JPH01128934A - Protease inhibitor - Google Patents
Protease inhibitorInfo
- Publication number
- JPH01128934A JPH01128934A JP62286188A JP28618887A JPH01128934A JP H01128934 A JPH01128934 A JP H01128934A JP 62286188 A JP62286188 A JP 62286188A JP 28618887 A JP28618887 A JP 28618887A JP H01128934 A JPH01128934 A JP H01128934A
- Authority
- JP
- Japan
- Prior art keywords
- extract
- protease
- active ingredient
- crude drug
- inhibitor
- 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.)
- Pending
Links
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims description 12
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 title claims description 8
- 239000000284 extract Substances 0.000 claims abstract description 22
- 241000196324 Embryophyta Species 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 235000018185 Betula X alpestris Nutrition 0.000 claims abstract description 3
- 235000018212 Betula X uliginosa Nutrition 0.000 claims abstract description 3
- 241000736199 Paeonia Species 0.000 claims abstract description 3
- 240000007164 Salvia officinalis Species 0.000 claims abstract description 3
- 244000269722 Thea sinensis Species 0.000 claims abstract description 3
- 241000411851 herbal medicine Species 0.000 claims description 8
- 244000105059 Geranium thunbergii Species 0.000 claims description 2
- 235000005491 Geranium thunbergii Nutrition 0.000 claims description 2
- 241000208690 Hamamelis Species 0.000 claims description 2
- 241000721662 Juniperus Species 0.000 claims description 2
- 235000006484 Paeonia officinalis Nutrition 0.000 claims description 2
- 235000017276 Salvia Nutrition 0.000 claims description 2
- 241000520028 Lamium Species 0.000 claims 1
- 244000147568 Laurus nobilis Species 0.000 claims 1
- 235000017858 Laurus nobilis Nutrition 0.000 claims 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 claims 1
- 241000894007 species Species 0.000 claims 1
- 108091005804 Peptidases Proteins 0.000 abstract description 19
- 239000004365 Protease Substances 0.000 abstract description 18
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- 206010016936 Folliculitis Diseases 0.000 abstract description 3
- 208000024891 symptom Diseases 0.000 abstract description 3
- 206010037888 Rash pustular Diseases 0.000 abstract description 2
- 230000006806 disease prevention Effects 0.000 abstract description 2
- 230000003054 hormonal effect Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 208000029561 pustule Diseases 0.000 abstract description 2
- 229940122393 Hyaluronidase inhibitor Drugs 0.000 abstract 2
- 241001256227 Clematis brevicaudata Species 0.000 abstract 1
- 241000208152 Geranium Species 0.000 abstract 1
- 241000208680 Hamamelis mollis Species 0.000 abstract 1
- 241000592238 Juniperus communis Species 0.000 abstract 1
- 244000303199 Lamium album Species 0.000 abstract 1
- 235000009199 Lamium album Nutrition 0.000 abstract 1
- 235000002912 Salvia officinalis Nutrition 0.000 abstract 1
- 206010041923 Staphylococcal impetigo Diseases 0.000 abstract 1
- 206010042731 Sycosis barbae Diseases 0.000 abstract 1
- 235000006468 Thea sinensis Nutrition 0.000 abstract 1
- 230000003325 follicular Effects 0.000 abstract 1
- 239000008820 moutan cortex Substances 0.000 abstract 1
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 239000001296 salvia officinalis l. Substances 0.000 abstract 1
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000191963 Staphylococcus epidermidis Species 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000186427 Cutibacterium acnes Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 208000033809 Suppuration Diseases 0.000 description 2
- FVDYHOGCIRNKAY-UHFFFAOYSA-N benzyl thiohypofluorite Chemical compound FSCC1=CC=CC=C1 FVDYHOGCIRNKAY-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 229940055019 propionibacterium acne Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- -1 'n ~ propatool Chemical compound 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 244000110797 Polygonum persicaria Species 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 206010041235 Snoring Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 208000002557 hidradenitis Diseases 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、新規なプロテアーゼ阻害剤に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to novel protease inhibitors.
さらに詳しくは表在性毛壷性膿庖を主症状とする毛紫炎
、尋常性毛庶、ポックハルトｌ１ｍ癲疹などのプロテア
ーゼに起因する疾患を予防、防止するための新規かつ安
全性の高いプロテアーゼ阻害剤に関する。More specifically, this is a novel and highly safe protease inhibitor for the prevention and prevention of diseases caused by proteases, such as purpura whose main symptom is superficial pilonidal pus, pilonidal vulgaris, and Pockhardt's 11m epidermis. Regarding.
（従来の技術〕
従来、人体におけるプロテアーゼは皮膚表層に存在する
プロピオニバクテリウム アクネス（Ｐｒｏｐｉｏｎｉ
ｂｏｃｔｅｒｉｕｎ＋ ａｃｎｅｓ ）やスタフィロコ
ッカス エピデルミゾイス（Ｓ ｔａｐｈｙｒｏｃｏｃ
ｃｕｓｅｐｉｄｅｒｍｉｄｅｓ）の表皮性ブドウ球菌な
どがその活性を有していることが知られている（ Ｊ、
Ａｐρ１゜Ｂａｃｔｅｒｉｏｌ 、 、 ５４．２６３
．１９８３．皮膚科の臨床、９，８゜６７３、１９６７
）。(Prior Art) Conventionally, protease in the human body is produced by Propionibacterium acnes (Propionibacterium acnes) present in the skin surface layer.
bocterium+ acnes) and Staphylococcus epidermizois (S taphyrococcus
Staphylococcus epidermidis (Cusepidermides) is known to have this activity (J,
Apρ1゜Bacteriol, , 54.263
．． 1983. Clinical Dermatology, 9,8゜673, 1967
).
表皮性ブドウ球菌は、コアグラーゼ生産能陰性、マンニ
ット分解能陰性で生物学的活性の低いもので、非病原性
菌とされているが、尋常性毛癒、毛昏炎等の表在性原皮
症では表在性プドア球菌の検出率はきわめて高く、しか
も表皮性ブドウ球菌の単独分離例がきわめて多い。さら
に毛蚤炎患者の定型的な身からは黄色ブドウ球菌のみが
分離され、毛 炎の病巣からは表皮性ブドウ球菌のみが
分離されそれぞれ起炎菌が異なることが証明されている
。そのため深在性膿皮症分鼾、朧、化膿性汗腺炎、汗腺
ＩＩＩ瘍等、および表在性原皮症のうちでも化Ｉｌ傾向
の強い伝染性Ｉｌｌ癲疹では黄色ブドウ球菌が起炎菌で
ありこれに反して表在性毛骨性膿庖を主症状とする毛
炎、尋常性毛唐、ポックハルトＨＷＨｆｍ疹などでは表
皮性ブドウ球菌が起炎菌、病原菌として重要な役割を果
していると考えられている。そして表皮性ブドウ球菌は
、前述のように生物学的活性が低く、病原性を示唆する
生物学的活性としては′溶血能がプロテアーゼ活性を有
している（皮膚科臨床、９． ８．６７３．１９６７）
。Staphylococcus epidermidis is negative for coagulase production, negative for mannitol decomposition, and has low biological activity, and is considered a nonpathogenic bacterium. In Japan, the detection rate of superficial P. epidermidis is extremely high, and there are many isolated cases of Staphylococcus epidermidis. Furthermore, only Staphylococcus aureus was isolated from the typical body of a patient with folliculitis, and only Staphylococcus epidermidis was isolated from the lesions of folliculitis, proving that the causative bacteria are different in each case. Therefore, Staphylococcus aureus is the causative agent of deep pyoderma, including snoring, haziness, hidradenitis suppurativa, and sweat gland III ulcers, as well as infectious epidermis Ill, which has a strong tendency to develop among superficial prodermatoses. Contrary to this, hair whose main symptom is superficial pilonidal pustules
Staphylococcus epidermidis is thought to play an important role as a causative agent and pathogenic bacterium in cases such as P. vulgaris and Pockhardt's HWHfm eruption. As mentioned above, Staphylococcus epidermidis has low biological activity, and biological activities that suggest pathogenicity include hemolytic ability and protease activity (Dermatology Clinical Practice, 9.8.673 .1967)
.
現在までにこのような酵素活性に注目し、この酵素を阻
害することにより、表在性毛奢性膿庖の予防又は治療を
目的とした薬剤はなかった。また現存するプロテアーゼ
阻害剤は、エラスチーゼ阻害体を用いたエラスチンまた
はその他の蛋白質に対するプロテアーゼの分解作用によ
り発病する病気、例えば肺気腫、成人呼吸困難症候群等
の経口治療薬として有用であり（特開昭６０−２０８９
４３公報、特開昭６０−２０８９５１公報）、外用とし
てはほかの配合成分との関係から十分な治療効果が発揮
できなかったり、局所的におれる安全性、有効性の点で
必ずしも満足しえない。Until now, there has been no drug aimed at preventing or treating superficial hairy pus by focusing on such enzyme activity and inhibiting this enzyme. In addition, existing protease inhibitors are useful as oral therapeutic agents for diseases caused by the degrading action of protease on elastin or other proteins, such as emphysema and adult respiratory distress syndrome (Japanese Patent Application Laid-Open No. 1983-1993). -2089
43, Japanese Patent Application Laid-Open No. 60-208951), for external use, it may not be possible to exert a sufficient therapeutic effect due to the relationship with other ingredients, or the safety and efficacy may not be satisfactory due to local irritation. do not have.
また、−数的な試薬として、フェニルメチルスルフオル
フルオライドが、プロテアーゼ阻害剤として知られてい
るが、安全性の面から医薬品、皮膚外用剤、化粧品とし
てまったく使用することはできない。Furthermore, as a numerical reagent, phenylmethylsulfur fluoride is known as a protease inhibitor, but due to safety reasons, it cannot be used at all in pharmaceuticals, external skin preparations, or cosmetics.
本発明は、現在するプロテアーゼ阻害剤の満足できない
点を考慮し、安全性が高く真にプロテアーゼ阻害効果に
優れた薬剤を得るべく鋭意研究を重ねた結果、現在他の
用途に使用されている数多くの生薬抽出エキスにプロテ
アーゼ阻害作用があるという全く新規な事実を見出し、
この知見にもとづいて本発明を完成するにいたった。The present invention was developed in consideration of the unsatisfactory points of current protease inhibitors, and as a result of intensive research to obtain a drug that is highly safe and truly has an excellent protease inhibitory effect. We discovered a completely new fact that the herbal medicine extract has a protease inhibitory effect.
Based on this knowledge, the present invention was completed.
すなわち本発明は、シャクヤク、オオレン、オオバク、
ボタンピ、ゲンノショウコ、茶、クジンシボタンツル、
オドリコソウ、サルビア、西洋ネズ、ハマメリスおよび
バーチからなる群の１種または２種以上から選ばれる生
薬、または上記群の１種または２種以上から選ばれた植
物の溶媒抽出エキスを有効成分とするプロテアーゼ阻害
剤を提供するものである。That is, the present invention can be applied to peonies, orensis, orientalis,
Botanpi, Gennoshoko, tea, Kujinshibutton vine,
A protease whose active ingredient is a herbal medicine selected from one or more of the group consisting of dead netherb, salvia, juniper, Hamamelis, and birch, or a solvent extracted extract of one or more plants selected from the above group. The present invention provides inhibitors.
以下、本発明について詳しく説明する。The present invention will be explained in detail below.
本発明における生薬とは植物体を乾燥し、粉砕したもの
であり、溶媒抽出−エキスとは、特に明記しない限り次
の方法によって得られる上記植物またはその生薬抽出液
、その希釈液、その濃縮エキスあるいはその乾燥床を意
味するものとする。In the present invention, the herbal medicine is a dried and pulverized plant, and the solvent extraction-extract is an extract of the above-mentioned plant or its herbal medicine obtained by the following method, its diluted solution, or its concentrated extract, unless otherwise specified. or its drying bed.
溶媒抽出エキスは、上記植物または生薬乾燥米を、水も
しくは有機溶媒（石油エーテル、シクロヘキサン、四塩
化炭素、トルエン、ベンゼン、ジクロルメタン、クロロ
ホルム、エーテル、酢酸エチル、ブタノール、アセトン
、′ｎ〜プロパツール、エタノール、メタノール、ピリ
ジン、ポリエチレングリコール、プロピレングリコール
）たとえば水性アルコールを用い、通常３℃〜７０℃で
抽出処理して得られる。以上の生薬、溶媒抽出エキスは
、そのまま、または希釈あるいは濃縮し、もしくは凍結
乾燥した後、粉末またはペースト上に調製し所望により
適宜製剤化しプロテアーゼ阻害剤として用いることがで
きる。The solvent extraction extract is the above-mentioned plant or herbal medicinal dried rice, water or organic solvent (petroleum ether, cyclohexane, carbon tetrachloride, toluene, benzene, dichloromethane, chloroform, ether, ethyl acetate, butanol, acetone, 'n ~ propatool, Ethanol, methanol, pyridine, polyethylene glycol, propylene glycol), for example, by extraction using aqueous alcohol, usually at 3°C to 70°C. The above herbal medicines and solvent-extracted extracts can be used as protease inhibitors as they are, or after being diluted, concentrated, or lyophilized, prepared into a powder or paste, and formulated into an appropriate formulation as desired.
本発明のプロテアーゼ阻害剤は以下に説明する実施例か
られかるようにプロテアーゼを強力かつ有効に抑制する
。さらに皮膚に対する刺激やホルモン様副作用を全く与
えないので皮膚に対して非常に安全である。The protease inhibitor of the present invention strongly and effectively inhibits protease as shown in the Examples described below. Furthermore, it is extremely safe for the skin as it does not cause any skin irritation or hormone-like side effects.
（実施例１）
（１１プロテアーゼの調製
プロテアーゼ（スタフィロコッカス属由来、Ｔｙｐｅ
Ｘ ■、 八ｃｔｉｖｉｔｙ： １ 〜３ ｕ
ｎｉｔｓ ｐｅｒ ｍｇｓｏｌｉｄ、シグマ社製）
を最終濃度が０ 、１ ｍｇ ／ ｍＱとなるように０
．１Ｍリン酸緩（近液ｐＨ７，５に８固型した。(Example 1) (11 Preparation of protease Protease (derived from Staphylococcus genus, Type
X ■, 8activity: 1 ~ 3 u
nits per mgsolid, manufactured by Sigma)
so that the final concentration is 0,1 mg/mQ.
．． 1M phosphoric acid (near liquid) pH 7.5 to 8 solid.
（２）溶媒抽出エキス試料の調製
乾燥し粉砕した生薬１〜１０ｇに１０倍量の水、メタノ
ールまたはこれらの混液を加え、振盪抽出するか、また
は加熱還流下に抽出した後上清と沈直に分離した。上清
を減圧下に濃縮乾固して溶媒抽出エキスを得、必要に応
じてこれを水またはメタノールで希釈して溶媒抽出エキ
ス試料とした。(2) Preparation of solvent-extracted extract sample Add 10 times the amount of water, methanol, or a mixture thereof to 1 to 10 g of dried and ground herbal medicine, and extract by shaking or extract under heating and reflux, and then settle with the supernatant. It was separated into The supernatant was concentrated to dryness under reduced pressure to obtain a solvent extracted extract, which was diluted with water or methanol as needed to prepare a solvent extracted extract sample.
（３）プロテアーゼ活性測定法
カゼイン（Ｈａｍｍａｒｓｔｅｎ） １．２ｇ （ｄ
ｒｙｗｔ ）に０．０５Ｍ Ｎａ２ ＨＰＯ４１６０Ｊ
を加えてよく分散させ温水中で１０分間加熱しながら攪
拌し冷却する。塩酸水溶液または水酸化ナトリウム水溶
液で調製しｐＨ７，５とし、蒸留水を加えて全量を２０
０ｒｄ２にした。(3) Protease activity measurement method Casein (Hammersten) 1.2g (d
rywt) to 0.05M Na2 HPO4160J
Add and disperse well, stir while heating in warm water for 10 minutes, and cool. Adjust the pH to 7.5 with an aqueous hydrochloric acid solution or an aqueous sodium hydroxide solution, and add distilled water to bring the total volume to 20.
I made it 0rd2.
ｆｌ）プロテアーゼの調製で調製した酵素液中に（２）
溶媒抽出エキス試料の調製で調製した生薬抽出エキスを
所定濃度添加し、３７℃で一定時間放置して処理酵素液
とした。fl) In the enzyme solution prepared in protease preparation (2)
The herbal medicine extract prepared in the preparation of the solvent extracted extract sample was added at a predetermined concentration and left at 37° C. for a certain period of time to obtain a treated enzyme solution.
コントロールとして、生薬抽出エキスのかわりに生薬抽
出エキスの濃度を調製する際に用いた溶媒を生薬抽出エ
キスと同量添加して、処理酵素液と同様に３７℃で一定
時間放置してコントロール酵素液とした。As a control, the same amount of the solvent used in preparing the concentration of the crude drug extract was added to the crude drug extract instead of the crude drug extract, and the control enzyme solution was left at 37°C for a certain period of time in the same way as the treated enzyme solution. And so.
α二蒙１
基質５−を５０−共栓付三角フラスコにとり３７°Ｃで
５分間予熱した。これに処理酵素液１−を加え３７℃で
１０分間作用させ、正確に１０分後トリクロル酢酸混液
５−を加えてよく振りまぜ、更に３７℃で３０分間放置
した後口過した（東洋口紙！１ｋＬ４直径１１ω）。口
液を水を対照に層長１０龍、波長２７５ｍμの吸光度Ｅ
ｌｌｌを測定した。The α-dimono1 substrate 5- was placed in a 50-meter Erlenmeyer flask with a stopper and preheated at 37°C for 5 minutes. To this, treated enzyme solution 1- was added and allowed to react at 37°C for 10 minutes, and after exactly 10 minutes, trichloroacetic acid mixture 5- was added and shaken well. After further standing at 37°C for 30 minutes, it was passed through the mouth (Toyo Kouchi paper). !1kL4 diameter 11ω). Oral fluid compared to water, layer length 10 times, absorbance E at wavelength 275 mμ
lll was measured.
別に空試験として処理酵素液１−を三角フラスコにとり
、トリクロル酢酸混液５−を加え混和しこれに基質５−
を加え、３７℃、３０分間放置した。Separately, as a blank test, the treated enzyme solution 1- was placed in an Erlenmeyer flask, and the trichloroacetic acid mixture 5- was added and mixed.
was added and left at 37°C for 30 minutes.
以下検体と同様に操作し吸光度Ｅｏを測定した。The absorbance Eo was then measured in the same manner as for the specimen.
又、チロシン標準液（１−／■）５−をとり０、ＩＮ塩
酸にて１００−とし、この液について水を対照に検体と
同様に吸光度ＥＳを測定した。別に０、ＩＮ塩酸につい
ても同様にＥｓｏを測定し式（１１のようにして酵素力
価を計算した。Further, a tyrosine standard solution (1-/■) 5- was adjusted to 0 and 100- with IN hydrochloric acid, and the absorbance ES of this solution was measured in the same manner as the sample using water as a control. Separately, Eso was similarly measured for 0 and IN hydrochloric acid, and the enzyme titer was calculated using the formula (11).
Ｗ （Ｕ／■） Ｅｓ −Ｅｓｏ １０分コン
トロール酵素液を処理酵素液と同様に活性を測定し、式
（１）に準じてコントロール酵素力価Ｅ′を計算した。W (U/■) Es -Eso 10 minutes The activity of the control enzyme solution was measured in the same manner as the treated enzyme solution, and the control enzyme titer E' was calculated according to formula (1).
処理酵素液が影響された程度を式（２）の阻害率で表し
、その結果を表−１に示した。The degree to which the treated enzyme solution was affected was expressed by the inhibition rate of formula (2), and the results are shown in Table 1.
（比較例１）
（１１プロテアーゼの調製
実施例１の（１）プロテアーゼの調製と同様に調製した
。(Comparative Example 1) (Preparation of 11 Protease) Protease was prepared in the same manner as in Example 1 (1) Preparation of protease.
（２）プロテアーゼ阻害剤の調製
プロテアーゼ阻害効果のある試薬として知られているフ
ェニルメチルスルフォニルフルオライド（Ｐｈｅｎｙ
ｍｅｔｈｙｌ ５ｕｌｆｏｎｙ ｆｌｕｏｒｉｄｅ ：
シグマ社製）をＪ固装した。(2) Preparation of protease inhibitor Phenylmethylsulfonyl fluoride (Phenyl fluoride) is known as a reagent with protease inhibitory effect.
Methyl 5ulfony fluoride:
(manufactured by Sigma) was J-packed.
（３）プロテアーゼ活性の測定法
実施例１の（３）プロテアーゼ活性の測定法に準じて操
作した。(3) Method for measuring protease activity The procedure was performed according to (3) Method for measuring protease activity in Example 1.
その結果を表−１に示した。The results are shown in Table-1.
表−１から明らかなように本発明に係るプロテアーゼ阻
害剤は生薬抽出エキス試料が反応系中にｏ、ｏｏｉ〜０
．１％存在する場合、２０〜９０％のプロテアーゼ阻害
作用を示すことがわかる。さらにプロテアーゼ阻害剤と
してしられているフェニルメチルスルフオルフルオライ
ドは、反応系中に０．０１％特許出願人 株式会社
資生堂As is clear from Table 1, the protease inhibitor according to the present invention has o, ooi to 0
．． It can be seen that when present at 1%, it exhibits a protease inhibitory effect of 20 to 90%. Furthermore, phenylmethyl sulfur fluoride, which is known as a protease inhibitor, is contained in the reaction system at a concentration of 0.01% by patent applicant Co., Ltd.
Shiseido
Claims (1)
ョウコ、茶、クジン、シボタンツル、オドリコソウ、サ
ルビア、西洋ネズ、ハマメリス、およびバーチからなる
群の１種または２種以上から選ばれる生薬、または上記
群の１種または２種以上から選ばれた植物の溶媒抽出エ
キスを有効成分とするプロテアーゼ阻害剤。Herbal medicines selected from one or more of the group consisting of peonies, oriental laurel, Japanese trumpet, botanypi, gennoshoko, tea, kujin, chinese vine, dead nettle, salvia, juniper, hamamelis, and birch, or one or two of the above groups. A protease inhibitor whose active ingredient is a solvent-extracted extract of plants selected from more than one species.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62286188A JPH01128934A (en) | 1987-11-12 | 1987-11-12 | Protease inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62286188A JPH01128934A (en) | 1987-11-12 | 1987-11-12 | Protease inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01128934A true JPH01128934A (en) | 1989-05-22 |
Family
ID=17701088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62286188A Pending JPH01128934A (en) | 1987-11-12 | 1987-11-12 | Protease inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01128934A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0377829A (en) * | 1989-08-18 | 1991-04-03 | Kiyuukiyuu Yakuhin Kogyo Kk | Crude drug plaster preparation |
| JPH11147834A (en) * | 1997-11-18 | 1999-06-02 | Noevir Co Ltd | Serine protease inhibitor |
| JP2000226324A (en) * | 1998-11-30 | 2000-08-15 | Kansai Koso Kk | Liquid agent composition for cleaning/wiping and for cosmetic water |
| JP2002003353A (en) * | 2000-06-19 | 2002-01-09 | Kansai Koso Kk | Methionase and/or protease inhibitor and composition for oral cavity |
| WO2008102997A1 (en) * | 2007-02-21 | 2008-08-28 | Biospectrum Inc. | Compositions for improving skin conditions comprising matrine or its oxidized derivatives |
| US7501136B2 (en) | 2003-09-30 | 2009-03-10 | Kao Corporation | Deodorant composition |
| JP2012051908A (en) * | 2011-10-05 | 2012-03-15 | Ichimaru Pharcos Co Ltd | Trypsin inhibitor |
| CN104984075A (en) * | 2015-07-31 | 2015-10-21 | 青岛海之星生物科技有限公司 | Traditional Chinese medicinal ointment for treating infant scalp folliculitis, and preparation method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55127309A (en) * | 1979-03-23 | 1980-10-02 | Kishiyouhin Kagaku Kaihou Kenkyusho:Kk | Cosmetic |
| JPS5838209A (en) * | 1981-08-29 | 1983-03-05 | Sunstar Inc | Tannin-containing composition for skin for external application |
| JPS5838208A (en) * | 1981-08-29 | 1983-03-05 | Sunstar Inc | Tannin-containing composition for oral cavity |
| JPS5973509A (en) * | 1982-10-18 | 1984-04-25 | Osaka Chem Lab | Cosmetic composition containing ogon |
| JPS59216810A (en) * | 1983-05-24 | 1984-12-06 | Osaka Chem Lab | Cosmetic composition containing catechin compound |
| JPS6150922A (en) * | 1984-08-20 | 1986-03-13 | Ichimaru Fuarukosu Kk | External drug for skin containing extracted component of "oubaku" |
| JPS62207224A (en) * | 1986-03-08 | 1987-09-11 | Nippon Haipotsukusu:Kk | Side effect reducing preparation for antitumor agent |
| JPS6450877A (en) * | 1987-08-20 | 1989-02-27 | Ichimaru Pharcos Inc | Oxygen radical catching and removing agent |
-
1987
- 1987-11-12 JP JP62286188A patent/JPH01128934A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55127309A (en) * | 1979-03-23 | 1980-10-02 | Kishiyouhin Kagaku Kaihou Kenkyusho:Kk | Cosmetic |
| JPS5838209A (en) * | 1981-08-29 | 1983-03-05 | Sunstar Inc | Tannin-containing composition for skin for external application |
| JPS5838208A (en) * | 1981-08-29 | 1983-03-05 | Sunstar Inc | Tannin-containing composition for oral cavity |
| JPS5973509A (en) * | 1982-10-18 | 1984-04-25 | Osaka Chem Lab | Cosmetic composition containing ogon |
| JPS59216810A (en) * | 1983-05-24 | 1984-12-06 | Osaka Chem Lab | Cosmetic composition containing catechin compound |
| JPS6150922A (en) * | 1984-08-20 | 1986-03-13 | Ichimaru Fuarukosu Kk | External drug for skin containing extracted component of "oubaku" |
| JPS62207224A (en) * | 1986-03-08 | 1987-09-11 | Nippon Haipotsukusu:Kk | Side effect reducing preparation for antitumor agent |
| JPS6450877A (en) * | 1987-08-20 | 1989-02-27 | Ichimaru Pharcos Inc | Oxygen radical catching and removing agent |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0377829A (en) * | 1989-08-18 | 1991-04-03 | Kiyuukiyuu Yakuhin Kogyo Kk | Crude drug plaster preparation |
| JPH11147834A (en) * | 1997-11-18 | 1999-06-02 | Noevir Co Ltd | Serine protease inhibitor |
| JP2000226324A (en) * | 1998-11-30 | 2000-08-15 | Kansai Koso Kk | Liquid agent composition for cleaning/wiping and for cosmetic water |
| JP2002003353A (en) * | 2000-06-19 | 2002-01-09 | Kansai Koso Kk | Methionase and/or protease inhibitor and composition for oral cavity |
| US7501136B2 (en) | 2003-09-30 | 2009-03-10 | Kao Corporation | Deodorant composition |
| WO2008102997A1 (en) * | 2007-02-21 | 2008-08-28 | Biospectrum Inc. | Compositions for improving skin conditions comprising matrine or its oxidized derivatives |
| JP2012051908A (en) * | 2011-10-05 | 2012-03-15 | Ichimaru Pharcos Co Ltd | Trypsin inhibitor |
| CN104984075A (en) * | 2015-07-31 | 2015-10-21 | 青岛海之星生物科技有限公司 | Traditional Chinese medicinal ointment for treating infant scalp folliculitis, and preparation method thereof |
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