記化合物88mgを得た。
1H-NMR (d6-DMSO) δ=3.06 (6H,br s), 4.39 (2H, s), 7.23-7.33 (3H, m), 7.40-7.42 (2H, m), 9.03 (1H,s).
【0055】
実施例2
3- ベンジルスルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化24】
3-ベンジルチオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例1)134mgの塩化メチレン溶液に氷冷下m-クロロ過安息香酸185mgを加え、得られた混合物を室温で4時間攪拌した。反応混合液に酢酸エチルと水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、カラムクロマトグラフィー(酢酸エチル/ヘキサン=1/2)にて精製して透明油状物として標記化合物69mgを得た。
1H-NMR (d6-DMSO) δ=2.93 (3H,br s), 3.06 (3H,br s), 4.90 (2H, s), 7.25-7.27 (2H, m), 7.33-7.35 (3H, m), 9.35 (1H, s); MS m/e (ESI) 611.15(2M+23)
【0056】
実施例3
3- ベンジルスルホニル -1- ジエチルカルバモイル -1H-1,2,4- トリアゾール
【化25】
ジエチルカルバモイルクロリドを用い、実施例1、2と同様に合成した。
1H-NMR(CDCl3) δ=1.12-1.29 (6H, m), 3.47 (4H,br s), 4.64 (2H, s), 7.25-7.34 (5H, m), 8.88 (1H, br s)
【0057】
実施例4
3-(4- フルオロベンジル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化26】
4-フルオロベンジルブロミドを用い、実施例1、2と同様に合成した。
1H-NMR(CDCl3) δ=3.17(6H, s), 4.61(2H, s), 7.02(2H, t, J=9Hz), 7.28(2H, dd, J=6, 9Hz), 8.88(1H, s)
【0058】
実施例5
3-(4-tert- ブチルベンジル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化27】
4-tert-ブチルベンジルブロミドを用い、実施例1、2と同様に合成した。
1H-NMR(CDCl3) δ=1.27(9H, s), 3.14(6H, s), 4.60(2H, s), 7.20(2H, d, J=8Hz), 7.33(2H, d, J=8Hz), 8.87(1H, s)
【0059】
実施例6
3-( ジフェニルメチル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化28】
ジフェニルメチルブロミドを用い、実施例1と同様に合成した。
1H-NMR(CDCl3) δ=2.84-3.14(6H, br.2peak), 6.08(1H, s), 7.22(2H, t, J=7Hz), 7.29(4H, t, J=7Hz), 7.45(4H, d, J=7Hz), 8.63(1H, s)
【0060】
実施例7
3-( ジフェニルメチル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化29】
3-(ジフェニルメチル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例6)を用い、実施例2と同様に合成した。
1H-NMR(CDCl3) δ=2.97(3H, s), 3.10(3H, s), 5.85(1H, s), 7.30-7.38(6H, m), 7.62(4H, dd, J=2, 7Hz), 8.73(1H, s)
【0061】
実施例8
3-[ ビス (4- フルオロフェニル ) メチル ] チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化30】
ビス(4-フルオロフェニル)メチルクロリドを用い、実施例1と同様に合成した。
1H-NMR(CDCl3) δ=3.04(6H, br.s), 6.06(1H, s), 6.99(4H, t, J=9Hz), 7.39(4H, dd, J=5, 9Hz), 8.64(1H, s)
【0062】
実施例9
3-[ ビス (4- フルオロフェニル ) メチル ] スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化31】
3-[ビス(4-フルオロフェニル)メチル]チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例8)を用い、実施例2と同様に合成した。
1H-NMR(CDCl3) δ=3.06(3H, br.s), 3.13(3H, br.s), 5.85(1H, s), 7.05(4H, t, J=9Hz), 7.58(4H, dd, J=5, 9Hz), 8.76(1H, s)
【0063】
実施例10
3-( クロマン -4- イル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化32】
a) 3-(クロマン-4-イル)チオ-1H-1,2,4-トリアゾール
トリホスゲン95mg、ジクロロメタン4mlの混合物を攪拌しながら、氷浴にて冷却下、ピリジン82μl、4-クロマノール150mgの順に加えた。更にピリジン82μlを加え、室温に戻し、2時間攪拌した。この反応液を3-メルカプト-1H-1,2,4-トリアゾール110mg、無水炭酸カリウム200mg、N,N-ジメチルホルムアミド2mlの混合物に加え、終夜攪拌した。反応液を水、ついで飽和食塩水で洗い濃縮した。残渣を50%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物110mgを得た。
1H-NMR(CDCl3) δ=2.25-2.32(1H, m), 2.41-2.51(1H, m), 4.28-4.35(1H, m), 4.42-4.50(1H, m), 5.04(1H, br.s), 6.83(1H, d, J=8Hz), 6.89(1H, t, J=8Hz), 7.18(1H, t, J=8Hz), 7.36(1H, d, J=8Hz), 8.17(1H, s)
【0064】
b) 3-(クロマン-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール 3-(クロマン-4-イル)チオ-1H-1,2,4-トリアゾールより、実施例1と同様にして標記化合物を得た。
1H-NMR(CDCl3) δ=2.28-2.36(1H, m), 2.42-2.52(1H, m), 3.25(6H, br.s), 4.28-4.35(1H, m), 4.43-4.51(1H, m), 5.05(1H, br.s), 6.83(1H, d, J=8Hz), 6.90(1H, t, J=8Hz), 7.17(1H, t, J=8Hz), 7.38(1H, d, J=8Hz), 8.78(1H, s)
【0065】
実施例11
3-( クロマン -4- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化33】
3-(クロマン-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例10)より、実施例2と同様にして標記化合物を得た。
1H-NMR(CDCl3) δ=2.28-2.39(1H, m), 2.54-2.62(1H, m), 3.19(3H, br.s), 3.21(3H, br.s), 4.24-4.30(1H, m), 4.54-4.62(1H, m), 4.72-4.76(1H, m), 6.86-6.92(2H, m), 7.25(1H, t, J=8Hz), 7.35(1H, d, J=8Hz), 8.91(1H, s)
【0066】
実施例12
3-(endo- ノルボルナン -2- イル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化34】
a) 3-(endo-ノルボルナン-2-イル)チオ-1H-1,2,4-トリアゾール
3-メルカプト-1H-1,2,4-トリアゾール5.0g、exo-2-ブロモノルボルナン6.4ml、無水炭酸カリウム10g、N,N-ジメチルホルムアミド25mlの混合物を80℃の油浴中で7時間加熱撹拌した。反応液を酢酸エチル-水で抽出、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を10〜20%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物5.01gを得た。
1H-NMR(CDCl3) δ=1.01-1.08(1H,m), 1.22-1.30(1H, m), 1.38-1.92(5H, m), 2.14-2.24(1H, m), 2.29(1H, br.s), 2.52(1H, br.s), 3.88-3.95(1H, m), 8.09(1H, s)
【0067】
b) 3-(endo-ノルボルナン-2-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(endo-ノルボルナン-2-イル)チオ-1H-1,2,4-トリアゾール500mg、ジメチルカルバモイルクロリド0.35ml、無水炭酸カリウム700mg、N,N-ジメチルホルムアミド2mlの混合物を室温で5時間撹拌した。反応液を酢酸エチル-水で抽出、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を10〜15%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物650mgを得た。
1H-NMR(CDCl3) δ=1.02-1.10(1H, m), 1.22-1.31(1H, m), 1.37-1.62(4H, m), 1.83-1.92(1H, m), 2.29(1H, br.s), 2.57(1H, br.s), 3.24(6H, br.s), 3.84-3.92(1H, m), 8.70(1H, s)
【0068】
実施例13
3-(endo- ノルボルナン -2- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化35】
3-(endo-ノルボルナン-2-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例12) 650mg、酢酸エチル5ml、m-クロロ過安息香酸1.12gの混合物を室温で一晩撹拌した。反応液に1モルチオ硫酸ナトリウム水溶液1mlを加え、酢酸エチル-水で抽出、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を20〜30%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、酢酸エチル-ヘキサンから再結晶し、標記化合物440mgを得た。
1H-NMR(CDCl3) δ=1.40-1.70(5H, m), 1.84-1.91(2H, m), 2.27-2.35(1H, m), 2.45(1H, br.s), 2.78(1H, br.s), 3.20(3H, s), 3.34(3H, s), 3.75-3.82(1H, m), 8.86(1H, s)
【0069】
以下以下実施例14〜21は実施例12、13と同様に合成した。
【0070】
実施例14
3- シクロヘキシルチオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化36】
ブロモシクロヘキサンを用い、実施例12と同様に合成した。
1H-NMR(CDCl3) δ=1.24-1.67(6H, m), 1.75-1.84(2H, m), 2.06-2.16(2H, m), 3.00-3.46(6H, br .peak), 3.62(1H, tt, J=4, 10Hz), 8.72(1H, s)
【0071】
実施例15
3- シクロヘキシルスルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化37】
3-シクロヘキシルチオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例14)を用い、実施例13と同様に合成した。
1H-NMR(CDCl3) δ=1.16-1.76(6H, m), 1.88-1.97(2H, m), 2.09-2.17(2H, m), 3.20(3H, br.s), 3.31(1H, tt, J=4, 12Hz), 3.34(3H, br.s), 8.89(1H, s)
【0072】
実施例16
3- シクロヘキシルメチルチオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化38】
シクロヘキシルメチルブロミドを用い、実施例12と同様に合成した。
1H-NMR(CDCl3) δ=0.94-1.30(5H, m), 1.60-1.78(4H, m), 1.85-1.93(2H, m), 3.04(2H, d, J=7Hz), 3.1-3.4(6H, br. peak), 8.70(1H, s)
【0073】
実施例17
3- シクロヘキシルメチルスルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化39】
3-シクロヘキシルメチルチオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例16)を用い、実施例13と同様に合成した。
1H-NMR(CDCl3) δ=-1.05-1.35(5H, m), 1.60-1.74(3H, m), 1.86-1.95(2H, m), 2.04-2.14(1H, m), 3.21(3H, br.s), 3.31(2H, d, J=7Hz), 3.34(3H, br.s), 8.88(1H, s)
【0074】
実施例18
3-(1- アダマンチルメチル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化40】
1-アダマンタンメタノールから調整した1-アダマンチルメチル メタンスルホネートを用い、実施例12と同様に合成した。
1H-NMR(CDCl3) δ=1.58-1.74(12H, m), 1.99(3H, br.s), 3.04(2H, s), 3.12-3.36(6H, br. Peak), 8.70(1H, s)
【0075】
実施例19
3-(1- アダマンチルメチル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化41】
3-(1-アダマンチルメチル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例18)を用い、実施例13と同様に合成した。
1H-NMR(CDCl3) δ=1.63-1.74(6H, m), 1.83(6H, d, J=3Hz), 1.99(3H, br.s), 3.20(3H, br.s), 3.25(2H, s), 3.34(3H, br.s), 8.86(1H, s)
【0076】
実施例20
3-(3- メチルブチル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化42】
1-ブロモ-3-メチルブタンを用い、実施例12、13と同様に合成した。
1H-NMR(CDCl3) δ=0.93(6H, d, J=7Hz), 1.67-1.75(3H, m), 3.20(3H, br.s), 3.34(3H, br.s), 3.36-3.42(2H, m), 8.90(1H, s)
【0077】
実施例21
3-(2- ジメチルプロピル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化43】
1-ブロモ-2,2-ジメチルプロパンを用い、実施例12、13と同様に合成した。
1H-NMR(CDCl3) δ=1.20(9H, s), 3.20(3H, br.s), 3.34(3H, br.s), 3.38(2H, s), 8.87(1H, s)
【0078】
実施例22
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- フェニルカルバモイル )-1H-1,2,4- トリアゾール
【化44】
a) 3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール
3-(endo-ノルボルナン-2-イル)チオ-1H-1,2,4-トリアゾール(実施例12-a) 1.0g、酢酸エチル10mlの混合物に室温でm-クロロ過安息香酸2.4gを加え撹拌した。はじめ発熱し、それが収まると同時に結晶が析出した。反応液を氷冷し結晶を濾取、酢酸エチル/ヘキサン(1/1)で洗い乾燥し標記化合物1.05gを得た。
1H-NMR(d6-DMSO) δ=1.22-1.66(6H, m), 1.75-1.85(1H, m), 2.07-2.16(1H, m), 2.34(1H, br.s), 2.54(1H, br.s), 3.76-3.83(1H, m), 8.88(1H, s)
【0079】
b) 3-(endo-ノルボルナン-2-イル)スルホニル-1-(N-メチル-N-フェニルカルバモイル)-1H-1,2,4-トリアゾール
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール100mg、N-メチル-N-フェニルカルバモイルクロリド75mg及び無水炭酸カリウム100mgをN,N-ジメチルホルムアミド2mlに懸濁し、室温にて、終夜撹拌した。反応液に水を加え、酢酸エチル抽出、有機層を水洗い、次いで飽和食塩水洗い、無水硫酸マグネシウム乾燥し、減圧濃縮した。残査を30-50%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない標記化合物65mgを得た。
1H-NMR(CDCl3)δ=1.24-1.44(4H, m), 1.50-1.66(3H, m), 2.08-2.20(1H, m), 2.36(1H, br.s), 2.54(1H, br.s), 3.35(1H, br.s), 3.55(3H, s), 7.10-7.20(2H, m), 7.30-7.42(3H, m), 8.75(1H, s)
【0080】
実施例23
3-(endo- ノルボルナン -2- イル ) スルホニル -1- ジアリルカルバモイル -1H-1,2,4- トリアゾール
【化45】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及びジアリルカルバモイルクロリドを用い、実施例22と同様にして標記化合物を合成した。
1H-NMR(CDCl3)δ=1.40-1.70(5H, m), 1.83-1.91(2H, m), 2.26-2.35(1H, m), 2.45(1H, br.s), 2.77(1H, br.s), 3.73-3.80(1H, m), 4.00-4.40(4H, m), 5.28(4H, br.s), 5.85-5.96(2H, m), 8.87(1H, s)
【0081】
実施例24
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- エチルカルバモイル )-1H-1,2,4- トリアゾール
【化46】
トリホスゲン28mgをジクロロメタン1mlに溶解した。氷水浴にて冷却下、この溶液にピリジン0.023mlを加え、析出した不溶物が溶解するまで撹拌した。次いで、3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)64mgを加え、更に20分間撹拌した。続いてN-メチルエチルアミン0.1mlを加え、室温に戻し撹拌した。反応液を50%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない標記化合物37mgを得た。
1H-NMR(CDCl3)δ=1.31(3H, br.s), 1.40-1.70(5H, m), 1.80-1.94(2H, m), 2.27-2.36(1H, m), 2.45(1H, br.s), 2.77(1H, br.s), 3.16(1.3H, br.s), 3.30(1.7H, br.s), 3.50-3.75(2H, m), 3.75-3.82(1H, m), 8.87(1H, br.s)
【0082】
実施例25
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(1,3- チアゾリジン -3- イル ) カルボニル -1H-1,2,4- トリアゾール
【化47】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
1,3-チアゾリジンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3) δ=1.40-1.71(5H, m), 1.84-1.92(2H, m), 2.26-2.34(1H, m), 2.46(1H, br.s), 2.78(1H, br.s), 3.07-3.21(2H, m), 3.74-3.82(1H, m), 4.00-4.08(1H, m), 4.25-4.35(1H, m), 4.78(1H, br.s), 4.98(1H, br.s), 8.98(1H, s)
【0083】
実施例26
3-(endo- ノルボルナン -2- イル ) スルホニル -1-( ピロリジン -1- イル ) カルボニル -1H-1,2,4- トリアゾール
【化48】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
ピロリジンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3) δ=1.40-1.70(5H, m), 1.84-2.08(6H, m), 2.27-2.36(1H, m), 2.45(1H, br.s), 2.77(1H, br.s), 3.70(2H, t, J=7Hz), 3.74-3.82(1H, m), 3.92-4.04(2H, m), 8.96(1H, s)
【0084】
実施例27
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- アリルカルバモイル )-1H-1,2,4- トリアゾール
【化49】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
N-メチルアリルアミンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3)δ=1.40-1.70(5H, m), 1.80-1.93(2H, m), 2.26-2.38(1H, m), 2.45(1H, br.s), 2.78(1H, br.s), 3.15(1.3H, br.s), 3.28(1.7H, br.s), 3.78(1H, br.s), 4.05-4.38(2H, m), 5.20-5.40(2H, m), 5.82-5.97(1H, m), 8.88(1H, br.s)
【0085】
実施例28
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- プロピルカルバモイル )-1H-1,2,4- トリアゾール
【化50】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
N-メチルプロピルアミンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3)δ=0.85-1.04(3H, m), 1.40-1.80(7H, m), 1.81-1.92(2H, m), 2.27-2.36(1H, m), 2.45(1H, br.s), 2.78(1H, br.s), 3.16(1.8H, br.s), 3.30(1.2H, br.s), 3.50(1.2H, br.s), 3.61(0.8H, br.s), 3.78(1H, br.s), 8.87(1H, s)
【0086】
実施例29
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- イソプロピルカルバモイル )-1H-1,2,4- トリアゾール
【化51】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
N-メチルイソプロピルアミンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3)δ=1.29(6H, d, J=7Hz), 1.40-1.70(5H, m), 1.85-1.94(2H, m), 2.28-2.37(1H, m), 2.45(1H, br.s), 2.78(1H, br.s), 3.08(3H, br.s), 3.75-3.82(1H, m), 4.60(1H, br.s), 8.84(1H, s)
【0087】
実施例30
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- イソブチルカルバモイル )-1H-1,2,4- トリアゾール
【化52】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
N-メチルイソブチルアミンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3)δ=0.88(2.4H, br.s), 0.99(3.6H, d, J=6Hz), 1.40-1.70(5H, m), 1.85-2.20(3H, m), 2.28-2.37(1H, m), 2.45(1H, br.s), 2.79(1H, br.s), 3.17(1.2H, br.s), 3.30(1.8H, br.s), 3.38(1.2H, d, J=7Hz), 3.60(0.8H, m), 3.78(1H, br.s), 8.86(1H, s)
【0088】
実施例31
3-(endo- ノルボルナン -2- イル ) スルホニル -1-(N- メチル -N- tert- ブチルカルバモイル )-1H-1,2,4- トリアゾール
【化53】
3-(endo-ノルボルナン-2-イル)スルホニル-1H-1,2,4-トリアゾール(実施例22-a)及び
N-メチル-tert-ブチルアミンを用い、実施例24と同様にして合成した。
1H-NMR(CDCl3)δ=1.40-1.70(5H, m), 1.51(9H, s), 1.84-1.93(2H, m), 2.27-2.36(1H, m), 2.45(1H, br.s), 2.79(1H, br.s), 3.02(3H, s), 3.76-3.82(1H, m), 8.77(1H, s)
【0089】
実施例32
3-(2,4,6- トリメチルフェニル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化54】
a) 3-(2,4,6-トリメチルフェニル)チオ-1H-1,2,4-トリアゾール
2,4,6-トリメチルアニリン13.5g、メタノール130ml、濃塩酸18.5mlの混合物を氷−食塩浴で冷却下、亜硝酸ナトリウム6.9gの水10ml溶液をゆっくり滴下し、そのまま30分撹拌した。
2-メルカプト-1H-1,2,4トリアゾール10.1g、メタノール70ml、水酸化カリウム13.4gの混合物を氷−食塩浴で冷却している中に、先の反応液を少しずつ加え、同温で30分、室温で1時間撹拌した。反応液に濃塩酸9mlを加え、酢酸エチル−水で抽出、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥し減圧濃縮した。残渣に酢酸エチルを加え加熱溶解し、少量のシリカゲルを通して濾過、酢酸エチルで洗った後、減圧濃縮した。残渣を酢酸エチル−ヘキサンで結晶化して標記化合物12.7gを得た。
1H-NMR(CDCl3) δ=2.31(3H, s), 2.43(6H, s), 7.04(2H, s), 7.94(1H, s)
【0090】
b) 3-(2,4,6-トリメチルフェニル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(2,4,6-トリメチルフェニル)チオ-1H-1,2,4-トリアゾール220mg、無水炭酸カリウム280mg、N,N-ジメチルホルムアミド1mlの混合物に、N,N-ジメチルカルバモイルクロライド0.14mlを加え、室温で2時間撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥し減圧濃縮した。残渣を10-15%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない標記化合物276mgを得た。
1H-NMR(CDCl3) δ=2.29(3H, s), 2.44(6H, s), 3.15(6H, br.s), 6.99(2H, s), 8.63(1H, s)
【0091】
実施例33
3-(2,4,6- トリメチルフェニル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化55】
3-(2,4,6-トリメチルフェニル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例32) 226mg、酢酸エチル1mlの混合物にm-クロロ過安息香酸360mgを加え、60℃の油浴で4時間加熱撹拌した。反応液に1モルチオ硫酸ナトリウム水溶液0.1ml、5モル炭酸カリウム水溶液0.25mlを加え、酢酸エチル−水で抽出、有機層を飽和食塩水で洗った後濃縮した。残渣を酢酸エチルで加熱溶解し、少量のシリカゲルを通して濾過、酢酸エチルで洗い濃縮した。残渣を酢酸エチル−ヘキサンから結晶化し標記化合物178mgを得た。
1H-NMR(CDCl3) δ=2.31(3H, s), 2.70(6H, s), 3.18(3H, br.s), 3.32(3H, br.s), 6.98(2H, s), 8.78(1H, s)
【0092】
実施例34
3-(2,4,6- トリメチルフェニル ) スルホニル -1- ジエチルカルバモイル -1H-1,2,4- トリアゾール
【化56】
実施例32、33と同様に合成した。
1H-NMR(CDCl3) δ=1.27(6H, t, J=6Hz), 2.30(3H, s), 2.70(6H, s), 3.51(2H, br.s), 3.61(2H, br.s), 6.97(2H, s), 8.81(1H, s)
【0093】
実施例35
3-(2,4,6- トリメチルフェニル ) スルホニル -1-(N- メチル -N- フェニルカルバモイル )-1H-1,2,4- トリアゾール
【化57】
a) 3-(2,4,6-トリメチルフェニル)スルホニル-1H-1,2,4-トリアゾール
オキソン一過硫酸塩化合物(OXONEョ)50gと水100mlの混合物を60℃の油浴中にて加温し、撹拌しながら3-(2,4,6-トリメチルフェニル)チオ-1H-1,2,4-トリアゾール(実施例32-a)5.00gとメタノール150mlの混合物を1時間かけて滴下した。滴下終了後、3時間加熱還流した。室温に戻し終夜撹拌し、析出した結晶を濾取、水で洗い標記化合物5.03gを得た。
1H-NMR(CDCl3)δ=2.31(3H, s), 2.70(6H, s), 6.99(2H, s), 8.54(1H, s)
【0094】
b) 3-(2,4,6-トリメチルフェニル)スルホニル-1-(N-メチル-N-フェニルカルバモイル)-1H-1,2,4-トリアゾール
3-(2,4,6-トリメチルフェニル)スルホニル-1H-1,2,4-トリアゾール及びN-メチル-N-フェニルカルバモイルクロリドを用い、実施例22と同様にして標記化合物を合成した。
1H-NMR(CDCl3)δ=2.30(3H, s), 2.45(6H, s), 3.51(3H, s), 6.89(2H, s), 7.07(2H, br.s), 7.20-7.30(3H, m), 8.71(1H, s)
【0095】
実施例36
3-(2,4,6- トリメチルフェニル ) スルホニル -1-(N- メチル -N- エチルカルバモイル )-1H-1,2,4- トリアゾール
【化58】
トリホスゲン20mgをジクロロメタン1mlに溶解した。氷水浴にて冷却下、この溶液にピリジン0.017mlを加え5分間撹拌した。次いで、3-(2,4,6-トリメチルフェニル)スルホニル-1H-1,2,4-トリアゾール(実施例35-a) 51mgを加え、更に10分間撹拌した。続いてN-メチルエチルアミン0.034mlを加え、室温に戻し6時間撹拌した。反応液を50%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない標記化合物52mgを得た。
1H-NMR(CDCl3)δ=1.28(3H, t, J=7Hz), 2.31(3H, s), 2.71(6H, s), 3.13(1.5H, br.s), 3.29(1.5H, br.s), 3.52-3.69(2H, m), 6.98(2H, s), 8.79(1H, s)
【0096】
実施例37
3-(2,4,6- トリメチルフェニル ) スルホニル -1-(N- メチル -N- プロピルカルバモイル )-1H-1,2,4- トリアゾール
【化59】
3-(2,4,6-トリメチルフェニル)スルホニル-1H-1,2,4-トリアゾール(実施例35-a)及びN-メチルプロピルアミンを用い、実施例36と同様にして合成した。
1H-NMR(CDCl3)δ=0.86(1.5H, br.s), 0.98(1.5H, br.s), 1.71(2H, br.s), 2.31(3H, s), 2.70(6H, s), 3.14(1.5H, br.s), 3.29(1.5H, br.s), 3.48(1H, br.s), 3.56(1H, br.s), 6.98(2H, s), 8.79(1H, s)
【0097】
実施例38
3-(2,4,6- トリメチルフェニル ) スルホニル -1-(N- メチル -N- イソプロピルカルバモイル )-1H-1,2,4- トリアゾール
【化60】
3-(2,4,6-トリメチルフェニル)スルホニル-1H-1,2,4-トリアゾール(実施例35-a)及びN-メチルイソプロピルアミンを用い、実施例36と同様にして合成した。
1H-NMR(CDCl3)δ=1.27(6H, d, J=7Hz), 2.31(3H, s), 2.71(6H, s), 2.90-3.15(3H, m), 4.35-4.65(1H, m), 6.97(2H, s), 8.76(1H, s)
【0098】
実施例39
3-(2,4,6- トリメチルフェニル ) スルフィニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化61】
a) 3-(2,4,6-トリメチルフェニル)スルフィニル-1H-1,2,4-トリアゾール
オキソン一過硫酸塩化合物(OXONEョ)3.02gと水30mlの混合物を室温にて撹拌しながら、3-(2,4,6-トリメチルフェニル)チオ-1H-1,2,4-トリアゾール(実施例32-a)1.08gとメタノール30mlの混合物を滴下した。滴下終了後、3時間撹拌し、水20mlを加えた。析出した結晶を濾取し、水、酢酸エチル、ヘキサンの順で洗い標記化合物820mgを得た。
1H-NMR(DMSO-d6)δ=2.26(3H, s), 2.45(6H, s), 6.95(2H, s), 8.68(1H, br.s)
【0099】
b) 3-(2,4,6-トリメチルフェニル)スルフィニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(2,4,6-トリメチルフェニル)スルフィニル-1H-1,2,4-トリアゾール及びジメチルカルバモイルクロリドを用い、実施例22と同様にして標記化合物を合成した。
1H-NMR(CDCl3)δ=2.30(3H, s), 2.54(6H, s), 3.17(3H, br.s), 3.34(3H, br.s), 6.91(2H, s), 8.78(1H, s)
【0100】
実施例40
3-[2-(2,2,2- トリフルオロエチル ) オキシ -6- メチルフェニル ] チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化62】
a) 2,2,2-トリフルオロエチル メタンスルホネート
2,2,2-トリフルオロエタノール5g、トリエチルアミン14ml、酢酸エチル120mlの混合物に、氷冷下塩化メタンスルホニル5.8mlを滴下し、同温で1時間撹拌した。反応液を少量のシリカゲル、ついでNHシリカゲルを通して濾過、酢酸エチルで洗った。濾液を減圧濃縮し標記化合物9.5gを得た。
1H-NMR(CDCl3) δ=3.15(3H, s), 4.54(2H, q, J=8Hz)
【0101】
b) 2-ニトロ-3-(2,2,2-トリフルオロエチル)オキシトルエン
3-ヒドロキシ-2-ニトロトルエン5g、2,2,2-トリフルオロエチル メタンスルホネート8.7g、無水炭酸カリウム9g、N,N-ジメチルホルムアミド40mlの混合物を80℃油浴中4時間、ついで100℃油浴中4時間加熱撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、希炭酸カリウム水溶液洗い、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後、NHシリカゲルを通して濾過、酢酸エチルで洗った。濾液を減圧濃縮し、5-10%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない標記化合物4.12gを得た。
1H-NMR(CDCl3) δ=2.33(3H, s), 4.42(2H, q, J=8Hz), 6.89(1H, d, J=8Hz), 6.99(1H, d, J=8Hz), 7.34(1H, t, J=8Hz),
【0102】
c) 2-アミノ-3-(2,2,2-トリフルオロエチル)オキシトルエン
2-ニトロ-3-(2,2,2-トリフルオロエチル)オキシトルエン4.12g、酢酸エチル30mlの混合物に触媒量の10%パラジウム/炭素を加え、水素雰囲気下4時間撹拌した。反応液から触媒を濾過して除き、濾液を減圧濃縮し、標記化合物3.71gを得た。
1H-NMR(CDCl3) δ=2.19(3H, s), 3.79(2H, br.s), 4.36(2H, q, J=8Hz), 6.62-6.70(2H, m), 6.80(1H, dd, J=2, 7Hz)
【0103】
d) 3-[2-(2,2,2-トリフルオロエチル)オキシ-6-メチルフェニル]チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
2-アミノ-3-(2,2,2-トリフルオロエチル)オキシトルエンを用いて、以下実施例32と同様に標記化合物を合成した。
1H-NMR(CDCl3) δ=2.51(3H, s), 3.17(6H, br.s), 4.32(2H, q, J=8Hz), 6.80(1H, d, J=8Hz), 7.06(1H, d, J=8Hz), 7.31(1H, t, J=8Hz), 8.62(1H, s)
【0104】
実施例41
3-[2-(2,2,2- トリフルオロエチル ) オキシ -6- メチルフェニル ] スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化63】
3-[2-(2,2,2-トリフルオロエチル)オキシ-6-メチルフェニル]チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例40)を用いて、実施例33と同様に合成した。
1H-NMR(CDCl3) δ=2.84(3H, s), 3.19(3H, br.s), 3.35(3H, br.s), 4.32(2H, q, J=8Hz), 6.84(1H, d, J=8Hz), 7.09(1H, d, J=8Hz), 7.49(1H, t, J=8Hz), 8.78(1H, s)
【0105】
実施例42
3-[2-(2- メトキシエチル ) オキシ -6- メチルフェニル ] チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化64】
2-ブロモエチルメチルエーテルを用いて、実施例40と同様に合成した。
1H-NMR(CDCl3) δ=2.48(3H, s), 3.14(6H, br.s), 3.33(3H, s), 3.61(2H, t, J=5Hz), 4.07(2H, t, J=5Hz), 6.80(1H, d, J=8Hz), 6.94(1H, d, J=8Hz), 7.27(1H, t, J=8Hz), 8.63(1H, s)
【0106】
実施例43
3-[2-(2- メトキシエチル ) オキシ -6- メチルフェニル ] スルホニル -1- ジメチルカル バモイル -1H-1,2,4- トリアゾール
【化65】
3-[2-(2-メトキシエチル)オキシ-6-メチルフェニル]チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例42)を用いて実施例33と同様に合成した。
1H-NMR(CDCl3) δ=2.81(3H, s), 3.17(3H, br.s), 3.25(3H, s), 3.31(3H, br.s), 3.49(2H, t, J=5Hz), 4.01(2H, t, J=5Hz), 6.82(1H, d, J=8Hz), 6.94(1H, d, J=8Hz), 7.42(1H, t, J=8Hz), 8.77(1H, s)
【0107】
実施例44
3-(4- シアノ -2,5- ジフルオロフェニル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化66】
2,4,5-トリフルオロベンゾニトリル1.6g、3-メルカプト-1H-1,2,4-トリアゾール1.2g、無水炭酸カリウム2.1g、N,N-ジメチルホルムアミド10mlの混合物を室温で2時間撹拌した。反応液を酢酸エチル−水で抽出し有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を真空乾燥して、薄層クロマトグラフィー上2スポットの固体として2.06gを得た。
この結晶240mg、無水炭酸カリウム280mg、N,N-ジメチルホルムアミド1mlの混合物に、ジメチルカルバモイルクロライド0.14mlを加え、室温で1時間撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、飽和食塩水洗い後濃縮した。残渣を15-20%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーを2回おこない、薄層クロマトグラフィー上変化したスポットである標記化合物114mgを得た。
1H-NMR(CDCl3) δ=3.20(3H, br.s), 3.29(3H, br.s), 7.36(1H, dd, J=5, 8Hz), 7.42(1H, dd, J=5, 8Hz), 8.84(1H, s)
【0108】
実施例45
3-(4- シアノ -2,5- ジフルオロフェニル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化67】
3-(4-シアノ-2,5-ジフルオロフェニル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例44)を用いて、実施例33と同様に合成した。
1H-NMR(CDCl3) δ=3.21(3H, s), 3.33(3H, s), 7.51(1H, dd, J=5, 8Hz), 8.05(1H, dd, J=5, 7Hz), 8.86(1H, s)
【0109】
実施例46
3-(3,5- ジメチルイソキサゾール -4- イル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化68】
a) 3-(2,4-ペンタンジオン-3-イル)チオ-1H-1,2,4-トリアゾール
水酸化カリウム13gのメタノール200ml溶液に氷冷下3-メルカプト-1H-1,2,4-トリアゾール20g、ついで3-クロロ-2,4-ペンタンジオン24mlを加え、そのまま室温で一晩撹拌した。反応液の不溶物を濾過して除き、濾液を減圧濃縮した。残渣を酢酸エチル−水で抽出し、有機層を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥後、少量のシリカゲルを通して濾過、酢酸エチルで洗い濾液を減圧濃縮した。残渣を酢酸エチル−ヘキサンで再結晶し標記化合物33.1gを得た。
1H-NMR(CDCl3) δ=2.42(6H, s), 8.15(1H, s)
【0110】
b) 3-(3,5-ジメチルイソキサゾール-4-イル)チオ-1H-1,2,4-トリアゾール
3-(2,4-ペンタンジオン-3-イル)チオ-1H-1,2,4-トリアゾール2g、塩酸ヒドロキシルアミン0.7g、トリエチルアミン1.4ml、エタノール10mlの混合物を100℃の油浴中5時間加熱撹拌した。反応液を減圧濃縮した後、酢酸エチル−水で抽出し、有機層を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥し減圧濃縮した。残渣を10-30%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない酢酸エチル−ヘキサンで結晶化し、標記化合物440mgを得た。
1H-NMR(CDCl3) δ=2.28(3H, s), 2.50(3H, s), 8.14(1H, s)
【0111】
c) 3-(3,5-ジメチルイソキサゾール-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(3,5-ジメチルイソキサゾール-4-イル)チオ-1H-1,2,4-トリアゾールを用いて実施例32と同様に合成した。
1H-NMR(CDCl3) δ=2.28(3H, s), 2.49(3H, s), 3.17(6H, br.s), 8.69(1H, s)
【0112】
実施例47
3-(3,5- ジメチルイソキサゾール -4- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化69】
3-(3,5-ジメチルイソキサゾール-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例46)を用いて、実施例33と同様に合成した。
1H-NMR(CDCl3) δ=2.50(3H, s), 2.76(3H, s), 3.20(3H, br.s), 3.33(3H, br.s), 8.83(1H, s)
【0113】
実施例48
3-(3,5- ジメチル -1- フェニルピラゾール -4- イル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化70】
a) 3-(3,5-ジメチル-1-フェニルピラゾール-4-イル)チオ-1H-1,2,4-トリアゾール
3-(2,4-ペンタンジオン-3-イル)チオ-1H-1,2,4-トリアゾール(実施例46-a) 2g、フェニルヒドラジン1ml、エタノール10mlの混合物を100℃の油浴中4時間加熱撹拌した。反応液を減圧濃縮した後、残渣をエタノール−酢酸エチルから結晶化して標記化合物1.42gを得た。
1H-NMR(d6-DMSO) δ=2.21(3H, s), 2.35(3H, s), 7.40-7.56(5H, m)
【0114】
b) 3-(3,5-ジメチル-1-フェニルピラゾール-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(3,5-ジメチル-1-フェニルピラゾール-4-イル)チオ-1H-1,2,4-トリアゾールを用いて、実施例32と同様に合成した。
1H-NMR(CDCl3) δ=2.35(3H, s), 2.40(3H, s), 3.18(6H, br.s), 7.36-7.51(5H, m), 8.69(1H, s)
【0115】
実施例49
3-(3,5- ジメチル -1- フェニルピラゾール -4- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化71】
3-(3,5-ジメチル-1-フェニルピラゾール-4-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例48)を用いて、実施例33と同様に合成した。
1H-NMR(CDCl3) δ=2.55(3H, s), 2.60(3H, s), 3.20(3H, br.s), 3.35(3H, br.s), 7.36-7.54(5H, m), 8.82(1H, s)
【0116】
実施例50
3-(2- メチルイミダゾ [1,2-a] ピリジン -3- イル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化72】
a) 2-メチルイミダゾ[1,2-a]ピリジン
2-アミノピリジン9.4g、クロロアセトン9.5ml、エタノール25mlの混合物を100℃の油浴中5時間加熱撹拌した。反応液を減圧濃縮し、酢酸エチル−炭酸カリウム水溶液で抽出し、有機層を飽和食塩水洗い、無水硫酸マグネシウム乾燥後減圧濃縮した。残渣を、NHシリカゲルを用い、20-30%酢酸エチル/ヘキサンでカラムクロマトグラフィーをおこない、標記化合物5.5gを得た。
1H-NMR(CDCl3) δ=2.46(3H, s), 6.72(1H, dt, J=1, 7Hz), 7.10(1H, ddd, J=1, 7, 9Hz), 7.33(1H, s), 7.50(1H, dt, J=9, 1Hz), 8.03(1H, dt, J=7, 1Hz)
【0117】
b) 3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)チオ-1H-1,2,4-トリアゾール3-メルカプト-1H-1,2,4-トリアゾール1.15g、N,N-ジメチルホルムアミド15mlの混合物に60%水素化ナトリウム450mgを加え、発泡が収まったら氷浴中N-クロロこはく酸イミドを少しずつ加え、同温で15分撹拌した後2-メチルイミダゾ[1,2-a]ピリジン1.0gを加え、室温で1時間、70℃の油浴中3時間加熱撹拌した。反応液を減圧濃縮し、残渣をジエチルエーテルで2回洗い、メタノールを加えて不溶物を濾去した。濾液を濃縮し、水を加えて析出した結晶を濾取、水洗、ジエチルエーテルで洗って乾燥し、標記化合物480mgを得た。
1H-NMR(d6-DMSO) δ=2.43(3H, s), 7.02(1H, dt, J=1, 7Hz), 7.39(1H, ddd, J=1, 7, 9Hz), 7.58(1H, d, J=9Hz), 8.38(1H, d, J=7Hz), 8.49(1H, br.s), 14.10(1H, br.s)
【0118】
c) 3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)チオ-1H-1,2,4-トリアゾールを用いて、実施例32と同様に合成した。
1H-NMR(CDCl3) δ=2.58(3H, s), 3.04(6H, s), 6.88(1H, dt, J=1, 7Hz), 7.29(1H, ddd, J=1, 7, 9Hz), 7.59(1H, dt, J=9, 1Hz), 8.28(1H, dt, J=7, 1Hz), 8.65(1H, s)
【0119】
実施例51
3-(2- メチルイミダゾ [1,2-a] ピリジン -3- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化73】
a) 3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)スルホニル-1H-1,2,4-トリアゾール
3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)チオ-1H-1,2,4-トリアゾール(実施例50-a) 230mg、アセトニトリル5ml、水5mlの混合物に、30℃の水浴中過炭酸ナトリウム630mgを少しずつ加え、その後同温で4時間撹拌した。反応液に水7.5mlを加え、氷浴中濃塩酸を滴下し、PHを約4に調節した。そのまま30分撹拌し、析出した結晶を濾取、水洗、乾燥して標記化合物139mgを得た。
1H-NMR(d6-DMSO) δ=2.62(3H, s), 7.27(1H, dt, J=1, 7Hz), 7.62(1H, ddd, J=1, 7, 9Hz), 7.73(1H, dt, J=9, 1Hz), 8.80(1H, s), 8.86(1H, dt, J=7, 1Hz)
【0120】
b) 3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)スルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(2-メチルイミダゾ[1,2-a]ピリジン-3-イル)スルホニル-1H-1,2,4-トリアゾール100mg、無水炭酸カリウム105mg、N,N-ジメチルホルムアミド0.5mlの混合物に、ジメチルカルバモイルクロライド0.06mlを加え室温で一晩撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、飽和食塩水洗いの後濃縮した。残渣を30-50%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物107mgを得た。
1H-NMR(CDCl3) δ=2.79(3H, s), 3.17(3H, br.s), 3.29(3H, br.s), 7.05(1H, dt, J=1, 7Hz), 7.48(1H, ddd, J=1, 7, 9Hz), 7.65(1H, dt, J=9, 1Hz), 8.77(1H, s), 9.04(1H, dt, J=1, 7Hz)
【0121】
実施例52
3-(6- ブロモ -2- ピリジル ) チオ -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化74】
a) 3-(6-ブロモ-2-ピリジル)チオ-1H-1,2,4-トリアゾール
3-メルカプト-1H-1,2,4-トリアゾール200mg、2,6-ジブロモピリジン560mg、無水炭酸カリウム420mg、N,N-ジメチルホルムアミド1mlの混合物を100℃の油浴中3時間加熱撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を5-30%(20% 2-プロパノール/酢酸エチル)/ヘキサンを用いてシリカゲルカラムクロマトグラフィーで精製し、標記化合物73mgを得た。
1H-NMR(CDCl3) δ=7.34(1H, d, J=8Hz), 7.40(1H, d, J=8Hz), 7.53(1H, t, J=8Hz), 8.12(1H, s)
【0122】
b) 3-(6-ブロモ-2-ピリジル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-(6-ブロモ-2-ピリジル)チオ-1H-1,2,4-トリアゾール73mg、ジメチルカルバモイルクロリド40μl 、無水炭酸カリウム80mg、N,N-ジメチルホルムアミド0.5mlの混合物を室温で2時間撹拌した。反応液を酢酸エチル−水で抽出し、有機層を水洗、飽和食塩水洗い、無水硫酸マグネシウムで乾燥後減圧濃縮した。残渣を20%(20% 2-プロパノール/酢酸エチル)/ヘキサンを用いてシリカゲルカラムクロマトグラフィーで精製し、標記化合物77mgを得た。
1H-NMR(CDCl3) δ=3.19(3H, br.s), 3.33(3H, br.s), 7.31(1H, dd, J=1, 8Hz), 7.34(1H, dd, J=1, 8Hz), 7.44(1H, t, J=8Hz), 8.85(1H, s)
【0123】
実施例53
3-(6- ブロモ -2- ピリジル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化75】
3-(6-ブロモ-2-ピリジル)チオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例52) 60mg、酢酸エチル0.5mlの混合物にm-クロロ過安息香酸84mgを加え、60℃の油浴中2時間加熱撹拌した。反応液にヘキサン0.5mlを加え、室温で結晶を濾取、酢酸エチル/ヘキサン(1/1)で洗い乾燥し、標記化合物45mgを得た。
1H-NMR(CDCl3) δ=3.20(3H, s), 3.37(3H, s), 7.74(1H, dd, J=1, 8Hz), 7.86(1H, t, J=8Hz), 8.28(1H, dd, J=1, 8Hz), 8.85(1H, s)
【0124】
実施例54
3-( ピペリジン -1- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化76】
a) 3-クロロスルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-ベンジルチオ-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例1) 45g、酢酸300ml、水75mlの混合物を氷−食塩浴中-5℃以下に冷却しておき、ここに塩素ガスを55分間通じた。反応液に水600ml加え、酢酸エチル/ヘキサン(1/1)で抽出し、有機層を水洗、炭酸水素ナトリウム水溶液洗い、飽和食塩水洗い、無水硫酸マグネシウムで乾燥し減圧濃縮し、標記化合物を33g得た。
1H-NMR(CDCl3) δ=3.23(3H, br.s), 3.37(3H, br.s), 8.96(1H, s)
【0125】
b) 3-(ピペリジン-1-イル)スルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-クロロスルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール240mg、酢酸エチル2mlの混合物に室温水浴中ピペリジン0.2mlを加え、同温で1時間撹拌した。反応液を水、ついで飽和食塩水で洗い濃縮した。残渣を20-30%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物29mgを得た。
1H-NMR(CDCl3) δ=1.50-1.72(6H, m), 3.20(3H, br.s), 3.30-3.387H, m), 8.84(1H, s)
【0126】
実施例55
3-(8- アザ - ビシクロ [3.2.1] オクタン -8- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化77】
a) 8-アザ-ビシクロ[3.2.1]オクタン塩酸塩
トロパン900mg、1-クロロエチルクロロホルメート1ml、トルエン20mlの混合物を6時間加熱還流した。次いで反応液にメタノール10mlを加え、4時間加熱還流した後、溶媒を留去し、標記化合物を850mg得た。
【0127】
b) 3-(8-アザ-ビシクロ[3.2.1]オクタン-8-イル)スルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール
3-クロロスルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例54-a)470mg、8-アザ-ビシクロ[3.2.1]オクタン塩酸塩350mg、トリエチルアミン0.7ml、酢酸エチル10mlの混合物を室温にて終夜撹拌した。反応液を水、ついで飽和食塩水で洗い濃縮した。残渣を50-100%酢酸エチル/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、標記化合物150mgを得た。
1H-NMR(CDCl3) δ=1.40-1.80(8H, m), 1.84-1.95(2H, m), 3.19(3H, br.s), 3.33(3H, br.s), 4.35-4.45(2H, m), 8.80(1H, s)
【0128】
実施例56
3-(3,5- ジメチルピラゾール -1- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化78】
3,5-ジメチルピラゾール100mg、3-クロロスルホニル-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール(実施例54-a)480mg、無水炭酸カリウム280mg、アセトニトリル1.5mlの混合物を50℃の油浴中2時間加熱撹拌した。反応液を酢酸エチル−水で抽出し、有機層を飽和食塩水で洗い濃縮した。残渣を20-30%(20% 2-プロパノール/酢酸エチル)/ヘキサンでシリカゲルカラムクロマトグラフィーをおこない、酢酸エチル−ヘキサンで結晶化して標記化合物210mgを得た。
1H-NMR(CDCl3) δ=2.22(3H, s), 2.62(3H, s), 3.18(3H, s), 3.33(3H, s), 6.03(1H, s), 8.81(1H, s)
【0129】
実施例57
3-(2,3- ジヒドロ -1H- インドール -1- イル ) スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化79】
2,3-ジヒドロ-1H-インドールを用いて、実施例56と同様に合成した。
1H-NMR(CDCl3) δ=3.12(2H, t, J=8Hz), 3.14(6H, s), 4.26(2H, t, J=8Hz), 7.00(1H, t, J=8Hz), 7.10-7.17(2H, m), 7.53(1H, d, J=8Hz), 8.75(1H, s)
【0130】
実施例58
3-[N-(4- クロロフェニル )-N- メチルアミノ ] スルホニル -1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化80】
N-メチル-4-クロロアニリンを用いて、実施例56と同様に合成した。
1H-NMR(CDCl3) δ=3.17(3H, br.s), 3.23(3H, br.s), 3.47(3H, s), 7.25(2H, d, J=9Hz), 7.30(2H, d, J=9Hz), 8.86(1H, s)
【0131】
実施例59
3-(4- トルエンスルホニル )-1- ジメチルカルバモイル -1H- ピラゾール
【化81】
a) 1-(4-トルエンスルホニル)-1H-ピラゾール
ピラゾール1gと4-トルエンスルホニルクロリド2.8gのピリジン懸濁液10mlを130℃で1時間攪拌した。反応混合物を冷却後、水を加えて白色懸濁液を得た。得られた白色懸濁液を濾取して、得られた白色固形物を水で3回洗浄した。減圧下、室温で乾燥して白色固形物500mgを得た。
1H-NMR(d6-DMSO)δ= 2.39(3H, s), 6.59-6.60 (1H, m), 7.47 (2H, d, J=8.2Hz), 7.85-7.88 (3H, m), 8.46 (1H, d, J=2.8Hz)
【0132】
b) 3-(4-トルエンスルホニル)-1-ジメチルカルバモイル-1H-ピラゾール
窒素雰囲気下、1-(4-トルエンスルホニル)-1H-ピラゾール500mgのテトラヒドロフラン10ml溶液に-70℃でtert-ブチルリチウムの1.6モルヘキサン溶液を滴下し、得られた黄色懸濁液を室温まで自然昇温し、100℃で14時間攪拌した。反応混合物を冷却後、飽和塩化アンモニウム水で希釈して得られた混合物を酢酸エチルで2回抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮して茶褐色油状物を残渣として得た。この残渣全量、ジメチルカルバモイルクロリド0.5mlおよび炭酸カリウム200mgのN,N-ジメチルホルムアミド懸濁液を室温下で30分攪拌した。反応混合液に酢酸エチルと水を加え、酢酸エチルで抽出した。得られた有機層を水で2回、飽和塩化アンモニウム水溶液で1回洗浄した後、硫酸マグネシウムで乾燥し、残渣をショートカラムクロマト(溶離液:n-ヘキサン/酢酸エチル=3/1)にて精製して透明油状物122mgを得た。
1H-NMR(CDCl3) δ=2.42(3H, s), 3.10-3.25(6H, m), 6.81(1H, d, J=2.8Hz), 7.32(2H,d, J=8.2Hz), 7.91(2H, d, J=8.4Hz), 8.11 (1H, d, J=2.8Hz)
【0133】
実施例60
3-(4- トルエンスルホニル )-1- ジメチルカルバモイル -1H-1,2,4- トリアゾール
【化82】
a) 1-(4-トルエンスルホニル)-1H-トリアゾール
1H-1,2,4-トリアゾール5gと4-トルエンスルホニルクロリド14.5gのN,N-ジメチルホルムアミド溶液に氷冷下、水素化ナトリウム2.9gを加え、反応混合液を氷冷化40分攪拌した。反応混合液に水を加え、得られた混合物を酢酸エチルで抽出した。得られた有機層を水で2回洗浄した後、硫酸マグネシウムで乾燥し、残渣をショートカラムクロマト(溶離液:n-ヘキサン/酢酸エチル=4/1)にて精製して白色固形物21.8gを得た。
1H-NMR (d6-DMSO) δ=2.42 (3H, s), 7.53 (2H, d, J=8.4Hz), 7.97 (2H, d, J=8.4Hz), 8.34(1H, s), 9.40 (1H, s)
【0134】
b) 3-トルエンスルホニル-1H-トリアゾール
1-トルエンスルホニル-1-テトラゾール1gとリチウムブロミド389mgのテトラヒドロフラン溶液に-78℃にて、ブチルリチウムの2.6モルヘキサン溶液を滴下した。反応混合物を-78℃で10分間攪拌後、室温下で3時間30分攪拌した。得られた反応混合液に氷冷下で飽和塩化アンモニウム水溶液を加え、得られた混合物を酢酸エチルで抽出した。得られた有機層を硫酸マグネシウムで乾燥し、残渣から溶媒を減圧留去して茶褐色固形物440mgを得た。
1H-NMR(d6-DMSO) δ=2.40 (3H, s), 7.47 (2H, d, J=7.8Hz), 7.85 (2H, d, J=8.0Hz), 8.80 (1H, s).
【0135】
c) 3-(4-トルエンスルホニル)-1-ジメチルカルバモイル-1H-1,2,4-トリアゾール3-(4-トルエンスルホニル)-1H-1,2,4-トリアゾール100mg、ジメチルカルバモイルクロリド62μlおよび炭酸カリウム124mgのN,N-ジメチルホルムアミド懸濁液を室温下で1時間10分攪拌した。反応混合液に酢酸エチルと水を加え、酢酸エチルで抽出した。得られた有機層を水で3回洗浄した後、硫酸マグネシウムで乾燥し、残渣をショートカラムクロマト(溶離液:n-ヘキサン/酢酸エチル=3/1)にて精製して透明油状物77mgを得た。
1H-NMR (CDCl3) δ=2.34(3H, s), 3.02(6H, br s), 7.48(2H, d, J=8.0Hz), 7.87(2H, d, J=8.0Hz), 9.22(1H, s)
【0136】
【試験例1】
DPPIV阻害作用の測定
反応用緩衝液(50mM Tris-HCl pH7.4, 0.1% BSA)にブタ腎臓より得られたDPP-IVを10mμ/mLになるよう溶解し、これを110μl添加した。さらに薬物を15μl添加した後、室温で20分間インキュベーションし、2mMに溶解したGly-Pro-p-nitroanilideを25μl(最終濃度0.33mM)加えて、酵素反応を開始した。反応時間は20分とし、1N リン酸溶液 25μl加え、反応を停止した。この405nmにおける吸光度を測定し、酵素反応阻害率を求めIC50を算出した。
【0137】
【表1】
【試験例2】
耐糖能改善作用の確認試験
【0138】
正常マウスの耐糖能に対する効果
動物:
各群5あるいは、6例の雄性C57BL/6Nマウス(日本チャールス・リバーより購入)
【0139】
被検化合物の調整及び投与:
実験.1及び実験.2について
下表に示した用量で、被検化合物を0.5%メチルセルロース水溶液に懸濁し、これを等容量のグルコース溶液と混合し、10ml/kgの容量で経口投与した。溶媒対照群は、0.5%メチルセルロース水溶液と等容量のグルコース溶液と混合し、10ml/kgの容量で経口投与した。グルコースは、2g/kgの用量で投与した。
【0140】
実験.3について
被検化合物は、下表に示した用量で、0.5%メチルセルロース水溶液に懸濁した。この被検化合物の懸濁液もしくは、溶媒対照群である0.5%メチルセルロース水溶液を10ml/kgの容量で経口投与し、その30分後に、グルコース溶液を10ml/kgの容量で経口投与した。グルコースは、2g/kgの用量で投与した。
【0141】
採血および血糖値の測定:
実験.1及び実験.2について
被検物質とグルコースの混合溶液の投与直前および投与後、30、60、120分後に尾静脈より採血し、血糖値を測定した。
【0142】
実験.3について
被検物質の投与直前とグルコース溶液の投与直前および投与後、30、60、120分後に尾静脈より採血し、血糖値を測定した。
【0143】
方法:
無麻酔下、マウスの尾静脈を剃刃で傷つけわずかに出血させる。血液10μlを採取し、直ちに0.6M過塩素酸14010μlに混合する。遠心分離(1500g、10分、4℃、冷却遠心機GS-6KR、ベックマン(株))して得た上清中のグルコースをグルコースCIIテストワコー(和光純薬工業)を用いて測定した。
【0144】
結果:
以下の表に示した。結果は、平均値±標準誤差で示した。
【0145】
正常マウスの耐糖能に対する効果
【表2】
【表3】
【表4】
以上のように、N−カルバモイルアゾール誘導体である実施例2、13、43の化合物は、経口投与により、正常マウスの耐糖能に対して明確な効果を示した。
【発明の効果】
本発明により、DPPIV阻害作用を示す1−カルバモイルアゾール誘導体化合物を提供することができた。
したがって本発明におけるDPPIV阻害剤は、例えば糖尿病治療剤、肥満治療剤、高脂血症治療剤、AIDS治療剤、骨粗鬆症治療剤、消化管障害治療剤、血管新生治療剤、不妊症治療剤、抗炎症剤、抗アレルギー剤、免疫調整剤、ホルモン調節剤、抗リウマチ剤、ガン治療剤等の治療・予防剤として有用である。
また経口投与による薬効を確認するため、耐糖能改善作用を指標とした試験をおこない、経口有効性を確認し、医薬としての有用性を見いだした。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical use based on the DPPIV inhibitory action of a 1-carbamoylazole derivative, and a pharmaceutical composition containing it as an active ingredient.
[0002]
[Prior art]
Dipeptidyl peptidase-IV (DPPIV) is a kind of serine protease that specifically hydrolyzes the X-Pro dipeptide from the free N-terminus of the polypeptide chain.
Glucagon-Like Peptide-1 and GIP (Glucose-dependent Insulinotropic Polypeptide) secreted from the intestinal tract after meal is rapidly degraded and inactivated by DPPIV It becomes. By suppressing the degradation by DPPIV, the action by incretin (GLP-1 and GIP) is enhanced, and insulin secretion from pancreatic β cells by glucose stimulation is enhanced. As a result, it has been clarified that hyperglycemia after the oral glucose tolerance test is improved. (Diabetologia 1999 Nov; 42 (11): 1324-31). In addition, GLP-1 has been shown to be involved in appetite and food intake suppression effects, and also to protect β cells based on the differentiation and proliferation promoting effects of GLP-1 on pancreatic β cells.
[0003]
From these facts, it can be expected that DPPIV inhibitors can be useful therapeutic agents and preventive agents for diseases involving GLP-1 and GIP such as obesity and diabetes.
[0004]
Furthermore, the relationship between various diseases described below and dipeptidyl peptidase IV has been reported, and from these facts, it can be expected that DPPIV inhibition can be a therapeutic agent for them.
(1) Prevention and treatment of AIDS (Science, 262, 2045-2050, 1993.)
(2) Prevention and treatment of osteoporosis (Clinical chemistry, 34, 2499-2501, 1988.)
(3) Preventive and therapeutic agents for intestinal disorder (Endcrinology, 141, 4013-4020, 2000.)
(4) Diabetes, obesity, hyperlipidemia prevention and treatment agent (Diabetes, 47, 1663-1670, 1998, Life Sci; 66 (2): 91-103, 2000)
(5) Angiogenesis prevention and treatment (Agents and actions, 32, 125-127, 1991.)
(6) Infertility prevention and treatment agent (WO00 / 56296)
(7) Inflammatory diseases, autoimmune diseases, prevention and treatment of rheumatoid arthritis (2001, 166, 2041-2048, The Journal of Immunology.)
(8) Prevention and treatment of cancer (Br J Cancer 1999 Mar; 79 (7-8): 1042-8, J Androl 2000 Mar-Apr; 21 (2): 220-6)
[0005]
As shown in US Pat. No. 5,510,320, US Pat. No. 5,338,720, US Pat. No. 5,258,361, US Pat. No. 3,308,131, US Pat. No. 5,424,279, JP-A-5-255318, JP-A-9-143181, and JP-A-11-80137. As described above, 1-carbamoylazole derivatives and the like are known to be useful as herbicides, but there is no report on DPPIV inhibitory action.
[0006]
DPPIV inhibitors are disclosed in US Pat. No. 6,303,661, US Pat. No. 6,011,155, US Pat. No. 2001020006, US Pat. No. 5,543,396, WO 00/34241, etc., but structurally clearly different from the present invention. ing.
[0007]
[Problems to be solved by the invention]
As described above, provision of DPPIV-inhibiting compounds useful as pharmaceuticals is anxious. However, no compound has yet been found that exhibits an excellent DPPIV inhibitory action and is highly useful as a medicine and acts effectively in clinical practice. That is, an object of the present invention is to search for and find a DPPIV inhibitory compound useful as a therapeutic / preventive / ameliorating agent for diabetic diseases and the like.
[Means for Solving the Problems]
As a result of intensive studies in view of the above circumstances, the present inventors have found that N-carbamoylazole derivatives have a DPPIV inhibitory action. That is, the feature of the present invention is that
<1> General formula
[Chemical formula 5]
[Wherein R1aIs C1-6Alkyl group, C3-8A cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, C6-10Aromatic hydrocarbon cyclic group, 4- to 10-membered heterocyclic group or C4-13Means a polycycloalkyl group; n means an integer of 0 to 2; W is a single bond, C1-6Alkylene group or formula
[Chemical 6]
(Where2Represents a nitrogen atom or a methine group, m represents an integer of 0 to 3, R1bIs C1-6Alkyl group, C3-8A cycloalkyl group, a 5- to 10-membered aromatic heterocyclic group, C6-10Aromatic hydrocarbon cyclic group, 4- to 10-membered heterocyclic group or C4-13Means a polycycloalkyl group. X represents a group represented by1And X2Each independently represents a nitrogen atom or a methine group;
[Chemical 7]
(Wherein R2aAnd R2bAre each independently C1-6Alkyl group, C2-6An alkenyl group or a phenyl group means Z2Means a sulfur atom or a methylene group. ). However, R1aAnd R1bAre: (1) halogen atom, (2) hydroxyl group, (3) C2-6Alkenyl group, (4) C2-6Alkynyl group, (5) phenyl group, (6) cyano group, (7) 1 to 3 halogen atoms or C1-6C optionally substituted with an alkoxy group1-6An alkoxy group and (8) 1-3 halogen atoms or C1-6C optionally substituted with an alkoxy group1-6It may be substituted with 1 to 3 substituents selected from the group consisting of alkyl groups. A dipeptidyl peptidase IV inhibitor comprising a compound represented by the formula:
<2> Z is the formula
[Chemical 8]
(Wherein R2bIs C1-6Alkyl group, C2-6An alkenyl group or a phenyl group is meant. The dipeptidyl peptidase IV inhibitor according to the above <1>, which is a group represented by
<3> R1aThe dipeptidyl peptidase IV inhibitor according to <1> or <2>, wherein is a phenyl group or a 4-pyrazolyl group;
<4> X1Is a nitrogen atom and X2The dipeptidyl peptidase IV inhibitor according to any one of <1> to <3>, wherein is a methine group;
<5> X1And X2The dipeptidyl peptidase IV inhibitor according to any one of <1> to <3>, wherein is a methine group;
<6> The dipeptidyl peptidase IV inhibitor according to any one of <1> to <5>, wherein n is 1 or 2;
<7> The dipeptidyl peptidase IV inhibitor according to <1>, which is a therapeutic / preventive agent for diabetic diseases;
<8> The dipeptidyl peptidase IV inhibitor according to <1>, which is a therapeutic / preventive agent for obesity;
<9> Hyperlipidemia treatment agent, AIDS treatment agent, osteoporosis treatment agent, digestive tract disorder treatment agent, angiogenesis treatment agent, infertility treatment agent, anti-inflammatory agent, antiallergic agent, immune regulator, hormone regulator, The present invention relates to an anti-rheumatic agent, the dipeptidyl peptidase IV inhibitor according to <1> above, which is a cancer therapeutic agent.
[0008]
Hereinafter, the meaning of terms, symbols, and the like described in the present specification will be described, and the present invention will be described in detail.
[0009]
In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but in the present invention, all geometric isomers generated in the structure of the compound, optical isomers based on asymmetric carbon Isomers such as stereoisomers and tautomers, and mixtures of isomers, and are not limited to the description of formulas for convenience, and may be either isomers or mixtures. Accordingly, it may have an asymmetric carbon atom in the molecule, and an optically active substance and a racemate may exist. However, the present invention is not particularly limited and includes any case. In addition, there may be crystal polymorphs, but there is no limitation, and any crystal form may be single or mixed, and may be either anhydrous or hydrated. .
[0010]
“C” represented in this specification1-6The term “alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n -Butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, 1-methylpropyl, 1,2-dimethylpropyl, 2-ethylpropyl Group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, Examples include 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group, 3-methylpentyl group and the like.
[0011]
“C” represented in this specification2-6The term “alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1- A buten-1-yl group, a 1-buten-2-yl group, a 1-buten-3-yl group, a 2-buten-1-yl group, a 2-buten-2-yl group, and the like, preferably allyl It is a group.
[0012]
“C” represented in this specification2-6The “alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a butynyl group, Examples thereof include a pentynyl group and a hexynyl group.
[0013]
“C” represented in this specification3-8“Cycloalkyl group” means a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, specifically, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclopropenyl. Group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group and the like.
[0014]
“C” represented in this specification1-6“Alkylene group” means the above-mentioned definition “C1-6It means a divalent group derived by further removing one hydrogen atom from an “alkyl group”, and specific examples include a methylene group, 1,2-ethylene group, 1,3-propylene group, and the like. A methylene group is preferred.
[0015]
The “halogen atom” represented in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
“C” represented in this specification1-6“Alkoxy group” means the above-defined “C1-6An oxy group to which an “alkyl group” is bonded, specifically, for example, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, t-butoxy group, n- Pentyloxy group, i-pentyloxy group, neopentyloxy group, n-hexyloxy group, 1-methylpropoxy group, 1,2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2 -Ethylbutoxy group, 1,3-dimethylbutoxyl group, 2-methylpentyloxy group, 3-methylpentyloxy group and the like.
[0016]
“C” represented in this specification6-10"Aromatic hydrocarbon cyclic group" refers to a hydrocarbon cyclic group having 6 to 10 carbon atoms, and specifically includes, for example, phenyl group, 1-naphthyl group, 2-naphthyl group, A phenyl group is preferred.
[0017]
The “hetero atom” represented in the present specification means a sulfur atom, an oxygen atom or a nitrogen atom.
[0018]
In the present specification, the “5- to 10-membered aromatic heterocyclic group” means that the number of atoms constituting the ring of the cyclic group is 5 to 10, and the atoms constituting the ring of the cyclic group An aromatic cyclic group containing 1 to a plurality of heteroatoms therein is meant. The “5- to 10-membered aromatic heterocyclic ring” in the “5- to 10-membered aromatic heterocyclic group” specifically includes, for example, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an oxazole ring, an isoxazole ring, Thiazole ring, isothiazole ring, imidazole ring, triazole ring, pyrazole ring, furazane ring, thiadiazole ring, oxadiazole ring, pyridazine ring, pyrimidine ring, pyrazine ring, indole ring, isoindole ring, indazole ring, chromene ring, quinoline Ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, naphthyridine ring, phthalazine ring, purine ring, pteridine ring, thienofuran ring, imidazothiazole ring, benzofuran ring, benzothiophene ring, benzoxazole ring, benzthiazole ring, benzthiadiazo Ring, benzimidazole ring, imidazo [1,2-a] pyridine ring, pyrrolopyridine ring, pyrrolopyrimidine ring, pyridopyrimidine ring, etc., preferably pyridine ring, thiophene ring, furan ring, pyrrole ring, oxazole Ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, triazole ring, pyrazole ring, thiadiazole ring, oxadiazole ring, pyridazine ring, pyrimidine ring, pyrazine ring and the like, more preferably pyridine ring, isoxazole Ring, thiazole ring, isothiazole ring, imidazole ring, triazole ring, pyrazole ring, pyridazine ring, pyrimidine ring, pyrazine ring and the like, more preferably pyridine ring, imidazole ring, triazole ring, pyrazole ring, pyridazine ring, Pil Examples include a midine ring and a pyrazine ring.
[0019]
“C4-13 polycyclic aliphatic hydrocarbon” means an aliphatic hydrocarbon having 4 to 13 carbon atoms and comprising two or more rings. Specifically, for example, bicyclo [1,1,0] butane, spiro [2,2] pentane, bicyclo [2,1,0] pentane, bicyclo [3,1,0] hexane, bicyclo [4,1, 0] heptane, norbornane, nortricyclane, quadricyclane, bicyclo [3,3,0] octane, bicyclo [2,2,2] octane, bicyclo [4,3,0] nonane, bicyclo [3,3 1] Nonane, bicyclo [4,4,0] decane, spiro [5,4] decane, perhydroquinacene, adamantane, bicyclo [3,3,3] undecane, perhydroanthracene and the like.
[0020]
“C” represented in this specification4-13The “polycycloalkyl group” means a cyclic aliphatic hydrocarbon group composed of two or more rings having 4 to 13 carbon atoms. Specifically, it means a monovalent group derived by removing one hydrogen atom at any position from the “C4-13 polycyclic aliphatic hydrocarbon”, specifically, endo-norbornane- It means 2-yl group or 1-adamantyl group.
[0021]
In the present specification, the “4- to 10-membered heterocyclic group” means that the number of atoms constituting the ring of the cyclic group is 4 to 10, and 1 in the atoms constituting the ring of the cyclic group. To a cyclic group containing a plurality of heteroatoms. However, those included in the “5- to 10-membered aromatic heterocyclic group” are excluded. The “4- to 10-membered heterocyclic ring” in the “4- to 10-membered heterocyclic group” specifically includes, for example, aziridine, azetidine, oxetane, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, piperazine, Thiazolidine, azepine, dioxane, dioxolane, imidazoline, thiazoline, tetrahydroquinoline, tetrahydroisoquinoline, dihydrobenzopyran, dihydrobenzofuran, chroman, dihydroindole, 8-azabicyclo [3,2,1] octane and the like.
[0022]
N in the general formula (I) which is the compound of the present invention means an integer of 0 to 2, but this n preferably means 1 or 2, more preferably 2.
[0023]
M in the general formula (I) which is the compound of the present invention means an integer of 0 to 3, and this m preferably means 0 or 1, more preferably 0.
[0024]
W in the general formula (I) which is the compound of the present invention is a single bond, C1-6Alkylene group or formula
[Chemical 9]
(Where2Represents a nitrogen atom or a methine group, m represents an integer of 0 to 3, R1bIs C1-6Alkyl group, C3-8A cycloalkyl group, a 5-10 membered aromatic heterocyclic group, C6-10Aromatic hydrocarbon cyclic group, C4-10Heterocyclic group or C4-13Means a polycycloalkyl group. Wherein W is preferably a single bond or C1-6An alkylene group, more preferably a single bond.
[0025]
Z in the general formula (I) which is the compound of the present invention is the formula
[Chemical Formula 10]
(Wherein R2aAnd R2bAre each independently C1-6Alkyl group, C2-6An alkenyl group or a phenyl group means Z2Means a sulfur atom or a methylene group. ), Wherein Z is preferably of the formula
Embedded image
(Wherein R2bAre each independently C1-6Alkyl group, C2-6An alkenyl group or a phenyl group is meant. ).
[0026]
The “salt” in the present invention refers to a pharmacologically acceptable salt and is not particularly limited as long as it forms an addition salt with the compound of the present invention. Preferred examples include hydrofluoric acid salts and hydrochlorides. , Hydrobromides, hydroiodides, etc .; sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, etc .; inorganic acid salts; acetates, Shu Acid carboxylate, maleate, tartrate, fumarate, etc .; methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate Organic sulfonates such as: amino acids such as aspartate and glutamate; trimethylamine, triethylamine, procaine, pyridine, phenethylbenzylamine Salts with any amine; sodium salts, alkali metal salts such as potassium salts; magnesium salts, alkaline earth metal salts such as calcium salts.
[0027]
[General synthesis method]
A typical method for producing the compound represented by the formula (I) according to the present invention is shown below.
[Production Method A]
Method for producing carbamoylazole derivative (a-3) from azole derivative (a-1)
Embedded image
(Where n, W, X1, X2, R1a, Z has the same meaning as defined above. X means a leaving group such as a halogen atom. )
[0028]
Step A-1 ((a-1) to (a-3))
The carbamoylazole derivative (a-3) can be obtained by reacting the azole derivative (a-1) with the carbamoylating reagent (a-2). The reaction is usually carried out in the presence of a base. Examples of the base include inorganic bases such as anhydrous potassium carbonate, sodium hydrogen carbonate and sodium hydride, organometallic bases such as butyl lithium, and organic bases such as triethylamine. The reaction solvent is usually a halogenated hydrocarbon solvent such as dichloromethane, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, an amide solvent such as N, N-dimethylformamide, and a basic solvent such as pyridine. It is done. The reaction temperature is generally −78 to 100 ° C., preferably −20 to 50 ° C.
[0029]
Step A-2 ((a-1) to (b-2))
This is a step of converting an azole derivative (a-1) to an active carbonyl azole derivative (b-2).
An active carbonyl azole derivative (b-2) can be obtained by reacting an azole derivative (a-1) with a carbonylating agent (b-1). However, although the active carbonyl azole derivative (b-2) can be isolated, it is usually used in the next step without isolation. The reaction is usually carried out in the presence of a base. As the base, an inorganic base such as anhydrous potassium carbonate, sodium hydrogen carbonate or sodium hydride, or an organic base such as triethylamine or pyridine is used. As the carbonylating agent, phosgene, phosgene dimer, triphosgene, carbonyldiimidazole and the like are used. As the reaction solvent, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, amide solvents such as N, N-dimethylformamide, and basic solvents such as pyridine are usually used. The reaction temperature is usually −78 to 100 ° C., preferably −20 to 25 ° C.
[0030]
Step A-3 ((b-2) to (a-3))
This is a step of converting an active carbonyl azole derivative (b-2) to a carbamoyl azole derivative (a-3). The carbamoylazole derivative (a-3) can be obtained by reacting the active carbonylazole derivative (b-2) with the organic amine compound (b-3). The reaction is usually carried out in the presence of a base. As the base, an inorganic base such as anhydrous potassium carbonate, sodium hydrogen carbonate or sodium hydride, or an organic base such as triethylamine or pyridine is used. As the reaction solvent, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, amide solvents such as N, N-dimethylformamide, and basic solvents such as pyridine are usually used. The reaction temperature is generally −78 to 100 ° C., preferably −20 to 50 ° C.
[0031]
[Production Method C]
Method for producing compound (b-4) which is sulfoxide or sulfone derivative
Embedded image
(Where n is 1 or 2, W, X1, X2, R1a, Z has the same meaning as defined above. ) Sulfide derivative (c-1) can be reacted with an appropriate oxidizing agent to obtain sulfoxide or sulfone derivative (b-4). As the oxidizing agent, m-chloroperbenzoic acid, hydrogen peroxide, persulfate, percarbonate and the like are used, and a metal salt such as tungsten may be used as a catalyst. As the reaction solvent, ester solvents such as ethyl acetate, halogenated hydrocarbon solvents such as dichloromethane, alcohol solvents such as ethanol, nitrile solvents such as acetonitrile, water, and mixed solvent systems thereof are usually used. The reaction temperature is usually -20 to 100 ° C, preferably 0 to 60 ° C. Sulphoxide and sulfone can be selectively obtained by adjusting the equivalent amount of the oxidizing agent and the reaction conditions.
[0032]
[Production Method D]
Process for producing aminosulfonylazole derivative (d-3)
Embedded image
(Where m, X1, X2, R1a, R1b, Z has the same meaning as defined above. X means a leaving group such as a halogen atom. )
An active sulfonyl azole derivative (d-1) and an organic amine derivative (d-2) can be reacted to obtain an aminosulfonyl azole derivative (d-3). The reaction is usually carried out in the presence of a base. As the base, an organic base such as pyridine or triethylamine, or an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide is used. As the reaction solvent, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane, and amide solvents such as N, N-dimethylformamide are usually used. The reaction temperature is -20 to 50 ° C, preferably 0 to 30 ° C.
[0033]
The azole derivative (a-1) used in step A includes intermediates used in the synthesis of herbicides as a prior art, and these intermediates have disclosed synthetic methods in these patents. Here, some of them are shown below for reference, but the present invention is not limited to this example, and a synthetic intermediate (azole derivative) of a carbamoylazole herbicide can be generally used in Step A.
[0034]
[Production Method E]
Step of conversion from mercaptoazole derivative (e-1) to thioazole derivative (e-3), further sulfinylazole derivative or sulfonylazole derivative (e-4)
Embedded image
(In the formula, n means 1 or 2, W, X1, X2, R1aMeans the same as defined above. XaMeans a leaving group such as a halogen atom, a methanesulfonyloxy group or a paratoluenesulfonyloxy group. WTenIs a single bond, C1-6Alkylene group or formula
Embedded image
Where m and R1bMeans the same as defined above. ). )
[0035]
Process E-1 ((e-1) to (e-3))
This is a step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (e-3).
The thioazole derivative (e-3) can be obtained by reacting the mercaptoazole derivative (e-1) with the electrophilic compound (e-2).
The reaction may be performed by adding a base. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and sodium hydride, and metal alkoxides such as sodium methoxide and potassium t-butoxide. Reaction solvents include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, amide solvents such as N, N-dimethylformamide, nitrile solvents such as acetonitrile, sulfoxide solvents such as dimethyl sulfoxide, and bases such as pyridine. An organic solvent, water, or a mixed solvent system thereof is used. The reaction temperature is -20 to 180 ° C, preferably 0 to 150 ° C.
[0036]
Process E-2 ((e-3) to (e-4))
This is a step of converting a thioazole derivative (e-3) to a sulfinyl derivative or a sulfonyl derivative (e-4). A sulfinyl derivative or a sulfonyl derivative (e-4) can be obtained by reacting a thioazole derivative (e-3) with an appropriate oxidizing agent. The reaction conditions are the same as in Production Method C.
[0037]
[Production Method F]
A step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (f-2), and further to a sulfinylazole derivative or a sulfonylazole derivative (f-3).
Embedded image
(In the formula, n is 1 or 2, X1, X2Means the same as defined above. X4a-Represents an anion (chlorine ion, sulfate ion, etc.) constituting the acid, and AraMeans an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group. )
Process F-1
This is a step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (f-2).
Mercaptoazole derivative (e-1) and aromatic amine (Ara-NH2The thioazole derivative (f-2) can be obtained by reacting with a diazonium salt (f-1) prepared from A general method can be used to prepare a diazonium salt from an aromatic amine. Usually, an aqueous solution in which two equivalents of an acid are added to an aromatic amine or a mixed solvent of water and an alcohol solvent is 5 ° C or lower. The reaction temperature can be adjusted by adding dropwise an equivalent amount of an aqueous solution of nitrite. By adding the solution or suspension of the diazonium salt thus prepared in a solution of a mercaptoazole derivative and two equivalents of base in water or an alcohol solvent or a mixed solvent thereof at a reaction temperature of 5 ° C. or less. Can be done. Inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid are usually used as the acid, and inorganic bases such as sodium hydroxide and potassium hydroxide are usually used as the base. The reaction temperature is -20 to 20 ° C.
[0038]
Process F-2
This is a step of converting a thioazole derivative (f-2) to a sulfinyl derivative or a sulfonyl derivative (f-3). A sulfinyl derivative or a sulfonyl derivative (f-3) can be obtained by reacting a thioazole derivative with (f-2) an appropriate oxidizing agent. The reaction conditions are the same as in Production Method C.
[0039]
[Production method G]
A step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (g-4).
Embedded image
(Where X1, X2Means the same as defined above. X is a leaving group such as a halogen atom, Y is O or ReRepresents -N. Rc, Rd, ReIs an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C6-14 aromatic Hydrocarbon cyclic group, optionally substituted 4- to 10-membered heterocyclic group, optionally substituted 5- to 14-membered aromatic heterocyclic group, optionally substituted C3-8 cycloalkyl group Means. )
[0040]
Process G-1
This is a step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (g-2).
The thioazole derivative (g-2) can be obtained by reacting the mercaptoazole derivative (e-1) with the 1,3-dicarbonyl derivative (g-1). The reaction is usually carried out in the presence of a base. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and sodium hydride, and metal alkoxides such as sodium methoxide and potassium t-butoxide. As the reaction solvent, an alcohol solvent such as methanol or ethanol, an amide solvent such as N, N-dimethylformamide, a sulfoxide solvent such as dimethyl sulfoxide, an ether solvent such as tetrahydrofuran or water, or a mixed solvent thereof is used. It is done. The reaction temperature is -20 to 100 ° C, preferably 0 to 60 ° C.
[0041]
Process G-2
This is a step of converting a thioazole derivative (g-2) to a thioazole derivative (g-4). The thioazole derivative (g-4) can be obtained by reacting the thioazole derivative (g-2) with the amine compound (g-3). The reaction may or may not use a base, but when the amine compound is a salt, a sufficient amount of base is used to neutralize it. As the base, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, or an organic base such as triethylamine is used. As the reaction solvent, an alcohol solvent such as methanol or ethanol, an amide solvent such as N, N-dimethylformamide, a sulfoxide solvent such as dimethyl sulfoxide, an ether solvent such as tetrahydrofuran or water, or a mixed solvent thereof is used. It is done. The reaction temperature is 0 to 120 ° C, preferably 20 to 100 ° C.
[0042]
[Production Method H]
A step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (h-3), and further to a sulfinyl derivative or a sulfonyl derivative (h-4).
Embedded image
(Where n is 1 or 2, X1, X2Means the same as defined above. ArbRepresents an aromatic hydrocarbon cyclic group or aromatic heterocyclic group having a high electron density, Arb H means what causes a so-called electrophilic substitution reaction such as halogenation or nitration with this hydrogen atom. )
[0043]
Process H-1
This is a step of converting a mercaptoazole derivative (e-1) to a thioazole derivative (h-3).
A mercaptoazole derivative (h-3) can be obtained by reacting a mercaptoazole derivative with a halogenating agent (h-1) and then reacting with an aromatic compound (h-2). The reaction is usually carried out in the presence of a base. Examples of the base include metal hydrides such as sodium hydride, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. As the halogenating agent, simple halogens such as chlorine and bromine, and N-haloimides such as N-chlorosuccinimide and N-bromosuccinimide are used. As the reaction solvent, alcohol solvents such as methanol and ethanol, and amide solvents such as N, N-dimethylformamide are preferably used. The reaction temperature is -80 to 150 ° C, preferably -70 to 120 ° C.
[0044]
Process H-2
This is a step of converting a thioazole derivative (h-3) to a sulfinylazole derivative or a sulfonylazole derivative (h-4). A sulfinyl derivative or a sulfonyl derivative (h-4) can be obtained by reacting a thioazole derivative (h-3) with an appropriate oxidizing agent. The reaction conditions are the same as in Production Method C.
[0045]
[Production Method I]
Step of conversion from N-sulfonylazole derivative (i-1) to C-sulfonylazole derivative (i-3) or (i-4)
Embedded image
(Where W, X1, X2, R1aMeans the same as defined above. )
By reacting the N-sulfonylazole derivative (i-1) with the lithiation reagent (i-2) and treating at an appropriate temperature, rearrangement occurs to obtain the C-sulfonylazole derivative (i-3). it can. (i-4) is a tautomer of (i-3). As the lithiating reagent, alkyllithium such as n-butyllithium, sec-butyllithium and t-butyllithium, lithium amide such as lithium diisopropylamide and the like are used. As the reaction solvent, an ether solvent such as tetrahydrofuran is preferably used. The reaction temperature is −100 to 100 ° C., preferably −78 to 80 ° C.
[0046]
[Production Method J]
A step of converting a benzylthioazole derivative to a chlorosulfonylazole derivative.
Embedded image
(Where X1, X2, Z has the same meaning as defined above. )
A chlorosulfonylazole derivative (j-2) can be obtained by reacting benzylthioazole derivative (j-1) with chlorine. The reaction is usually carried out in acetic acid, water, or a mixed solvent thereof, and is achieved by passing 3 to 6 equivalents of chlorine gas. The reaction temperature is usually from -10 to 15 ° C.
[0047]
[Production method K]
A step of converting the secondary amine compound (b-3) to carbamoyl chloride (k-2).
Embedded image
(In the formula, Z has the same meaning as defined above.)
The carbamoyl chloride (k-2) can be obtained by reacting the secondary amine compound (b-3) with the chlorocarbonylating agent (k-1). As the chlorocarbonylating agent, phosgene, phosgene dimer, triphosgene or the like is used. As the base, organic bases such as pyridine and triethylamine, and inorganic bases such as anhydrous potassium carbonate are usually used.
[0048]
Various isomers obtained for the compound represented by the formula (I) according to the present invention can be purified and isolated by using a usual separation means (for example, recrystallization, chromatography, etc.).
[0049]
The compound according to the present invention or a salt thereof or a hydrate thereof can be converted into tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories by conventional methods. , Injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions and the like. Formulation aids commonly used for formulation (eg, excipients, binders, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH) Preparation agents, preservatives, antioxidants, etc.) can be used. In general, ingredients used as raw materials for pharmaceutical preparations are blended to prepare a preparation by a conventional method. For example, in order to produce an oral preparation, the compound according to the present invention or a pharmacologically acceptable salt and excipient thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring agent. After adding, etc., it is made into powders, fine granules, granules, tablets, coated tablets, capsules and the like by conventional methods. Examples of these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; cetostearyl alcohol and behenyl alcohol Higher alcohols; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers Water-soluble such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methylcellulose Molecules; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate Body and purified water. Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like, and examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, Shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, Examples of lubricants include calcium citrate, dextrin, pectin, carboxymethylcellulose and calcium, etc. Um, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, mint brain, aroma powder, mint oil, dragon brain , Cinnamon powder and the like are used. Of course, these tablets and granules may be appropriately coated with sugar coating or other necessary. Further, when producing a liquid preparation such as a syrup or an injectable preparation, a compound according to the present invention or a pharmacologically acceptable salt thereof, a pH adjuster, a solubilizer, an isotonic agent, etc. are necessary. Add a solubilizing agent, stabilizer, etc. accordingly, and formulate it by a conventional method. The method for producing the external preparation is not limited and can be produced by a conventional method. That is, as a base material used for formulation, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of base materials to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, Examples include raw materials such as water-soluble polymers, clay minerals, and purified water. If necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. may be added. However, the base material of the external preparation according to the present invention is not limited thereto. Moreover, components having differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary. In addition, the addition amount of the said base raw material is an amount used as the density | concentration normally set in manufacture of an external preparation.
[0050]
When the compound according to the present invention or a salt thereof or a hydrate thereof is administered, the form is not particularly limited, and it may be administered orally or parenterally by a commonly used method. For example, tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, etc. It can be formulated and administered as an agent. The dosage of the medicament according to the present invention can be appropriately selected according to the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, and the like.
[0051]
Although the dose of the DPPIV inhibitor according to the present invention varies markedly depending on the type of disease, the degree of symptoms, the age, sex of the patient, differences in sensitivity to drugs, etc., it is usually about 0.03- 1000 mg, preferably 0.1-500 mg, more preferably 0.1-100 mg is administered in one to several times a day, or divided into several times a day. In the case of an injection, it is usually about 1 μg / kg-3000 μg / kg, preferably about 3 μg / kg-1000 μg / kg.
[0052]
The compound concerning this invention can be manufactured by the method described in the following example, for example. However, these are illustrative, and the compound according to the present invention is not limited to the following specific examples in any case.
[0053]
【Example】
Example 1
3- Benzylthio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
a) 3-Benzylthio-1H-1,2,4-triazole
100 ml of 3-mercapto-1H-1,2,4-triazole and 2 ml of a dimethylformamide solution of 118 μl of benzyl bromide were stirred at room temperature for 23 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture at room temperature, and the resulting mixture was extracted once with ethyl acetate. The organic layer was washed successively with water three times and saturated brine once and then dried over anhydrous sodium sulfate. The residue was filtered, and the solvent was distilled off from the resulting filtrate under reduced pressure to obtain 172 mg of the title compound as a white solid.
1H-NMR (d6-DMSO) δ = 4.35 (2H, s), 7.22-7.31 (3H, m), 7.35-7.38 (2H, m), 8.43 (1H, s)
[0054]
b) 3-Benzylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole
A suspension of 172 mg of 3-benzylthio-1H-1,2,4-triazole, 248 μl of dimethylcarbamoyl chloride and 621 mg of anhydrous potassium carbonate in 4 ml of dimethylformamide was stirred at room temperature for 1 hour and 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water three times and once with saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off from the residue under reduced pressure to obtain a transparent oil. The resulting oil was purified by column chromatography (ethyl acetate / hexane = 1/5) to give 88 mg of the title compound as a clear oil.
1H-NMR (d6-DMSO) δ = 3.06 (6H, br s), 4.39 (2H, s), 7.23-7.33 (3H, m), 7.40-7.42 (2H, m), 9.03 (1H, s).
[0055]
Example 2
3- Benzylsulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
3-Benzylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 1) To a solution of 134 mg of methylene chloride was added 185 mg of m-chloroperbenzoic acid under ice-cooling, and the resulting mixture was mixed with 4 at room temperature. Stir for hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and purified by column chromatography (ethyl acetate / hexane = 1/2) to give 69 mg of the title compound as a clear oil.
1H-NMR (d6-DMSO) δ = 2.93 (3H, br s), 3.06 (3H, br s), 4.90 (2H, s), 7.25-7.27 (2H, m), 7.33-7.35 (3H, m) , 9.35 (1H, s); MS m / e (ESI) 611.15 (2M + 23)
[0056]
Example 3
3- Benzylsulfonyl -1- Diethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 1 and 2 using diethylcarbamoyl chloride.
1H-NMR (CDClThree) δ = 1.12-1.29 (6H, m), 3.47 (4H, br s), 4.64 (2H, s), 7.25-7.34 (5H, m), 8.88 (1H, br s)
[0057]
Example 4
3- (4- Fluorobenzyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 1 and 2 using 4-fluorobenzyl bromide.
1H-NMR (CDClThree) δ = 3.17 (6H, s), 4.61 (2H, s), 7.02 (2H, t, J = 9Hz), 7.28 (2H, dd, J = 6, 9Hz), 8.88 (1H, s)
[0058]
Example 5
3- (4-tert- Butyl benzyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 1 and 2 using 4-tert-butylbenzyl bromide.
1H-NMR (CDClThree) δ = 1.27 (9H, s), 3.14 (6H, s), 4.60 (2H, s), 7.20 (2H, d, J = 8Hz), 7.33 (2H, d, J = 8Hz), 8.87 (1H, s)
[0059]
Example 6
3- ( Diphenylmethyl ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 1 using diphenylmethyl bromide.
1H-NMR (CDClThree) δ = 2.84-3.14 (6H, br.2peak), 6.08 (1H, s), 7.22 (2H, t, J = 7Hz), 7.29 (4H, t, J = 7Hz), 7.45 (4H, d, J = 7Hz), 8.63 (1H, s)
[0060]
Example 7
3- ( Diphenylmethyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 2 using 3- (diphenylmethyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 6).
1H-NMR (CDClThree) δ = 2.97 (3H, s), 3.10 (3H, s), 5.85 (1H, s), 7.30-7.38 (6H, m), 7.62 (4H, dd, J = 2, 7Hz), 8.73 (1H, s)
[0061]
Example 8
3- [ Screw (Four- Fluorophenyl ) Methyl ] Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 1 using bis (4-fluorophenyl) methyl chloride.
1H-NMR (CDClThree) δ = 3.04 (6H, br.s), 6.06 (1H, s), 6.99 (4H, t, J = 9Hz), 7.39 (4H, dd, J = 5, 9Hz), 8.64 (1H, s)
[0062]
Example 9
3- [ Screw (Four- Fluorophenyl ) Methyl ] Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 2 using 3- [bis (4-fluorophenyl) methyl] thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 8).
1H-NMR (CDClThree) δ = 3.06 (3H, br.s), 3.13 (3H, br.s), 5.85 (1H, s), 7.05 (4H, t, J = 9Hz), 7.58 (4H, dd, J = 5, 9Hz ), 8.76 (1H, s)
[0063]
Example 10
3- ( Chroman -Four- Il ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
a) 3- (Chroman-4-yl) thio-1H-1,2,4-triazole
While stirring, a mixture of 95 mg of triphosgene and 4 ml of dichloromethane was added in the order of 82 μl of pyridine and 150 mg of 4-chromanol under cooling in an ice bath. Further, 82 μl of pyridine was added, the temperature was returned to room temperature, and the mixture was stirred for 2 hours. This reaction solution was added to a mixture of 110 mg of 3-mercapto-1H-1,2,4-triazole, 200 mg of anhydrous potassium carbonate, and 2 ml of N, N-dimethylformamide, and stirred overnight. The reaction mixture was washed with water and then with saturated brine and concentrated. The residue was subjected to silica gel column chromatography with 50% ethyl acetate / hexane to give 110 mg of the title compound.
1H-NMR (CDClThree) δ = 2.25-2.32 (1H, m), 2.41-2.51 (1H, m), 4.28-4.35 (1H, m), 4.42-4.50 (1H, m), 5.04 (1H, br.s), 6.83 ( 1H, d, J = 8Hz), 6.89 (1H, t, J = 8Hz), 7.18 (1H, t, J = 8Hz), 7.36 (1H, d, J = 8Hz), 8.17 (1H, s)
[0064]
b) 3- (chroman-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole Conducted from 3- (chroman-4-yl) thio-1H-1,2,4-triazole The title compound was obtained in the same manner as in Example 1.
1H-NMR (CDClThree) δ = 2.28-2.36 (1H, m), 2.42-2.52 (1H, m), 3.25 (6H, br.s), 4.28-4.35 (1H, m), 4.43-4.51 (1H, m), 5.05 ( 1H, br.s), 6.83 (1H, d, J = 8Hz), 6.90 (1H, t, J = 8Hz), 7.17 (1H, t, J = 8Hz), 7.38 (1H, d, J = 8Hz) , 8.78 (1H, s)
[0065]
Example 11
3- ( Chroman -Four- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
The title compound was obtained in the same manner as in Example 2 from 3- (chroman-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 10).
1H-NMR (CDClThree) δ = 2.28-2.39 (1H, m), 2.54-2.62 (1H, m), 3.19 (3H, br.s), 3.21 (3H, br.s), 4.24-4.30 (1H, m), 4.54- 4.62 (1H, m), 4.72-4.76 (1H, m), 6.86-6.92 (2H, m), 7.25 (1H, t, J = 8Hz), 7.35 (1H, d, J = 8Hz), 8.91 (1H , s)
[0066]
Example 12
3- (endo- Norbornane -2- Il ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
a) 3- (endo-norbornan-2-yl) thio-1H-1,2,4-triazole
Heat a mixture of 3-mercapto-1H-1,2,4-triazole 5.0 g, exo-2-bromonorbornane 6.4 ml, anhydrous potassium carbonate 10 g, N, N-dimethylformamide 25 ml in an oil bath at 80 ° C. for 7 hours. Stir. The reaction mixture was extracted with ethyl acetate-water, the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 10-20% (20% 2-propanol / ethyl acetate) / hexane to give 5.01 g of the title compound.
1H-NMR (CDClThree) δ = 1.01-1.08 (1H, m), 1.22-1.30 (1H, m), 1.38-1.92 (5H, m), 2.14-2.24 (1H, m), 2.29 (1H, br.s), 2.52 ( 1H, br.s), 3.88-3.95 (1H, m), 8.09 (1H, s)
[0067]
b) 3- (endo-norbornan-2-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
A mixture of 3- (endo-norbornan-2-yl) thio-1H-1,2,4-triazole 500 mg, dimethylcarbamoyl chloride 0.35 ml, anhydrous potassium carbonate 700 mg, N, N-dimethylformamide 2 ml is stirred at room temperature for 5 hours. did. The reaction mixture was extracted with ethyl acetate-water, the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 10-15% (20% 2-propanol / ethyl acetate) / hexane to give 650 mg of the title compound.
1H-NMR (CDClThree) δ = 1.02-1.10 (1H, m), 1.22-1.31 (1H, m), 1.37-1.62 (4H, m), 1.83-1.92 (1H, m), 2.29 (1H, br.s), 2.57 ( 1H, br.s), 3.24 (6H, br.s), 3.84-3.92 (1H, m), 8.70 (1H, s)
[0068]
Example 13
3- (endo- Norbornane -2- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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3- (endo-norbornan-2-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 12) 650 mg, ethyl acetate 5 ml, m-chloroperbenzoic acid 1.12 g And stirred overnight. 1 ml of 1 molar sodium thiosulfate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate-water. The organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 20-30% (20% 2-propanol / ethyl acetate) / hexane and recrystallized from ethyl acetate-hexane to obtain 440 mg of the title compound.
1H-NMR (CDClThree) δ = 1.40-1.70 (5H, m), 1.84-1.91 (2H, m), 2.27-2.35 (1H, m), 2.45 (1H, br.s), 2.78 (1H, br.s), 3.20 ( 3H, s), 3.34 (3H, s), 3.75-3.82 (1H, m), 8.86 (1H, s)
[0069]
Hereinafter, Examples 14 to 21 were synthesized in the same manner as Examples 12 and 13.
[0070]
Example 14
3- Cyclohexylthio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 12 using bromocyclohexane.
1H-NMR (CDClThree) δ = 1.24-1.67 (6H, m), 1.75-1.84 (2H, m), 2.06-2.16 (2H, m), 3.00-3.46 (6H, br .peak), 3.62 (1H, tt, J = 4 , 10Hz), 8.72 (1H, s)
[0071]
Example 15
3- Cyclohexylsulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 13 using 3-cyclohexylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 14).
1H-NMR (CDClThree) δ = 1.16-1.76 (6H, m), 1.88-1.97 (2H, m), 2.09-2.17 (2H, m), 3.20 (3H, br.s), 3.31 (1H, tt, J = 4, 12Hz ), 3.34 (3H, br.s), 8.89 (1H, s)
[0072]
Example 16
3- Cyclohexylmethylthio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 12 using cyclohexylmethyl bromide.
1H-NMR (CDClThree) δ = 0.94-1.30 (5H, m), 1.60-1.78 (4H, m), 1.85-1.93 (2H, m), 3.04 (2H, d, J = 7Hz), 3.1-3.4 (6H, br. peak) ), 8.70 (1H, s)
[0073]
Example 17
3- Cyclohexylmethylsulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 13 using 3-cyclohexylmethylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 16).
1H-NMR (CDClThree) δ = -1.05-1.35 (5H, m), 1.60-1.74 (3H, m), 1.86-1.95 (2H, m), 2.04-2.14 (1H, m), 3.21 (3H, br.s), 3.31 (2H, d, J = 7Hz), 3.34 (3H, br.s), 8.88 (1H, s)
[0074]
Example 18
3- (1- Adamantylmethyl ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 12 using 1-adamantylmethyl methanesulfonate prepared from 1-adamantane methanol.
1H-NMR (CDClThree) δ = 1.58-1.74 (12H, m), 1.99 (3H, br.s), 3.04 (2H, s), 3.12-3.36 (6H, br. Peak), 8.70 (1H, s)
[0075]
Example 19
3- (1- Adamantylmethyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 13 using 3- (1-adamantylmethyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 18).
1H-NMR (CDClThree) δ = 1.63-1.74 (6H, m), 1.83 (6H, d, J = 3Hz), 1.99 (3H, br.s), 3.20 (3H, br.s), 3.25 (2H, s), 3.34 ( 3H, br.s), 8.86 (1H, s)
[0076]
Example 20
3- (3- Methyl butyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 12 and 13 using 1-bromo-3-methylbutane.
1H-NMR (CDClThree) δ = 0.93 (6H, d, J = 7Hz), 1.67-1.75 (3H, m), 3.20 (3H, br.s), 3.34 (3H, br.s), 3.36-3.42 (2H, m), 8.90 (1H, s)
[0077]
Example 21
3- (2- Dimethylpropyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 12 and 13 using 1-bromo-2,2-dimethylpropane.
1H-NMR (CDClThree) δ = 1.20 (9H, s), 3.20 (3H, br.s), 3.34 (3H, br.s), 3.38 (2H, s), 8.87 (1H, s)
[0078]
Example 22
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Phenylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
a) 3- (endo-Norbornan-2-yl) sulfonyl-1H-1,2,4-triazole
To a mixture of 1.0 g of 3- (endo-norbornan-2-yl) thio-1H-1,2,4-triazole (Example 12-a) and 10 ml of ethyl acetate, 2.4 g of m-chloroperbenzoic acid was added at room temperature. Stir. At first, heat was generated, and at the same time, crystals precipitated. The reaction mixture was ice-cooled, and the crystals were collected by filtration, washed with ethyl acetate / hexane (1/1) and dried to obtain 1.05 g of the title compound.
1H-NMR (d6-DMSO) δ = 1.22-1.66 (6H, m), 1.75-1.85 (1H, m), 2.07-2.16 (1H, m), 2.34 (1H, br.s), 2.54 (1H, br.s), 3.76-3.83 (1H, m), 8.88 (1H, s)
[0079]
b) 3- (endo-norbornan-2-yl) sulfonyl-1- (N-methyl-N-phenylcarbamoyl) -1H-1,2,4-triazole
Suspend 3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole 100 mg, N-methyl-N-phenylcarbamoyl chloride 75 mg and anhydrous potassium carbonate 100 mg in 2 ml N, N-dimethylformamide. And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 30-50% ethyl acetate / hexane to give 65 mg of the title compound.
1H-NMR (CDClThree) δ = 1.24-1.44 (4H, m), 1.50-1.66 (3H, m), 2.08-2.20 (1H, m), 2.36 (1H, br.s), 2.54 (1H, br.s), 3.35 ( 1H, br.s), 3.55 (3H, s), 7.10-7.20 (2H, m), 7.30-7.42 (3H, m), 8.75 (1H, s)
[0080]
Example 23
3- (endo- Norbornane -2- Il ) Sulfonyl -1- Diallylcarbamoyl -1H-1,2,4- Triazole
Embedded image
The title compound was synthesized in the same manner as in Example 22 using 3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and diallylcarbamoyl chloride.
1H-NMR (CDClThree) δ = 1.40-1.70 (5H, m), 1.83-1.91 (2H, m), 2.26-2.35 (1H, m), 2.45 (1H, br.s), 2.77 (1H, br.s), 3.73- 3.80 (1H, m), 4.00-4.40 (4H, m), 5.28 (4H, br.s), 5.85-5.96 (2H, m), 8.87 (1H, s)
[0081]
Example 24
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Ethylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
28 mg of triphosgene was dissolved in 1 ml of dichloromethane. Under cooling in an ice-water bath, 0.023 ml of pyridine was added to this solution, and the mixture was stirred until the precipitated insoluble material was dissolved. Next, 64 mg of 3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) was added, and the mixture was further stirred for 20 minutes. Subsequently, 0.1 ml of N-methylethylamine was added, and the mixture was warmed to room temperature and stirred. The reaction solution was subjected to silica gel column chromatography with 50% ethyl acetate / hexane to give 37 mg of the title compound.
1H-NMR (CDClThree) δ = 1.31 (3H, br.s), 1.40-1.70 (5H, m), 1.80-1.94 (2H, m), 2.27-2.36 (1H, m), 2.45 (1H, br.s), 2.77 ( 1H, br.s), 3.16 (1.3H, br.s), 3.30 (1.7H, br.s), 3.50-3.75 (2H, m), 3.75-3.82 (1H, m), 8.87 (1H, br .s)
[0082]
Example 25
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (1,3- Thiazolidine -3- Il ) Carbonyl -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using 1,3-thiazolidine.
1H-NMR (CDClThree) δ = 1.40-1.71 (5H, m), 1.84-1.92 (2H, m), 2.26-2.34 (1H, m), 2.46 (1H, br.s), 2.78 (1H, br.s), 3.07- 3.21 (2H, m), 3.74-3.82 (1H, m), 4.00-4.08 (1H, m), 4.25-4.35 (1H, m), 4.78 (1H, br.s), 4.98 (1H, br.s ), 8.98 (1H, s)
[0083]
Example 26
3- (endo- Norbornane -2- Il ) Sulfonyl -1- ( Pyrrolidine -1- Il ) Carbonyl -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using pyrrolidine.
1H-NMR (CDClThree) δ = 1.40-1.70 (5H, m), 1.84-2.08 (6H, m), 2.27-2.36 (1H, m), 2.45 (1H, br.s), 2.77 (1H, br.s), 3.70 ( 2H, t, J = 7Hz), 3.74-3.82 (1H, m), 3.92-4.04 (2H, m), 8.96 (1H, s)
[0084]
Example 27
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Allylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using N-methylallylamine.
1H-NMR (CDClThree) δ = 1.40-1.70 (5H, m), 1.80-1.93 (2H, m), 2.26-2.38 (1H, m), 2.45 (1H, br.s), 2.78 (1H, br.s), 3.15 ( 1.3H, br.s), 3.28 (1.7H, br.s), 3.78 (1H, br.s), 4.05-4.38 (2H, m), 5.20-5.40 (2H, m), 5.82-5.97 (1H , m), 8.88 (1H, br.s)
[0085]
Example 28
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Propylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using N-methylpropylamine.
1H-NMR (CDClThree) δ = 0.85-1.04 (3H, m), 1.40-1.80 (7H, m), 1.81-1.92 (2H, m), 2.27-2.36 (1H, m), 2.45 (1H, br.s), 2.78 ( 1H, br.s), 3.16 (1.8H, br.s), 3.30 (1.2H, br.s), 3.50 (1.2H, br.s), 3.61 (0.8H, br.s), 3.78 (1H , br.s), 8.87 (1H, s)
[0086]
Example 29
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Isopropylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using N-methylisopropylamine.
1H-NMR (CDClThree) δ = 1.29 (6H, d, J = 7Hz), 1.40-1.70 (5H, m), 1.85-1.94 (2H, m), 2.28-2.37 (1H, m), 2.45 (1H, br.s), 2.78 (1H, br.s), 3.08 (3H, br.s), 3.75-3.82 (1H, m), 4.60 (1H, br.s), 8.84 (1H, s)
[0087]
Example 30
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- Isobutylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using N-methylisobutylamine.
1H-NMR (CDClThree) δ = 0.88 (2.4H, br.s), 0.99 (3.6H, d, J = 6Hz), 1.40-1.70 (5H, m), 1.85-2.20 (3H, m), 2.28-2.37 (1H, m ), 2.45 (1H, br.s), 2.79 (1H, br.s), 3.17 (1.2H, br.s), 3.30 (1.8H, br.s), 3.38 (1.2H, d, J = 7Hz ), 3.60 (0.8H, m), 3.78 (1H, br.s), 8.86 (1H, s)
[0088]
Example 31
3- (endo- Norbornane -2- Il ) Sulfonyl -1- (N- Methyl -N- tert- Butylcarbamoyl ) -1H-1,2,4- Triazole
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3- (endo-norbornan-2-yl) sulfonyl-1H-1,2,4-triazole (Example 22-a) and
Synthesis was performed in the same manner as in Example 24 using N-methyl-tert-butylamine.
1H-NMR (CDClThree) δ = 1.40-1.70 (5H, m), 1.51 (9H, s), 1.84-1.93 (2H, m), 2.27-2.36 (1H, m), 2.45 (1H, br.s), 2.79 (1H, br.s), 3.02 (3H, s), 3.76-3.82 (1H, m), 8.77 (1H, s)
[0089]
Example 32
3- (2,4,6- Trimethylphenyl ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
a) 3- (2,4,6-Trimethylphenyl) thio-1H-1,2,4-triazole
While cooling a mixture of 13.5 g of 2,4,6-trimethylaniline, 130 ml of methanol and 18.5 ml of concentrated hydrochloric acid in an ice-salt bath, a solution of 6.9 g of sodium nitrite in 10 ml of water was slowly added dropwise and stirred for 30 minutes.
While cooling a mixture of 10.1 g of 2-mercapto-1H-1,2,4 triazole, 70 ml of methanol and 13.4 g of potassium hydroxide in an ice-salt bath, the above reaction solution was added little by little at the same temperature. Stir for 30 minutes at room temperature for 1 hour. Concentrated hydrochloric acid (9 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate-water. The organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and dissolved by heating, filtered through a small amount of silica gel, washed with ethyl acetate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 12.7 g of the title compound.
1H-NMR (CDClThree) δ = 2.31 (3H, s), 2.43 (6H, s), 7.04 (2H, s), 7.94 (1H, s)
[0090]
b) 3- (2,4,6-Trimethylphenyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
To a mixture of 3- (2,4,6-trimethylphenyl) thio-1H-1,2,4-triazole 220 mg, anhydrous potassium carbonate 280 mg, N, N-dimethylformamide 1 ml, N, N-dimethylcarbamoyl chloride 0.14 ml And stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 10-15% (20% 2-propanol / ethyl acetate) / hexane to give 276 mg of the title compound.
1H-NMR (CDClThree) δ = 2.29 (3H, s), 2.44 (6H, s), 3.15 (6H, br.s), 6.99 (2H, s), 8.63 (1H, s)
[0091]
Example 33
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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3- (2,4,6-trimethylphenyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 32) To a mixture of 226 mg and 1 ml of ethyl acetate was added 360 mg of m-chloroperbenzoic acid. The mixture was heated and stirred in an oil bath at 60 ° C. for 4 hours. To the reaction solution were added 0.1 ml of 1 mol sodium thiosulfate aqueous solution and 0.25 ml of 5 mol potassium carbonate aqueous solution, followed by extraction with ethyl acetate-water, and the organic layer was washed with saturated brine and concentrated. The residue was dissolved by heating with ethyl acetate, filtered through a small amount of silica gel, washed with ethyl acetate and concentrated. The residue was crystallized from ethyl acetate-hexane to obtain 178 mg of the title compound.
1H-NMR (CDClThree) δ = 2.31 (3H, s), 2.70 (6H, s), 3.18 (3H, br.s), 3.32 (3H, br.s), 6.98 (2H, s), 8.78 (1H, s)
[0092]
Example 34
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- Diethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Examples 32 and 33.
1H-NMR (CDClThree) δ = 1.27 (6H, t, J = 6Hz), 2.30 (3H, s), 2.70 (6H, s), 3.51 (2H, br.s), 3.61 (2H, br.s), 6.97 (2H, s), 8.81 (1H, s)
[0093]
Example 35
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- (N- Methyl -N- Phenylcarbamoyl ) -1H-1,2,4- Triazole
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a) 3- (2,4,6-Trimethylphenyl) sulfonyl-1H-1,2,4-triazole
A mixture of 50 g of oxone monopersulfate compound (OXONE®) and 100 ml of water was heated in an oil bath at 60 ° C. and stirred with 3- (2,4,6-trimethylphenyl) thio-1H-1, A mixture of 5.00 g of 2,4-triazole (Example 32-a) and 150 ml of methanol was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was heated to reflux for 3 hours. The mixture was returned to room temperature and stirred overnight, and the precipitated crystals were collected by filtration and washed with water to obtain 5.03 g of the title compound.
1H-NMR (CDClThree) δ = 2.31 (3H, s), 2.70 (6H, s), 6.99 (2H, s), 8.54 (1H, s)
[0094]
b) 3- (2,4,6-Trimethylphenyl) sulfonyl-1- (N-methyl-N-phenylcarbamoyl) -1H-1,2,4-triazole
The title compound was synthesized in the same manner as in Example 22 using 3- (2,4,6-trimethylphenyl) sulfonyl-1H-1,2,4-triazole and N-methyl-N-phenylcarbamoyl chloride.
1H-NMR (CDClThree) δ = 2.30 (3H, s), 2.45 (6H, s), 3.51 (3H, s), 6.89 (2H, s), 7.07 (2H, br.s), 7.20-7.30 (3H, m), 8.71 (1H, s)
[0095]
Example 36
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- (N- Methyl -N- Ethylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
20 mg of triphosgene was dissolved in 1 ml of dichloromethane. Under cooling in an ice-water bath, 0.017 ml of pyridine was added to this solution and stirred for 5 minutes. Next, 51 mg of 3- (2,4,6-trimethylphenyl) sulfonyl-1H-1,2,4-triazole (Example 35-a) was added, and the mixture was further stirred for 10 minutes. Subsequently, 0.034 ml of N-methylethylamine was added, and the mixture was returned to room temperature and stirred for 6 hours. The reaction solution was subjected to silica gel column chromatography with 50% ethyl acetate / hexane to give 52 mg of the title compound.
1H-NMR (CDClThree) δ = 1.28 (3H, t, J = 7Hz), 2.31 (3H, s), 2.71 (6H, s), 3.13 (1.5H, br.s), 3.29 (1.5H, br.s), 3.52- 3.69 (2H, m), 6.98 (2H, s), 8.79 (1H, s)
[0096]
Example 37
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- (N- Methyl -N- Propylcarbamoyl ) -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 36 using 3- (2,4,6-trimethylphenyl) sulfonyl-1H-1,2,4-triazole (Example 35-a) and N-methylpropylamine.
1H-NMR (CDClThree) δ = 0.86 (1.5H, br.s), 0.98 (1.5H, br.s), 1.71 (2H, br.s), 2.31 (3H, s), 2.70 (6H, s), 3.14 (1.5H , br.s), 3.29 (1.5H, br.s), 3.48 (1H, br.s), 3.56 (1H, br.s), 6.98 (2H, s), 8.79 (1H, s)
[0097]
Example 38
3- (2,4,6- Trimethylphenyl ) Sulfonyl -1- (N- Methyl -N- Isopropylcarbamoyl ) -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 36 using 3- (2,4,6-trimethylphenyl) sulfonyl-1H-1,2,4-triazole (Example 35-a) and N-methylisopropylamine.
1H-NMR (CDClThree) δ = 1.27 (6H, d, J = 7Hz), 2.31 (3H, s), 2.71 (6H, s), 2.90-3.15 (3H, m), 4.35-4.65 (1H, m), 6.97 (2H, s), 8.76 (1H, s)
[0098]
Example 39
3- (2,4,6- Trimethylphenyl ) Sulfinyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 3- (2,4,6-Trimethylphenyl) sulfinyl-1H-1,2,4-triazole
3- (2,4,6-trimethylphenyl) thio-1H-1,2,4-triazole with a mixture of 3.02 g of oxone monopersulfate compound (OXONE) and 30 ml of water at room temperature Example 32-a) A mixture of 1.08 g and 30 ml of methanol was added dropwise. After completion of the dropwise addition, the mixture was stirred for 3 hours, and 20 ml of water was added. The precipitated crystals were collected by filtration and washed with water, ethyl acetate and hexane in this order to obtain 820 mg of the title compound.
1H-NMR (DMSO-d6) δ = 2.26 (3H, s), 2.45 (6H, s), 6.95 (2H, s), 8.68 (1H, br.s)
[0099]
b) 3- (2,4,6-Trimethylphenyl) sulfinyl-1-dimethylcarbamoyl-1H-1,2,4-triazole
The title compound was synthesized in the same manner as in Example 22 using 3- (2,4,6-trimethylphenyl) sulfinyl-1H-1,2,4-triazole and dimethylcarbamoyl chloride.
1H-NMR (CDClThree) δ = 2.30 (3H, s), 2.54 (6H, s), 3.17 (3H, br.s), 3.34 (3H, br.s), 6.91 (2H, s), 8.78 (1H, s)
[0100]
Example 40
3- [2- (2,2,2- Trifluoroethyl ) Oxy -6- Methylphenyl ] Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 2,2,2-trifluoroethyl methanesulfonate
To a mixture of 2,2,2-trifluoroethanol (5 g), triethylamine (14 ml) and ethyl acetate (120 ml), 5.8 ml of methanesulfonyl chloride was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction was filtered through a small amount of silica gel and then NH silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 9.5 g of the title compound.
1H-NMR (CDClThree) δ = 3.15 (3H, s), 4.54 (2H, q, J = 8Hz)
[0101]
b) 2-Nitro-3- (2,2,2-trifluoroethyl) oxytoluene
Mixture of 5 g of 3-hydroxy-2-nitrotoluene, 8.7 g of 2,2,2-trifluoroethyl methanesulfonate, 9 g of anhydrous potassium carbonate, and 40 ml of N, N-dimethylformamide in an 80 ° C. oil bath for 4 hours, then 100 ° C. oil The mixture was heated and stirred in the bath for 4 hours. The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water, diluted with potassium carbonate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through NH silica gel, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography with 5-10% ethyl acetate / hexane to obtain 4.12 g of the title compound.
1H-NMR (CDClThree) δ = 2.33 (3H, s), 4.42 (2H, q, J = 8Hz), 6.89 (1H, d, J = 8Hz), 6.99 (1H, d, J = 8Hz), 7.34 (1H, t, J = 8Hz),
[0102]
c) 2-Amino-3- (2,2,2-trifluoroethyl) oxytoluene
To a mixture of 4.12 g of 2-nitro-3- (2,2,2-trifluoroethyl) oxytoluene and 30 ml of ethyl acetate, a catalytic amount of 10% palladium / carbon was added, and the mixture was stirred for 4 hours under a hydrogen atmosphere. The catalyst was removed from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure to obtain 3.71 g of the title compound.
1H-NMR (CDClThree) δ = 2.19 (3H, s), 3.79 (2H, br.s), 4.36 (2H, q, J = 8Hz), 6.62-6.70 (2H, m), 6.80 (1H, dd, J = 2, 7Hz )
[0103]
d) 3- [2- (2,2,2-trifluoroethyl) oxy-6-methylphenyl] thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
The title compound was synthesized in the same manner as in Example 32 using 2-amino-3- (2,2,2-trifluoroethyl) oxytoluene.
1H-NMR (CDClThree) δ = 2.51 (3H, s), 3.17 (6H, br.s), 4.32 (2H, q, J = 8Hz), 6.80 (1H, d, J = 8Hz), 7.06 (1H, d, J = 8Hz ), 7.31 (1H, t, J = 8Hz), 8.62 (1H, s)
[0104]
Example 41
3- [2- (2,2,2- Trifluoroethyl ) Oxy -6- Methylphenyl ] Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Example using 3- [2- (2,2,2-trifluoroethyl) oxy-6-methylphenyl] thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 40) Synthesized in the same manner as 33.
1H-NMR (CDClThree) δ = 2.84 (3H, s), 3.19 (3H, br.s), 3.35 (3H, br.s), 4.32 (2H, q, J = 8Hz), 6.84 (1H, d, J = 8Hz), 7.09 (1H, d, J = 8Hz), 7.49 (1H, t, J = 8Hz), 8.78 (1H, s)
[0105]
Example 42
3- [2- (2- Methoxyethyl ) Oxy -6- Methylphenyl ] Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
Synthesis was performed in the same manner as in Example 40 using 2-bromoethyl methyl ether.
1H-NMR (CDClThree) δ = 2.48 (3H, s), 3.14 (6H, br.s), 3.33 (3H, s), 3.61 (2H, t, J = 5Hz), 4.07 (2H, t, J = 5Hz), 6.80 ( 1H, d, J = 8Hz), 6.94 (1H, d, J = 8Hz), 7.27 (1H, t, J = 8Hz), 8.63 (1H, s)
[0106]
Example 43
3- [2- (2- Methoxyethyl ) Oxy -6- Methylphenyl ] Sulfonyl -1- Dimethylcal Vamoyl -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 33 using 3- [2- (2-methoxyethyl) oxy-6-methylphenyl] thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 42). .
1H-NMR (CDClThree) δ = 2.81 (3H, s), 3.17 (3H, br.s), 3.25 (3H, s), 3.31 (3H, br.s), 3.49 (2H, t, J = 5Hz), 4.01 (2H, t, J = 5Hz), 6.82 (1H, d, J = 8Hz), 6.94 (1H, d, J = 8Hz), 7.42 (1H, t, J = 8Hz), 8.77 (1H, s)
[0107]
Example 44
3- (4- Cyano -2,5- Difluorophenyl ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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A mixture of 1.6 g of 2,4,5-trifluorobenzonitrile, 1.2 g of 3-mercapto-1H-1,2,4-triazole, 2.1 g of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide was stirred at room temperature for 2 hours. did. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dried in vacuo to give 2.06 g as a 2 spot solid on thin layer chromatography.
To a mixture of 240 mg of crystals, 280 mg of anhydrous potassium carbonate, and 1 ml of N, N-dimethylformamide, 0.14 ml of dimethylcarbamoyl chloride was added and stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine and concentrated. The residue was subjected to silica gel column chromatography twice with 15-20% (20% 2-propanol / ethyl acetate) / hexane to give 114 mg of the title compound, which was a spot changed on thin layer chromatography.
1H-NMR (CDClThree) δ = 3.20 (3H, br.s), 3.29 (3H, br.s), 7.36 (1H, dd, J = 5, 8Hz), 7.42 (1H, dd, J = 5, 8Hz), 8.84 (1H , s)
[0108]
Example 45
3- (4- Cyano -2,5- Difluorophenyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 33 using 3- (4-cyano-2,5-difluorophenyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 44).
1H-NMR (CDClThree) δ = 3.21 (3H, s), 3.33 (3H, s), 7.51 (1H, dd, J = 5, 8Hz), 8.05 (1H, dd, J = 5, 7Hz), 8.86 (1H, s)
[0109]
Example 46
3- (3,5- Dimethyl isoxazole -Four- Il ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
Embedded image
a) 3- (2,4-Pentanedione-3-yl) thio-1H-1,2,4-triazole
To a 200 ml methanol solution of 13 g of potassium hydroxide was added 20 g of 3-mercapto-1H-1,2,4-triazole and then 24 ml of 3-chloro-2,4-pentanedione under ice-cooling, and the mixture was stirred at room temperature overnight. Insoluble matters in the reaction solution were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through a small amount of silica gel, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 33.1 g of the title compound.
1H-NMR (CDClThree) δ = 2.42 (6H, s), 8.15 (1H, s)
[0110]
b) 3- (3,5-Dimethylisoxazol-4-yl) thio-1H-1,2,4-triazole
A mixture of 2 g of 3- (2,4-pentanedione-3-yl) thio-1H-1,2,4-triazole, 0.7 g of hydroxylamine hydrochloride, 1.4 ml of triethylamine and 10 ml of ethanol in an oil bath at 100 ° C. for 5 hours Stir with heating. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with 10-30% (20% 2-propanol / ethyl acetate) / hexane and crystallized with ethyl acetate-hexane to obtain 440 mg of the title compound.
1H-NMR (CDClThree) δ = 2.28 (3H, s), 2.50 (3H, s), 8.14 (1H, s)
[0111]
c) 3- (3,5-Dimethylisoxazol-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
Synthesis was performed in the same manner as in Example 32 using 3- (3,5-dimethylisoxazol-4-yl) thio-1H-1,2,4-triazole.
1H-NMR (CDClThree) δ = 2.28 (3H, s), 2.49 (3H, s), 3.17 (6H, br.s), 8.69 (1H, s)
[0112]
Example 47
3- (3,5- Dimethyl isoxazole -Four- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 33 using 3- (3,5-dimethylisoxazol-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 46).
1H-NMR (CDClThree) δ = 2.50 (3H, s), 2.76 (3H, s), 3.20 (3H, br.s), 3.33 (3H, br.s), 8.83 (1H, s)
[0113]
Example 48
3- (3,5- Dimethyl -1- Phenylpyrazole -Four- Il ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 3- (3,5-Dimethyl-1-phenylpyrazol-4-yl) thio-1H-1,2,4-triazole
3- (2,4-pentanedione-3-yl) thio-1H-1,2,4-triazole (Example 46-a) 2 g, phenylhydrazine 1 ml, ethanol 10 ml were mixed in a 100 ° C. oil bath. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to obtain 1.42 g of the title compound.
1H-NMR (d6-DMSO) δ = 2.21 (3H, s), 2.35 (3H, s), 7.40-7.56 (5H, m)
[0114]
b) 3- (3,5-Dimethyl-1-phenylpyrazol-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
Synthesis was performed in the same manner as in Example 32 using 3- (3,5-dimethyl-1-phenylpyrazol-4-yl) thio-1H-1,2,4-triazole.
1H-NMR (CDClThree) δ = 2.35 (3H, s), 2.40 (3H, s), 3.18 (6H, br.s), 7.36-7.51 (5H, m), 8.69 (1H, s)
[0115]
Example 49
3- (3,5- Dimethyl -1- Phenylpyrazole -Four- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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Synthesis similar to Example 33 using 3- (3,5-dimethyl-1-phenylpyrazol-4-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 48) did.
1H-NMR (CDClThree) δ = 2.55 (3H, s), 2.60 (3H, s), 3.20 (3H, br.s), 3.35 (3H, br.s), 7.36-7.54 (5H, m), 8.82 (1H, s)
[0116]
Example 50
3- (2- Methylimidazo [1,2-a] Pyridine -3- Il ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 2-Methylimidazo [1,2-a] pyridine
A mixture of 9.4 g of 2-aminopyridine, 9.5 ml of chloroacetone, and 25 ml of ethanol was heated and stirred in an oil bath at 100 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate-potassium carbonate aqueous solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography using NH silica gel with 20-30% ethyl acetate / hexane to obtain 5.5 g of the title compound.
1H-NMR (CDClThree) δ = 2.46 (3H, s), 6.72 (1H, dt, J = 1, 7Hz), 7.10 (1H, ddd, J = 1, 7, 9Hz), 7.33 (1H, s), 7.50 (1H, dt , J = 9, 1Hz), 8.03 (1H, dt, J = 7, 1Hz)
[0117]
b) 3- (2-Methylimidazo [1,2-a] pyridin-3-yl) thio-1H-1,2,4-triazole 3-mercapto-1H-1,2,4-triazole 1.15 g, N , N-dimethylformamide (15 ml) was added with 60% sodium hydride (450 mg), and when foaming subsided, N-chlorosuccinimide was added little by little in the ice bath, stirred at the same temperature for 15 minutes, and then 2-methylimidazo [1 , 2-a] pyridine (1.0 g) was added, and the mixture was heated and stirred at room temperature for 1 hour and in an oil bath at 70 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was washed twice with diethyl ether, methanol was added, and the insoluble material was removed by filtration. The filtrate was concentrated, water was added and the precipitated crystals were collected by filtration, washed with water, washed with diethyl ether and dried to give 480 mg of the title compound.
1H-NMR (d6-DMSO) δ = 2.43 (3H, s), 7.02 (1H, dt, J = 1, 7Hz), 7.39 (1H, ddd, J = 1, 7, 9Hz), 7.58 (1H, d , J = 9Hz), 8.38 (1H, d, J = 7Hz), 8.49 (1H, br.s), 14.10 (1H, br.s)
[0118]
c) 3- (2-Methylimidazo [1,2-a] pyridin-3-yl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
Synthesis was performed in the same manner as in Example 32 using 3- (2-methylimidazo [1,2-a] pyridin-3-yl) thio-1H-1,2,4-triazole.
1H-NMR (CDClThree) δ = 2.58 (3H, s), 3.04 (6H, s), 6.88 (1H, dt, J = 1, 7Hz), 7.29 (1H, ddd, J = 1, 7, 9Hz), 7.59 (1H, dt , J = 9, 1Hz), 8.28 (1H, dt, J = 7, 1Hz), 8.65 (1H, s)
[0119]
Example 51
3- (2- Methylimidazo [1,2-a] Pyridine -3- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 3- (2-Methylimidazo [1,2-a] pyridin-3-yl) sulfonyl-1H-1,2,4-triazole
3- (2-Methylimidazo [1,2-a] pyridin-3-yl) thio-1H-1,2,4-triazole (Example 50-a) To a mixture of 230 mg, acetonitrile 5 ml, water 5 ml, 30 630 mg of sodium percarbonate was added little by little in a water bath at 0 ° C., and then stirred at the same temperature for 4 hours. 7.5 ml of water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise in an ice bath to adjust the pH to about 4. The mixture was stirred as it was for 30 minutes, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 139 mg of the title compound.
1H-NMR (d6-DMSO) δ = 2.62 (3H, s), 7.27 (1H, dt, J = 1, 7Hz), 7.62 (1H, ddd, J = 1, 7, 9Hz), 7.73 (1H, dt , J = 9, 1Hz), 8.80 (1H, s), 8.86 (1H, dt, J = 7, 1Hz)
[0120]
b) 3- (2-Methylimidazo [1,2-a] pyridin-3-yl) sulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole
To a mixture of 3- (2-methylimidazo [1,2-a] pyridin-3-yl) sulfonyl-1H-1,2,4-triazole 100 mg, anhydrous potassium carbonate 105 mg, N, N-dimethylformamide 0.5 ml, Dimethylcarbamoyl chloride 0.06ml was added and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine and concentrated. The residue was subjected to silica gel column chromatography with 30-50% (20% 2-propanol / ethyl acetate) / hexane to give 107 mg of the title compound.
1H-NMR (CDClThree) δ = 2.79 (3H, s), 3.17 (3H, br.s), 3.29 (3H, br.s), 7.05 (1H, dt, J = 1, 7Hz), 7.48 (1H, ddd, J = 1 , 7, 9Hz), 7.65 (1H, dt, J = 9, 1Hz), 8.77 (1H, s), 9.04 (1H, dt, J = 1, 7Hz)
[0121]
Example 52
3- (6- Bromo -2- Pyridyl ) Thio -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 3- (6-Bromo-2-pyridyl) thio-1H-1,2,4-triazole
A mixture of 200 mg of 3-mercapto-1H-1,2,4-triazole, 560 mg of 2,6-dibromopyridine, 420 mg of anhydrous potassium carbonate and 1 ml of N, N-dimethylformamide was heated and stirred in an oil bath at 100 ° C. for 3 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5-30% (20% 2-propanol / ethyl acetate) / hexane to give 73 mg of the title compound.
1H-NMR (CDClThree) δ = 7.34 (1H, d, J = 8Hz), 7.40 (1H, d, J = 8Hz), 7.53 (1H, t, J = 8Hz), 8.12 (1H, s)
[0122]
b) 3- (6-Bromo-2-pyridyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole
A mixture of 3- (6-bromo-2-pyridyl) thio-1H-1,2,4-triazole 73 mg, dimethylcarbamoyl chloride 40 μl, anhydrous potassium carbonate 80 mg, N, N-dimethylformamide 0.5 ml was stirred at room temperature for 2 hours. did. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water, saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20% (20% 2-propanol / ethyl acetate) / hexane to obtain 77 mg of the title compound.
1H-NMR (CDClThree) δ = 3.19 (3H, br.s), 3.33 (3H, br.s), 7.31 (1H, dd, J = 1, 8Hz), 7.34 (1H, dd, J = 1, 8Hz), 7.44 (1H , t, J = 8Hz), 8.85 (1H, s)
[0123]
Example 53
3- (6- Bromo -2- Pyridyl ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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3- (6-Bromo-2-pyridyl) thio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 52) To a mixture of 60 mg and ethyl acetate 0.5 ml was added 84 mg of m-chloroperbenzoic acid. The mixture was heated and stirred in an oil bath at 60 ° C. for 2 hours. 0.5 ml of hexane was added to the reaction solution, and the crystals were collected by filtration at room temperature, washed with ethyl acetate / hexane (1/1) and dried to obtain 45 mg of the title compound.
1H-NMR (CDClThree) δ = 3.20 (3H, s), 3.37 (3H, s), 7.74 (1H, dd, J = 1, 8Hz), 7.86 (1H, t, J = 8Hz), 8.28 (1H, dd, J = 1 , 8Hz), 8.85 (1H, s)
[0124]
Example 54
3- ( Piperidine -1- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 3-Chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole
3-Benzylthio-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 1) A mixture of 45 g, 300 ml of acetic acid and 75 ml of water was cooled to −5 ° C. or lower in an ice-salt bath, and Chlorine gas was passed for 55 minutes. Add 600 ml of water to the reaction mixture, extract with ethyl acetate / hexane (1/1), wash the organic layer with water, wash with aqueous sodium bicarbonate, wash with saturated brine, dry over anhydrous magnesium sulfate and concentrate under reduced pressure to obtain 33 g of the title compound. It was.
1H-NMR (CDClThree) δ = 3.23 (3H, br.s), 3.37 (3H, br.s), 8.96 (1H, s)
[0125]
b) 3- (Piperidin-1-yl) sulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole
To a mixture of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (240 mg) and ethyl acetate (2 ml) was added 0.2 ml of piperidine in a room temperature water bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and then with saturated brine and concentrated. The residue was subjected to silica gel column chromatography with 20-30% (20% 2-propanol / ethyl acetate) / hexane to give 29 mg of the title compound.
1H-NMR (CDClThree) δ = 1.50-1.72 (6H, m), 3.20 (3H, br.s), 3.30-3.387H, m), 8.84 (1H, s)
[0126]
Example 55
3- (8- Aza - Bicyclo [3.2.1] Octane -8- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 8-Aza-bicyclo [3.2.1] octane hydrochloride
A mixture of 900 mg of tropane, 1 ml of 1-chloroethyl chloroformate and 20 ml of toluene was heated to reflux for 6 hours. Next, 10 ml of methanol was added to the reaction solution, and the mixture was heated to reflux for 4 hours, and then the solvent was distilled off to obtain 850 mg of the title compound.
[0127]
b) 3- (8-Aza-bicyclo [3.2.1] octane-8-yl) sulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole
3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a) 470 mg, 8-aza-bicyclo [3.2.1] octane hydrochloride 350 mg, triethylamine 0.7 ml, ethyl acetate 10 ml The mixture was stirred at room temperature overnight. The reaction mixture was washed with water and then with saturated brine and concentrated. The residue was subjected to silica gel column chromatography with 50-100% ethyl acetate / hexane to give 150 mg of the title compound.
1H-NMR (CDClThree) δ = 1.40-1.80 (8H, m), 1.84-1.95 (2H, m), 3.19 (3H, br.s), 3.33 (3H, br.s), 4.35-4.45 (2H, m), 8.80 ( 1H, s)
[0128]
Example 56
3- (3,5- Dimethylpyrazole -1- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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A mixture of 100 mg of 3,5-dimethylpyrazole, 480 mg of 3-chlorosulfonyl-1-dimethylcarbamoyl-1H-1,2,4-triazole (Example 54-a), 280 mg of anhydrous potassium carbonate and 1.5 ml of acetonitrile was mixed at 50 ° C. The mixture was heated and stirred for 2 hours in an oil bath. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine and concentrated. The residue was subjected to silica gel column chromatography with 20-30% (20% 2-propanol / ethyl acetate) / hexane and crystallized with ethyl acetate-hexane to obtain 210 mg of the title compound.
1H-NMR (CDClThree) δ = 2.22 (3H, s), 2.62 (3H, s), 3.18 (3H, s), 3.33 (3H, s), 6.03 (1H, s), 8.81 (1H, s)
[0129]
Example 57
3- (2,3- Dihydro -1H- Indole -1- Il ) Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 56 using 2,3-dihydro-1H-indole.
1H-NMR (CDClThree) δ = 3.12 (2H, t, J = 8Hz), 3.14 (6H, s), 4.26 (2H, t, J = 8Hz), 7.00 (1H, t, J = 8Hz), 7.10-7.17 (2H, m ), 7.53 (1H, d, J = 8Hz), 8.75 (1H, s)
[0130]
Example 58
3- [N- (4- Chlorophenyl ) -N- Methylamino ] Sulfonyl -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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Synthesis was performed in the same manner as in Example 56 using N-methyl-4-chloroaniline.
1H-NMR (CDClThree) δ = 3.17 (3H, br.s), 3.23 (3H, br.s), 3.47 (3H, s), 7.25 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz), 8.86 (1H, s)
[0131]
Example 59
3- (4- Toluenesulfonyl ) -1- Dimethylcarbamoyl -1H- Pyrazole
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a) 1- (4-Toluenesulfonyl) -1H-pyrazole
10 ml of a pyridine suspension of 1 g of pyrazole and 2.8 g of 4-toluenesulfonyl chloride was stirred at 130 ° C. for 1 hour. After cooling the reaction mixture, water was added to obtain a white suspension. The resulting white suspension was collected by filtration, and the resulting white solid was washed 3 times with water. Drying at room temperature under reduced pressure gave 500 mg of a white solid.
1H-NMR (d6-DMSO) δ = 2.39 (3H, s), 6.59-6.60 (1H, m), 7.47 (2H, d, J = 8.2Hz), 7.85-7.88 (3H, m), 8.46 (1H , d, J = 2.8Hz)
[0132]
b) 3- (4-Toluenesulfonyl) -1-dimethylcarbamoyl-1H-pyrazole
Under a nitrogen atmosphere, 1- (4-toluenesulfonyl) -1H-pyrazole (500 mg) in tetrahydrofuran (10 ml) was added dropwise with a 1.6 molar hexane solution of tert-butyllithium at -70 ° C, and the resulting yellow suspension was allowed to rise to room temperature. Warm and stir at 100 ° C. for 14 h. After cooling the reaction mixture, the mixture obtained by diluting with saturated aqueous ammonium chloride was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a brown oil as a residue. An N, N-dimethylformamide suspension of the entire residue, 0.5 ml of dimethylcarbamoyl chloride and 200 mg of potassium carbonate was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with water and once with a saturated aqueous ammonium chloride solution and then dried over magnesium sulfate, and the residue was subjected to short column chromatography (eluent: n-hexane / ethyl acetate = 3/1). Purification gave 122 mg of a clear oil.
1H-NMR (CDClThree) δ = 2.42 (3H, s), 3.10-3.25 (6H, m), 6.81 (1H, d, J = 2.8Hz), 7.32 (2H, d, J = 8.2Hz), 7.91 (2H, d, J = 8.4Hz), 8.11 (1H, d, J = 2.8Hz)
[0133]
Example 60
3- (4- Toluenesulfonyl ) -1- Dimethylcarbamoyl -1H-1,2,4- Triazole
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a) 1- (4-Toluenesulfonyl) -1H-triazole
To an N, N-dimethylformamide solution of 5 g of 1H-1,2,4-triazole and 14.5 g of 4-toluenesulfonyl chloride was added 2.9 g of sodium hydride under ice cooling, and the reaction mixture was stirred for 40 minutes with ice cooling. . Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with water and then dried over magnesium sulfate, and the residue was purified by short column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to obtain 21.8 g of a white solid. Got.
1H-NMR (d6-DMSO) δ = 2.42 (3H, s), 7.53 (2H, d, J = 8.4Hz), 7.97 (2H, d, J = 8.4Hz), 8.34 (1H, s), 9.40 ( 1H, s)
[0134]
b) 3-Toluenesulfonyl-1H-triazole
A 2.6 molar hexane solution of butyllithium was added dropwise to a tetrahydrofuran solution of 1 g of 1-toluenesulfonyl-1-tetrazole and 389 mg of lithium bromide at -78 ° C. The reaction mixture was stirred at -78 ° C for 10 minutes and then at room temperature for 3 hours 30 minutes. A saturated aqueous ammonium chloride solution was added to the resulting reaction mixture under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off from the residue under reduced pressure to obtain 440 mg of a brown solid.
1H-NMR (d6-DMSO) δ = 2.40 (3H, s), 7.47 (2H, d, J = 7.8Hz), 7.85 (2H, d, J = 8.0Hz), 8.80 (1H, s).
[0135]
c) 3- (4-Toluenesulfonyl) -1-dimethylcarbamoyl-1H-1,2,4-triazole 3- (4-toluenesulfonyl) -1H-1,2,4-triazole 100 mg, dimethylcarbamoyl chloride 62 μl and A suspension of 124 mg of potassium carbonate in N, N-dimethylformamide was stirred at room temperature for 1 hour and 10 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed 3 times with water and dried over magnesium sulfate, and the residue was purified by short column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain 77 mg of a transparent oily substance. Obtained.
1H-NMR (CDClThree) δ = 2.34 (3H, s), 3.02 (6H, br s), 7.48 (2H, d, J = 8.0Hz), 7.87 (2H, d, J = 8.0Hz), 9.22 (1H, s)
[0136]
[Test Example 1]
Measurement of DPPIV inhibitory action
DPP-IV obtained from pig kidney was dissolved in a reaction buffer (50 mM Tris-HCl pH 7.4, 0.1% BSA) so as to be 10 mμ / mL, and 110 μl thereof was added. Further, 15 μl of the drug was added, followed by incubation at room temperature for 20 minutes, and 25 μl of Gly-Pro-p-nitroanilide dissolved in 2 mM (final concentration 0.33 mM) was added to start the enzyme reaction. The reaction time was 20 minutes, and 25 μl of 1N phosphoric acid solution was added to stop the reaction. The absorbance at 405 nm is measured to determine the enzyme reaction inhibition rate and the IC50Was calculated.
[0137]
[Table 1]
[Test Example 2]
Confirmation test for improving glucose tolerance
[0138]
Effect on glucose tolerance in normal mice
animal:
5 or 6 male C57BL / 6N mice in each group (purchased from Charles River, Japan)
[0139]
Preparation and administration of test compounds:
About Experiment 1 and Experiment 2.
The test compound was suspended in an aqueous 0.5% methylcellulose solution at the dose shown in the table below, mixed with an equal volume of glucose solution, and orally administered at a volume of 10 ml / kg. The solvent control group was mixed with 0.5% methylcellulose aqueous solution and an equal volume of glucose solution and orally administered at a volume of 10 ml / kg. Glucose was administered at a dose of 2 g / kg.
[0140]
About Experiment 3.
The test compound was suspended in a 0.5% aqueous methylcellulose solution at the dose shown in the table below. This test compound suspension or 0.5% methylcellulose aqueous solution as a solvent control group was orally administered in a volume of 10 ml / kg, and 30 minutes later, a glucose solution was orally administered in a volume of 10 ml / kg. Glucose was administered at a dose of 2 g / kg.
[0141]
Blood sampling and blood glucose measurement:
About Experiment 1 and Experiment 2.
Blood samples were collected from the tail vein immediately before and after the administration of the mixed solution of the test substance and glucose, and 60, 120 minutes after the administration, and the blood glucose level was measured.
[0142]
About Experiment 3.
Blood was collected from the tail vein immediately before administration of the test substance, immediately before and after administration of the glucose solution, and 30, 60, and 120 minutes later, and blood glucose level was measured.
[0143]
Method:
Under anesthesia, the tail vein of the mouse is injured with a razor blade and slightly bled. Collect 10 μl of blood and immediately mix with 14010 μl of 0.6 M perchloric acid. Glucose in the supernatant obtained by centrifugation (1500 g, 10 minutes, 4 ° C., refrigerated centrifuge GS-6KR, Beckman Co., Ltd.) was measured using Glucose CII Test Wako (Wako Pure Chemical Industries).
[0144]
result:
It is shown in the following table. The results are shown as mean ± standard error.
[0145]
Effect on glucose tolerance in normal mice
[Table 2]
[Table 3]
[Table 4]
As described above, the compounds of Examples 2, 13, and 43, which are N-carbamoylazole derivatives, showed a clear effect on the glucose tolerance of normal mice by oral administration.
【The invention's effect】
According to the present invention, a 1-carbamoylazole derivative compound exhibiting a DPPIV inhibitory action could be provided.
Therefore, the DPPIV inhibitor in the present invention includes, for example, a therapeutic agent for diabetes, a therapeutic agent for obesity, a therapeutic agent for hyperlipidemia, a therapeutic agent for AIDS, a therapeutic agent for osteoporosis, a therapeutic agent for gastrointestinal tract, a therapeutic agent for angiogenesis, a therapeutic agent for infertility, It is useful as a therapeutic / preventive agent for inflammatory agents, antiallergic agents, immune regulators, hormone regulators, antirheumatic agents, cancer therapeutic agents and the like.
In addition, in order to confirm the drug efficacy by oral administration, a test using the glucose tolerance improving effect as an index was conducted to confirm the oral efficacy and find utility as a medicine.
Claims (9)
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