JP3088137B2 - 1,4-dihydronaphthoquinone derivative and method for producing the same - Google Patents
1,4-dihydronaphthoquinone derivative and method for producing the sameInfo
- Publication number
- JP3088137B2 JP3088137B2 JP03172221A JP17222191A JP3088137B2 JP 3088137 B2 JP3088137 B2 JP 3088137B2 JP 03172221 A JP03172221 A JP 03172221A JP 17222191 A JP17222191 A JP 17222191A JP 3088137 B2 JP3088137 B2 JP 3088137B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- residue
- acids
- carboxylic
- amino
- 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 - Lifetime
Links
Landscapes
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医療品として優れた作
用を有するビタミンＫの活性体である 1,4−ジヒドロナ
フトキノン誘導体およびその製造法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a 1,4-dihydronaphthoquinone derivative which is an active form of vitamin K having excellent action as a medical product, and a method for producing the same.
【０００２】[0002]
【従来の技術】ビタミンＫ製剤としては、ビタミンK2お
よびビタミンK1が医療用として用いられている。これら
のビタミンＫ類は水に不溶性の化合物である。したがっ
て、ビタミンＫ類の水溶性製剤の調製には、大量の非イ
オン性界面活性剤の添加による可溶化の方法が通常用い
られている。一方、ビタミンＫ類は体内で還元され、1,
4 −ジヒドロビタミンＫとなって活性を示すことが知ら
れており、そのカルボン酸エステルとしてジヒドロビタ
ミンＫの酢酸エステルが知られている（メルクインデッ
クス, 第９版,9684, 9686）。2. Description of the Related Art As vitamin K preparations, vitamin K 2 and vitamin K 1 are used for medical purposes. These vitamin Ks are water-insoluble compounds. Therefore, a method of solubilization by adding a large amount of a nonionic surfactant is usually used for preparing a water-soluble preparation of vitamin Ks. On the other hand, vitamin K is reduced in the body,
It is known that 4-dihydrovitamin K exhibits an activity, and acetic acid ester of dihydrovitamin K is known as a carboxylic acid ester thereof (Merck Index, 9th edition, 9684, 9686).
【０００３】[0003]
【発明が解決しようとする課題】非イオン性界面活性剤
を使用して注射剤を製することは、ショックなどを起こ
す可能性があり好ましくない。またジヒドロビタミンＫ
の酢酸エステルもビタミンＫ類と同様に水に不溶性であ
り、注射剤には適さない。そこで、水に対する溶解性が
高く、生体内において容易にジヒドロビタミンＫを生成
するようなビタミンＫ誘導体が求められている。The production of an injection using a nonionic surfactant is not preferred because it may cause a shock or the like. Dihydrovitamin K
Acetates are insoluble in water like vitamin Ks and are not suitable for injections. Therefore, a vitamin K derivative which has high solubility in water and easily generates dihydrovitamin K in a living body has been demanded.
【０００４】[0004]
【課題を解決するための手段】本発明者等は、この様な
条件を満足するビタミンＫ誘導体の開発を目的として、
長年にわたり種々検索研究を重ねた結果、ようやく上記
の目的を満足する新規なビタミンＫ誘導体を見いだし、
本発明を完成した。即ち、本発明は、次の一般式（Ｉ）
で表される 1,4−ジヒドロナフトキノンのカルボン酸エ
ステル類およびその製造法に係わるものである。Means for Solving the Problems The inventors of the present invention aimed at developing a vitamin K derivative satisfying such conditions.
As a result of various search studies over the years, we finally found a new vitamin K derivative that satisfies the above purpose,
The present invention has been completed. That is, the present invention provides the following general formula (I)
Carboxylic acid esters of 1,4-dihydronaphthoquinone represented by the formula:
【０００５】[0005]
【化７】 Embedded image
【０００６】（式中、R1およびR2はそれぞれ水素原子ま
たは窒素置換基を有するカルボン酸残基を意味し、R1,
R2の少なくとも一方は窒素置換基を有するカルボン酸残
基である。R3は水素原子またはメチル基を意味する。R4
は[0006] (wherein, means a carboxylic acid residue having R 1 and R 2 are each a hydrogen atom or a nitrogen substituent, R 1,
At least one of R 2 is a carboxylic acid residue having a nitrogen substituent. R 3 represents a hydrogen atom or a methyl group. R 4
Is
【０００７】[0007]
【化８】 Embedded image
【０００８】n は１〜14の整数を意味する。) 一般式（Ｉ）におけるR1，R2の定義に見られる窒素置換
基を有するカルボン酸残基としては、アミノ酸、 N−ア
シルアミノ酸、N−アルキルアミノ酸、 N,N−ジアルキ
ルアミノ酸、ピリジンカルボン酸、およびそれらのハロ
ゲン化水素酸塩、アルキルスルホン酸塩等の残基が挙げ
られる。N represents an integer of 1 to 14. ) The carboxylic acid residue having a nitrogen substituent found in the definition of R 1 and R 2 in the general formula (I) includes amino acids, N-acyl amino acids, N-alkyl amino acids, N, N-dialkyl amino acids, and pyridine carboxylic acids. Acids and their residues such as hydrohalides and alkylsulfonates.
【０００９】前記一般式（Ｉ）で表わされる本発明化合
物の製造方法は種々考えられるが、代表的な方法を述べ
れば以下の通りである。製造方法 Various methods for producing the compound of the present invention represented by the above general formula (I) are conceivable, and typical methods are as follows. Production method
【００１０】 [0010]
【化９】 Embedded image
【００１１】一般式（II）で表されるビタミンＫ類を還
元剤で還元し、一般式（III)で表される 1,4−ジヒドロ
ナフトキノンとし、この 1,4−ジヒドロナフトキノン
と、窒素置換基を有するカルボン酸、若しくはその反応
性酸誘導体またはこれらのハロゲン化水素酸塩とを常法
によりエステル化反応を行なうことにより、本発明の目
的物質（Ｉ）を得ることができる。ここで用いられる還
元剤はビタミンＫ類のキノン骨格をジヒドロキノンに還
元するものであり、水素化ホウ素ナトリウム、ハイドロ
サルファイトナトリウム、トリ−n −ブチルホスフィ
ン、塩化亜鉛、塩化第一スズなどを挙げることができ
る。[0011] Vitamin Ks represented by the general formula (II) are reduced with a reducing agent to give 1,4-dihydronaphthoquinone represented by the general formula (III). The target substance (I) of the present invention can be obtained by subjecting a carboxylic acid having a group, a reactive acid derivative thereof or a hydrohalide thereof to an esterification reaction in a conventional manner. The reducing agent used here reduces the quinone skeleton of vitamin Ks to dihydroquinone, and includes sodium borohydride, sodium hydrosulfite, tri-n-butylphosphine, zinc chloride, stannous chloride and the like. be able to.
【００１２】1,4 −ジヒドロナフトキノンのエステル化
反応は常法に従うが、１級、２級アミノ基あるいは側鎖
に水酸基、チオール基を有するアミノ酸のエステル化を
行なう際は、tert−ブトキシカルボニル基（以下 t−BO
C 基と略記) 、ベンジルオキシカルボニル基（以下Ｚ基
と略記) などの適切な保護基で保護して用い、N,N −ジ
アルキルアミノ酸はハロゲン化水素酸塩を用いて、ジシ
クロヘキシルカルボジイミド（以下DCC と略記) 、N,N
−ジサクシニミドオキザレート（以下DSO と略記) など
の活性エステル化試薬の存在下に反応を行なうことが好
ましい結果を与える。この際溶媒としては無水ピリジン
が好ましい。また、反応性酸誘導体を用いる方法では、
酸ハロゲナイトとりわけ、酸クロリドを用いる方法が好
ましい結果を与える。この際溶媒としては無水ベンゼン
−無水ピリジン混合物が好ましい。ハロゲン化水素酸塩
およびアルキルスルホン酸塩は常法により遊離のアミノ
酸エステルとハロゲン化水素酸またはアルキルスルホン
酸を反応させて製造する。また、 N−アシルアミノ酸エ
ステルを製造した後、常法によりハロゲン化水素酸で脱
保護基化することによってハロゲン化水素酸塩を製造す
ることができる。The esterification of 1,4-dihydronaphthoquinone is carried out in a conventional manner, but when esterifying a primary or secondary amino group or an amino acid having a hydroxyl group or a thiol group in the side chain, a tert-butoxycarbonyl group is used. (Hereinafter t-BO
C), benzyloxycarbonyl group (hereinafter abbreviated as Z group) and the like, and protected with an appropriate protecting group. N, N-dialkylamino acid is prepared by using dihydrohexylcarbodiimide (hereinafter DCC) using a hydrohalide. Abbreviation), N, N
It is preferable to carry out the reaction in the presence of an active esterification reagent such as -disuccinimide oxalate (hereinafter abbreviated as DSO). In this case, anhydrous pyridine is preferable as the solvent. In the method using a reactive acid derivative,
The method using acid halides, especially acid chlorides, gives favorable results. In this case, the solvent is preferably a mixture of anhydrous benzene and anhydrous pyridine. The hydrohalide and alkyl sulfonate are produced by reacting a free amino acid ester with hydrohalic acid or alkyl sulfonic acid by a conventional method. After the N-acyl amino acid ester is produced, a hydrohalide can be produced by deprotection with a hydrohalic acid according to a conventional method.
【００１３】本発明で得られる目的物質（Ｉ）は、生体
内で容易に加水分解され、ジヒドロビタミンＫを生成
し、更にビタミンＫを生成する。また、ハロゲン化水素
酸塩およびアルキルスルホン酸塩は結晶性の粉末であ
り、製剤技術上取り扱いが容易且つ簡便であり、比較的
高い水溶性を有する。したがって、静脈内投与が可能な
ビタミンＫ水性注射剤あるいは点眼剤として有用であ
る。また、経口製剤として投与すると、吸収過程におい
てビタミンＫに変換され薬効を示す。The target substance (I) obtained in the present invention is easily hydrolyzed in a living body to produce dihydrovitamin K, and further produces vitamin K. In addition, hydrohalides and alkyl sulfonates are crystalline powders, which are easy and easy to handle in terms of formulation technology, and have relatively high water solubility. Therefore, it is useful as an aqueous vitamin K injection or eye drop that can be administered intravenously. When administered as an oral preparation, it is converted to vitamin K during the absorption process and exhibits a medicinal effect.
【００１４】[0014]
【発明の効果】本目的化合物の有用性を具体的に示すた
め、以下に動物実験の結果を示す。動物実験 Ａ）静脈内投与 1) 方法 Wistar系雄性ラット（体重 330〜340 ｇ）を３匹１群で
用い、エーテル麻酔下ラット左大腿静脈内に 1,4−ジヒ
ドロメナキノン４−1,4 −ジ−N,N −ジメチルグリシネ
ート塩酸塩（以下DHMQ４−di−DMGHClと略記する）の水
溶液（メナキノン４（以下MQ４と略記する）当量10mg／
ml）を投与し（投与量はMQ４当量８mg／kg）、経時的に
採血し、血漿中のMQ４および1,4 −ジヒドロメナキノン
４−1,4 −ジ−N,N −ジメチルグリシネート（以下DHMQ
４−di−DMG と略記する）濃度を高速液体クロマトグラ
フィー(HPLC)で測定した。同様に、イオン性界面活性剤
で溶解させた市販のMQ４製剤を８mg／kg投与し、血漿中
のMQ４濃度を測定した。 HPLC条件：カラムはwakosil 5 C4、溶媒はメタノール−
酢酸緩衝液（pH5.0 、0.1M) 、85：15、流速1.0 ml／mi
n 、検出は275nm の吸光度と螢光光度（励起275 nm、螢
光340nm)で行なった。EFFECT OF THE INVENTION The usefulness of the present compound has been specifically demonstrated.
The results of animal experiments are shown below.Animal experimentation A) Intravenous administration 1) Method Three male Wistar rats (body weight 330-340 g)
1,4-Dihi was injected into the left femoral vein of the rat under ether anesthesia.
Dromenaquinone 4-1,4-di-N, N-dimethylglycine
Water of sodium hydrochloride (hereinafter abbreviated as DHMQ4-di-DMGHCl)
Solution (menaquinone 4 (hereinafter abbreviated as MQ4) equivalent 10 mg /
ml) (the dose is 8 mg / kg of MQ4 equivalent) and
Blood collected and MQ4 and 1,4-dihydromenaquinone in plasma
4-1,4-di-N, N-dimethylglycinate (hereinafter referred to as DHMQ
The concentration is abbreviated as 4-di-DMG).
It was measured by fee (HPLC). Similarly, ionic surfactants
8 mg / kg of a commercially available MQ4 preparation dissolved in
Was measured for MQ4 concentration. HPLC conditions: wakosil 5 C4 for column, methanol for solvent
Acetate buffer (pH 5.0, 0.1 M), 85:15, flow rate 1.0 ml / mi
n, detection is absorbance and fluorescence at 275 nm (excitation 275 nm, fluorescence
Light 340 nm).
【００１５】2) 結果 結果を図１および図２に示す。図１は、DHMQ４−di−DM
GHCl投与後の血漿中動態を検討した結果を示し、横軸は
投与後の時間を表し、縦軸は血漿中のMQ４およびDHMQ４
−di−DMG の量を表す。図１から明らかな様に、投与後
速やかに血漿中のMQ４濃度が高くなった。したがって、
DHMQ４−di−DMGHClは、投与後速やかにラット体内で加
水分解してジヒドロビタミンK2となり、更に体内で酸化
されてMQ４を生成することが明らかである。図２は、DH
MQ４−di−DMGHClを投与した場合と、市販MQ４製剤を投
与した場合の血漿中のMQ４濃度の時間推移を示してい
る。血漿中のMQ４濃度は、投与後１時間まではMQ４自身
を投与する市販製剤の方が高いが、驚くべきことに、２
時間以降は本発明化合物であるDHMQ４−di−DMGHClを投
与した方が高くなった。即ち、本発明化合物は市販製剤
よりも長時間にわたって血漿中の遊離MQ４レベルを維持
できることが明らかである。2) Results The results are shown in FIGS. 1 and 2. FIG. 1 shows DHMQ4-di-DM
The results of examining the plasma kinetics after administration of GHCl are shown. The horizontal axis represents the time after administration, and the vertical axis represents MQ4 and DHMQ4 in plasma.
-Di- Indicates the amount of DMG. As is clear from FIG. 1, the MQ4 concentration in the plasma increased immediately after the administration. Therefore,
DHMQ4-di-DMGHCl is dihydro vitamin K 2 next hydrolyzed by rapidly in rats after administration, it is apparent that to produce a MQ4 are further oxidized in the body. Figure 2 shows DH
The time course of the concentration of MQ4 in plasma when MQ4-di-DMGHCl is administered and when a commercial MQ4 preparation is administered is shown. The concentration of MQ4 in plasma is higher for commercial formulations that administer MQ4 itself up to 1 hour after administration, but surprisingly,
After time, the dose was higher when the compound of the present invention, DHMQ4-di-DMGHCl, was administered. That is, it is clear that the compound of the present invention can maintain the free MQ4 level in plasma for a longer time than the commercial preparation.
【００１６】Ｂ）経口投与 1) 方法 Wistar系雄性ラット（体重 300〜325 ｇ）を３匹１群と
し、16時間絶食後、軽くエーテル麻酔し、経口ゾンデを
用いて試料を投与した。投与液はDHMQ４−di−DMGHClを
蒸留水に溶解し、MQ４として５mg／kg, 10mg／kgをラッ
ト体重100 ｇ当たり 0.1mlの投与容量に調製し投与し
た。また生物学的利用率を計算するため、A)と同様の方
法によりMQ４を５mg／kg静脈内投与した。投与後一定時
間毎に外頸静脈からヘパリン処理した注射器で0.35ml採
血し、血漿中のMQ４をHPLCにより測定した。 HPLC条件：分離カラムcapcellpak C18 4.6×250mm(Shis
eido Company, Ltd)、還元カラムCosmosil Zn 4.6 ×50
mm(Nakalai tesque Inc.) 、溶媒はメタノール（0.01Ｍ
酢酸、0.01Ｍ酢酸ナトリウム及び0.1 ％塩化亜鉛を含
む）、流速は1.0 ml／min 、検出は蛍光光度法（励起波
長275 nm，蛍光波長340 nm）で行った。B) Oral administration 1) Method Three Wistar male rats (body weight: 300 to 325 g) were grouped in groups of three, fasted for 16 hours, lightly anesthetized with ether, and administered with an oral probe. The administration solution was prepared by dissolving DHMQ4-di-DMGHCl in distilled water, and adjusting the dose of MQ4 to 5 mg / kg and 10 mg / kg in a dosage volume of 0.1 ml per 100 g rat body weight, and administered. In order to calculate the bioavailability, MQ4 was intravenously administered at 5 mg / kg in the same manner as in A). At regular intervals after administration, 0.35 ml of blood was collected from the external jugular vein using a heparinized syringe, and MQ4 in the plasma was measured by HPLC. HPLC conditions: separation column capcellpak C 18 4.6 × 250mm (Shis
eido Company, Ltd), Cosmosil Zn 4.6 × 50 reduction column
mm (Nakalai tesque Inc.), the solvent is methanol (0.01M
Acetic acid, 0.01 M sodium acetate and 0.1% zinc chloride were contained), the flow rate was 1.0 ml / min, and the detection was carried out by a fluorometric method (excitation wavelength: 275 nm, emission wavelength: 340 nm).
【００１７】2) 結果 結果を図３に示す。図３は、DHMQ４−di−DMGHCl経口投
与後10時間までの平均血漿中のMQ４濃度の推移を示す。
MQ４レベルは投与後２時間までは高くなり、その後低下
した。MQ４を静脈内投与後のMQ４の血中濃度時間曲線下
面積（ＡＵＣ）, DHMQ４−di−DMGHClを経口投与後のMQ
４のＡＵＣ及び生物学的利用率（ＢＡ）を表１に示し
た。DHMQ４−di−DMGHCl投与後の、MQ４としてのＢＡは
５mg／kgの投与量の場合13.5％、10mg／kgの場合12.3％
であり、経口投与後にもMQ４が血中に出現し、薬効を表
し得ることが明らかとなった。またＢＡ値がほぼ同一で
あったことから、この投与量範囲においては、吸収の飽
和は認められなかった。2) Results The results are shown in FIG. FIG. 3 shows changes in the average concentration of MQ4 in plasma up to 10 hours after oral administration of DHMQ4-di-DMGHCl.
MQ4 levels increased up to 2 hours after administration and then decreased. Area under the blood concentration time curve of MQ4 after intravenous administration of MQ4 (AUC), MQ after oral administration of DHMQ4-di-DMGHCl
The AUC and bioavailability (BA) of 4 are shown in Table 1. BA as MQ4 after administration of DHMQ4-di-DMGHCl is 13.5% at 5 mg / kg dose and 12.3% at 10 mg / kg
Thus, it was revealed that MQ4 appeared in the blood even after oral administration and could exhibit a medicinal effect. Since the BA values were almost the same, no saturation of absorption was observed in this dose range.
【００１８】[0018]
【表１】 [Table 1]
【００１９】[0019]
【実施例】次に本発明の実施例を示すが、本発明がこれ
らに限定されることがないことは言うまでもない。 実施例１〜２６ 下記の製造方法Ａ〜Ｆに示す方法により表２〜６に示す
１，４ −ジヒドロナフトキノン誘導体を製造した。ま
た、得られた物質の質量スペクトル、1H- NMR スペクト
ルを表７〜９に示す。EXAMPLES Next, examples of the present invention will be described, but it goes without saying that the present invention is not limited to these examples. Examples 1 to 26 The 1,4-dihydronaphthoquinone derivatives shown in Tables 2 to 6 were produced by the following production methods A to F. Tables 7 to 9 show the mass spectrum and 1 H-NMR spectrum of the obtained substance.
【００２０】製造方法Ａ アミノ酸0.1molを蒸留水−ジオキサン（１：１ v／v) 1
00mlに溶解し、トリエチルアミン30mlを加え、ジ−tert
−ブチルジカルボネートを徐々に加え30分間室温で撹拌
する。減圧下ジオキサンを留去し、炭酸水素ナトリウム
水溶液（0.5M)50mlを加え酢酸エチル100 mlで洗う。酢
酸エチル層を50mlの炭酸水素ナトリウム液で洗い、水層
を合わせて氷冷下でクエン酸水溶液(0.5M)を加えて酸性
（pH３）とし、塩化ナトリウムを飽和させた後、酢酸エ
チルで抽出する(100ml×３回）、抽出液を無水硫酸ナト
リウムで脱水後減圧下溶媒を留去し、油状残渣をイソプ
ロピルエーテルを加えるか、または冷却にて結晶化させ
て、 N− t− BOC−アミノ酸を得る。ビタミンＫ6.75mm
olをイソプロピルエーテル40mlに溶解し、水素化ホウ素
ナトリウム47mmolをメタノール15mlに溶解して加え、溶
液の黄色が無色になるまで室温で撹拌する。反応液にイ
ソプロピルエーテル60mlと蒸留水100 mlを加え、イソプ
ロピルエーテル層を分離し、更に水層にイソプロピルエ
ーテル100 mlを加えて可溶分画を抽出し、イソプロピル
エーテル層を合わせて無水硫酸ナトリウムで脱水後減圧
下濃縮する。残渣に n−ヘキサンを加えて白色沈殿を析
出させて1,4 −ジヒドロビタミンＫを得る。Production Method A 0.1 mol of an amino acid is distilled water-dioxane (1: 1 v / v) 1
Dissolved in 100 ml of triethylamine.
Add butyl dicarbonate slowly and stir for 30 minutes at room temperature. Dioxane was distilled off under reduced pressure, 50 ml of aqueous sodium hydrogen carbonate solution (0.5 M) was added, and the mixture was washed with 100 ml of ethyl acetate. The ethyl acetate layer was washed with 50 ml of sodium bicarbonate solution, and the aqueous layers were combined, acidified (pH 3) by adding an aqueous citric acid solution (0.5 M) under ice cooling, saturated with sodium chloride, and extracted with ethyl acetate. The extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the oily residue was crystallized by adding isopropyl ether or cooling to give N-t-BOC-amino acid. Get. Vitamin K 6.75mm
is dissolved in 40 ml of isopropyl ether, 47 mmol of sodium borohydride dissolved in 15 ml of methanol are added and the mixture is stirred at room temperature until the yellow color of the solution becomes colorless. 60 ml of isopropyl ether and 100 ml of distilled water are added to the reaction solution, the isopropyl ether layer is separated, 100 ml of isopropyl ether is further added to the aqueous layer to extract a soluble fraction, and the isopropyl ether layers are combined and combined with anhydrous sodium sulfate. After dehydration, concentrate under reduced pressure. N-Hexane is added to the residue to precipitate a white precipitate to obtain 1,4-dihydrovitamin K.
【００２１】1,4 −ジヒドロビタミンＫ、 N− t− BOC
−アミノ酸13.55mmol 、 DCC 13.55mmolを無水ピリジン
50mlに加え室温で20時間撹拌する。溶媒を減圧下留去
し、残渣に酢酸エチルを加えて可溶分画を抽出する(100
ml×２回）、抽出液を減圧下濃縮し、残渣をシリカゲル
カラムクロマトグラフィー（溶離溶媒； n−ヘキサン−
イソプロピルエーテル、１：１）で分離精製し、1,4 −
ジヒドロビタミンＫ 1,4−ジ− N− t−BOC−アミノ酸
を得る。1,4 −ジヒドロビタミンＫ 1,4−ジ− N− t−
BOC−アミノ酸を少量のアセトンに溶解し、塩酸−ジオ
キサン(2.5〜4.0N) をエステル量の約20倍モル量の塩酸
量に相当する量加え１時間撹拌後、減圧下溶媒を留去す
る。残渣をアセトン−メタノール系で再結晶して1,4 −
ジヒドロビタミンＫ 1,4−ジ−N,N −ジ−アルキルアミ
ノ酸の塩酸塩を得る。1,4-dihydrovitamin K, Nt-BOC
-13.55 mmol of amino acids, 13.55 mmol of DCC in anhydrous pyridine
Add to 50 ml and stir at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue to extract a soluble fraction (100
ml × 2), the extract was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane-
Isolation and purification with isopropyl ether, 1: 1) to give 1,4-
The dihydrovitamin K 1,4-di-N-t-BOC-amino acid is obtained. 1,4-dihydrovitamin K 1,4-di-N-t-
The BOC-amino acid is dissolved in a small amount of acetone, hydrochloric acid-dioxane (2.5 to 4.0N) is added in an amount corresponding to a hydrochloric acid amount of about 20 times the molar amount of the ester, and after stirring for 1 hour, the solvent is distilled off under reduced pressure. The residue was recrystallized from acetone-methanol to give 1,4-
This gives the hydrochloride salt of dihydrovitamin K 1,4-di-N, N-di-alkylamino acid.
【００２２】製造方法Ｂ ビタミンＫ6.75mmolをイソプロピルエーテル40mlに溶解
し、水素化ホウ素ナトリウム47mmolをメタノール15mlに
溶解して加え、溶液の黄色が無色なるまで室温で撹拌す
る。反応液にイソプロピルエーテル60mlと蒸留水100 ml
を加え、イソプロピルエーテル層を分離し、更に水層に
イソプロピルエーテル100 mlを加えて可溶分画を抽出、
イソプロピルエーテル層を合わせて無水硫酸ナトリウム
で脱水後減圧下濃縮する。残渣に n−ヘキサンを加えて
白色沈殿を析出させて 1,4−ジヒドロビタミンＫを得
る。 1,4−ジヒドロビタミンＫ、塩酸 N,N−ジアルキル
アミノ酸13.55 mmol、DCC 13.55mmol を無水ピリジン50
mlに加え室温で20時間撹拌する。溶媒を減圧下留去し、
残渣を、蒸留水に懸濁させ炭酸水素ナトリウムを加えて
溶液のpHを７〜８にした後に酢酸エチルで抽出する(100
ml×３回）、抽出液を無水硫酸ナトリウムで脱水後減圧
下溶媒を留去し、残渣をシリカゲルカラムクロマトグラ
フィー（溶離溶媒；イソプロピルエーテル−酢酸エチ
ル、１：１）で分離精製し、1,4 −ジヒドロビタミンＫ
1,4−ジ− N,N−ジアルキルアミノ酸を得る。Production method B Vitamin K (6.75 mmol) is dissolved in isopropyl ether (40 ml), sodium borohydride (47 mmol) is dissolved in methanol (15 ml), and the mixture is stirred at room temperature until the yellow color of the solution becomes colorless. 60 ml of isopropyl ether and 100 ml of distilled water are added to the reaction solution.
Was added, and the isopropyl ether layer was separated.The aqueous layer was further added with 100 ml of isopropyl ether to extract a soluble fraction,
The isopropyl ether layers are combined, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. N-Hexane is added to the residue to precipitate a white precipitate to obtain 1,4-dihydrovitamin K. 1,4-Dihydrovitamin K, 13.55 mmol of N, N-dialkylamino acid hydrochloride and 13.55 mmol of DCC were added to anhydrous pyridine 50
Add to the mixture and stir at room temperature for 20 hours. The solvent is distilled off under reduced pressure,
The residue is suspended in distilled water, and the pH of the solution is adjusted to 7 to 8 by adding sodium hydrogen carbonate, followed by extraction with ethyl acetate (100%).
The extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: isopropyl ether-ethyl acetate, 1: 1). 4-dihydrovitamin K
1,4-Di-N, N-dialkyl amino acids are obtained.
【００２３】製造方法Ｃ ビタミンＫ6.75mmolをイソプロピルエーテル40mlに溶解
し、ハイドロサルファイトナトリウム50mmolを蒸留水50
mlに溶解して加え、イソプロピルエーテルが褐色を呈
し、さらに無色になるまで室温で撹拌する。イソプロピ
ルエーテル層を分離し、更に水層にイソプロピルエーテ
ル100 mlを加えて可溶分画を抽出、イソプロピルエーテ
ル層を合わせて無水硫酸ナトリウムで脱水後減圧下濃縮
する。残渣に n−ヘキサンを加えて白色沈殿を析出させ
て1,4 −ジヒドロビタミンＫを得る。1,4−ジヒドロビ
タミンＫに塩酸N,N−ジアルキルアミノ酸6.75mmol、DCC
6.75mmolを加え無水ピリジン50ml中で20時間撹拌す
る。溶媒を減圧下留去し、残渣を、蒸留水に懸濁させ炭
酸水素ナトリウムを加えて溶液のpHを７〜８にした後酢
酸エチルで抽出する(100ml×３回）、抽出液を無水硫酸
ナトリウムで脱水後減圧下溶媒を留去し、残渣をシリカ
ゲルカラムクロマトグラフィー（溶離溶媒；イソプロピ
ルエーテル−酢酸エチル、３：２）で分離精製し、1,4
−ジヒドロビタミンＫ 1−N,N −ジアルキルアミノ酸お
よび1,4 −ジヒドロビタミンＫ 4− N,N−ジアルキルア
ミノ酸を得る。Production Method C 6.75 mmol of vitamin K is dissolved in 40 ml of isopropyl ether, and 50 mmol of sodium hydrosulfite is added to 50 ml of distilled water.
Dissolve in isopropyl ether and stir at room temperature until the isopropyl ether turns brown and becomes more colorless. The isopropyl ether layer is separated, 100 ml of isopropyl ether is further added to the aqueous layer to extract a soluble fraction, the isopropyl ether layers are combined, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure. N-Hexane is added to the residue to precipitate a white precipitate to obtain 1,4-dihydrovitamin K. N, N-dialkylamino acid hydrochloride 6.75 mmol in 1,4-dihydrovitamin K, DCC
6.75 mmol is added and stirred in 50 ml of anhydrous pyridine for 20 hours. The solvent is distilled off under reduced pressure, the residue is suspended in distilled water, the pH of the solution is adjusted to 7 to 8 by adding sodium hydrogen carbonate, and the mixture is extracted with ethyl acetate (100 ml × 3 times). After dehydration with sodium, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: isopropyl ether-ethyl acetate, 3: 2).
To obtain dihydrovitamin K1-N, N-dialkylamino acids and 1,4-dihydrovitamin K4-N, N-dialkylamino acids.
【００２４】製造方法Ｄ ビタミンＫ6.75mmolをイソプロピルエーテル40mlに溶解
し、水素化ホウ素ナトリウム47mmolをメタノール15mlに
溶解して加え、溶液の黄色が無色になるまで室温で撹拌
する。反応液にイソプロピルエーテル60mlと蒸留水100
mlを加え、イソプロピルエーテル層を分離し、更に水層
にイソプロピルエーテル100 mlを加えて可溶分画を抽
出、イソプロピルエーテル層を合わせて無水硫酸ナトリ
ウムで脱水後減圧下濃縮する。残渣に n−ヘキサンを加
えて白色沈殿を析出させて 1,4−ジヒドロビタミンＫを
得る。1,4 −ジヒドロビタミンＫを無水ベンゼン−無水
ピリジン（１：１、 v／v)30mlに溶解し、塩酸ピリジン
カルボン酸クロリドを加え室温で３時間撹拌する。不溶
物を濾過で取り除き、濾液を減圧下濃縮する。残渣を蒸
留水100 mlに懸濁させ、炭酸水素ナトリウムを加え(pH
７〜８)、酢酸エチルに可溶分画を抽出する(100ml×３
回) 、抽出液を減圧下濃縮し、残渣をシリカゲルカラム
クロマトグラフィー（溶離溶媒；イソプロピルエーテル
−酢酸エチル、9 ：１）で分離精製し、1,4 −ジヒドロ
ビタミンＫ 1,4−ジ−ピリジンカルボン酸を得る。Production method D 6.75 mmol of vitamin K are dissolved in 40 ml of isopropyl ether, 47 mmol of sodium borohydride are dissolved in 15 ml of methanol, and the mixture is stirred at room temperature until the yellow color of the solution becomes colorless. 60 ml of isopropyl ether and 100 parts of distilled water
Then, 100 ml of isopropyl ether was added to the aqueous layer to extract a soluble fraction. The isopropyl ether layers were combined, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. N-Hexane is added to the residue to precipitate a white precipitate to obtain 1,4-dihydrovitamin K. 1,4-Dihydrovitamin K is dissolved in 30 ml of anhydrous benzene-anhydrous pyridine (1: 1, v / v), pyridinecarboxylic acid hydrochloride chloride is added, and the mixture is stirred at room temperature for 3 hours. The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was suspended in 100 ml of distilled water, and sodium hydrogen carbonate was added (pH
7-8), extract the fraction soluble in ethyl acetate (100 ml x 3)
Times), the extract was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent: isopropyl ether-ethyl acetate, 9: 1) to give 1,4-dihydrovitamin K 1,4-di-pyridine. A carboxylic acid is obtained.
【００２５】製造方法Ｅ 1,4 −ジヒドロビタミンＫ 1,4−ジ− N,N−ジアルキル
アミノ酸又は 1,4−ジヒドロビタミンＫ 1,4−ジ−ピリ
ジンカルボン酸２mmolをアセトン20mlに溶解し、塩酸−
ジオキサン(2.5〜4.0 N)を塩酸量がエステルの10倍モル
量に相当する量加え、溶媒を減圧下留去し、残渣をアセ
トン−メタノールで再結晶して1,4−ジヒドロビタミン
Ｋ 1,4−ジ− N,N−ジアルキルアミノ酸又は 1,4−ジヒ
ドロビタミンＫ 1,4−ジ−ピリジンカルボン酸の塩酸塩
を得る。Production method E 2 mmol of 1,4-dihydrovitamin K 1,4-di-N, N-dialkylamino acid or 1,4-dihydrovitamin K 1,4-dipyridinecarboxylic acid was dissolved in 20 ml of acetone. Hydrochloric acid-
Dioxane (2.5 to 4.0 N) was added in an amount corresponding to 10 times the molar amount of hydrochloric acid of the ester, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone-methanol to give 1,4-dihydrovitamin K 1, This gives the hydrochloride salt of 4-di-N, N-dialkylamino acid or 1,4-dihydrovitamin K 1,4-di-pyridinecarboxylic acid.
【００２６】製造方法Ｆ 1,4 −ジヒドロビタミンＫ 1,4−ジ− N,N−ジアルキル
アミノ酸又は 1,4−ジヒドロビタミンＫ 1,4−ジ−ピリ
ジンカルボン酸２mmolをジクロロメタン20mlに溶解し、
アルキルスルホン酸２mmolを加え撹拌する。析出する結
晶を濾取して1,4 −ジヒドロビタミンＫ 1,4−ジ− N,N
−ジアルキルアミノ酸又は 1,4−ジヒドロビタミンＫ
1,4−ジ−ピリジンカルボン酸のアルキルスルホン酸塩
を得る。Production Method F 2 mmol of 1,4-dihydrovitamin K 1,4-di-N, N-dialkylamino acid or 1,4-dihydrovitamin K 1,4-dipyridinecarboxylic acid is dissolved in 20 ml of dichloromethane.
2 mmol of alkylsulfonic acid is added and stirred. The precipitated crystals are collected by filtration and 1,4-dihydrovitamin K 1,4-di-N, N
-Dialkylamino acids or 1,4-dihydrovitamin K
An alkyl sulfonate of 1,4-di-pyridinecarboxylic acid is obtained.
【００２７】[0027]
【表２】 [Table 2]
【００２８】[0028]
【表３】 [Table 3]
【００２９】[0029]
【表４】 [Table 4]
【００３０】[0030]
【表５】 [Table 5]
【００３１】[0031]
【表６】 [Table 6]
【００３２】[0032]
【表７】 [Table 7]
【００３３】[0033]
【表８】 [Table 8]
【００３４】[0034]
【表９】 [Table 9]
【図１】DHMQ４−di−DMGHClを静脈内投与後のDHMQ４−
di−DMG 及びMQ４の血漿中濃度推移を示すグラフであ
る。FIG. 1. DHMQ4-di-DMGHCl after intravenous administration of DHMQ4-
It is a graph which shows the plasma concentration transition of di-DMG and MQ4.
【図２】DHMQ４−di−DMGHCl又は市販MQ４製剤を静脈内
投与した場合の血漿中MQ４の時間推移を示すグラフであ
る。FIG. 2 is a graph showing the time course of plasma MQ4 when DHMQ4-di-DMGHCl or a commercially available MQ4 preparation is administered intravenously.
【図３】DHMQ４−di−DMGHClを経口投与した場合の血漿
中MQ４の時間推移を示すグラフである。FIG. 3 is a graph showing the time course of MQ4 in plasma when DHMQ4-di-DMGHCl is orally administered.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ Ｃ０７Ｃ 269/06 Ｃ０７Ｃ 269/06 Ｃ０７Ｄ 213/80 Ｃ０７Ｄ 213/80 (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 271/22 C07C 227/18 C07C 229/08 C07C 229/12 C07C 229/28 C07C 269/06 C07D 213/80 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 7 identification code FI C07C 269/06 C07C 269/06 C07D 213/80 C07D 213/80 (58) Investigated field (Int.Cl. 7 , DB name) C07C 271/22 C07C 227/18 C07C 229/08 C07C 229/12 C07C 229/28 C07C 269/06 C07D 213/80 CA (STN) REGISTRY (STN)
Claims (2)
酸、N −アシルアミノ酸、N −アルキルアミノ酸、N,N
−ジアルキルアミノ酸、ピリジンカルボン酸及びそれら
のハロゲン化水素酸塩又はアルキルスルホン酸塩の残基
から選ばれる窒素置換基を有するカルボン酸残基（但
し、アミノ酸はグリシン、アラニン、フェニルアラニ
ン、トラネキサミン酸及びアミノカプロン酸から選ばれ
る）を意味し、R1, R2の少なくとも一方は窒素置換基を
有するカルボン酸残基である。R3は水素原子またはメチ
ル基を意味する。R4は 【化２】 n は１〜14の整数を意味する。)で表される1,4 −ジヒ
ドロナフトキノンのカルボン酸エステル類。1. A compound of the general formula (I) (Wherein R 1 and R 2 are each a hydrogen atom or an amino
Acid, N-acyl amino acid, N-alkyl amino acid, N, N
-Dialkyl amino acids, pyridine carboxylic acids and the like
Residue of a hydrohalide or alkyl sulfonate
Carboxylic acid residue having a nitrogen substituent selected from (but
Amino acids are glycine, alanine, phenylalanine
Tranexamic acid and aminocaproic acid
At least one of R 1 and R 2 is a carboxylic acid residue having a nitrogen substituent. R 3 represents a hydrogen atom or a methyl group. R 4 is n means an integer of 1 to 14. ) Carboxylic acid esters of 1,4-dihydronaphthoquinone represented by).
類を還元して得られる一般式（III) 【化５】 （式中、R3, R4は前記の意味を有する。)で表される 1,
4−ジヒドロナフトキノンと、アミノ酸、N −アシルア
ミノ酸、N−アルキルアミノ酸、N,N −ジアルキルアミ
ノ酸、ピリジンカルボン酸から選ばれる窒素置換基を有
するカルボン酸（但し、アミノ酸はグリシン、アラニ
ン、フェニルアラニン、トラネキサミン酸及びアミノカ
プロン酸から選ばれる）若しくはその酸ハロゲナイト、
又はこれらのハロゲン化水素酸塩とをエステル化反応さ
せることを特徴とする一般式（Ｉ） 【化６】 （式中、R1およびR2はそれぞれ水素原子、またはアミノ
酸、N −アシルアミノ酸、N −アルキルアミノ酸、N,N
−ジアルキルアミノ酸、ピリジンカルボン酸及びそれら
のハロゲン化水素酸塩又はアルキルスルホン酸塩の残基
から選ばれる窒素置換基を有するカルボン酸残基（但
し、アミノ酸はグリシン、アラニン、フェニルアラニ
ン、トラネキサミン酸及びアミノカプロン酸から選ばれ
る）を意味し、R1, R2の少なくとも一方は窒素置換基を
有するカルボン酸残基である。R3, R4は前記の意味を有
する。)で表される 1,4−ジヒドロナフトキノンのカル
ボン酸エステル類の製造法。2. A compound of the general formula (II) (Wherein, R 3 represents a hydrogen atom or a methyl group. R 4 represents n means an integer of 1 to 14. Vitamin K represented by)
Of the general formula (III) obtained by reduction of the compounds (Wherein, R 3 and R 4 have the above-mentioned meanings)
4-dihydronaphthoquinone and an amino acid, N-acyla
Amino acids, N-alkylamino acids, N, N-dialkylamido
Carboxylic acids having a nitrogen substituent selected from carboxylic acids and pyridine carboxylic acids (wherein amino acids are glycine and alanine)
Phenylalanine, tranexamic acid and aminoca
Selected from pronic acid ) or its acid halogenite ,
Or an esterification reaction of these hydrohalides with the general formula (I): (Wherein R 1 and R 2 are each a hydrogen atom or an amino
Acid, N-acyl amino acid, N-alkyl amino acid, N, N
-Dialkyl amino acids, pyridine carboxylic acids and the like
Residue of a hydrohalide or alkyl sulfonate
Carboxylic acid residue having a nitrogen substituent selected from (but
Amino acids are glycine, alanine, phenylalanine
Tranexamic acid and aminocaproic acid
At least one of R 1 and R 2 is a carboxylic acid residue having a nitrogen substituent. R 3 and R 4 have the meaning described above. )), A process for producing carboxylic acid esters of 1,4-dihydronaphthoquinone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03172221A JP3088137B2 (en) | 1990-07-18 | 1991-07-12 | 1,4-dihydronaphthoquinone derivative and method for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2-190207 | 1990-07-18 | ||
| JP19020790 | 1990-07-18 | ||
| JP03172221A JP3088137B2 (en) | 1990-07-18 | 1991-07-12 | 1,4-dihydronaphthoquinone derivative and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH054951A JPH054951A (en) | 1993-01-14 |
| JP3088137B2 true JP3088137B2 (en) | 2000-09-18 |
Family
ID=26494653
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP03172221A Expired - Lifetime JP3088137B2 (en) | 1990-07-18 | 1991-07-12 | 1,4-dihydronaphthoquinone derivative and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3088137B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021187314A1 (en) | 2020-03-17 | 2021-09-23 | 学校法人福岡大学 | Mitochondrial dysfunction improving agent |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LT4716B (en) | 1998-10-19 | 2000-10-25 | Alfredo Vlado Balandžio Įmonė | Method of producing concrete product |
| JP4818500B2 (en) * | 2000-09-05 | 2011-11-16 | 株式会社ペンタプラストア | Tocotrienol derivative and method for producing the same |
| JP4959914B2 (en) * | 2003-10-15 | 2012-06-27 | 株式会社コーセー | Topical skin preparation |
| WO2006080463A1 (en) * | 2005-01-28 | 2006-08-03 | Fukuoka University | Therapeutic agent for cancer and recurrence preventive each containing vitamin k hydroquinone derivative |
| JP2008231077A (en) * | 2007-03-23 | 2008-10-02 | Univ Fukuoka | Dermatological preparation for external use |
| WO2016208742A1 (en) * | 2015-06-25 | 2016-12-29 | 参天製薬株式会社 | Injection |
| JP7394433B2 (en) * | 2019-03-19 | 2023-12-08 | 学校法人福岡大学 | Vitamin K preparations applied under light exposure, external skin preparations, eye drops, and eye ointments using the same |
-
1991
- 1991-07-12 JP JP03172221A patent/JP3088137B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021187314A1 (en) | 2020-03-17 | 2021-09-23 | 学校法人福岡大学 | Mitochondrial dysfunction improving agent |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH054951A (en) | 1993-01-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4443475A (en) | Amides of acyl-carnitines, process for preparing same and pharmaceutical compositions containing such amides | |
| AU2003284808B2 (en) | The derivatives of pyridone and the use of them | |
| US5232913A (en) | Antihepatopathic composition | |
| JP2804177B2 (en) | Brain-retaining compound and its use | |
| JP3088137B2 (en) | 1,4-dihydronaphthoquinone derivative and method for producing the same | |
| US5196412A (en) | Gallium compounds | |
| JPH0333127B2 (en) | ||
| EP0420121B1 (en) | Antitumor composition | |
| US5254579A (en) | N-(5-thioxo-L-prolyl)-L-cysteine, derivatives thereof, processes for the preparation thereof and pharmaceutical compositions containing them | |
| US4496584A (en) | Amidine derivatives with anti-complement activity | |
| EP0420224B1 (en) | Antihepatopathic composition | |
| JP5015781B2 (en) | Pharmaceutical disulfide salts | |
| US6602899B1 (en) | β-D-5 thioxylose derivatives, preparation method and therapeutic use | |
| JP2569060B2 (en) | Glutamylcysteine derivative, method for producing the same, and tissue glutathione level enhancer containing the same as an active ingredient | |
| US4189499A (en) | Lysine 4-allyloxy-3-chlorophenylacetate and method of its preparation | |
| KR101172472B1 (en) | Quaternary ammonium compound, process for producing the same, therapeutic agent for cerebrovascular disorder, and therapeutic agent for heart disease | |
| US4133890A (en) | Hypolipidemic compositions and method employing derivatives of 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid | |
| FR2729668A1 (en) | NOVEL MERCAPTOALCANOYLDIPEPTIDES DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| CA1311477C (en) | 1-hydroxy-5-oxo-5h-pyrido¬3,2-a|phenoxazine -3-carboxylic acid esters | |
| US4218475A (en) | Hypolipidemic benzylaminobenzene alkanoic or alkenoic acids | |
| JPH05105627A (en) | New medicinal composition used for treatment of functional disease of intenstine, process for preparing sameand method for preparing therapeutic medicine | |
| US5616741A (en) | Process for the preparation of glycine-conjugated bile acids | |
| JPH06256185A (en) | Vitamin e derivative and antiulcer agent containing the same as active ingerdient | |
| JPH0570402A (en) | New lignans, intermediate thereof and production of the same intermediate | |
| JPH0248574A (en) | Bis (methylenedioxy) biphenyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313111 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090714 Year of fee payment: 9 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20090714 Year of fee payment: 9 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100714 Year of fee payment: 10 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110714 Year of fee payment: 11 |
|
| EXPY | Cancellation because of completion of term |