JPH02111722A - Preventive and remedy for ischemic organopathy - Google Patents
Preventive and remedy for ischemic organopathyInfo
- Publication number
- JPH02111722A JPH02111722A JP1003545A JP354589A JPH02111722A JP H02111722 A JPH02111722 A JP H02111722A JP 1003545 A JP1003545 A JP 1003545A JP 354589 A JP354589 A JP 354589A JP H02111722 A JPH02111722 A JP H02111722A
- Authority
- JP
- Japan
- Prior art keywords
- preventive
- active ingredient
- remedy
- ischemic
- ascorbic acid
- 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
- 230000000302 ischemic effect Effects 0.000 title claims abstract description 15
- 230000003449 preventive effect Effects 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 230000008816 organ damage Effects 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- -1 peroxide lipid Chemical class 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 208000028867 ischemia Diseases 0.000 abstract description 7
- 208000010125 myocardial infarction Diseases 0.000 abstract description 7
- 150000005690 diesters Chemical class 0.000 abstract description 5
- 230000001603 reducing effect Effects 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 241000124008 Mammalia Species 0.000 abstract description 3
- 208000035475 disorder Diseases 0.000 abstract description 3
- WTTKTIBMFBIUSE-RXSVEWSESA-N (2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;sodium Chemical compound [Na].OC[C@H](O)[C@H]1OC(=O)C(O)=C1O WTTKTIBMFBIUSE-RXSVEWSESA-N 0.000 abstract description 2
- 208000002177 Cataract Diseases 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000002537 cosmetic Substances 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000006188 syrup Substances 0.000 abstract description 2
- 235000020357 syrup Nutrition 0.000 abstract description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229940126701 oral medication Drugs 0.000 abstract 1
- 239000003826 tablet Substances 0.000 abstract 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 22
- 229960005070 ascorbic acid Drugs 0.000 description 14
- 241000700159 Rattus Species 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 8
- 239000002211 L-ascorbic acid Substances 0.000 description 7
- 235000000069 L-ascorbic acid Nutrition 0.000 description 7
- 239000011668 ascorbic acid Substances 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 229960000984 tocofersolan Drugs 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229940087168 alpha tocopherol Drugs 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 239000002076 α-tocopherol Substances 0.000 description 3
- 235000004835 α-tocopherol Nutrition 0.000 description 3
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 208000017657 Menopausal disease Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000026062 Tissue disease Diseases 0.000 description 1
- JUIUXBHZFNHITF-IEOSBIPESA-N [(2r)-2,5,7,8-tetramethyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] dihydrogen phosphate Chemical compound OP(=O)(O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C JUIUXBHZFNHITF-IEOSBIPESA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000012374 esterification agent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940118019 malondialdehyde Drugs 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、虚血性臓器障害の予防・治療剤、更に詳しく
は虚血が原因で引き起こされる、例えば心臓などの臓器
障害の予防・治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a prophylactic/therapeutic agent for ischemic organ damage, and more particularly to a prophylactic/therapeutic agent for organ damage caused by ischemia, such as the heart.
従来の技術
成人に多くみられる、例えば心臓、腎臓、脳などの臓器
疾患は、基礎病変として虚血状態によって引き起こされ
る細胞や組織の障害が主因をなしていることが多い。こ
の障害は血流の低下あるいは停止によるエネルギー源の
供給が減少することあるいは途絶えることに原因してい
る。虚血性臓器組織における病変の進展、即ち細胞機能
の低下。BACKGROUND OF THE INVENTION Diseases of organs such as the heart, kidneys, and brain that are common in adults are often primarily caused by damage to cells and tissues caused by ischemic conditions as the underlying lesions. This disorder is caused by a reduced or interrupted supply of energy sources due to reduced or stopped blood flow. Progression of lesions in ischemic organ tissues, i.e. decline in cellular function.
細胞膜障害、細胞破壊あるいはその壊死等は、虚血にさ
らされている時間の長さおよび臓器細胞の耐用性に依存
している。Cell membrane damage, cell destruction, necrosis, etc. depend on the length of time exposed to ischemia and the tolerance of organ cells.
このため、これまで虚血性臓器障害の予防ないし治療に
は、臓器への血液供給を増加させる作用のある血管拡張
薬あるいは臓器細胞のエネルギー源要を減少させ１１性
を増強する作用のあるβ遮断薬やＣａ拮抗薬などが用い
られてきた。For this reason, for the prevention or treatment of ischemic organ damage, vasodilators that increase blood supply to organs or beta-blockers that reduce the energy source of organ cells and enhance 11 activity have been used. Medications and Ca antagonists have been used.
ところが、最近の研究では病変巣の進展には細胞膜を構
成する成分である不飽和脂肪酸の変化（すなわち過酸化
脂質等の生成）およびその生理活性代謝物（例えば、プ
ロスタグランジン類、ロイコトリエン類等）の有害な作
用が深く関与していることが明らかになった。However, recent studies have shown that the progression of lesion foci is due to changes in unsaturated fatty acids, which are components of cell membranes (i.e., production of lipid peroxides, etc.) and their physiologically active metabolites (e.g., prostaglandins, leukotrienes, etc.). ) was found to be deeply involved in the harmful effects of
近年、このような基礎的研究に立脚する新しいタイプの
薬剤の開発が注目されているが、未だ満足すべき薬剤は
、見い出されていない。In recent years, the development of new types of drugs based on such basic research has attracted attention, but a satisfactory drug has not yet been found.
発明の構成
本発明者等は、リン酸が有する３個の水酸基のうちの１
つがアスコルビン酸の２位の水酸基で、また他の１つが
α−トコフェロールなどの各種トコフェロールの水酸基
でエステル化された構造のリン酸ジエステル化合物の薬
理作用について検討した結果、アスコルビン酸あるいは
トコフェロールそれぞれ単独成分とは別に、本化合物特
有の薬理作用を見いだした。Structure of the Invention The present inventors discovered that one of the three hydroxyl groups that phosphoric acid has
As a result of studying the pharmacological effects of phosphodiester compounds with a structure in which one is esterified with the 2-hydroxyl group of ascorbic acid and the other is esterified with the hydroxyl group of various tocopherols such as α-tocopherol, we found that ascorbic acid or tocopherol are each a single component. Apart from this, we also discovered a unique pharmacological action of this compound.
すなわち、本化合物が、動物実験において過酸化脂質生
成抑制作用、さらには虚血／再潅流モデルにおける心筋
梗塞巣の縮小作用を有することを見い出し、これら知見
に基づいてさらに検討の結果、本発明を完成した。That is, the present compound was found to have an effect of inhibiting lipid peroxide production in animal experiments and an effect of reducing myocardial infarction lesions in an ischemia/reperfusion model.Based on these findings, as a result of further studies, the present invention was achieved. completed.
すなわち、本発明は一般式
１式中、Ｒ１＋Ｒ１”よびＲ３は同一または異なってメ
チル基または水素原子を示すコで表わされる化合物また
はその塩を有効成分として含有する虚血性臓器障害の予
防・治療剤である。That is, the present invention provides a prophylactic/therapeutic agent for ischemic organ damage containing as an active ingredient a compound or a salt thereof represented by formula 1, in which R1+R1'' and R3 are the same or different and represent a methyl group or a hydrogen atom. It is.
本発明において有効成分として用いる化合物［１］は、
文献収載の化合物であり、たとえばα−トコフェロール
に、三塩化ホスホリルなどの７Ｘロリン酸エステル化剤
を反応させ、得られた反応生成物に、５，６−位の水酸
基をインプロピリデンなどの保護基で保護したアスコル
ビン酸を反応させ、次いで生成物の保護基を脱離させる
ことによって５２をすることができる。例えば、特開昭
５９−２１９２９５号、特開昭６２−２０５０９１号各
公報に詳細な製造法が記載されている。The compound [1] used as an active ingredient in the present invention is
This is a compound listed in literature, for example, by reacting α-tocopherol with a 7X phosphoric acid esterification agent such as phosphoryl trichloride, and protecting the hydroxyl groups at the 5 and 6-positions with inpropylidene or the like in the resulting reaction product. 52 can be prepared by reacting a group-protected ascorbic acid and then removing the protecting group on the product. For example, detailed manufacturing methods are described in JP-A-59-219295 and JP-A-62-205091.
式［＋］で示される化合物の塩としては、例えば、ナト
リウム塩、カリウム塩などのアルカリ金属塩あるいはカ
ルシウム塩、マグネシウム塩などのアルカリ土類金属塩
を挙げることができる。Examples of the salt of the compound represented by the formula [+] include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts.
上記化合物［１］およびその塩として、具体的には、例
えばし−アスコルビン酸・ＤＬ−α−トコフェロールリ
ン酸ジエステル、そのカリウム塩、ナトリウム塩または
カルシウム塩、Ｌ−アスコルビン酸・ＤＬ−β−トコフ
ェロールリン酸ジエステルまたはそのナトリウム塩、Ｌ
−アスコルビン酸・ＤＬ−γ−トコフェロールリン酸ジ
エステルまたはそのナトリウム塩、し−アスコルビン酸
・Ｄδ−トコフェロールリン酸ジエステルまたはそのカ
リウム塩などを挙げることができる。Examples of the above compound [1] and its salts include, for example, ascorbic acid/DL-α-tocopherol phosphate diester, its potassium salt, sodium salt, or calcium salt, L-ascorbic acid/DL-β-tocopherol Phosphoric acid diester or its sodium salt, L
Examples include -ascorbic acid/DL-γ-tocopherol phosphate diester or its sodium salt, and -ascorbic acid/Dδ-tocopherol phosphate diester or its potassium salt.
因みに、これら化合物は、従来、抗炎症剤、白内障や更
年期障害の予防治療剤あるいは美肌作用を有する化粧品
用剤として知られている。Incidentally, these compounds have been conventionally known as anti-inflammatory agents, preventive and therapeutic agents for cataracts and menopausal disorders, and cosmetic agents having skin beautifying effects.
本発明の虚血性臓器障害予防・治療剤は上記化合物また
はその塩を有効成分として含有する。The preventive/therapeutic agent for ischemic organ damage of the present invention contains the above compound or a salt thereof as an active ingredient.
本発明の予防治療剤は経口的もしくは非経口的にヒトな
どの哺乳動物に投与することができる。The prophylactic and therapeutic agent of the present invention can be administered orally or parenterally to mammals such as humans.
このためには薬理学的に許容されるそれ自体公知の担体
、賦形剤、希釈剤などを用いて常法に従って、例えば注
射剤などの非経口剤あるいは錠剤。For this purpose, parenteral preparations such as injections or tablets can be prepared according to conventional methods using pharmacologically acceptable carriers, excipients, diluents, etc. that are known per se.
カプセル剤、シロップ剤などの経口用剤として調製し、
これを投与すればよい。Prepared as oral preparations such as capsules and syrups,
Just administer this.
投与量は、投与対象、投与経路、障害・病態の程度など
によっても異なるが、一般には成人に対し、化合物［■
１として、１同量０ 、 Ｉ ＩＯｇ／ ｋｇ体重以上
、通常５〜１０００ ｍｇ／ ｍａｎ、好ましくは５〜
３００ｍｇ／ｍａｎを１日１〜３回投与する。The dosage varies depending on the subject, administration route, degree of disorder/pathological condition, etc., but in general, for adults, the compound [■
As 1, the same amount of 1 IOg/kg body weight or more, usually 5 to 1000 mg/man, preferably 5 to
Administer 300 mg/man 1-3 times a day.
発明の効果
本発明の予防治療剤の有効成分である化合物［１］また
はその塩は、ラット脳ホモジネートを用いた試験管内実
験で過酸化脂質生成抑制作用を示し、さらにラット心臓
における虚血／再潅流モデルにおいてその機能障害を改
善する作用が認められた。Effects of the Invention Compound [1] or a salt thereof, which is an active ingredient of the preventive and therapeutic agent of the present invention, has shown an inhibitory effect on lipid peroxide production in in vitro experiments using rat brain homogenate, and has also been shown to inhibit ischemia/reactivation in rat hearts. In the perfusion model, the effect of improving the functional impairment was observed.
しかも、本発明の予防治療剤の有効成分は極めて毒性が
低く、たとえばＬ−アスコルビン酸・ＤＬ−α−トコフ
ェロールリン酸ジエステルナトリウムのＬＤ、。は経口
投与１０ｇ／ｋｇ（ラット）以上、皮下投与７９３ｍｇ
／ｋｇ（ラット）である。Moreover, the active ingredients of the preventive and therapeutic agent of the present invention have extremely low toxicity, such as LD of sodium L-ascorbic acid/DL-α-tocopherol phosphate diester. Oral administration 10g/kg or more (rat), subcutaneous administration 793mg
/kg (rat).
したがって、本発明の予防・治療剤はヒトなどの哺乳動
物における虚血性心臓障害（例えば、心筋梗塞、心不全
、不整脈などの虚血に基づく諸種心疾患）、虚血性脳組
織障害（例えば、脳梗塞、脳卒中などの脳血管障害）、
虚血性腎障害（例えば、腎不全）などの予防・治療剤と
して有用である。Therefore, the preventive/therapeutic agent of the present invention is useful for ischemic heart disorders (e.g., various heart diseases based on ischemia such as myocardial infarction, heart failure, and arrhythmia) and ischemic brain tissue disorders (e.g., cerebral infarction) in mammals such as humans. , cerebrovascular disorders such as stroke),
It is useful as a prophylactic/therapeutic agent for ischemic renal damage (eg, renal failure).
以下、実施例を挙げて本発明を、更に具体的に説明する
。Hereinafter, the present invention will be explained in more detail with reference to Examples.
以下の説明で使用する化合物の略記号は次の通りである
。The abbreviations of compounds used in the following description are as follows.
ａ ＥＰＣＮａ（ＤＬ）：（Ｒ＋−５＝ｃ）ＩＪし一
アスコルビン酸・ＤＬ−α−トコフェロールリン酸ジエ
ステルナトリウム
β−ＥＰＣＫ（ＤＬ）：（Ｒ＋、Ｒ５＝Ｃ！Ｉｓ：Ｒｅ
・Ｈ）し−アスコルビン酸・ＤＬ−β−トコフェロール
リン酸ジエステルカリウム
γ−ＥＰＣ−Ｋ（Ｄ）： （Ｒ１・Ｈ：Ｒｔ、 Ｒｓ・
ＣＨ３）Ｌ−アスコルビン酸・Ｄ−γ−トコフェロール
リン酸ジエステルカリウム
δ−ＥＰＣ−Ｋ（Ｄ）：（Ｒ１、Ｒ２・Ｈ；Ｒ，＝Ｃ１
１，）Ｌ−アスコルビン酸・Ｄ−δ−トコフェロールリ
ン酸ジエステルカリウム
Ｔ Ｐ ＣＮ ａ （Ｄ Ｌ） ： （Ｒ８−ｓ−Ｈ）
Ｌ−アスコルビン酸・ＤＬ−１−フリルリン酸ジエステ
ルナトリウム
実施例１
ラット脳ホモジネートにおける過酸化脂質生成抑制作用
についての実験
（ｉ）実験方法
雄性ＳＤラット（１０〜１２週令）をベンドパルビター
ル麻酔下に瀉血したのち、脳組織を摘出した。この脳組
織をリン酸緩衝液（ｐＨ７，４）中でホモジナイズし、
５％（ｗ／Ｖ）ホモジネートとして用いた。a EPCNa (DL): (R+-5=c) IJ monoascorbic acid/DL-α-tocopherol phosphate diester sodium β-EPCK (DL): (R+, R5=C!Is:Re
・H) Shi-ascorbic acid DL-β-tocopherol phosphate diester potassium γ-EPC-K (D): (R1・H: Rt, Rs・
CH3) L-ascorbic acid/D-γ-tocopherol phosphate diester potassium δ-EPC-K(D): (R1, R2・H; R,=C1
1,) L-ascorbic acid/D-δ-tocopherol phosphate diester potassium TPCNa (DL): (R8-s-H)
L-ascorbic acid/sodium DL-1-furyl phosphate diester Example 1 Experiment on the inhibitory effect on lipid peroxide production in rat brain homogenate (i) Experimental method Male SD rats (10 to 12 weeks old) were anesthetized with bendoparbital. After bloodletting, brain tissue was removed. This brain tissue was homogenized in phosphate buffer (pH 7,4),
It was used as a 5% (w/v) homogenate.
同ホモジネートを３７℃で１時間インキュベートした後
、Ｏｈｋａｗａ等のアナリティカル・バイオケミストリ
ー ［Ａｎａｌｙｔｉｃａｌ Ｂｉｏｃｈｅｍｉｓｔ
ｒｙ、 ９５＋３５１ （１９７９）］の記載にした
がって、マロンジアルデヒド量をチオバルビッール酸（
ＴＢＡ）法によって測定し、過酸化脂質生成量の指標と
した。After incubating the same homogenate at 37°C for 1 hour, it was incubated with the analytical biochemist
ry, 95+351 (1979)], the amount of malondialdehyde was changed to thiobarbylic acid (
It was measured by the TBA) method and used as an index of the amount of lipid peroxide produced.
被験薬物としてはα−ＥＰＣ−Ｎａ（ＤＬ）、β−ＥＰ
Ｃ−Ｋ（ＤＬ）、γ−ＥＰＣ−Ｋ（Ｄ）、δ−ＥＰＣ−
Ｋ（Ｄ）およびＴＰＣ−Ｎａ（ＤＬ）を用い、これをイ
ンキュベーションする前に５％ホモジネート中へ最終濃
度が１０−’Ｍとなるように添加した。Test drugs include α-EPC-Na (DL) and β-EP.
C-K (DL), γ-EPC-K (D), δ-EPC-
K (D) and TPC-Na (DL) were added to a final concentration of 10-'M into the 5% homogenate before incubation.
過酸化脂質生成の抑制作用は、溶媒ジメチルスルホキシ
ド（ＤＭＳＯ）添加群と比較して抑制率をパーセントと
して表わした。The inhibitory effect on lipid peroxide production was expressed as a percentage inhibition rate compared to the group to which the solvent dimethyl sulfoxide (DMSO) was added.
比較被験薬物としてＤＬ−α−トコフェロール。DL-α-tocopherol as a comparative test drug.
Ｌ−アスコルビン酸を用いて、それぞれ同様の実験を行
なった。Similar experiments were conducted using L-ascorbic acid.
（ｉｉ）実験結果 実験結果を法衣（表１）に示した。(ii) Experimental results The experimental results are shown in the vestibule (Table 1).
表１： ラット脳ホモジネートにおけろ過酸化脂質生成
抑制作用
上表から明らかなように、過酸化脂質生成抑制作用にお
いて、水溶性の上記化合物が脂溶性のα−トコフェロー
ルに匹敵するか、あるいはそれ以上の値を示したことは
、本発明に係る化合物が満足すべき薬剤であることを示
唆するものといえる。Table 1: Filtration oxidized lipid production inhibitory effect in rat brain homogenate As is clear from the above table, the above water-soluble compounds are comparable to or better than fat-soluble α-tocopherol in terms of the lipid peroxide production inhibitory effect. This value suggests that the compound according to the present invention is a satisfactory drug.
なお、Ｌ−アスコルビン酸それ自体に抑制作用は認めら
れなかった。Note that no inhibitory effect was observed in L-ascorbic acid itself.
実施例２
ラット冠動脈閉鎖−再潅流による心筋梗塞巣に対するα
−ＥＰＣ−Ｎａの縮小作用についての実験
（ｉ）実験方法
Ｗｉｓｔａｒ雄性ラット（体重２７６−３３０ｇ）を使
ってベンドパルビタール麻酔下に正中にて開胸し、左冠
動脈前下行技（ＬＡＤ）をその起始部で１時間閉鎖し、
続いて再潅流した。再潅流３０〜６０分後に開胸し、覚
醒下に保った。２４時間後に再び麻酔下にて心臓を摘出
し、その左心室を輪切りにした。トリフェニルテトラゾ
リウムクロライド（Ｔ Ｔ Ｃ）を用いて３７℃で１５
分間染色し梗塞巣を秤量した。Example 2 α for myocardial infarction caused by rat coronary artery occlusion-reperfusion
- Experiment on the reduction effect of EPC-Na (i) Experimental method Wistar male rats (weight 276-330 g) were opened in the midline under bendoparbital anesthesia, and left anterior descending coronary artery maneuver (LAD) was performed. Closed for one hour at the starting point,
This was followed by reperfusion. The chest was opened 30-60 minutes after reperfusion and the animals were kept awake. After 24 hours, the heart was removed again under anesthesia, and its left ventricle was sliced into rounds. 15 at 37°C using triphenyltetrazolium chloride (TTC).
The cells were stained for minutes and the infarcts were weighed.
α−ＥＰＣ−Ｎａは、生理食塩水に溶解したのち、ＬＡ
Ｄ閉鎖閉鎖３浚
および５ ｍｇｌ ｋｇの用量で投与した。対照群には
生理食塩水のみを投与した。After dissolving α-EPC-Na in physiological saline, LA
D-closure was administered at a dose of 3 ml and 5 mgl kg. The control group received only physiological saline.
（ｉｉ）実験結果 実験結果を法衣（表２）に示した。(ii) Experimental results The experimental results are shown in the vestibule (Table 2).
表２： ラット虚血−再潅流による心筋梗塞巣に対する
αーＥＰＣーＮａの縮小作用
上表から明らかなようにαーＥＰＣーＮａは用量依存的
に心筋梗塞巣を縮小させる作用が認められ、５ ■／
ｋｇの用量では、心筋梗塞巣の大きさを約１／２に縮小
させる作用のあることが判明した。Table 2: Reducing effect of α-EPC-Na on myocardial infarction due to rat ischemia-reperfusion As is clear from the above table, α-EPC-Na has a dose-dependent effect on reducing myocardial infarction. 5 ■/
It was found that a dose of 1 kg was effective in reducing the size of myocardial infarction by about 1/2.
実施例３ 下記成分を用い、常套の手段により錠剤を調製する。Example 3 Tablets are prepared by conventional means using the ingredients listed below.
・Ｌ−アスコルビン酸・ＤＬ −ａ−１−コフェロール
リン酸ジエステルナトリウム５０ｍｇ・コーンスターチ
９０＋ｎｇ・ラクトース
３０ＩＩ１ｇ・ヒドロキシプロピルセルロー・L-ascorbic acid ・DL-a-1-copherol diester sodium phosphate 50mg ・Corn starch 90+ng ・Lactose
30II1g hydroxypropyl cellulose
Claims (3)
ってメチル基または水素原子を示す］で表わされる化合
物またはその塩を有効成分として含有する虚血性臓器障
害予防・治療剤。(1) Contains a compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1, R_2 and R_3 are the same or different and represent a methyl group or a hydrogen atom] or a salt thereof as an active ingredient. A preventive/therapeutic agent for ischemic organ damage.
１）記載の虚血性臓器障害予防・治療剤。(2) In the general formula, R_3 is a methyl group (
1) The agent for preventing and treating ischemic organ damage as described above.
ち、少なくとも２つ以上がメチル基である請求項（１）
記載の虚血性臓器障害予防・治療剤。(3) Claim (1) wherein at least two or more of R_1, R_2 and R_3 in the general formula are methyl groups.
The agent for preventing and treating ischemic organ damage described above.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP354589A JP2714678B2 (en) | 1988-01-11 | 1989-01-10 | Prevention and treatment of ischemic organ damage |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-4480 | 1988-01-11 | ||
| JP448088 | 1988-01-11 | ||
| JP354589A JP2714678B2 (en) | 1988-01-11 | 1989-01-10 | Prevention and treatment of ischemic organ damage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02111722A true JPH02111722A (en) | 1990-04-24 |
| JP2714678B2 JP2714678B2 (en) | 1998-02-16 |
Family
ID=26337154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP354589A Expired - Fee Related JP2714678B2 (en) | 1988-01-11 | 1989-01-10 | Prevention and treatment of ischemic organ damage |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2714678B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0687411A1 (en) | 1994-06-14 | 1995-12-20 | Senju Pharmaceutical Co., Ltd. | Hepatic graft preservative composition and a method for viable preservation of the hepatic graft |
| WO1999039719A1 (en) * | 1998-02-06 | 1999-08-12 | Cci Corporation | Preventives and remedies for ischemic reflow disorder |
| US5965750A (en) * | 1995-10-17 | 1999-10-12 | Showa Denko K.K. | High- purity tocopherol phosphates, process for the preparation thereof, methods for analysis thereof, and cosmetics |
| US6277834B1 (en) | 1998-06-19 | 2001-08-21 | Senju Pharmaceutical Co. Ltd. | Agents for relieving side effects of adrenal cortex hormone |
-
1989
- 1989-01-10 JP JP354589A patent/JP2714678B2/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0687411A1 (en) | 1994-06-14 | 1995-12-20 | Senju Pharmaceutical Co., Ltd. | Hepatic graft preservative composition and a method for viable preservation of the hepatic graft |
| US5965750A (en) * | 1995-10-17 | 1999-10-12 | Showa Denko K.K. | High- purity tocopherol phosphates, process for the preparation thereof, methods for analysis thereof, and cosmetics |
| US6046181A (en) * | 1995-10-17 | 2000-04-04 | Showa Denko K.K. | Highly purified tocopheryl phosphate, process for producing the same, analytical method therefor and cosmetic |
| WO1999039719A1 (en) * | 1998-02-06 | 1999-08-12 | Cci Corporation | Preventives and remedies for ischemic reflow disorder |
| US6277834B1 (en) | 1998-06-19 | 2001-08-21 | Senju Pharmaceutical Co. Ltd. | Agents for relieving side effects of adrenal cortex hormone |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2714678B2 (en) | 1998-02-16 |
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