JP4548884B2 - 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative - Google Patents
4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative Download PDFInfo
- Publication number
- JP4548884B2 JP4548884B2 JP34437399A JP34437399A JP4548884B2 JP 4548884 B2 JP4548884 B2 JP 4548884B2 JP 34437399 A JP34437399 A JP 34437399A JP 34437399 A JP34437399 A JP 34437399A JP 4548884 B2 JP4548884 B2 JP 4548884B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- tetrahydrothieno
- pyridine derivative
- alkyl group
- hydrogen atom
- 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
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体に関するものであり、更に詳しくはＴＮＦ−α産生阻害作用を有する４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体に関する。
【０００２】
【従来の技術】
ＴＮＦ（腫瘍壊死因子）−αは、活性化マクロファージが産生するサイトカインの一種で腫瘍部位に出血性壊死を誘発させる因子として１９７５年に発見されたが、現在では炎症反応・免疫機構に広く関わるメディエーターとして認識されている。しかしながら、ＴＮＦ−αの産生調節機構の破綻、例えば持続的かつ過剰な産生が組織障害を引き起こす等の様々な病気の原因や増悪をもたらす要因となりうることが考えられる。従って、ＴＮＦ−αの過剰産生や作用を防止または障害することは数多くの炎症性・感染性・免疫性または悪性疾患に対する有用な治療剤と成り得る可能性もある。その様な疾患としては、アレルギー、気管支喘息、敗血症、関節炎（関節リウマチ・変形性関節症等）、糖尿病、乾癬、クローン病、潰瘍性大腸炎等が挙げられる。
【０００３】
この様な技術背景のもと、ＴＮＦ−α産生阻害作用を有する化合物の報告が数多くなされている。しかしながら、４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体の開示は勿論、それを示唆する記載は見当たらない。また、特開昭４９−１５９３号公報またはＤＤ２７２０７８号公報には４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体が記載されているが、これらいずれの化合物にもＴＮＦ−α産生阻害作用を示唆する記載は見当たらない。
【０００４】
【発明が解決しようとする課題】
本発明の目的はＴＮＦ−αにより誘導される疾患の予防薬または治療薬として有用なＴＮＦ−α産生阻害剤を提供することにある。
【０００５】
【課題を解決するための手段】
本発明者等は、上記の課題を受けて鋭意検討した結果、４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体に優れたＴＮＦ−α産生阻害作用を有することを見出し、本発明を完成するに至った。すなわち、本発明は一般式（Ｉ）：
【０００６】
【化２】
［式中、Ｒは低級アルキル基、低級アルカノイル基、シクロアルキルカルボニル基またはアリールアルキル基を示し、Ｒ1及びＲ2はそれぞれ水素原子、置換基を有していてもよい低級アルキル基、シクロアルキル基、または複素環基を示し、またはＲ1及びＲ2は隣接窒素原子と共に更に窒素原子、酸素原子又は硫黄原子を１〜２個有していてもよい５〜６員の飽和複素環基を示し、Ｒ3は水素原子または低級アルキル基を示し、Ｒ4は低級アルキル基を示す。］で表される４，５，６，７−テトラヒドロチエノ〔２，３−ｃ〕ピリジン誘導体、及び該誘導体またはその水和物或いはこれらの薬理学上許容しうる塩を有効成分とするＴＮＦ−α産生阻害剤。
【０００８】
【発明の実態の形態】
以下、本発明を更に詳細に説明する。上記一般式（Ｉ）で示される化合物においてＲは低級アルキル基、低級アルカノイル基、シクロアルキルカルボニル基またはアリールアルキル基を示す。低級アルキル基としては、例えばメチル、エチル、プロピル、イソプロピル、ブチル、ｔｅｒｔ−ブチル、ペンチル、ヘキシル基等のＣ1〜Ｃ6の直鎖又は分枝鎖状アルキル基が挙げられ，好ましくはＣ1〜Ｃ4のアルキル基、特にエチル基が挙げられる。
低級アルカノイル基とは、好ましくはＣ2〜Ｃ5の低級アルカノイル基を意味し、例えばアセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル基等が挙げられ、とりわけアセチル基が好ましい。
シクロアルキルカルボニル基とは、Ｃ3〜Ｃ7のシクロアルキルカルボニル基を意味し、例えばシクロプロピルカルボニル基、シクロブチルカルボニル基等が挙げられ、とりわけシクロプロピルカルボニル基が好ましい。
アリールアルキル基の具体例としては、例えばＣ7〜Ｃ11のベンジル、フェネチル、ナフチルメチル基等が挙げられる。
【０００９】
Ｒ1及びＲ2はそれぞれ水素原子、置換基を有していてもよい低級アルキル基、シクロアルキル基、または複素環基を示し、または隣接窒素原子と共に更に窒素原子、酸素原子又は硫黄原子を１〜２個有していてもよい５〜６員の飽和複素環基を示す。低級アルキル基は、上記と同一意味を表す。また、低級アルキル基に置換可能な置換基としては、Ｃ3〜Ｃ7のシクロアルキル基、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル基等、またはジ置換アミノ基、例えばジメチルアミノ、ジエチルアミノ基等、または低級アルコキシカルボニル基、例えばメトキシカルボニル、エトキシカルボニル基等、またはアリール基、例えばフェニル、ナフチル基等を挙げることができる。シクロアルキル基としては、Ｃ3〜Ｃ7のシクロアルキル基を挙げることができる。
複素環基としては、ピリジル、モルホリノ、キノリル、チアゾリル基等を挙げることができる。好ましいＲ1及びＲ2の定義のおける隣接窒素原子と共に５〜６員の飽和複素環基を示す例としては、ピペリジノ、モルホリノ、チアゾリジニル、ピペラジニル基等が挙げられ、好ましくはモルホリノまたはチアゾリジニル、特にモルホリノ基が挙げられる。
【００１０】
Ｒ3は水素原子または低級アルキル基を示す。低級アルキル基は上記と同じ範囲を表す。Ｒ3は、好ましくは水素原子またはＣ1〜Ｃ3のアルキル基、特に水素原子を表す。Ｒ4は低級アルキル基を示し、好ましくはＣ1〜Ｃ4のアルキル基、特にエチル基を表す。
【００１１】
本発明では、式（Ｉ）で表される化合物の好ましい具体例としては、以下の化合物が挙げられる。
Ｎ，Ｎ−ジエチル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ，Ｎ−ジエチル−Ｎ’−メチル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
６−アセチル−３−エトキシカルボニル−２−［（３−チアゾリジニル）カルボニルアミノ］−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン
６−アセチル−３−エトキシカルボニル−２−［（４−メチルピペリジノ）カルボニルアミノ］−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン
６−アセチル−３−エトキシカルボニル−２−モルホリノカルボニルアミノ−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン
６−アセチル−３−エトキシカルボニル−２−チオモルホリノカルボニルアミノ−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン
【００１２】
６−シクロプロピルカルボニル−３−エトキシカルボニル−２−モルホリノカルボニルアミノ−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン
Ｎ−（メトキシカルボニル−フェニル）メチル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ−シクロプロピルメチル−Ｎ−プロピル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ−３−（ジメチルアミノ）プロピル−Ｎ−メチル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ−モルホリノ−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ，Ｎ−ジエチル−Ｎ’−［６−シクロプロピルカルボニル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
Ｎ，Ｎ，Ｎ’−トリエチル−Ｎ’−［６−シクロプロピルカルボニル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレア
【００１３】
本発明の化合物は、場合により、水和物を形成するがそれらも本発明に包含されることは言うまでもない。本発明の化合物は、常法によって製造されるが、これらのうち代表的な方法を挙げれば以下の通りである。
（製造法）
【００１４】
【化３】
（式中、Ｒ、Ｒ1、Ｒ2及びＲ3は前記の意味を有する。）即ち、式（II）で表される化合物にテトラヒドロフラン、ジメトキシエタン、ジグライム、トルエン、ベンゼン等の溶媒中ホスゲンを反応させた後、該当するアミン化合物を縮合反応させ、式（Ｉ'）で表される化合物を得ることが出来る。なお、本反応はホスゲンの代わりにトリホスゲン（炭酸ビストリクロロメチル）を用いて行うと容易にかつ安全に合成することが出来る。更に式（Ｉ'）を適当な塩基でメタル化後、該当するハロゲン化アルキルＲ3Ｘを反応させることにより目的物質である式（Ｉ）を得ることが出来る。
【００１６】
各反応段階において、例えば乾燥不活性ガス（窒素ガス、アルゴンガス等）雰囲気下、無溶媒またはトルエン、キシレン、クロロホルム、ジクロロメタン、テトラヒドロフラン、ジメチルホルムアミド等の反応に関与しない溶媒を使用してもよい。
反応温度は、通常室温〜２００℃の範囲であり、好ましくは２５℃〜１００℃の範囲である。反応時間は３０分〜４８時間で、通常は３０分〜２時間で完結する。
【００１７】
反応は、炭酸水素ナトリウム、炭酸ナトリウム、水酸化ナトリウムの如き無機塩類、水素化ナトリウム、水素化カリウムの如き水素化アルカリ金属類、あるいはトリエチルアミン、ピリジン、ピペラジンの如き有機塩類の存在下脱ハロゲン化反応等を行うことにより好ましい結果が得られる。
これらの方法で得られた式(Ｉ)の化合物は公知の処理手段（例えば、抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー等）によって、遊離のまま、あるいはその塩として単離、精製することが出来る。
【００１８】
本発明に係る化合物はＴＮＦ−α産生阻害作用を有することから、例えばアレルギー性疾患、慢性関節リウマチ、潰瘍性大腸炎等に有効である。
本発明に係る化合物を抗リウマチ薬および抗炎症薬として使用する場合には、経口または非経口等の適当な投与方法により投与することができる。経口投与用の形態としては、例えば錠剤、顆粒剤、カプセル剤、丸剤、散剤等が、また非経口投与用の形態としては、例えば注射剤、吸入剤、座剤、液剤等が挙げられる。
これら医薬投与用組成物の製剤化に際しては、本発明の化合物またはその塩を用い常法に従い調製することができる。
【００１９】
例えば経口剤の場合には、乳糖、ブドウ糖、コーンスターチ、ショ糖等の賦形剤、カルボキシメチルセルロースカルシウム、ヒドロキシプロピルセルロース等の崩壊剤、ステアリン酸カルシウム、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、硬化油等の滑沢剤、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ポリビニルアルコール、ゼラチン、アラビアゴム等の結合剤、グリセリン、エチレングリコール等の湿潤剤、その他必要に応じて界面活性剤、矯味剤等を使用して所望の投与剤型に調製することができる。また非経口剤の場合には、水、エタノール、グリセリン、プロピレングリコール、ポリエチレングリコール、寒天、トラガラントガム等の希釈剤を用いて、必要に応じて溶解補助剤、緩衝剤、保存剤、香料、着色剤等を使用することができる。
【００２０】
本発明の化合物を抗アレルギー剤として処方する場合、その投与単位は本発明化合物として、成人一人当たり、経口投与の場合１日１〜３００mg、好ましくは１〜１００mg、非経口投与の場合１日０．１〜１００mg、好ましくは０．５〜３０mgの範囲で投与され、それぞれ１日１〜３回の分割投与により所望の治療効果が期待できる。
【００２１】
【実施例】
次に本発明に係る化合物の合成例、製剤例、試験例を実施例として示す。以下に本発明の代表的な実施例を示すが、本発明がそれらにのみ限定されることがないことは言うまでもない。尚、出発物質の製造方法は製造例として示した。また、文中1Ｈ−ＮＭＲデータは、ＴＭＳを内部標準としたケミカルシフト値を示す。
製造例１
６−アセチル−２−アミノ−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジンの製造
１−アセチル−４−ピペリドン４．０ｇ、イオウ１．４ｇ、シアノ酢酸エチル６．５ｇをＮ，Ｎ−ジメチルホルムアミド４０ｍｌに溶かし、６０℃でトリエチルアミン５．０ｍｌを加えた。反応終了後、水、酢酸エチルを加え抽出した。有機層をブラインで洗浄後、硫酸マグネシウムで脱水し、減圧濃縮し、シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝７０：１）で精製することにより、目的物質４．８ｇを得た。
【００２２】
製造例２
２−アミノ−３−エトキシカルボニル−６−エチル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジンの製造
１−エチル−４−ピペリドン４．０ｇ、イオウ１．４ｇ、シアノ酢酸エチル６．５ｇをＮ，Ｎ−ジメチルホルムアミド４０ｍｌに溶かし、６０℃でトリエチルアミン５．０ｍｌを加えた。反応終了後、水、酢酸エチルを加え抽出した。有機層をブラインで洗浄後、硫酸マグネシウムで脱水し、減圧濃縮し、シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝７０：１）で精製することにより、目的物質４．８ｇを得た。
【００２３】
実施例１
Ｎ，Ｎ−ジエチル−Ｎ’−［６−アセチル−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン−２−イル］ウレアの合成
６−アセチル−２−アミノ−３−エトキシカルボニル−４，５，６，７−テトラヒドロチエノ［２，３−ｃ］ピリジン１２．４ｇ、トリホスゲン１３．７ｇの塩化メチレン２００ｍｌ溶液を加え、アルゴン気流中、氷冷下にてトリエチルアミン１．２７ｍｌを加えた。室温で２．５時間撹拌後、さらにトリエチルアミン０．６４ｍｌを加え１７時間撹拌反応させた。これにジエチルアミン３８．１ｍｌを３０分間かけて滴下した。更に５０分間撹拌反応後、飽和重曹水で中和し塩化メチレンで抽出した。有機層をブラインで洗浄後、硫酸マグネシウムで脱水し、減圧濃縮し、シリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝５０：１）で精製することにより、目的化合物１２．２ｇを得た。
【００２４】
実施例１と同様な方法で製造できる化合物の構造及び1Ｈ−ＮＭＲのデータを以下の表１−１〜表１−７に示す。
【００２５】
【化４】
【表１】
【表２】
【表３】
【表４】
【表５】
【表６】
【表７】
製剤例１(錠剤の調製)
本発明化合物（実施例１） ２５０ｇ
乳糖 ６２０ｇ
コーンスターチ ４００ｇ
ヒドロキシプロピルセルロース ２０ｇ
ステアリン酸マグネシウム １０ｇ
上記の本発明化合物、乳糖及びコーンスターチを均一になるまで混合した後、ヒドロキシプロピルセルロースの５Ｗ／Ｖ％エタノール溶液を加えて練合、顆粒化する。１６メッシュの篩に通し整粒した後、常法により打錠し、１錠当たりの重量１３０ｍｇ、直径７ｍｍ、主薬含量２５ｍｇの錠剤とした。
【００３４】
試験例１（ＴＮＦ−α産生阻害作用試験）
ラットをペントバルビタール麻酔下にてヘパリン処置した試験管に採血を行った。採血した血液と等量のＲＰＭＩ−１６４０を加え、２４ｗｅｌｌ ｐｌａｔｅに分注し、溶媒（ＤＭＳＯ）、または溶媒に溶かした被験薬を添加し、３０分間、３７℃、５％ＣＯ2でプレインキュベーションを行った。反応はＬＰＳ（リポポリサッカライド）を添加して開始し、４時間、３７℃、５％ＣＯ2でインキュベーションを行い、氷浴にて反応を停止した。反応停止後、３０００ｒｐｍ、４℃、１５分間遠心分離し、上清中のＴＮＦ−αをＥＬＩＳＡ法にて測定した。
被験薬の活性は溶媒対照群に対する産生抑制率を求め、ＴＮＦ−α産生を５０％抑制する被験薬濃度を求め評価した。試験結果を表２に示した。
【００３５】
【表８】
試験例２（反復投与毒性）
本発明化合物（実施例１）をマウス（８匹）に１００ｍｇ／ｋｇを１４日間経口投与したが、死亡例および肉眼的異常は認められなかった。
【００３７】
【発明の効果】
本発明化合物は優れたＴＮＦ−α産生阻害作用を有している。従ってＴＮＦ−αの産生を阻害することは数多くの疾患、特に炎症疾患、例えば関節リウマチ等の自己免疫疾患、アレルギー疾患、急性及び慢性肺障害等に非常に効果的な作用を示し、今までにない新しいタイプの予防薬または治療薬として有用で有る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative, and more specifically, 4,5,6,7-tetrahydrothieno [2] having an inhibitory effect on TNF-α production. , 3-c] pyridine derivatives.
[0002]
[Prior art]
TNF (Tumor Necrosis Factor) -α is a kind of cytokine produced by activated macrophages and was discovered in 1975 as a factor that induces hemorrhagic necrosis at the tumor site. Currently, it is a mediator that is widely involved in inflammatory reactions and immune mechanisms. It is recognized as. However, it is considered that failure of the TNF-α production regulatory mechanism, for example, sustained and excessive production, can cause various diseases such as tissue damage and cause deterioration. Therefore, preventing or inhibiting the overproduction or action of TNF-α may be a useful therapeutic agent for many inflammatory, infectious, immune or malignant diseases. Examples of such diseases include allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis, osteoarthritis, etc.), diabetes, psoriasis, Crohn's disease, ulcerative colitis and the like.
[0003]
Based on such a technical background, there have been many reports of compounds having an inhibitory effect on TNF-α production. However, the disclosure of 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivatives is not to mention, and there is no description suggesting it. JP-A-49-1593 or DD272078 describes 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivatives, and any of these compounds includes TNF- There is no description suggesting an α production inhibitory action.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a TNF-α production inhibitor useful as a prophylactic or therapeutic agent for diseases induced by TNF-α.
[0005]
[Means for Solving the Problems]
As a result of intensive studies in view of the above problems, the present inventors have found that 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivatives have an excellent TNF-α production inhibitory action. The present invention has been completed. That is, the present invention relates to the general formula (I):
[0006]
[Chemical 2]
[Wherein, R represents a lower alkyl group, a lower alkanoyl group, a cycloalkylcarbonyl group or an arylalkyl group, and R 1 and R 2 each represent a hydrogen atom, an optionally substituted lower alkyl group, or a cycloalkyl group. A group or a heterocyclic group, or R 1 and R 2 represent a 5- or 6-membered saturated heterocyclic group which may further have 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms together with adjacent nitrogen atoms. R 3 represents a hydrogen atom or a lower alkyl group, and R 4 represents a lower alkyl group. And a pharmacologically acceptable salt thereof as an active ingredient. 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative represented by the formula: α production inhibitor.
[0008]
[Form of the present invention]
Hereinafter, the present invention will be described in more detail. In the compound represented by the general formula (I), R represents a lower alkyl group, a lower alkanoyl group, a cycloalkylcarbonyl group or an arylalkyl group. The lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, pentyl, include linear or branched alkyl group of C 1 -C 6, such as a hexyl group, preferably C 1 alkyl group -C 4, include especially ethyl.
The lower alkanoyl group preferably means a C 2 to C 5 lower alkanoyl group, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, and isovaleryl groups, with an acetyl group being particularly preferred.
The cycloalkylcarbonyl group means a C 3 to C 7 cycloalkylcarbonyl group, and examples thereof include a cyclopropylcarbonyl group and a cyclobutylcarbonyl group, with a cyclopropylcarbonyl group being particularly preferred.
Specific examples of the arylalkyl group include C 7 to C 11 benzyl, phenethyl, and naphthylmethyl groups.
[0009]
R 1 and R 2 each represent a hydrogen atom, an optionally substituted lower alkyl group, a cycloalkyl group, or a heterocyclic group, or a nitrogen atom, an oxygen atom, or a sulfur atom in addition to the adjacent nitrogen atom. -5-6 membered saturated heterocyclic group which may have -2 piece is shown. The lower alkyl group has the same meaning as described above. Examples of the substituent that can be substituted on the lower alkyl group include C 3 to C 7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups, or disubstituted amino groups such as dimethylamino and diethylamino. A lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl group, or an aryl group such as phenyl or naphthyl group. Examples of the cycloalkyl group include C 3 to C 7 cycloalkyl groups.
Examples of the heterocyclic group include pyridyl, morpholino, quinolyl, and thiazolyl groups. Examples of 5 to 6-membered saturated heterocyclic groups together with adjacent nitrogen atoms in the definition of R 1 and R 2 include piperidino, morpholino, thiazolidinyl, piperazinyl groups, etc., preferably morpholino or thiazolidinyl, especially morpholino Groups.
[0010]
R 3 represents a hydrogen atom or a lower alkyl group. A lower alkyl group represents the same range as described above. R 3 preferably represents a hydrogen atom or a C 1 -C 3 alkyl group, in particular a hydrogen atom. R 4 represents a lower alkyl group, preferably a C 1 -C 4 alkyl group, particularly an ethyl group.
[0011]
In the present invention, preferred specific examples of the compound represented by the formula (I) include the following compounds.
N, N-diethyl-N ′-[6-acetyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N, N-diethyl-N '-Methyl-N'-[6-acetyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea 6-acetyl-3-ethoxycarbonyl- 2-[(3-Thiazolidinyl) carbonylamino] -4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3-ethoxycarbonyl-2-[(4-methylpiperidino) carbonylamino] -4,5,6,7-tetrahydrothieno [2,3-c] pyridine 6-acetyl-3-ethoxycarbonyl-2-morpholinocarbonylamino-4,5,6,7-tetrahi Rochieno [2,3-c] pyridine-6-acetyl-3-ethoxycarbonyl-2-thiomorpholinocarbonyl-amino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine [0012]
6-cyclopropylcarbonyl-3-ethoxycarbonyl-2-morpholinocarbonylamino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine N- (methoxycarbonyl-phenyl) methyl-N ′-[6 -Acetyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N-cyclopropylmethyl-N-propyl-N '-[6-acetyl- 3-Ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N-3- (dimethylamino) propyl-N-methyl-N ′-[6-acetyl -3-Ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N-morpholino-N ′-[6-acetyl- 3-Ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N, N-diethyl-N ′-[6-cyclopropylcarbonyl-3-ethoxycarbonyl- 4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea N, N, N′-triethyl-N ′-[6-cyclopropylcarbonyl-3-ethoxycarbonyl-4, 5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea
It will be appreciated that the compounds of the present invention optionally form hydrates which are also encompassed by the present invention. Although the compound of this invention is manufactured by a conventional method, if the typical method is mentioned among these, it will be as follows.
(Production method)
[0014]
[Chemical 3]
(In the formula, R, R 1 , R 2 and R 3 have the above-mentioned meanings.) That is, phosgene in a solvent such as tetrahydrofuran, dimethoxyethane, diglyme, toluene and benzene is added to the compound represented by the formula (II). After the reaction, the corresponding amine compound is subjected to a condensation reaction to obtain a compound represented by the formula (I ′). This reaction can be easily and safely synthesized by using triphosgene (bistrichloromethyl carbonate) instead of phosgene. Further, after formulating the formula (I ′) with an appropriate base, the corresponding halogenated alkyl R 3 X is reacted to obtain the target formula (I).
[0016]
In each reaction step, for example, a solvent that does not participate in the reaction such as toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, dimethylformamide or the like may be used in a dry inert gas (nitrogen gas, argon gas, etc.) atmosphere.
The reaction temperature is usually in the range of room temperature to 200 ° C, preferably in the range of 25 ° C to 100 ° C. The reaction time is 30 minutes to 48 hours, usually 30 minutes to 2 hours.
[0017]
The reaction is a dehalogenation reaction in the presence of an inorganic salt such as sodium hydrogen carbonate, sodium carbonate or sodium hydroxide, an alkali metal hydride such as sodium hydride or potassium hydride, or an organic salt such as triethylamine, pyridine or piperazine. A favorable result is obtained by performing etc.
The compound of the formula (I) obtained by these methods is left free or a salt thereof by a known processing means (for example, extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatography, etc.). Can be isolated and purified as
[0018]
Since the compound according to the present invention has a TNF-α production inhibitory action, it is effective for allergic diseases, rheumatoid arthritis, ulcerative colitis and the like.
When the compound according to the present invention is used as an anti-rheumatic drug or anti-inflammatory drug, it can be administered by an appropriate administration method such as oral or parenteral. Examples of forms for oral administration include tablets, granules, capsules, pills, powders, and examples of forms for parenteral administration include injections, inhalants, suppositories, and liquids.
When these pharmaceutical administration compositions are formulated, they can be prepared according to a conventional method using the compound of the present invention or a salt thereof.
[0019]
For example, in the case of oral preparations, excipients such as lactose, glucose, corn starch, sucrose, disintegrants such as carboxymethylcellulose calcium and hydroxypropylcellulose, calcium stearate, magnesium stearate, talc, polyethylene glycol, hydrogenated oil, etc. Lubricants, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, binders such as polyvinyl alcohol, gelatin, gum arabic, etc., wetting agents such as glycerin and ethylene glycol, and other surfactants and corrigents as necessary And can be prepared into a desired dosage form. In the case of parenteral agents, using diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, tragarant gum, etc., if necessary, solubilizers, buffers, preservatives, fragrances, Coloring agents and the like can be used.
[0020]
When the compound of the present invention is formulated as an antiallergic agent, the dosage unit of the compound of the present invention is 1 to 300 mg per day for adults, preferably 1 to 100 mg per day for adults, preferably 0 to 100 mg for parenteral administration. .1 to 100 mg, preferably 0.5 to 30 mg, and the desired therapeutic effect can be expected by dividing each dose 1 to 3 times a day.
[0021]
【Example】
Next, synthesis examples, formulation examples, and test examples of the compounds according to the present invention are shown as examples. Although the typical Example of this invention is shown below, it cannot be overemphasized that this invention is not limited only to them. In addition, the manufacturing method of the starting material was shown as a manufacture example. In the text, 1 H-NMR data indicates a chemical shift value using TMS as an internal standard.
Production Example 1
Preparation of 6-acetyl-2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 4.0 g of 1-acetyl-4-piperidone, 1.4 g of sulfur, cyano 6.5 g of ethyl acetate was dissolved in 40 ml of N, N-dimethylformamide, and 5.0 ml of triethylamine was added at 60 ° C. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent; chloroform: methanol = 70: 1) to obtain 4.8 g of the desired substance.
[0022]
Production Example 2
Preparation of 2-amino-3-ethoxycarbonyl-6-ethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine 4.0 g of 1-ethyl-4-piperidone, 1.4 g of sulfur, cyano 6.5 g of ethyl acetate was dissolved in 40 ml of N, N-dimethylformamide, and 5.0 ml of triethylamine was added at 60 ° C. After completion of the reaction, water and ethyl acetate were added for extraction. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent; chloroform: methanol = 70: 1) to obtain 4.8 g of the desired substance.
[0023]
Example 1
Synthesis of N, N-diethyl-N ′-[6-acetyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridin-2-yl] urea 6-acetyl-2 -Amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine (12.4 g) and triphosgene (13.7 g) in methylene chloride (200 ml) were added, and the mixture was cooled with ice in an argon stream. Then 1.27 ml of triethylamine was added. After stirring at room temperature for 2.5 hours, 0.64 ml of triethylamine was further added and allowed to react for 17 hours. Diethylamine 38.1ml was dripped at this over 30 minutes. The mixture was further stirred for 50 minutes, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1) to obtain 12.2 g of the target compound.
[0024]
The structures of compounds that can be produced by the same method as in Example 1 and 1 H-NMR data are shown in Tables 1-1 to 1-7 below.
[0025]
[Formula 4]
[Table 1]
[Table 2]
[Table 3]
[Table 4]
[Table 5]
[Table 6]
[Table 7]
Formulation Example 1 (Preparation of tablets)
Compound of the present invention (Example 1) 250 g
Lactose 620g
Cornstarch 400g
Hydroxypropylcellulose 20g
Magnesium stearate 10g
The above compound of the present invention, lactose and corn starch are mixed until uniform, and then a 5 W / V% ethanol solution of hydroxypropyl cellulose is added and kneaded and granulated. After sizing through a 16-mesh sieve, the tablets were tableted by a conventional method to obtain tablets each having a weight of 130 mg, a diameter of 7 mm, and an active ingredient content of 25 mg.
[0034]
Test Example 1 (TNF-α production inhibitory action test)
Rats were bled into test tubes treated with heparin under pentobarbital anesthesia. Add an equal amount of RPMI-1640 to the collected blood, dispense into a 24-well plate, add solvent (DMSO), or a test drug dissolved in the solvent, and pre-incubate at 37 ° C, 5% CO 2 for 30 minutes. went. The reaction was started by adding LPS (lipopolysaccharide), incubated for 4 hours at 37 ° C., 5% CO 2 , and stopped in an ice bath. After stopping the reaction, the mixture was centrifuged at 3000 rpm, 4 ° C. for 15 minutes, and TNF-α in the supernatant was measured by ELISA.
The activity of the test drug was evaluated by determining the production inhibition rate relative to the solvent control group and determining the test drug concentration at which TNF-α production was inhibited by 50%. The test results are shown in Table 2.
[0035]
[Table 8]
Test Example 2 (Repeated dose toxicity)
The compound of the present invention (Example 1) was orally administered to mice (8 animals) at 100 mg / kg for 14 days, but no deaths or gross abnormalities were observed.
[0037]
【The invention's effect】
The compound of the present invention has an excellent TNF-α production inhibitory action. Therefore, inhibiting the production of TNF-α has shown a very effective action on many diseases, especially inflammatory diseases such as autoimmune diseases such as rheumatoid arthritis, allergic diseases, acute and chronic lung disorders, etc. Not useful as a new type of prophylactic or therapeutic agent.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34437399A JP4548884B2 (en) | 1999-12-03 | 1999-12-03 | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34437399A JP4548884B2 (en) | 1999-12-03 | 1999-12-03 | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001158789A JP2001158789A (en) | 2001-06-12 |
| JP4548884B2 true JP4548884B2 (en) | 2010-09-22 |
Family
ID=18368746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34437399A Expired - Fee Related JP4548884B2 (en) | 1999-12-03 | 1999-12-03 | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4548884B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1602655A4 (en) | 2003-03-07 | 2010-06-09 | Kowa Co | Benzofuran derivative |
| WO2004089296A2 (en) | 2003-04-03 | 2004-10-21 | The Regents Of The University Of California | Improved inhibitors for the soluble epoxide hydrolase |
| WO2005089380A2 (en) | 2004-03-16 | 2005-09-29 | The Regents Of The University Of California | Reducing nephropathy with inhibitors of soluble epoxide hydrolase and epoxyeicosanoids |
| CA2584342C (en) | 2004-10-20 | 2013-04-30 | The Regents Of The University Of California | Improved inhibitors for the soluble epoxide hydrolase |
| WO2006044826A2 (en) * | 2004-10-20 | 2006-04-27 | Compass Pharmaceuticals Llc | Thiophens and their use as anti-tumor agents |
| AR059826A1 (en) * | 2006-03-13 | 2008-04-30 | Univ California | UREA INHIBITORS CONFORMATIONALLY RESTRICTED OF SOLUBLE HYDROLASSE EPOXIDE |
| EP2528604B1 (en) | 2010-01-29 | 2017-11-22 | The Regents of the University of California | Acyl piperidine inhibitors of soluble epoxide hydrolase |
| CN101863902B (en) * | 2010-06-29 | 2012-06-27 | 天津药物研究院 | Preparation method and application of 2-substituted phenyl-2-(4,5,6,7-thiophane [3,2-c] pyridine-5(4H)-group) acetic acid (substituted alkyl alcohol) ester |
| CN113135891B (en) * | 2021-04-15 | 2022-05-10 | 南方医科大学 | N-aryl-N' - (2-thienyl) thiourea (urea) derivative and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001151780A (en) * | 1999-11-30 | 2001-06-05 | Nikken Chem Co Ltd | 4,5,6,7-TETRAHYDROTHIENO[2,3-c]PYRIDINE COMPOUND |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4107521A1 (en) * | 1991-03-08 | 1992-09-10 | Boehringer Ingelheim Kg | NEW ACYLAMINOSUBSTITUTED HETRAZEPINE |
| JPH1036374A (en) * | 1996-04-25 | 1998-02-10 | Takeda Chem Ind Ltd | Thienopyridine derivative and medicine containing the same |
| JPH11147876A (en) * | 1997-09-12 | 1999-06-02 | Kanebo Ltd | Tetrahydroisoquinoline derivative and medicine containing the same as active ingredient |
| US5939432A (en) * | 1997-10-29 | 1999-08-17 | Medco Research, Inc. | Thiophenes useful for modulating the adenosine receptor |
-
1999
- 1999-12-03 JP JP34437399A patent/JP4548884B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001151780A (en) * | 1999-11-30 | 2001-06-05 | Nikken Chem Co Ltd | 4,5,6,7-TETRAHYDROTHIENO[2,3-c]PYRIDINE COMPOUND |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001158789A (en) | 2001-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3702351B1 (en) | Formulation comprising a mek inhibitor | |
| EP1167355B1 (en) | A crystalline form of celecoxib | |
| JPH054983A (en) | Isoquinolinone derivative, its production and 5-ht3 receptor antagonist containing the derivative as active component | |
| CA2164119A1 (en) | 1-substituted isatin and oxindole derivatives as inhibitors of acetylcholinesterase | |
| KR20080003599A (en) | Gentisate of pyrrolopyrimidinone derivative and process for preparing it | |
| JP4548884B2 (en) | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine derivative | |
| CN102471273B (en) | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof | |
| JP2707936B2 (en) | β-oxo-β-benzenepropanethioamide derivative | |
| JP4548882B2 (en) | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine compound | |
| LU86421A1 (en) | 1,4-DISUBSTITUTED PIPERAZINE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THEM, AND PROCESS FOR OBTAINING THE SAME | |
| WO1998025900A1 (en) | Compounds having antitumor activity | |
| JPH03204893A (en) | 6-o-methylerythromycin a oxime derivative | |
| HUT70174A (en) | New 3-phenyl-sulphonyl-3,7-diazabicyclo [3.3.1] nonane compounds and pharmaceutical compounds containing the same | |
| JP2726999B2 (en) | Imidazo [2,1-b] benzothiazole derivatives and anti-ulcer agents containing the compounds as active ingredients | |
| CA2204007A1 (en) | Remedy for diseases caused by infection with helicobacter | |
| JP4502435B2 (en) | 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-based compound | |
| WO1992019638A1 (en) | 1-β-D-ARABINOFURANOSYL-(E)-5-(2-HALOGENOVINYL)-URACIL DERIVATIVE | |
| JPS6056996A (en) | 2'-deoxy-5-trifluoromethyluridine derivative, its preparation, and antitumor agent containing it | |
| JPS63222170A (en) | Ergolinylheterocycles | |
| US6291482B1 (en) | N-hydroxyurea derivative and pharmaceutical composition containing the same | |
| JP2004502780A (en) | Adenosine compound and pharmaceutical composition containing the same | |
| JP3142993B2 (en) | Water-soluble benstatin derivatives and their pharmaceutical uses | |
| JP4155150B2 (en) | New anti-tumor indolopyrrolocarbazole derivatives | |
| JPH02134382A (en) | Bisbenzylisoquinoline derivative | |
| JP2002030073A (en) | 4-(3-(4-morphol inobutylam ino)phenyl)-2h-phthalazin-1-one methane sulfonate monohydrate and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20061030 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20070620 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20070620 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A132 Effective date: 20100323 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100608 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100706 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130716 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |