JPH06327488A - Production of optically active 7-amidinonaphthalene derivative - Google Patents
Production of optically active 7-amidinonaphthalene derivativeInfo
- Publication number
- JPH06327488A JPH06327488A JP11862293A JP11862293A JPH06327488A JP H06327488 A JPH06327488 A JP H06327488A JP 11862293 A JP11862293 A JP 11862293A JP 11862293 A JP11862293 A JP 11862293A JP H06327488 A JPH06327488 A JP H06327488A
- Authority
- JP
- Japan
- Prior art keywords
- oxy
- naphthyl
- amidino
- phenyl
- pyrrolidinyl
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、血液凝固抑制剤又は血
栓若しくは塞栓の予防・治療剤として有用な、光学活性
２−〔４−〔〔（３Ｓ）−１−アセトイミドイル−３−
ピロリジニル〕オキシ〕フェニル〕−３−〔７−アミジ
ノ−２−ナフチル〕プロピオン酸又はその塩の製造法に
関する。The present invention relates to an optically active 2- [4-[[(3S) -1-acetimidoyl-3-, which is useful as a blood coagulation inhibitor or a prophylactic / therapeutic agent for thrombus or embolus.
It relates to a method for producing pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof.
【０００２】[0002]
【従来の技術及び発明が解決しようとする課題】従来、
血栓形成抑制剤として抗トロンビン剤の開発が行われて
きたが、この抗トロンビン剤は抗凝固作用とともにトロ
ンビンによる血小板の凝集作用も併せて抑制することか
ら出血傾向をきたす危険のあることが知られており、凝
固能のコントロールを容易に行えるものではなかった。
そこで、トロンビン阻害作用以外の作用機序に基づく抗
凝固剤の開発が行われ、本出願人は活性化血液凝固第Ｘ
因子（以下ＦＸａと略す）を可逆的に阻害して強力な抗
凝固作用を示す芳香族アミジン誘導体又はその塩が、良
好な水溶性を有し、経口投与においても強くＦＸａを特
異的かつ可逆的に阻害し強力な抗凝固作用を示し、血栓
・塞栓に基づく種々の疾病の予防並びに治療薬として有
用であることを見出し、先に特許出願した（特願平４−
２９２８９２号）。2. Description of the Related Art Conventionally, the problems to be solved by the invention
Although an antithrombin agent has been developed as a thrombus formation inhibitor, it is known that this antithrombin agent has a risk of causing a bleeding tendency because it suppresses the platelet aggregation effect by thrombin together with the anticoagulant effect. Therefore, it was not possible to easily control the coagulation ability.
Therefore, the development of an anticoagulant based on a mechanism of action other than the thrombin inhibitory effect has been carried out, and the present applicant has proposed that activated blood coagulation No. X
An aromatic amidine derivative or a salt thereof that exhibits a strong anticoagulant effect by reversibly inhibiting a factor (hereinafter abbreviated as FXa) has good water solubility, and is strong and specific for FXa even in oral administration. It was found to be useful as a prophylactic and therapeutic drug for various diseases caused by thrombosis and embolism, and it applied for a patent (Patent Application No. 4-
292892).
【０００３】これらの芳香族アミジン誘導体又はその塩
のうち、光学活性２−〔４−〔〔（３Ｓ）−１−アセト
イミドイル−３−ピロリジニル〕オキシ〕フェニル〕−
３−〔７−アミジノ−２−ナフチル〕プロピオン酸又は
その塩は、エチル（２ＲＳ）−２−〔４−〔〔（３Ｓ）
−１−アセトイミドイル−３−ピロリジニル〕オキシ〕
フェニル〕−３−〔７−アミジノ−２−ナフチル〕プロ
ピオネート又はその塩の前駆体であるエチル（２ＲＳ）
−２−〔４−〔〔（３Ｓ）−１−ｔｅｒｔ−ブトキシカ
ルボニル−３−ピロリジニル〕オキシ〕フェニル〕−３
−〔７−シアノ−２−ナフチル〕〕プロピオネートより
分別結晶化により分割し、それらをエチル２−〔４−
〔〔（３Ｓ）−１−アセトイミドイル−３−ピロリジニ
ル〕オキシ〕フェニル〕−３−〔７−アミジノ−２−ナ
フチル〕プロピオネート又はその塩に誘導した後、塩酸
によるエステル加水分解を行うことにより製造される。Of these aromatic amidine derivatives or salts thereof, optically active 2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]-
3- [7-amidino-2-naphthyl] propionic acid or its salt is ethyl (2RS) -2- [4-[[(3S)
-1-acetamidoyl-3-pyrrolidinyl] oxy]
Ethyl (2RS) which is a precursor of phenyl] -3- [7-amidino-2-naphthyl] propionate or a salt thereof.
-2- [4-[[((3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] -3
-[7-Cyano-2-naphthyl]] propionate was resolved by fractional crystallization and these were separated from ethyl 2- [4-
By derivatizing [[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionate or a salt thereof, ester hydrolysis with hydrochloric acid is performed. Manufactured.
【０００４】しかしながら、これらの方法では、分別結
晶化の操作が繁雑であり、工業的に有利に目的化合物を
得ることができないという問題があった。従って、光学
活性２−〔４−〔〔（３Ｓ）−１−アセトイミドイル−
３−ピロリジニル〕オキシ〕フェニル〕−３−〔７−ア
ミジノ−２−ナフチル〕プロピオン酸又はその塩を穏和
な条件下で簡便に得る方法が望まれていた。However, these methods have a problem that the operation of fractional crystallization is complicated and the target compound cannot be obtained industrially advantageously. Therefore, optically active 2- [4-[[(3S) -1-acetimidoyl-
A method for easily obtaining 3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof under mild conditions has been desired.
【０００５】[0005]
【課題を解決するための手段】かかる実情において、本
発明者らは鋭意研究を行った結果、アルキル−２−〔４
−〔〔（３Ｓ）−１−アセトイミドイル−３−ピロリジ
ニル〕オキシ〕フェニル〕−３−〔７−アミジノ−２−
ナフチル〕プロピオネート又はその塩を、微生物、その
培養液及びこれらの分画物からなる群から選ばれる１種
又は２種以上で処理してエステル加水分解すれば、光学
活性２−〔４−〔〔（３Ｓ）−１−アセトイミドイル−
３−ピロリジニル〕オキシ〕フェニル〕−３−〔７−ア
ミジノ−２−ナフチル〕プロピオン酸又はその塩が穏和
な条件下で簡便に得られることを見出し、本発明を完成
した。Under these circumstances, the inventors of the present invention have earnestly studied and found that alkyl-2- [4
-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-
Naphthyl] propionate or a salt thereof is treated with one or more selected from the group consisting of a microorganism, a culture solution thereof and a fraction thereof, and ester hydrolyzed to give an optically active 2- [4-[[[ (3S) -1-acetimidoyl-
The present invention was completed by finding that 3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof can be easily obtained under mild conditions.
【０００６】すなわち、本発明は、一般式（２）That is, the present invention is based on the general formula (2)
【０００７】[0007]
【化７】 [Chemical 7]
【０００８】（式中、Ｒは炭素数１〜６の低級アルキル
基を示す）で表わされるアルキル−２−〔４−〔〔（３
Ｓ）−１−アセトイミドイル−３−ピロリジニル〕オキ
シ〕フェニル〕−３−〔７−アミジノ−２−ナフチル〕
プロピオネート又はその塩を、微生物、その培養液及び
これらの分画物からなる群から選ばれる１種又は２種以
上で処理することを特徴とする一般式（１）(Wherein R represents a lower alkyl group having 1 to 6 carbon atoms) alkyl-2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl]
General formula (1) characterized in that propionate or a salt thereof is treated with one or more selected from the group consisting of microorganisms, culture solutions thereof and fractions thereof.
【０００９】[0009]
【化８】 [Chemical 8]
【００１０】で表わされる光学活性２−〔４−〔〔（３
Ｓ）−１−アセトイミドイル−３−ピロリジニル〕オキ
シ〕フェニル〕−３−〔７−アミジノ−２−ナフチル〕
プロピオン酸又はその塩の製造法を提供するものであ
る。Optical activity represented by 2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl]
The present invention provides a method for producing propionic acid or a salt thereof.
【００１１】本発明において、原料化合物として用いら
れるアルキル−２−〔４−〔〔（３Ｓ）−１−アセトイ
ミドイル−３−ピロリジニル〕オキシ〕フェニル〕−３
−〔７−アミジノ−２−ナフチル〕プロピオネート又は
その塩は、前記一般式（２）で表わされるものであり、
例えば特願平４−２９２８９２号公報に記載の方法によ
り製造することができる。一般式（２）中、Ｒで示され
る炭素数１〜６のアルキル基としては、例えばメチル
基、エチル基、プロピル基、イソプロピル基、ブチル
基、ペンチル基、ヘキシル基等が挙げられ、特にエチル
基が好ましい。In the present invention, alkyl-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3 used as a starting material compound
-[7-amidino-2-naphthyl] propionate or a salt thereof is represented by the general formula (2),
For example, it can be manufactured by the method described in Japanese Patent Application No. 4-292892. In the general formula (2), examples of the alkyl group having 1 to 6 carbon atoms represented by R include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, and the like. Groups are preferred.
【００１２】これらの原料化合物は、０．１〜１０重量
％、特に０．１〜１．０％の濃度のものを用いるのが好
ましい。These starting compounds are preferably used in a concentration of 0.1 to 10% by weight, particularly 0.1 to 1.0%.
【００１３】また、本発明で用いられる微生物、その培
養液及びこれらの分画物としては、酵母のデバイロマイ
セス属、並びに細菌のブレビバクテリウム属、シトファ
ーガ属、スフィンゴバクテリウム属、並びに糸状菌アス
ペルギルス属、シラシネラ属、クアバラリア属、モルチ
エレラ属に属する微生物、その培養液及びこれらの分画
物等が使用される。これらの微生物のうち、デバイロマ
イセス属の好ましい種としてはデバイロマイセス スピ
ーシーズ；ブレビバクテリウム属の好ましい種としては
ブレビバクテリウム リネンス；シトファーガ属の好ま
しい種としてはシトファーガ アーベンシコラ；スフィ
ンゴバクテリウム属の好ましい種としてはスフィンゴバ
クテリウム スピリチボルム；アスペルギルス属の好ま
しい種としてはアスペルギルス フミゲタス、アスペル
ギルス ユニラテラリス、アスペルギルス ニギア、ア
スペルギルス ウサミ；シラシネラ属の好ましい種とし
てはシラシネラ ムコロイデス；クアバラリア属の好ま
しい種としてはクアバラリア トリフォリ；モルチネラ
属の好ましい種としてはモルチネラ イサベリナを挙げ
ることができる。The microorganisms used in the present invention, their culture solutions and fractions thereof include yeasts of the genus Debyromyces, and the bacteria of genus Brevibacterium, genus Sitophaga, sphingobacterium, and filamentous fungus Aspergillus. , Microorganisms belonging to the genus Silacinera, the genus Cuavararia, the genus Mortierella, culture solutions thereof, fractions thereof, and the like are used. Among these microorganisms, Debyromyces species are preferred as Debyromyces spp .; Brevibacterium linens is preferred as Brevibacterium spp. Aspergillus humigetus, Aspergillus unilateraris, Aspergillus nigia, Aspergillus usami; Preferable species of Syracinella spp. Mention may be made of Morcinera Isabella.
【００１４】微生物の培養液としては、当該微生物を適
当な培地で培養したものを挙げることができる。また、
分画物としては微生物の菌体又は培養液を水又は適当な
緩衝液で抽出したもの；液体培地で培養を行った場合に
は、培養物の濾液、該当抽出液又は濾液に硫安又はアル
コールを加えることにより得られる沈澱物；該当抽出液
又は濾液をゲル濾過、限外濾過、イオン交換クロマトグ
ラフィー等を用いて分画したもの；菌体の破砕物；及び
該当破砕物を上記の分画方法を用いて分画したもの等を
挙げることができる。培地には、使用微生物が資化しう
る炭素源、窒素源、無機塩類及び微量の栄養分が含まれ
る。すなわち、炭素源としては、グルコース、マルトー
ス、デキストロース等の炭水化物；窒素源としては、酵
母エキス、コーンスティープリカー、ペプトン、肉エキ
ス、混合アミノ酸パウダーなどの天然有機窒素源；無機
塩としてはマグネシウム、鉄、銅、マンガン、カリウ
ム、ナトリウムなどの塩が適宜用いられる。更に、必要
に応じて微生物の生育に必要な各種有機物、無機物、あ
るいは通常用いられている消泡剤などを添加することが
できる。Examples of the culture solution of the microorganism include those obtained by culturing the microorganism in an appropriate medium. Also,
As the fractionated product, microbial cells or a culture solution of a microorganism are extracted with water or an appropriate buffer solution; when the culture is carried out in a liquid medium, the culture filtrate, ammonium sulfate or alcohol is added to the extract or the filtrate. Precipitate obtained by adding; the extract or filtrate concerned was fractionated by using gel filtration, ultrafiltration, ion exchange chromatography, etc .; crushed cells; and the crushed product as described above And the like. The medium contains a carbon source, a nitrogen source, inorganic salts and trace amounts of nutrients that can be assimilated by the microorganism used. That is, carbon sources include carbohydrates such as glucose, maltose, and dextrose; nitrogen sources include natural organic nitrogen sources such as yeast extract, corn steep liquor, peptone, meat extract, and mixed amino acid powder; inorganic salts include magnesium and iron. Salts of copper, manganese, potassium, sodium and the like are appropriately used. Further, if necessary, various organic substances, inorganic substances, or commonly used defoaming agents necessary for the growth of microorganisms can be added.
【００１５】これらの微生物の菌体、培養液、分画物の
使用量は特に制限されないが、原料化合物に対して１〜
３０重量倍であるのが好ましい。The amounts of these microorganisms, cultures, and fractions used are not particularly limited, but may be 1 to the starting compound.
It is preferably 30 times by weight.
【００１６】なお、微生物として糸状菌を用いた場合に
は、原料のラセミ体のうち（＋）−体が選択的に加水分
解され、（＋）−２−〔４−〔〔（３Ｓ）−１−アセト
イミドイル−３−ピロリジニル〕オキシ〕フェニル〕−
３−〔７−アミジノ−２−ナフチル〕プロピオン酸が有
利に得られる。一方、微生物として酵母又は細菌を用い
た場合には（−）−体が選択的に加水分解され、（−）
−２−〔４−〔〔（３Ｓ）−１−アセトイミドイル−３
−ピロリジニル〕オキシ〕フェニル〕−３−〔７−アミ
ジノ−２−ナフチル〕プロピオン酸が有利に得られる。
従って、微生物を選択することにより、（＋）−体又は
（−）−体を作り分けることが可能である。When a filamentous fungus is used as the microorganism, the (+)-form of the racemic raw material is selectively hydrolyzed to give (+)-2- [4-[[(3S)- 1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]-
3- [7-Amidino-2-naphthyl] propionic acid is advantageously obtained. On the other hand, when yeast or bacteria is used as the microorganism, the (-)-form is selectively hydrolyzed,
-2- [4-[[(3S) -1-acetimidoyl-3
Pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid is advantageously obtained.
Therefore, the (+)-form or the (-)-form can be produced separately by selecting the microorganism.
【００１７】反応は、原料化合物溶液と微生物の菌体等
を、１０〜５０℃、好ましくは２０〜４０℃において、
pH４〜８、好ましくは５〜７の範囲で３〜４８時間、好
ましくは７２時間程度攪拌することにより行われる。反
応終了後、反応液を濾過、減圧濃縮、限外濾過、カラム
クロマトグラフィー等の公知の手段を行うことにより、
高純度の目的化合物を単離することができる。The reaction is carried out at 10 to 50 ° C., preferably 20 to 40 ° C., by mixing the raw material compound solution with the microbial cells.
It is carried out by stirring at pH 4 to 8, preferably 5 to 7, for 3 to 48 hours, preferably for about 72 hours. After completion of the reaction, the reaction solution is subjected to known means such as filtration, concentration under reduced pressure, ultrafiltration, column chromatography, etc.
A highly pure target compound can be isolated.
【００１８】このようにして得られる目的化合物は、更
に、通常の方法により医薬的に許容し得る塩にすること
ができる。かかる塩としては、例えば塩酸塩、臭化水素
酸塩、ヨウ化水素酸塩、燐酸塩、硝酸塩、硫酸塩等の鉱
酸塩類；メタンスルホン酸塩、２−ヒドロキシエタンス
ルホン酸塩、ｐ−トルエンスルホン酸塩等の有機スルホ
ン酸塩類；並びに酢酸塩、プロピオン酸塩、シュウ酸
塩、マロン酸塩、コハク酸塩、グルタル酸塩、アジピン
酸塩、酒石酸塩、マレイン酸塩、リンゴ酸塩、マンデル
酸塩等の有機カルボン酸塩類が挙げられる。The target compound thus obtained can be further converted into a pharmaceutically acceptable salt by a conventional method. Examples of such a salt include mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate; methanesulfonate, 2-hydroxyethanesulfonate, p-toluene. Organic sulfonates such as sulfonates; as well as acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate, mandel Organic carboxylic acid salts such as acid salts may be mentioned.
【００１９】[0019]
【発明の効果】本発明によれば、血液凝固抑制剤又は血
栓若しくは塞栓の予防・治療剤として有用な、光学活性
２−〔４−〔〔（３Ｓ）−１−アセトイミドイル−３−
ピロリジニル〕オキシ〕フェニル〕−３−〔７−アミジ
ノ−２−ナフチル〕プロピオン酸又はその塩を穏和な条
件下において簡便な方法で、容易に高純度で得ることが
でき、工業的にも有利である。INDUSTRIAL APPLICABILITY According to the present invention, an optically active 2- [4-[[(3S) -1-acetimidoyl-3-, which is useful as a blood coagulation inhibitor or a prophylactic / therapeutic agent for thrombus or embolus.
Pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof can be easily obtained in high purity by a simple method under mild conditions, and is industrially advantageous. is there.
【００２０】[0020]
【実施例】次に、実施例を挙げて本発明を更に説明する
が、本発明はこれら実施例に限定されるものではない。EXAMPLES Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.
【００２１】参考例１ グルコースペプトン液体培地８５０mlに、糸状菌（アス
ペルギルス フミゲタス ＩＦＯ−８８６６；財団法人
発酵研究所から購入）を接種し、３０℃で３日間振盪培
養した。この培養物の糸状菌体と、培養液を反応に用い
た。Reference Example 1 850 ml of glucose peptone liquid medium was inoculated with a filamentous fungus (Aspergillus fumigatus IFO-8866; purchased from Fermentation Research Institute) and shake-cultured at 30 ° C. for 3 days. The filamentous fungus body of this culture and the culture solution were used for the reaction.
【００２２】実施例１ （＋）−２−〔４−〔〔（３Ｓ）−１−アセトイミドイ
ル−３−ピロリジニル〕オキシ〕フェニル〕−３−〔７
−アミジノ−２−ナフチル〕プロピオン酸塩酸塩の製
造：エチル（２ＲＳ）−２−〔４−〔〔（３Ｓ）−１−
アセトイミドイル−３−ピロリジニル〕オキシ〕フェニ
ル〕−３−〔７−アミジノ−２−ナフチル〕プロピオネ
ート塩酸塩のラセミ体８５０mgを、参考例１の培養物に
溶解し、３０℃で７２時間振盪培養した。反応終了後、
反応液を高速液体クロマトグラフィーで分析したとこ
ろ、（＋）−２−〔４−〔〔（３Ｓ）−１−アセトイミ
ドイル−３−ピロリジニル〕オキシ〕フェニル〕−３−
〔７−アミジノ−２−ナフチル〕プロピオン酸の生成率
は４９％であった。得られた反応液を、濾過し、濾液を
減圧下濃縮し、吸着樹脂により精製し、目的化合物を含
む分画を減圧下濃縮した。得られた残渣に１Ｎ−ＨＣｌ
５０mlを加え、塩酸塩化した後、吸着樹脂により脱塩
し、減圧下濃縮し、含水エタノールより結晶化し、目的
の化合物（＋）−２−〔４−〔〔（３Ｓ）−１−アセト
イミドイル−３−ピロリジニル〕オキシ〕フェニル〕−
３−〔７−アミジノ−２−ナフチル〕プロピオン酸塩酸
塩を５１９mg得た。得られた目的化合物の機器分析デー
タは、以下のとおりであった。また、このものを光学異
性体分離クロマトグラフィーにより分析したところ、化
合物の光学純度は９９％e.e.であった。Example 1 (+)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7
-Preparation of amidino-2-naphthyl] propionate hydrochloride: ethyl (2RS) -2- [4-[[(3S) -1-
Acetoimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionate hydrochloride (850 mg) was dissolved in the culture of Reference Example 1 and shake-cultured at 30 ° C for 72 hours. did. After the reaction,
When the reaction solution was analyzed by high performance liquid chromatography, it was found that (+)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3-
The production rate of [7-amidino-2-naphthyl] propionic acid was 49%. The obtained reaction solution was filtered, the filtrate was concentrated under reduced pressure, purified by an adsorption resin, and the fraction containing the target compound was concentrated under reduced pressure. 1N-HCl was added to the obtained residue.
After adding 50 ml and hydrochloric acid salification, desalting with an adsorption resin, concentration under reduced pressure, crystallization from water-containing ethanol, and the desired compound (+)-2- [4-[[(3S) -1-acetimidoyl] -3-Pyrrolidinyl] oxy] phenyl]-
519 mg of 3- [7-amidino-2-naphthyl] propionate hydrochloride was obtained. The instrumental analysis data of the obtained target compound were as follows. When this product was analyzed by optical isomer separation chromatography, the optical purity of the compound was 99% ee.
【００２３】〔α〕D 24＝＋５７．４°（ｃ＝１．００
０，Ｈ2Ｏ）（４０℃で溶解、同温３０分加温の後測
定）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ：２．２０−２．３５
（２Ｈ，ｍ），２．２９（１．５Ｈ，ｓ），２．３２
（１．５Ｈ，ｓ），２．８０−２．９５（１Ｈ，ｍ），
３．３０−４．００（６Ｈ，ｍ），５．１６（０．５
Ｈ，ｂｒ），５．２２（０．５Ｈ，ｂｒ），６．９０−
７．００（２Ｈ，ｍ），７．４５−７．５１（２Ｈ，
ｍ），７．５７（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．６
６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９３（１Ｈ，
ｄ，Ｊ＝８．３Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝８．
３Ｈｚ），８．１１（１Ｈ，ｓ），８．６８（１Ｈ，ｂ
ｒ），８．７０−９．３０（ｂｒ），１１．５０−１
２．２０（ｂｒ） Ｘ線分析より本化合物は（＋）−２−〔４−〔（３Ｓ）
−１−アセトイミドイル−３−ピロリジニル〕オキシ〕
フェニル〕−３−〔７−アミジノ−２−ナフチル〕プロ
ピオン酸であると判断された。[Α] D 24 = + 57.4 ° (c = 1.00
0, H 2 O) (dissolved at 40 ° C., measured after heating at the same temperature for 30 minutes) 1 H-NMR (DMSO-d 6 ) δ: 2.20-2.35
(2H, m), 2.29 (1.5H, s), 2.32
(1.5H, s), 2.80-2.95 (1H, m),
3.30-4.00 (6H, m), 5.16 (0.5
H, br), 5.22 (0.5H, br), 6.90-
7.00 (2H, m), 7.45-7.51 (2H,
m), 7.57 (1H, d, J = 8.3 Hz), 7.6
6 (1H, d, J = 8.3 Hz), 7.93 (1H,
d, J = 8.3 Hz), 7.97 (1H, d, J = 8.
3Hz), 8.11 (1H, s), 8.68 (1H, b
r), 8.70-9.30 (br), 11.50-1
2.20 (br) X-ray analysis showed that this compound was (+)-2- [4-[(3S)
-1-acetamidoyl-3-pyrrolidinyl] oxy]
It was determined to be phenyl] -3- [7-amidino-2-naphthyl] propionic acid.
【００２４】実施例２ （＋）−２−〔４−〔〔（３Ｓ）−１−アセトイミドイ
ル−３−ピロリジニル〕オキシ〕フェニル〕−３−〔７
−アミジノ−２−ナフチル〕プロピオン酸塩酸塩の製
造：表１に示す糸状菌とその培養液を参考例１と同様の
操作により得、実施例１と同様にして反応を行った。反
応終了液を高速液体クロマトグラフィーにて分析した結
果を表１に示す。Example 2 (+)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7
-Amidino-2-naphthyl] propionate hydrochloride production: The filamentous fungi shown in Table 1 and the culture solution thereof were obtained by the same operation as in Reference Example 1 and reacted in the same manner as in Example 1. Table 1 shows the results of analysis of the reaction completed liquid by high performance liquid chromatography.
【００２５】[0025]
【表１】 [Table 1]
【００２６】参考例２ グルコースペプトン液体培地８５０mlに、酵母（デバイ
ロマイセス スピーシーズ ＨＵＴ−７０６０；広島大
学工学部発酵工学教室から購入）を接種し、３０℃で３
日間振盪培養した。この培養物の酵母と培養液を反応に
用いた。Reference Example 2 850 ml of glucose peptone liquid medium was inoculated with yeast (Debyromyces species HUT-7060; purchased from Department of Fermentation Engineering, Faculty of Engineering, Hiroshima University) and incubated at 30 ° C. for 3 days.
Culture was carried out with shaking for one day. The yeast of this culture and the culture solution were used for the reaction.
【００２７】実施例３ （−）−２−〔４−〔〔（３Ｓ）−１−アセトイミドイ
ル−３−ピロリジニル〕オキシ〕フェニル〕−３−〔７
−アミジノ−２−ナフチル〕プロピオン酸塩酸塩の製
造：参考例２で得られた培養物に、実施例１と同様の操
作によりエチル（２ＲＳ）−２−〔４−〔〔（３Ｓ）−
１−アセトイミドイル−３−ピロリジニル〕オキシ〕フ
ェニル〕−３−〔７−アミジノ−２−ナフチル〕プロピ
オネート塩酸塩８５０mgを反応させた。反応終了液を高
速液体クロマトグラフィーにて分析したところ、水解体
の生成率は４６．６％であった。反応終了液を実施例１
と同様に精製し、（−）−２−〔４−〔〔（３Ｓ）−１
−アセトイミドイル−３−ピロリジニル〕オキシ〕フェ
ニル〕−３−〔７−アミジノ−２−ナフチル〕プロピオ
ン酸塩酸塩を４９４mg得た。得られた目的化合物の機器
分析データは、以下のとおりであった。また、このもの
を光学異性体分離クロマトグラフィーにより分析したと
ころ、化合物の光学純度は９８％e.e.であった。Example 3 (-)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7
-Production of amidino-2-naphthyl] propionate hydrochloride: Ethyl (2RS) -2- [4-[[(3S)-was added to the culture obtained in Reference Example 2 by the same procedure as in Example 1.
850 mg of 1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionate hydrochloride were reacted. When the reaction-completed liquid was analyzed by high performance liquid chromatography, the production rate of hydrolyzed products was 46.6%. The reaction-terminated liquid was used in Example 1.
Purify in the same manner as in (-)-2- [4-[[(3S) -1
494 mg of -acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionate hydrochloride were obtained. The instrumental analysis data of the obtained target compound were as follows. When this product was analyzed by optical isomer separation chromatography, the optical purity of the compound was 98% ee.
【００２８】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6）δ：２．０
５−２．４（２Ｈ，ｍ），２．２８（１．５Ｈ，ｓ），
２．３１（１．５Ｈ，ｓ），３．１０−３．３０（１
Ｈ，ｍ），３．４０−４．１０（６Ｈ，ｍ），５．１３
（０．５Ｈ，ｂｒ），５．２０（０．５Ｈ，ｂｒ），
６．９０−７．００（２Ｈ，ｍ），７．３５−７．４０
（２Ｈ，ｍ），７．６０（１Ｈ，ｄ，Ｊ＝８．３Ｈ
ｚ），７．８１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８
４（１Ｈ，ｓ），７．９４（１Ｈ，ｄ，Ｊ＝８．３Ｈ
ｚ），８．０６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．４
２（１Ｈ，ｓ），８．５５（０．５Ｈ，ｂｒ），８．６
４（０．５Ｈ，ｂｒ），９．３０−９．７０（５Ｈ）Ｈ
ＰＬＣ カラム：Ｄ−ペニシラミンを光学活性部位とす
る配位子交換型カラム（ＳＵＭＩＣＨＩＲＡＬ ＯＡ−
５０００ ４．６φ×１５０mm 住化分析センター） 溶 媒：２mM 硫酸銅水溶液：アセトニトリル＝８５：
１５（ｖ／ｖ） 流 速：１ml／分 カラム温度：６０℃ 保持時間：３８．１４分 1 H-NMR (DMSO-d 6 ) δ: 2.0
5-2.4 (2H, m), 2.28 (1.5H, s),
2.31 (1.5H, s), 3.10-3.30 (1
H, m), 3.40-4.10 (6H, m), 5.13.
(0.5H, br), 5.20 (0.5H, br),
6.90-7.00 (2H, m), 7.35-7.40
(2H, m), 7.60 (1H, d, J = 8.3H
z), 7.81 (1H, d, J = 8.3 Hz), 7.8
4 (1H, s), 7.94 (1H, d, J = 8.3H
z), 8.06 (1H, d, J = 8.3 Hz), 8.4
2 (1H, s), 8.55 (0.5H, br), 8.6
4 (0.5H, br), 9.30-9.70 (5H) H
PLC column: Ligand exchange type column having D-penicillamine as an optically active site (SUMICHIRAL OA-
5000 4.6φ x 150 mm Sumika Chemical Analysis Service Center) Solvent: 2 mM Copper sulfate aqueous solution: Acetonitrile = 85:
15 (v / v) Flow rate: 1 ml / min Column temperature: 60 ° C Retention time: 38.14 min
【００２９】参考例３ 普通ブイヨン液体培地８５０mlに、細菌（ブレビバクテ
リウム リネンス ＪＣＭ−１３２７；理化学研究所か
ら購入）を接種し、３０℃で３日間振盪培養した。この
培養物の細菌菌体と培養液を反応に用いた。Reference Example 3 Bacteria (Brevibacterium linens JCM-1327; purchased from RIKEN) were inoculated into 850 ml of a normal broth liquid medium and cultured at 30 ° C. for 3 days with shaking. The bacterial cells of this culture and the culture solution were used for the reaction.
【００３０】実施例４ （−）−２−〔４−〔〔（３Ｓ）−１−アセトイミドイ
ル−３−ピロリジニル〕オキシ〕フェニル〕−３−〔７
−アミジノ−２−ナフチル〕プロピオン酸塩酸塩の製
造：参考例３で得られた培養物に、実施例１と同様の操
作によりエチル（２ＲＳ）−２−〔４−〔〔（３Ｓ）−
１−アセトイミドイル−３−ピロリジニル〕オキシ〕フ
ェニル〕−３−〔７−アミジノ−２−ナフチル〕プロピ
オネート塩酸塩８５０mgを反応させた。反応終了液を高
速液体クロマトグラフィーにて分析したところ、水解体
の生成率は４１．２％であった。反応終了液を実施例１
と同様に精製し、（−）−２−〔４−〔〔（３Ｓ）−１
−アセトイミドイル−３−ピロリジニル〕オキシ〕フェ
ニル〕−３−〔７−アミジノ−２−ナフチル〕プロピオ
ン酸塩酸塩を４３６mg得た。得られた目的化合物の機器
分析データは、実施例３のそれと完全に一致した。ま
た、実施例３と同様の分析条件により、このものを光学
異性体分離クロマトグラフィーにより分析したところ、
化合物の光学純度は９４％e.e.であった。Example 4 (-)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7
-Production of amidino-2-naphthyl] propionate hydrochloride: Ethyl (2RS) -2- [4-[[(3S)-was added to the culture obtained in Reference Example 3 by the same procedure as in Example 1.
850 mg of 1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionate hydrochloride were reacted. When the reaction completed liquid was analyzed by high performance liquid chromatography, the production rate of hydrolyzed product was 41.2%. The reaction-terminated liquid was used in Example 1.
Purify in the same manner as in (-)-2- [4-[[(3S) -1
436 mg of -acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propione hydrochloride was obtained. The instrumental analysis data of the obtained target compound completely agreed with those of Example 3. In addition, when this product was analyzed by optical isomer separation chromatography under the same analysis conditions as in Example 3,
The optical purity of the compound was 94% ee.
【００３１】実施例５ （−）−２−〔４−〔〔（３Ｓ）−１−アセトイミドイ
ル−３−ピロリジニル〕オキシ〕フェニル〕−３−〔７
−アミジノ−２−ナフチル〕プロピオン酸塩酸塩の製
造：表２に示す細菌菌体と培養液を参考例３と同様の操
作により得、実施例３と同様にして反応を行った。反応
終了液を高速液体クロマトグラフィーにて分析した結果
を表２に示す。Example 5 (-)-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7
-Amidino-2-naphthyl] propionate hydrochloride production: The bacterial cells and the culture solution shown in Table 2 were obtained by the same operation as in Reference Example 3, and the reaction was carried out in the same manner as in Example 3. Table 2 shows the results of analysis of the reaction completed liquid by high performance liquid chromatography.
【００３２】[0032]
【表２】 [Table 2]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 (Ｃ１２Ｐ 17/10 Ｃ１２Ｒ 1:13） (Ｃ１２Ｐ 17/10 Ｃ１２Ｒ 1:01） (Ｃ１２Ｐ 17/10 Ｃ１２Ｒ 1:16） ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Office reference number FI technical display location (C12P 17/10 C12R 1:13) (C12P 17/10 C12R 1:01) (C12P 17/10 C12R 1:16)
Claims (3)
表わされるアルキル−２−〔４−〔〔（３Ｓ）−１−ア
セトイミドイル−３−ピロリジニル〕オキシ〕フェニ
ル〕−３−〔７−アミジノ−２−ナフチル〕プロピオネ
ート又はその塩を、微生物、その培養液及びこれらの分
画物からなる群から選ばれる１種又は２種以上で処理す
ることを特徴とする一般式（１） 【化２】 で表わされる光学活性２−〔４−〔〔（３Ｓ）−１−ア
セトイミドイル−３−ピロリジニル〕オキシ〕フェニ
ル〕−３−〔７−アミジノ−２−ナフチル〕プロピオン
酸又はその塩の製造法。1. A compound represented by the general formula (2): (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms) alkyl-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3 -[7-amidino-2-naphthyl] propionate or a salt thereof is treated with one or more selected from the group consisting of a microorganism, a culture solution thereof, and a fraction thereof. 1) [Chemical formula 2] A method for producing optically active 2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof .
表わされるアルキル−２−〔４−〔〔（３Ｓ）−１−ア
セトイミドイル−３−ピロリジニル〕オキシ〕フェニ
ル〕−３−〔７−アミジノ−２−ナフチル〕プロピオネ
ート又はその塩を、糸状菌、その培養液及びこれらの分
画物からなる群から選ばれる１種又は２種以上で処理す
ることを特徴とする一般式（３） 【化４】 で表わされる光学活性（＋）−２−〔４−〔〔（３Ｓ）
−１−アセトイミドイル−３−ピロリジニル〕オキシ〕
フェニル〕−３−〔７−アミジノ−２−ナフチル〕プロ
ピオン酸又はその塩の製造法。2. A compound represented by the general formula (2): (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms) alkyl-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3 -[7-amidino-2-naphthyl] propionate or a salt thereof is treated with one or more selected from the group consisting of filamentous fungi, culture solutions thereof and fractions thereof. (3) [Chemical 4] Optical activity represented by (+)-2- [4-[[(3S)
-1-acetamidoyl-3-pyrrolidinyl] oxy]
A method for producing phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof.
表わされるアルキル−２−〔４−〔〔（３Ｓ）−１−ア
セトイミドイル−３−ピロリジニル〕オキシ〕フェニ
ル〕−３−〔７−アミジノ−２−ナフチル〕プロピオネ
ート又はその塩を、酵母、細菌、これらの培養液及びこ
れらの分画物からなる群から選ばれる１種又は２種以上
で処理することを特徴とする一般式（４） 【化６】 で表わされる光学活性（−）−２−〔４−〔〔（３Ｓ）
−１−アセトイミドイル−３−ピロリジニル〕オキシ〕
フェニル〕−３−〔７−アミジノ−２−ナフチル〕プロ
ピオン酸又はその塩の製造法。3. A compound represented by the general formula (2): (In the formula, R represents a lower alkyl group having 1 to 6 carbon atoms) alkyl-2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3 -[7-amidino-2-naphthyl] propionate or a salt thereof is treated with one kind or two or more kinds selected from the group consisting of yeast, bacteria, culture solutions thereof and fractions thereof. General formula (4) Optical activity represented by (-)-2- [4-[[(3S)
-1-acetamidoyl-3-pyrrolidinyl] oxy]
A method for producing phenyl] -3- [7-amidino-2-naphthyl] propionic acid or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11862293A JP3388803B2 (en) | 1993-05-20 | 1993-05-20 | Method for producing optically active 7-amidinonaphthalene derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11862293A JP3388803B2 (en) | 1993-05-20 | 1993-05-20 | Method for producing optically active 7-amidinonaphthalene derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06327488A true JPH06327488A (en) | 1994-11-29 |
| JP3388803B2 JP3388803B2 (en) | 2003-03-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11862293A Expired - Fee Related JP3388803B2 (en) | 1993-05-20 | 1993-05-20 | Method for producing optically active 7-amidinonaphthalene derivative |
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| Country | Link |
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| JP (1) | JP3388803B2 (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5721214A (en) * | 1995-06-07 | 1998-02-24 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US5919765A (en) * | 1995-06-07 | 1999-07-06 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| US6022861A (en) * | 1995-06-07 | 2000-02-08 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6046169A (en) * | 1995-06-07 | 2000-04-04 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| US6069130A (en) * | 1995-06-07 | 2000-05-30 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6133256A (en) * | 1997-04-14 | 2000-10-17 | Cor Therapeutics Inc | Selective factor Xa inhibitors |
| WO2000066545A1 (en) * | 1999-05-04 | 2000-11-09 | Sanofi-Synthelabo | 6-[[(aryl and heteroaryl)oxy] methyl]naphthalene -2-carboximidamide derivatives, preparation and therapeutic application thereof |
| US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| US6204268B1 (en) | 1997-04-14 | 2001-03-20 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6245743B1 (en) | 1996-06-05 | 2001-06-12 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6369063B1 (en) | 1997-04-14 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6525076B1 (en) | 1996-10-11 | 2003-02-25 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
| US6562828B1 (en) | 1998-04-10 | 2003-05-13 | Japan Tobacco Inc. | Amidine compounds |
| EP1110556A4 (en) * | 1998-09-03 | 2004-01-28 | Daiichi Seiyaku Co | Preventives/remedies for multiple organ failure |
| EP2982668A2 (en) | 2002-12-03 | 2016-02-10 | Pharmacyclics LLC | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders |
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1993
- 1993-05-20 JP JP11862293A patent/JP3388803B2/en not_active Expired - Fee Related
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5721214A (en) * | 1995-06-07 | 1998-02-24 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US5919765A (en) * | 1995-06-07 | 1999-07-06 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| US6022861A (en) * | 1995-06-07 | 2000-02-08 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6046169A (en) * | 1995-06-07 | 2000-04-04 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
| US6069130A (en) * | 1995-06-07 | 2000-05-30 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6197748B1 (en) | 1995-06-07 | 2001-03-06 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
| US6245743B1 (en) | 1996-06-05 | 2001-06-12 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
| US6525076B1 (en) | 1996-10-11 | 2003-02-25 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
| US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| US6204268B1 (en) | 1997-04-14 | 2001-03-20 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6369063B1 (en) | 1997-04-14 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6133256A (en) * | 1997-04-14 | 2000-10-17 | Cor Therapeutics Inc | Selective factor Xa inhibitors |
| US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6562828B1 (en) | 1998-04-10 | 2003-05-13 | Japan Tobacco Inc. | Amidine compounds |
| EP1110556A4 (en) * | 1998-09-03 | 2004-01-28 | Daiichi Seiyaku Co | Preventives/remedies for multiple organ failure |
| FR2793247A1 (en) * | 1999-05-04 | 2000-11-10 | Synthelabo | 6 - [[(ARYL AND HETEROARYL) OXY] METHYL] NAPHTHALENE-2-CARBOXIMIDAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| WO2000066545A1 (en) * | 1999-05-04 | 2000-11-09 | Sanofi-Synthelabo | 6-[[(aryl and heteroaryl)oxy] methyl]naphthalene -2-carboximidamide derivatives, preparation and therapeutic application thereof |
| EP2982668A2 (en) | 2002-12-03 | 2016-02-10 | Pharmacyclics LLC | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders |
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| Publication number | Publication date |
|---|---|
| JP3388803B2 (en) | 2003-03-24 |
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