JPS62239989A - Promoter for hydrolase activity - Google Patents
Promoter for hydrolase activityInfo
- Publication number
- JPS62239989A JPS62239989A JP61084455A JP8445586A JPS62239989A JP S62239989 A JPS62239989 A JP S62239989A JP 61084455 A JP61084455 A JP 61084455A JP 8445586 A JP8445586 A JP 8445586A JP S62239989 A JPS62239989 A JP S62239989A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- promoter
- blood
- hydrolase activity
- blood coagulation
- 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
- 230000000694 effects Effects 0.000 title claims abstract description 31
- 102000004157 Hydrolases Human genes 0.000 title claims abstract description 24
- 108090000604 Hydrolases Proteins 0.000 title claims abstract description 24
- -1 cyclic organic compound Chemical class 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 150000001923 cyclic compounds Chemical group 0.000 claims abstract description 6
- 150000004696 coordination complex Chemical class 0.000 claims description 8
- 102000012479 Serine Proteases Human genes 0.000 claims description 6
- 108010022999 Serine Proteases Proteins 0.000 claims description 6
- 108010014173 Factor X Proteins 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 210000002966 serum Anatomy 0.000 abstract description 12
- 150000002430 hydrocarbons Chemical group 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 3
- 229910052782 aluminium Inorganic materials 0.000 abstract description 2
- 229910052742 iron Inorganic materials 0.000 abstract description 2
- 229910052759 nickel Inorganic materials 0.000 abstract description 2
- 239000012266 salt solution Substances 0.000 abstract description 2
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical group O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 abstract 1
- 150000001455 metallic ions Chemical class 0.000 abstract 1
- 230000023555 blood coagulation Effects 0.000 description 34
- 210000004369 blood Anatomy 0.000 description 17
- 239000008280 blood Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 11
- 150000004698 iron complex Chemical class 0.000 description 8
- 238000009534 blood test Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- LNTHITQWFMADLM-UHFFFAOYSA-N anhydrous gallic acid Natural products OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 235000004515 gallic acid Nutrition 0.000 description 3
- 229940074391 gallic acid Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 2
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 2
- 229920002079 Ellagic acid Polymers 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000000429 Factor XII Human genes 0.000 description 2
- 108010080865 Factor XII Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000010876 biochemical test Methods 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 235000004132 ellagic acid Nutrition 0.000 description 2
- 229960002852 ellagic acid Drugs 0.000 description 2
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 2
- HCZKYJDFEPMADG-UHFFFAOYSA-N nordihydroguaiaretic acid Chemical compound C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 229920003002 synthetic resin Polymers 0.000 description 2
- 239000000057 synthetic resin Substances 0.000 description 2
- 150000007577 5-membered cyclic compounds Chemical class 0.000 description 1
- 150000007578 6-membered cyclic compounds Chemical class 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000004700 cobalt complex Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate group Chemical group [N+](=O)([O-])[O-] NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012508 resin bead Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
Landscapes
- Investigating Or Analysing Biological Materials (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は加水分解酵素活性促進剤、特に血液凝固第ＸＩ
Ｉ因子などのセリンプロテアーゼ前駆体の活性化および
活性化された該因子の酵素活性を促進し、血液凝固促進
剤として有用な加水分解酵素活性促進剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a hydrolase activity enhancer, particularly blood coagulation enzyme XI.
The present invention relates to a hydrolase activity promoter that promotes the activation of serine protease precursors such as factor I and the enzymatic activity of the activated factors, and is useful as a blood coagulation promoter.
（従来の技術）
検査技術の目覚ましい進歩とあいまって血清生化学検査
、血清免疫学検査、血球検査などの血液検査が広く普及
し、病気予防や早期診断に役立っている。血液検査の多
くは血清検査であり、その検査に要する血清は１通常、
血液検査用容器に採取した血液を凝固させた後、遠心分
離によって。(Prior Art) With the remarkable progress in testing technology, blood tests such as serum biochemical tests, serum immunological tests, and blood cell tests have become widely used, and are useful for disease prevention and early diagnosis. Most blood tests are serum tests, and the serum required for the test is usually 1.
Blood collected in a blood test container is coagulated and then centrifuged.
比重の異なる血餅（フィブリンと血球が混合したゲル様
塊状物）から分離し、ピペットを用いて。Use a pipette to separate blood clots (gel-like lumps of fibrin and blood cells) with different specific gravities.
あるいはデカンテーションにより採取している。Alternatively, it is collected by decantation.
被験者から採取された血液が凝固するには比較的長時間
を必要とする。例えば、血液凝固時間が比較的短いとさ
れるガラス製検査容器を用いても血液が凝固するまでに
４０〜６０分を必要とし１合成樹脂製検査容器を用いる
と、実に４時間以上の放置時間が必要となる。そのため
、検査に必要な血清を迅速に確保できないという欠点を
有する。これは、特に緊急に検査を実施する必要のある
場合に問題となる。Blood taken from a subject requires a relatively long time to coagulate. For example, even if a glass test container, which has a relatively short blood coagulation time, is used, it takes 40 to 60 minutes for the blood to coagulate.1If a synthetic resin test container is used, it will take more than 4 hours to leave the blood. Is required. Therefore, it has the disadvantage that serum necessary for testing cannot be quickly secured. This becomes a problem especially when there is a need to carry out an inspection urgently.
血液を速やかに凝固させるため血液凝固促進剤が使用さ
れる。例えば、血液中の第ＸＩＩ因子（接触因子）を活
性化する血液凝固促進剤が用いられる。第ＸＩＩ因子は
血液凝固に係る蛋白質加水分解酵素前駆体の一種であり
、これが活性化することにより血液中の他の血液凝固因
子が連鎖的に活性化され血液凝固が始まる。第ＸＩＩ因
子活性促進剤としては、従来からガラス、カオリン、ベ
ントナイト、シリカなどの無機微粒子やエラジン酸が知
られているが、これらを血液凝固促進剤として用いても
、その純度や組成により血液凝固時間などにバラツキが
ある。発明者は、血液凝固促進剤に利用されうる加水分
解酵素活性促進剤として下記一般式で示され、かつ、該
式中の隣接するカルボニル基が実質的に同一平面上に存
在する環式有機化合物を提案している（特開昭６０−１
１５５１９号公報）：（ここで、Ａは環式化合物の残基
を示す）。Blood coagulation promoters are used to quickly coagulate blood. For example, a blood coagulation promoter that activates factor XII (contact factor) in blood is used. Factor XII is a type of proteolytic enzyme precursor involved in blood coagulation, and when it is activated, other blood coagulation factors in the blood are activated in a chain manner, and blood coagulation begins. Inorganic fine particles such as glass, kaolin, bentonite, and silica, as well as ellagic acid, have been known as factor There are variations in time etc. The inventor has developed a cyclic organic compound represented by the general formula below as a hydrolase activity promoter that can be used as a blood coagulation promoter, and in which adjacent carbonyl groups exist substantially on the same plane. (Unexamined Japanese Patent Publication No. 60-1)
15519): (Here, A represents a residue of a cyclic compound).
上記化合物としては例えば、没食子酸アルキルエステル
酸化物、エラジン酸酸化物などが挙げられる。これらの
加水分解酵素活性促進剤は比較的短時間で血液を凝固さ
せることができ、血液凝固に要する時間にも大きなバラ
ツキがない。Examples of the above-mentioned compounds include gallic acid alkyl ester oxides and elladic acid oxides. These hydrolase activity promoters can coagulate blood in a relatively short time, and there is no large variation in the time required for blood coagulation.
（発明が解決しようとする問題点）
発明者は上記環式化合物をさらに検討し、優れた血液凝
固促進剤となりうる加水分解酵素活性促進剤の開発を試
みた。本発明の目的は、優れた血液凝固促進剤となりう
る加水分解酵素活性促進剤を提供することにある。(Problems to be Solved by the Invention) The inventor further studied the above-mentioned cyclic compounds and attempted to develop a hydrolase activity promoter that can be an excellent blood coagulation promoter. An object of the present invention is to provide a hydrolase activity promoter that can serve as an excellent blood coagulation promoter.
（問題点を解決するための手段および作用）本発明の加
水分解酵素活性促進剤は、下記一般式で示され、かつ、
咳式中の隣接するカルボニル基が実質的に同一平面上に
存在する環式有機化合物（Ｉ）を配位子とする金属錯体
からなり、そのことにより上記目的が達成される：
（ここで、Ａは環式化合物の残基を示す）。(Means and effects for solving the problems) The hydrolase activity promoter of the present invention is represented by the following general formula, and
It consists of a metal complex having a cyclic organic compound (I) as a ligand in which adjacent carbonyl groups in the formula are substantially coplanar, whereby the above object is achieved: (herein, A represents a residue of a cyclic compound).
本発明の加水分解酵素活性促進剤である金属錯体の配位
子成分である上記（Ｉ）式で表される化合物は、同素環
式化合物であっても異部環式化合物であってもよく、ま
た、単環式化合物であっても、多環式化合物であっても
よい。このような環式化合物としては、上記２個のカル
ボニル炭素を含む環が６員環または５員環であることが
好ましい。The compound represented by the above formula (I), which is the ligand component of the metal complex that is the hydrolase activity promoter of the present invention, may be a homocyclic compound or a heterocyclic compound. It may also be a monocyclic compound or a polycyclic compound. In such a cyclic compound, the ring containing the two carbonyl carbons is preferably a 6-membered ring or a 5-membered ring.
同素環式化合物のうち好ましい６員環式化合物としては
下記一般式（ＩＩ）で示される０−キノン環を有する化
合物が挙げられる：
（ここで、 Ｒ，、Ｒ２，Ｒ，およびＲ４は、水素。Among the homocyclic compounds, preferable 6-membered cyclic compounds include compounds having an 0-quinone ring represented by the following general formula (II): (wherein, R,, R2, R, and R4 are hydrogen.
炭化水素基、極性置換基または多環式化合物における残
基を示す）。(represents a hydrocarbon group, a polar substituent or a residue in a polycyclic compound).
上記式において炭化水素基は特に限定されないが。In the above formula, the hydrocarbon group is not particularly limited.
アルキル基、特に炭素数１〜１８のアルキル基が好まし
い。極性置換基も特に限定されない。例えば２カルボキ
シル基、カルボン酸エステル基、水酸基。Alkyl groups, particularly alkyl groups having 1 to 18 carbon atoms, are preferred. The polar substituent is also not particularly limited. For example, 2 carboxyl group, carboxylic acid ester group, hydroxyl group.
アミノ酸、メルカプト基などがある。Ｏ−キノン環を有
する化合物としては、０−キノンをはじめ。These include amino acids and mercapto groups. Examples of compounds having an O-quinone ring include O-quinone.
下記式（Ｉ）〜（■）で示される化合物が挙げられる：
（以下余白）
没食子酸アルキルエステル酸化物
Ｏ
Ｈ
（ここで＋ Ｒ５はアルキル基を示す。）エラジン酸部
分酸化物
ニラジン酸完全酸化物
１・４−ジ（３・４−ジヒドロキシフェニル）２・３−
ジメチルブタン部分酸化物
■０
（Ｖｌ）
■・４−ジ（３・４−ジヒドロキシフェニル）２・３−
ジメチルブタン完全酸化物
υ
（■）
同素環式化合物のうち５員環式化合物の好ましい具体例
としては、下記式（■）で示される１・２・３−トリケ
トヒドロインデンが挙げられる。Compounds represented by the following formulas (I) to (■) are mentioned: (Hereinafter blank) Gallic acid alkyl ester oxide O H (Here, + R5 represents an alkyl group.) Elazinic acid partial oxide Niladic acid complete oxidation 1,4-di(3,4-dihydroxyphenyl)2,3-
Dimethylbutane partial oxide ■0 (Vl) ■・4-di(3.4-dihydroxyphenyl)2.3-
Dimethylbutane complete oxide υ (■) Among the homocyclic compounds, a preferred specific example of the 5-membered cyclic compound is 1,2,3-triketohydroindene represented by the following formula (■).
異節環式化合物としては９例えば２次の一般式（ＩＸ）
で示される化合物が挙げられる。As a heterocyclic compound, 9, for example, the second general formula (IX)
Examples include compounds represented by:
（ここで＋ Ｒ６は水素、炭化水素または多環式化合物
における残基を示し、 Ｒ７およびＲ８は水素、炭化水
素基、極性置換基または多環式化合物における残基を示
す。炭化水素基および極性置換基については（ｎ）式と
同様である。）
（ＩＸ）式で示される化合物の好ましい具体例としては
２例えば２次式で表されるイサチンがある。(Here + R6 represents hydrogen, a hydrocarbon or a residue in a polycyclic compound, R7 and R8 represent hydrogen, a hydrocarbon group, a polar substituent or a residue in a polycyclic compound. Hydrocarbon group and polar The substituents are the same as those in formula (n).) A preferred specific example of the compound represented by formula (IX) is isatin, for example, represented by the quadratic formula.
錯体を形成する金属は、０．〇−配位性を有するアルカ
リ金属以外の金属である。特にＦｅ、 Ｃｏ。The metal forming the complex is 0. 〇-It is a metal other than an alkali metal that has coordinating properties. Especially Fe, Co.
Ｎｉ、 ＡＩなどを含む錯体が取り扱いが容易であるた
め好適である。本発明の加水分解酵素活性促進剤である
金属錯体は上記配位子となる化合物（Ｉ）に上記金属イ
オンを含む塩溶液を加えて得られる。Complexes containing Ni, AI, etc. are suitable because they are easy to handle. The metal complex which is the hydrolase activity promoter of the present invention can be obtained by adding a salt solution containing the above metal ion to the above-mentioned ligand compound (I).
例えば、没食子酸プロピル酸化物の鉄錯体は、没食子酸
プロピル酸化物を含む溶液に塩化第二鉄溶液を混合する
ことにより得られる。このような金属錯体には、錯体内
部の電気的中性を保つためにハロゲン根、硫酸根、硝酸
根、アンモニウム根の１種または２種以上を含む配位子
が含有されていてもよい。水が配位子として含有されて
いてもよい。For example, an iron complex of propyl gallate oxide can be obtained by mixing a ferric chloride solution with a solution containing propyl gallate oxide. Such a metal complex may contain a ligand containing one or more of a halogen group, a sulfate group, a nitrate group, and an ammonium group in order to maintain electrical neutrality inside the complex. Water may be contained as a ligand.
本発明の加水分解酵素活性促進剤を血液凝固促進剤とし
て利用する場合は、血液１ ｍｌにつきこの加水分解酵
素活性促進剤（金属錯体）をＩ Ｘｌ０−１０〜１ｘｌ
ｏ−’ｇの割合で使用する。過少であると血液凝固促進
効果が乏しい。過剰であっても使用量に比例した効果は
得られない。When the hydrolase activity enhancer of the present invention is used as a blood coagulation promoter, the hydrolase activity enhancer (metal complex) is used in an amount of IXl0-10 to 1xl per ml of blood.
Use at a ratio of o-'g. If the amount is too low, the effect of promoting blood coagulation will be poor. Even if it is used in excess, the effect will not be proportional to the amount used.
使用される血液検査用容器はガラス製であっても樹脂製
であってもよい。血液を凝固させるには。The blood test container used may be made of glass or resin. To coagulate blood.
例えば容器中に採取した血液に血液凝固促進剤を加えて
もよく、血液凝固促進剤をあらかじめ容器内部に付与し
ておいてもよい。血液凝固促進剤は。For example, a blood coagulation promoter may be added to the blood collected in the container, or the blood coagulation promoter may be applied to the inside of the container in advance. Blood clotting promoters.
例えば粉末状のまま利用してもよく、あらかじめ適当な
溶媒に溶解もしくは分散させておいてもよい。血液凝固
促進剤を粉末状で、あるいは高濃度の溶液として利用す
る場合に、血液の一部示高濃度の金属錯体と接触して血
液中の蛋白成分が変質するおそれのあるときには、上記
血液凝固促進剤を比表面積の大きい担体に担持させるこ
とが推奨される。For example, it may be used in powder form, or it may be dissolved or dispersed in an appropriate solvent in advance. When using a blood coagulation promoter in powder form or as a highly concentrated solution, if there is a risk that some of the blood may come into contact with highly concentrated metal complexes and alter the protein components in the blood, the above-mentioned blood coagulation promoter may be used. It is recommended that the accelerator be supported on a carrier with a large specific surface area.
このような方法に利用される担体としては、血液検査に
有害な影響を与えず、大きい比表面積を有するものであ
れば、特に限定されない。例えば。The carrier used in such a method is not particularly limited as long as it does not have a harmful effect on blood tests and has a large specific surface area. for example.
不織布、織布、樹脂ビーズなどが好適に用いられる。こ
のような担体に上記血液凝固促進剤を担持させるには２
例えば、その溶液や分散液を担体に塗布したり、溶液や
分散液中に担体を浸漬して含浸させた後、乾燥させる。Nonwoven fabrics, woven fabrics, resin beads, etc. are preferably used. To make such a carrier support the above-mentioned blood coagulation promoter, 2
For example, the solution or dispersion is applied to a carrier, or the carrier is immersed in the solution or dispersion to be impregnated, and then dried.
アラビアゴムなどの適宜の助剤を含む血液凝固促進剤の
水分散液を調製し、これを急速凍結乾燥して血液凝固促
進剤担持粒子状物を得ることもできる。It is also possible to prepare an aqueous dispersion of a blood coagulation promoter containing an appropriate auxiliary agent such as gum arabic, and quickly freeze-dry this to obtain blood coagulation promoter-supported particles.
本発明加水分解酵素活性促進剤は、蛋白質分解酵素、特
に、セリンプロテアーゼの活性を促進する。セリンプロ
テアーゼは、ペプチド鎖におけるＡｒｇと任意のアミノ
酸残基、およびＬｙｓと任意のアミノ酸残基、との間の
結合を加水分解により切断する能力を有する。そのため
本発明の加水分解酵素活性促進剤を血液凝固促進剤とし
て利用するとセリンプロテアーゼ前駆体である第ＸＩＩ
因子の活性化および活性化された該因子の酵素活性が促
進され、その結果、短時間で血液が凝固する。血液凝固
に要する時間は、金属錯体の種類や量、容器の材質９周
囲の温度などにより異なるが１合成樹脂製容器の場合は
２通常２０〜３０分である。The hydrolase activity promoter of the present invention promotes the activity of proteases, particularly serine proteases. Serine protease has the ability to hydrolytically cleave the bond between Arg and any amino acid residue, and between Lys and any amino acid residue in a peptide chain. Therefore, when the hydrolase activity promoter of the present invention is used as a blood coagulation promoter, serine protease precursor XII
Activation of the factor and enzyme activity of the activated factor are promoted, and as a result, blood coagulates in a short time. The time required for blood coagulation varies depending on the type and amount of the metal complex, the material of the container, the ambient temperature, etc. 1. In the case of a container made of synthetic resin, 2. it is usually 20 to 30 minutes.
本発明の化合物は、金属錯体であるため１発明者が先に
開発した加水分解酵素活性促進剤である環式有機化合物
（Ｉ）に比べて、さらに熱安定性に優れる。上記環式有
機化合物を血液凝固促進剤として利用したときには、血
液中の金属成分と錯体を形成し血清成分に変化を与える
おそれがあるが１本発明の化合物は血液中の金属成分と
反応することがないため、正確な検査値が得られる。Since the compound of the present invention is a metal complex, it has better thermal stability than the cyclic organic compound (I), which is a hydrolase activity promoter previously developed by one of the inventors. When the above-mentioned cyclic organic compound is used as a blood coagulation promoter, it may form a complex with metal components in the blood and change serum components. Accurate test values can be obtained because there is no
（実施例） 以下に本発明を実施例につき説明する。(Example) The invention will be explained below with reference to examples.
尖立尉土
没食子酸ｎ−プロピル酸化物鉄錯体（血液凝固促進剤）
の０．１重量％生理食塩水分散液５０μｌを市販のポリ
メチルメタクリレート製スピッツに入れ、これに大所鮮
血５ ｍｌを採取し、２３℃で静置した。血餅収縮が始
まり、血清の滲出が認められた時間を血液凝固時間とし
た。血清の滲出が認められたら直ちに遠心分離器を用い
、 １００ＯＧで５分間遠心分離を行い、血清の分離状
態を目視観察した。それぞれの結果を下表に示す。実施
例２〜８および比較例１〜２の結果もあわせて下表に示
す。Tateritateto Gallic acid n-propyl oxide iron complex (blood coagulation promoter)
50 μl of a 0.1% by weight physiological saline dispersion was placed in a commercially available polymethyl methacrylate Spitz, 5 ml of fresh large blood was collected therein, and the mixture was allowed to stand at 23°C. The time when blood clot contraction started and serum exudation was observed was defined as the blood coagulation time. Immediately after serum oozing was observed, centrifugation was performed at 100OG for 5 minutes using a centrifuge, and the state of serum separation was visually observed. The respective results are shown in the table below. The results of Examples 2 to 8 and Comparative Examples 1 to 2 are also shown in the table below.
去胤皿Ｉ
血液凝固促進剤としてエラジン酸酸化物（７頁（Ｖ）弐
で示される化合物）の鉄錯体を用いたこと以外は実施例
１と同様である。Seed Dish I This was the same as Example 1 except that an iron complex of ellagic acid oxide (compound shown in (V) 2 on page 7) was used as a blood coagulation promoter.
去施炭ユ
血液凝固促進剤として１・２・３〜トリケトヒドロイン
デンの鉄錯体を用いたこと以外は実施例１と同様である
。The procedure was the same as in Example 1 except that an iron complex of 1, 2, 3 to triketohydroindene was used as the charcoalizing blood coagulation promoter.
尖施値工
血液凝固促進剤としてイサチンの鉄錯体を用いたこと以
外は実施例１と同様である。The procedure was the same as in Example 1 except that an iron complex of isatin was used as the blood coagulation promoter.
実施±１
血液凝固促進剤として１・４−ジ（３・４−ジヒドロキ
シフェニル）２・３−ジメチルブタン酸化物の鉄錯体を
用いたこと以外は実施例１と同様である。Implementation ±1 The same as Example 1 except that an iron complex of 1,4-di(3,4-dihydroxyphenyl)2,3-dimethylbutane oxide was used as the blood coagulation promoter.
実ｌｌ辻ｌ
鉄錯体の代わりにコバルト錯体を用いたこと以外は実施
例２と同様である。Same as Example 2 except that a cobalt complex was used instead of an iron complex.
裏庭±１
鉄錯体の代わりにニッケル錯体を用いたこと以外は実施
例２と同様である。Backyard±1 Same as Example 2 except that a nickel complex was used instead of an iron complex.
１施±１
鉄錯体の代わりにアルミニウム錯体を用いたこと以外は
実施例２と同様である。Example 1 ±1 Same as Example 2 except that an aluminum complex was used instead of an iron complex.
ル較■上
血液凝固促進剤を使用しなかったこと以外は実施例１と
同様である。The procedure was the same as in Example 1 except that no blood coagulation promoter was used.
正数±１
ガラス製スピッツを用い、かつ血液凝固促進剤を使用し
なかったこと以外は実施例１と同様である。Positive number ±1 Same as Example 1 except that a glass spitz was used and no blood coagulation promoter was used.
（以下余白）
（発明の効果）
本発明によれば、このように、蛋白質加水分解酵素活性
促進剤が得られる。この活性促進剤は。(Hereinafter in the margin) (Effects of the Invention) According to the present invention, a proteolytic enzyme activity promoter can be obtained in this way. This activity enhancer.
特にセリンプロテアーゼの活性を促進する。このような
化合物を血液凝固促進剤として利用すると血液が短時間
のうちに凝固する。しかも、血清成分を変化させること
がないため、血清を用いた各種検査の検査値が常時正確
かつ安定に得られうる。In particular, it promotes the activity of serine proteases. When such compounds are used as blood coagulation promoters, blood coagulates within a short period of time. Moreover, since serum components are not changed, test values of various tests using serum can be obtained accurately and stably at all times.
本発明の加水分解酵素活性促進剤はその製造および精製
が簡単である。しかも、それ自体、比較的熱に安定であ
るため長期保存にも適する。このような加水分解酵素活
性促進剤は、血液凝固促進剤として、あるいは各種生化
学試験用に好適に利用されうる。The hydrolase activity promoter of the present invention is easy to produce and purify. Moreover, it is itself relatively stable against heat, making it suitable for long-term storage. Such a hydrolase activity promoter can be suitably used as a blood coagulation promoter or for various biochemical tests.
以上that's all
Claims (1)
ボニル基が実質的に同一平面上に存在する環式有機化合
物（ I ）を配位子とする金属錯体からなる加水分解酵
素活性促進剤： ▲数式、化学式、表等があります▼（ I ） （ここで、Ａは環式化合物の残基を示す）。 ２、前記加水分解酵素がセリンプロテアーゼである特許
請求の範囲第１項に記載の加水分解酵素活性促進剤。 ３、前記加水分解酵素が血液凝固第Ｘ I I 因子である
特許請求の範囲第２項に記載の加水分解酵素活性促進剤
。[Claims] 1. A metal complex having as a ligand a cyclic organic compound (I) represented by the following general formula, in which adjacent carbonyl groups exist substantially on the same plane. Hydrolase activity promoter consisting of: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (Here, A indicates the residue of a cyclic compound). 2. The hydrolase activity promoter according to claim 1, wherein the hydrolase is a serine protease. 3. The hydrolase activity promoter according to claim 2, wherein the hydrolase is blood coagulation factor X II.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61084455A JPH084499B2 (en) | 1986-04-11 | 1986-04-11 | Hydrolase activity promoter |
| US07/036,886 US5041558A (en) | 1986-04-11 | 1987-04-10 | Accelerator of the activity of hydrolase |
| CA000534473A CA1313997C (en) | 1986-04-11 | 1987-04-10 | Accelerator of the activity of hydrolase |
| EP87303182A EP0241314B1 (en) | 1986-04-11 | 1987-04-10 | An accelerator of the activity of hydrolase |
| AU71424/87A AU619442C (en) | 1986-04-11 | 1987-04-10 | An accelerator of the activity of hydrolase |
| KR1019870003408A KR950006614B1 (en) | 1986-04-11 | 1987-04-10 | How to promote blood clotting |
| DE3750344T DE3750344T2 (en) | 1986-04-11 | 1987-04-10 | Accelerator of hydrolase activity. |
| US08/135,755 US5413786A (en) | 1986-04-11 | 1993-10-13 | Method of accelerating blood coagulation using a metal complex of oxidized ellagic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61084455A JPH084499B2 (en) | 1986-04-11 | 1986-04-11 | Hydrolase activity promoter |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62239989A true JPS62239989A (en) | 1987-10-20 |
| JPH084499B2 JPH084499B2 (en) | 1996-01-24 |
Family
ID=13831094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61084455A Expired - Lifetime JPH084499B2 (en) | 1986-04-11 | 1986-04-11 | Hydrolase activity promoter |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH084499B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001255332A (en) * | 2000-03-08 | 2001-09-21 | Internatl Reagents Corp | Tissue factor-containing composition |
| JP2002214238A (en) * | 2001-01-03 | 2002-07-31 | Sienco Inc | Method for testing activated clotting time low in sensitivity to presence of aprotinin and method for evaluating adrotinin sensitivity |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9810588B2 (en) | 2012-06-06 | 2017-11-07 | Toshiba Mitsubishi-Electric Industrial Systems Corporation | Optical fiber temperature sensor |
-
1986
- 1986-04-11 JP JP61084455A patent/JPH084499B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001255332A (en) * | 2000-03-08 | 2001-09-21 | Internatl Reagents Corp | Tissue factor-containing composition |
| JP4526152B2 (en) * | 2000-03-08 | 2010-08-18 | シスメックス株式会社 | Prothrombin time measuring reagent |
| JP2002214238A (en) * | 2001-01-03 | 2002-07-31 | Sienco Inc | Method for testing activated clotting time low in sensitivity to presence of aprotinin and method for evaluating adrotinin sensitivity |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH084499B2 (en) | 1996-01-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nelsestuen et al. | Interaction of vitamin K dependent proteins with membranes | |
| Marler et al. | The molecular weight of the polypeptide chains of L-glutamate dehydrogenase | |
| Scheller et al. | Adsorption behaviour of globular proteins at the water/mercury interface | |
| Vroman et al. | Possible involvement of fibrinogen and proteolysis in surface activation | |
| CA1313997C (en) | Accelerator of the activity of hydrolase | |
| JPS62239989A (en) | Promoter for hydrolase activity | |
| Swan | The inhibition of hen egg-white lysozyme by imidazole and indole derivatives | |
| JPS62240616A (en) | Promoter for blood coagulation | |
| Constantinidis et al. | Isoelectric focusing purity criteria and proton NMR detectable spectroscopic heterogeneity in the major isolated monomer hemoglobins from Glycera dibranchiata | |
| JPS63275954A (en) | Container for blood test | |
| Brown et al. | Hydrogen-tritium exchange of partially and fully reconstituted zinc and cobalt alkaline phosphatase of Escherichia coli | |
| JPS6383669A (en) | Blood agglutination accelerator | |
| JPH0546502B2 (en) | ||
| Asakura et al. | Solution electron paramagnetic resonance spectra of hemoproteins at room temperature | |
| Wadsworth et al. | The anticoagulative action of organic acids, and of heparin and the organic base, diethylamine | |
| Brubaker et al. | Models for metal-protein interaction: copper (II) complexes with some substituted cyclic dipeptides | |
| JPS63275953A (en) | Blood coagulation accelerator | |
| Miller et al. | Utilization of Glutamine and Asparagine and their Peptides by Micro-organisms | |
| JPS62240617A (en) | Promoter for blood coagulation | |
| JPS60115519A (en) | Promotor for blood clotting | |
| JPS60186760A (en) | Blood coagulation accelerator | |
| Bishop | The Role of Calcium in the Clotting of Blood as Determined by the Effect of Specific Agents Upon Clotting Time | |
| Vulpis et al. | Some effects of metal cations on blood coagulation | |
| SU518679A1 (en) | Method of histochemical detection of liver tissue red blood cell damage | |
| JPH02128700A (en) | Precipitating liquid for precipitation of lipoprotein-bound enzyme in blood serum |