JPH01249723A - Immunosuppressive agent containing fr-66973 - Google Patents
Immunosuppressive agent containing fr-66973Info
- Publication number
- JPH01249723A JPH01249723A JP7735988A JP7735988A JPH01249723A JP H01249723 A JPH01249723 A JP H01249723A JP 7735988 A JP7735988 A JP 7735988A JP 7735988 A JP7735988 A JP 7735988A JP H01249723 A JPH01249723 A JP H01249723A
- Authority
- JP
- Japan
- Prior art keywords
- immunosuppressant
- substance
- suppressant
- administered
- transplantation
- 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
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 12
- 229940125721 immunosuppressive agent Drugs 0.000 title description 2
- 239000000126 substance Substances 0.000 claims abstract description 15
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 10
- 230000001861 immunosuppressant effect Effects 0.000 claims abstract description 9
- 239000007924 injection Substances 0.000 abstract description 4
- 238000002347 injection Methods 0.000 abstract description 4
- 230000004727 humoral immunity Effects 0.000 abstract description 3
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 abstract description 2
- 206010046851 Uveitis Diseases 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 abstract description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 abstract 1
- 238000010322 bone marrow transplantation Methods 0.000 abstract 1
- 230000007969 cellular immunity Effects 0.000 abstract 1
- 208000024908 graft versus host disease Diseases 0.000 abstract 1
- 210000000056 organ Anatomy 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 abstract 1
- 238000002054 transplantation Methods 0.000 abstract 1
- 239000002504 physiological saline solution Substances 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000427 antigen Substances 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 210000000628 antibody-producing cell Anatomy 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- -1 troches Substances 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 230000004520 agglutination Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000035931 haemagglutination Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 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
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 235000000126 Styrax benzoin Nutrition 0.000 description 1
- 235000008411 Sumatra benzointree Nutrition 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002130 benzoin Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000019382 gum benzoic Nutrition 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000009959 type I hypersensitivity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は新規な免疫抑制剤に関し、詳細には化学式
で示される１１−アセチル−８−カルバモイルオキシメ
チル−４−ホルミル−１４−オキサ−１゜１１−ジアザ
テトラシクロ［７，４，１，０’・７゜０１０・１２］
テトラゾカー２．４．６−ドリエンー６．９−ジイルニ
ジアセテート（この明細書ではＦＲ−６［１９７３物貿
という）を含有する免疫抑制剤に関するものである。Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel immunosuppressant, and in particular, 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1, which is represented by the chemical formula:゜11-Diazatetracyclo[7,4,1,0'・7゜010.12]
The present invention relates to an immunosuppressant containing tetrazocar 2,4,6-driene-6,9-diylnidiacetate (referred to as FR-6 [1973 Materials Co., Ltd.] in this specification).
［従来の技術］
免疫抑制作用を有する物質としては、副腎皮質ステロイ
ド、アザチオプリン、ナイトロジェンマスタード、メト
トレキサート等が知られている。[Prior Art] As substances having an immunosuppressive effect, corticosteroids, azathioprine, nitrogen mustard, methotrexate, etc. are known.
［発明が解決しようとする課題］
上記の物質は効力や副作用などの点で必ずしも満足でき
るものではなく、新しい免疫抑制剤の創出が望まれてい
る。[Problems to be Solved by the Invention] The above-mentioned substances are not necessarily satisfactory in terms of efficacy and side effects, and the creation of new immunosuppressants is desired.
［発明の目的］
この発明は新しい免疫抑制剤の提供を目的とするもので
ある。[Object of the invention] This invention aims to provide a new immunosuppressant.
［発明の構成］
この発明は前記化学式［Ｉコで示されるＦＲ−６６９７
３物質またはその医薬として許容される塩類を含有する
免疫抑制剤である。[Structure of the Invention] This invention relates to FR-6697 represented by the chemical formula [I]
It is an immunosuppressant containing three substances or their pharmaceutically acceptable salts.
この物質［Ｉ］は既知の化合物であり例えばストレプト
ミセス・サンダエンシスＣｓｔｒｅｐｔｏｍｙｃｅｓｓ
ａｎｄａｅｎｓｉｓ） Ｎｏ、５８９７ （微工研条寄
第７９２号）が産生ずるＦＲ−９００４８２物質をトリ
アセチル化することにより得られ、強い抗腫瘍作用を有
することが知られている（特開昭６１−１０５９０号公
報）。This substance [I] is a known compound, such as Streptomyces sandaensis Cstreptomyces.
It is obtained by triacetylating the FR-900482 substance produced by F. andaensis) No. 5897 (Feikoken Jokyo No. 792), and is known to have a strong antitumor effect (Japanese Unexamined Patent Publication No. 1983-1999). 10590).
この発明の免疫抑制剤は、ヒトを含む咄乳動物に、カプ
セル剤、マイクロカプセル剤、錠剤、顆粒剤、粉末、ト
ローチ剤、丸剤、軟膏剤、坐剤、注射液、シロップ剤等
の慣用の医薬製剤の形で、経口または非経口投与するこ
とができる。The immunosuppressant of this invention can be administered to mammals including humans in the form of capsules, microcapsules, tablets, granules, powders, troches, pills, ointments, suppositories, injections, syrups, etc. It can be administered orally or parenterally in the form of a pharmaceutical preparation.
この発明の抗腫瘍効果増強剤は、例えばスクロース、で
ん粉、マンニット、ソルビット、ラクトース、グルコー
ス、セルロース、タルク、燐酸カルシウム、炭酸カルシ
ウム等の賦形剤：例えばセルロース、メチルセルロース
、ヒドロキシメチルセルロース、ポリプロとルビロリド
ン、ゼラチン、アラビアゴム、ポリエチレングリコール
、スクロース、でん粉等の結合剤：例えばでん粉、カル
ボキシメチルセルロース、ヒドロキシプロピルでん粉、
炭酸水素ナトリウム、燐酸カルシウム、クエン酸カルシ
ウム等の崩壊剤；例えばステアリン酸マグネシウム、エ
アロシル、タルク、ラウリル硫酸ナトリウム等の滑沢剤
；例えばクエン酸、メントール、グリシン、オレンジ末
等の矯味剤；例えば安息香酸ナトリウム、重亜硫酸ナト
リウム、メチルパラベン、プロピルパラベン等の保存剤
；例えばクエン酸、クエン酸ナトリウム、酢酸等の安定
化剤；例えばメチルセルロース、ポリビニルピロリドン
、ステアリン酸アルミニウム等の懸濁化剤；例えばヒド
ロキシプロピルメチルセルロース等の分散剤；例えば水
等の希釈剤；例えばカカオバター、白色ワセリン、ポリ
エチレングリコール等の基材ワックス；等のような製剤
化に慣用の有機または無機の各種担体を用いる常法によ
っても製造することができる。The antitumor effect enhancer of the present invention includes excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate; for example, cellulose, methylcellulose, hydroxymethylcellulose, polypropylene, and rubirolidone. , gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc. Binders such as starch, carboxymethyl cellulose, hydroxypropyl starch,
Disintegrants such as sodium bicarbonate, calcium phosphate, and calcium citrate; Lubricants such as magnesium stearate, aerosil, talc, and sodium lauryl sulfate; Flavoring agents such as citric acid, menthol, glycine, and orange powder; For example, benzoin Preservatives such as sodium acid, sodium bisulfite, methylparaben, propylparaben; stabilizers such as citric acid, sodium citrate, acetic acid; suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; such as hydroxypropyl It can also be produced by conventional methods using various organic or inorganic carriers commonly used in formulations, such as dispersants such as methylcellulose; diluents such as water; base waxes such as cocoa butter, white petrolatum, and polyethylene glycol; etc. can do.
有効成分である化合物［Ｉ］の投与量は、患者の体重お
よび／または年令ならびに／または疾病の程度さらには
投与経路のような種々の要因によフて適宜選択されるが
、通常は、注射により、１日当たり０６１〜１００ ｍ
ｇ、好ましくは０．５〜５０ｍｇを投与する。有効な１
回投与量は、患１者の体重１ｋｇあたり０．０１〜２０
ｍｇの範囲、好ましくは０．１〜１０ｍｇの範囲内で選
択される。The dosage of Compound [I], which is the active ingredient, is appropriately selected depending on various factors such as the weight and/or age of the patient, the severity of the disease, and the route of administration. 061-100 m per day by injection
g, preferably 0.5 to 50 mg. valid 1
The dosage is 0.01 to 20 per kg of patient's body weight.
mg, preferably within the range of 0.1 to 10 mg.
この発明の免疫抑制剤は次項において説明する様に体液
性免疫および細胞性免疫のいずれに対しても優れた免疫
抑制作用を発揮するので、心臓、腎臓、肝臓、骨髄、皮
膚等の臓器あるいは組織の移植に対する拒絶反応、骨髄
８植によって起こる穆植片宿主反応、慢性関節リウマチ
、全身性エリテマトーデス、橋本甲状腺炎、多発性硬化
症、重症筋無力症、■型糖尿病、ブドウ膜炎等の自己免
疫疾患等の治療および予防に有用である。As explained in the next section, the immunosuppressive agent of this invention exhibits excellent immunosuppressive effects on both humoral immunity and cell-mediated immunity, so it Rejection of transplants, graft host reactions caused by 8 bone marrow transplants, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type II diabetes, uveitis, and other autoimmune diseases. It is useful for treating and preventing diseases.
［発明の効果］
この発明の免疫抑制剤に使用されるＰＲ−６８９７３物
質［Ｈの有用性を示すために、化合物［Ｉ］の薬理試験
結果を以下に述べる。[Effects of the Invention] In order to demonstrate the usefulness of PR-68973 substance [H used in the immunosuppressant of this invention, the results of pharmacological tests of compound [I] will be described below.
（Ａ）マウスの体液性免 応答に対する作用（１）動物
８週令の雌性マウス［（Ｃ５７ＢＬ／６Ｘ ＤＢＡ／２
） Ｆ＋（ＢＤＦ＋）系］を用い、１群を５匹とした。(A) Effect on the humoral immune response of mice (1) Female mice aged 8 weeks [(C57BL/6X DBA/2
) F+ (BDF+) series], and each group consisted of 5 animals.
体重は２０．１〜２３．６ｇである。Weight is 20.1-23.6g.
（２）薬剤
Ｆ Ｒ−６６９７３物質［１１を用い、１０，１゜０．
１．０．０１ 、０．００１ｍｇ／ｋｇの投与量となる
様に生理食塩水中に溶解した。投与容量は１５ｍ１／ｋ
ｇとし、免疫の２日前から２日後まで、合計５日間連続
して尾静脈内に投与した。尚対照群には生理食塩水を１
５ｍ１／ｋｇ投与した。(2) Drug FR-66973 substance [11 was used, 10.1°0.
It was dissolved in physiological saline to give a dosage of 1.0.01 mg/kg and 0.001 mg/kg. Administration volume is 15m1/k
g and was administered intravenously into the tail vein for a total of 5 consecutive days, from 2 days before to 2 days after immunization. The control group received 1 dose of physiological saline.
5ml/kg was administered.
（３）免疫
羊赤血球の１％懸濁液０．２ｍｌ （赤血球数にして
約２ Ｘ １０’個に相当・）を尾静脈より投与した。(3) 0.2 ml of a 1% suspension of immunized sheep red blood cells (equivalent to approximately 2×10' red blood cells) was administered through the tail vein.
（４）牌蔵中抗体産生細胞数および血中抗体価免疫後５
ローの牌蔵を摘出し、抗体産生細胞数をカニンガムのＰ
ＦＣ測定法［ＣｕｎｎｉｎｇｈａｍＡ、Ｊ、ａｎｄＳｚ
ｅｎｂｅｒｇ Ａ、：Ｉｍｍｕｎｏｌｏｇｙ １４．５
９９（１９６８）参照］に従って測定した。また血中凝
集抗体価については血球凝集反応（ＨＡ）法に従って測
定し、総ＨＡタイター（ＩｇＭ＋ＩｇＧ）と２−メルカ
プトエタノール抵抗性ＨＡタイター（主にＩｇＧ）を測
定したときの凝集反応を示す血清の最大希釈倍率を、２
を底とする対数（ｌｏｇ２）で表示した（第１表）。(4) Number of antibody-producing cells in the cellar and blood antibody titer 5 after immunization
The number of antibody-producing cells was determined by Cunningham's P.
FC measurement method [Cunningham A, J, and Sz
enberg A,: Immunology 14.5
99 (1968)]. In addition, the blood agglutination antibody titer was measured according to the hemagglutination (HA) method. The maximum dilution factor is 2
It is expressed as a logarithm (log2) with the base being (Table 1).
（５）結果
第１表に示す様に、ＩｇＭおよびＩｇＧ抗体産生細胞数
並びに血中凝集抗体価については、１０ｍｇ／ｋｇ投与
例と１ｍｇ／ｋｇ投与例で免疫抑制効果が認められ、有
核細胞数については１ｏｍｇ／ｋｇ投与例で抑制効果が
認められた。これらの結果、１〜１０ ｍｇ／ｋｇ投与
では体液性免疫の抑制効果が認められ、０．１ｍｇ／ｋ
ｇ投与以下では体液性抗体産生に影晋を与えないことが
分かった。(5) Results As shown in Table 1, regarding the number of IgM and IgG antibody-producing cells and the blood agglutination antibody titer, an immunosuppressive effect was observed in the 10 mg/kg and 1 mg/kg administered cases, and nucleated cells Regarding the number, an inhibitory effect was observed in the case of administration of 1 omg/kg. As a result, a suppressive effect on humoral immunity was observed when administered at 1 to 10 mg/kg, and when administered at 0.1 mg/kg,
It was found that doses of less than 1.5 g did not affect humoral antibody production.
（Ｂ）マウスの遅Ｉ型過敢症に対する作用（１） ａ物
試験（Ａ）と同じ、但し体重は１９．５〜２４．５ｇ
。(B) Effect on late type I hypersensitivity in mice (1) Same as A test (A), but weight is 19.5 to 24.5 g
.
（２）薬剤
試験（Ａ） と同じ、但し低濃度側としてｏ、ｏｏｏ
ｔｍｇ／ｋｇ 、 ｏ、ｏｏｏｏｔｍｇ／ｋｇのものも
調製した。(2) Same as drug test (A), but o, ooo on the lower concentration side
tmg/kg, o, ooootmg/kg were also prepared.
（３）抗原
片血清アルブミン（ＢＳＡ：シグマ社製）とメタノール
を塩酸々性下で反応させ、メチル化ＢＳＡを得てこれを
抗原とした。この抗原を生理食塩水に溶解し、これと同
容量のフロイントの不完全アジュバント（デイフコ社）
と混和してＷ１０型エマルジョンを作成した。尚惹起用
抗原としてはメチル化ＢＳＡを用いた。(3) Antigen fragment Serum albumin (BSA: manufactured by Sigma) and methanol were reacted under hydrochloric acid to obtain methylated BSA, which was used as an antigen. Dissolve this antigen in physiological saline and add the same volume of incomplete Freund's adjuvant (Difco).
A W10 type emulsion was prepared by mixing with Note that methylated BSA was used as the antigen for challenge.
（４）免疫および反応惹起
薬剤投与後３日目にＷ１０型エマルジョン（メチル化Ｂ
ＳＡを１００μｇ含有）をマウスの背部皮下に０．１ｍ
ｌ注射し免疫した。免疫５日後にメチル化Ｂ Ｓ Ａ
２０ ｔｉｇｌｏ、０４ｍ１をマウスの右後肢足蹟に皮
下投与し反応を惹起させた。対照足（左後肢足蹟）には
生理食塩水を皮下注射した。そして２４時間後および４
８時間後に足蹟厚を測定し、その肥厚差を増加値として
判定した（第２表）。(4) W10 type emulsion (methylated B
(containing 100 μg of SA) was placed 0.1 m subcutaneously on the back of the mouse.
Immunized with 1 injection. Methylated BSA 5 days after immunization
20 tiglo, 04m1 was subcutaneously administered to the right hind foot pad of a mouse to induce a reaction. A control paw (left hind footpad) was subcutaneously injected with physiological saline. and after 24 hours and 4
Eight hours later, the footpad thickness was measured, and the difference in the thickening was determined as an increase (Table 2).
（５）結果
第２表に示す如く、ｆ Ｏｍｇ／ｋｇ投与群では２４時
間後および４８時間後の測定で有意の差が誌められた。(5) Results As shown in Table 2, in the f Omg/kg administration group, a significant difference was noted in the measurements after 24 and 48 hours.
尚１ ｍｇ／ｋｇおよびｏ、ｏｘｍｇ／ｋｇ投与群では
、２４時間後に有意（但し軽度）の免疫促進が見られた
。但しこの促進効果は４８時間後には認められず、また
投与量依存性も認められないので、明確な促進作用を示
すものとは考えられない。これらの結果１ｏ ｍｇ／ｋ
ｇ投与では細胞性免疫の抑制効果が認められ、１ ｍｇ
／ｋｇ投与以下では細胞性免疫に影響を与えないことが
分かった。In addition, in the 1 mg/kg and o, ox mg/kg administration groups, significant (but mild) immune promotion was observed 24 hours later. However, this promoting effect was not observed after 48 hours, and no dose dependence was observed, so it is not considered that it exhibits a clear promoting effect. These results 1o mg/k
A suppressive effect on cell-mediated immunity was observed when administered at 1 mg.
It was found that cell-mediated immunity was not affected at doses below 1.2 kg.
［実施例］
以下、実施例によりこの発明を説明するが、この発明は
この実施例に限定されるものではない。[Examples] The present invention will be described below with reference to Examples, but the present invention is not limited to these Examples.
実施例
ＦＲ−６６９７３物ｐＩｔ３０ｍｇ
ＨＣＯ６０３，４５ｇ
［ポリオキシエチレン硬化ヒマシ油、
日本サーファクタント（株）製造］
生理食塩水 通量ＨＣＯ６０（
３，４５ｇ）を少量の生理食塩水に溶解した後さらに生
理食塩水を加えて３４．５ｍｌとし、１０ Ｗ ／ Ｖ
％ＨＣＯ６０−生理食塩水溶液を調製する。Example FR-66973 pIt 30 mg HCO 603.45 g [Polyoxyethylene hydrogenated castor oil, manufactured by Nippon Surfactant Co., Ltd.] Physiological saline Volume HCO 60 (
After dissolving 3.45 g) in a small amount of physiological saline, further physiological saline was added to make 34.5 ml, and 10 W / V
Prepare a %HCO60-saline solution.
ＦＲ−６６９７３物′Ｉｔ（３０ｇ）を１０ Ｗ ／
Ｖ％Ｈ’Ｃ０６０−生理食塩水溶液（１５ａ＋１）に溶
解する。この溶液のうち６．５１をとり、１０ｗ／ｖ％
ＨＣＯ６０−生理食塩水溶液（８，５ｍｌ）を加えて１
３．０ｍｌとする。同様の操作を計３回繰り返してＦＲ
−６６９７３物質の２．５ ｍｇ／ １０ ＋＊ｌ溶液
（１３ｍｌ）を得る。FR-66973 material (30g) at 10W/
V%H'C060-dissolve in saline solution (15a+1). Take 6.51 of this solution and make 10w/v%
Add HCO60-physiological saline solution (8.5 ml) to 1
The volume should be 3.0 ml. Repeat the same operation 3 times in total to FR
Obtain a 2.5 mg/10+*l solution (13 ml) of -66973 substance.
Claims (1)
。[Claims] An immunosuppressant containing the FR-66973 substance represented by the chemical formula ▲ Numerical formula, chemical formula, table, etc. ▼.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7735988A JPH01249723A (en) | 1988-03-29 | 1988-03-29 | Immunosuppressive agent containing fr-66973 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7735988A JPH01249723A (en) | 1988-03-29 | 1988-03-29 | Immunosuppressive agent containing fr-66973 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01249723A true JPH01249723A (en) | 1989-10-05 |
Family
ID=13631714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7735988A Pending JPH01249723A (en) | 1988-03-29 | 1988-03-29 | Immunosuppressive agent containing fr-66973 |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01249723A (en) |
-
1988
- 1988-03-29 JP JP7735988A patent/JPH01249723A/en active Pending
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