JPH02250828A - New immunosuppressive agent - Google Patents
New immunosuppressive agentInfo
- Publication number
- JPH02250828A JPH02250828A JP6934689A JP6934689A JPH02250828A JP H02250828 A JPH02250828 A JP H02250828A JP 6934689 A JP6934689 A JP 6934689A JP 6934689 A JP6934689 A JP 6934689A JP H02250828 A JPH02250828 A JP H02250828A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- immunosuppressive agent
- active ingredient
- corpuscle
- lymphatic
- 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 abstract 4
- VKFOCULFEFSDPI-GOSISDBHSA-N Butyl-cycloheptyl-prodiginine Natural products CCCC[C@@H]1CCCCCCc2[nH]c(C=C3N=C(C=C3OC)c4ccc[nH]4)cc12 VKFOCULFEFSDPI-GOSISDBHSA-N 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 8
- 230000001861 immunosuppressant effect Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 13
- 210000000056 organ Anatomy 0.000 abstract description 6
- 241001494479 Pecora Species 0.000 abstract description 5
- 210000003743 erythrocyte Anatomy 0.000 abstract description 5
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 5
- 230000001629 suppression Effects 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 3
- 231100000433 cytotoxic Toxicity 0.000 abstract description 3
- 230000001472 cytotoxic effect Effects 0.000 abstract description 3
- 230000003394 haemopoietic effect Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 208000002177 Cataract Diseases 0.000 abstract description 2
- 208000026935 allergic disease Diseases 0.000 abstract description 2
- 230000005784 autoimmunity Effects 0.000 abstract description 2
- 208000007475 hemolytic anemia Diseases 0.000 abstract description 2
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 2
- 206010028417 myasthenia gravis Diseases 0.000 abstract description 2
- 238000007911 parenteral administration Methods 0.000 abstract description 2
- 239000003270 steroid hormone Substances 0.000 abstract description 2
- 208000025865 Ulcer Diseases 0.000 abstract 1
- 230000037396 body weight Effects 0.000 abstract 1
- 230000002500 effect on skin Effects 0.000 abstract 1
- 230000003902 lesion Effects 0.000 abstract 1
- 238000002054 transplantation Methods 0.000 abstract 1
- 231100000397 ulcer Toxicity 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- 108010062580 Concanavalin A Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229920006008 lipopolysaccharide Polymers 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000035584 blastogenesis Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000016784 immunoglobulin production Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- -1 oral preparation Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 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 3
- 239000001913 cellulose Chemical class 0.000 description 3
- 229920002678 cellulose Chemical class 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000008216 juvenile development Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 101100005766 Caenorhabditis elegans cdf-1 gene Proteins 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
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000001176 lymphocytolytic effect Effects 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
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940046781 other immunosuppressants in atc Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、ブチルシクロヘプチルプロディギニンを有効
成功と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 an immunosuppressant that uses butylcycloheptylprodiginine as an effective agent.
従来免疫抑制剤として、アルキル化剤、代謝拮抗剤、抗
生物質、ステロイド剤、葉酸拮抗剤、植物アルカロイド
などが知られている。Conventionally known immunosuppressants include alkylating agents, antimetabolites, antibiotics, steroids, folate antagonists, and plant alkaloids.
従来の免疫抑制剤のうち、ステロイド剤は消炎作用リン
パ球溶解作用等により免疫抑制を示すといわれ、作用が
多岐にわたるため、様々な副作用を伴うことは周知であ
る。その他の免疫抑制剤は、いわゆる細胞毒性物質に属
し、とりわけ核酸合成系に作用するものが多く造血器等
の臓器にｒＩＬ篤な副作用を発現し易いことが知られて
いる。リンパ球等の免疫担当細胞にのみ選択的に作用し
、免疫抑制作用以外の副作用が可及的に軽微な薬剤が望
まれている。Among conventional immunosuppressants, steroids are said to exhibit immunosuppression due to anti-inflammatory and lymphocytolytic effects, etc., and it is well known that they are accompanied by various side effects because of their wide-ranging effects. Other immunosuppressants belong to so-called cytotoxic substances, and many of them act particularly on the nucleic acid synthesis system, and it is known that they are likely to cause rIL serious side effects in organs such as hematopoietic organs. There is a desire for a drug that selectively acts only on immunocompetent cells such as lymphocytes and has as few side effects as possible other than immunosuppressive effects.
そこで１発明者らは、種々検討した結果、式（１）で表
されるブチルシクロヘプチルプロディギニンが免疫抑制
作用が有するこを見い出した０本発明は、上記知見に基
づき完成されたものである。Therefore, as a result of various studies, the inventors discovered that butylcycloheptylprodiginine represented by formula (1) has an immunosuppressive effect.The present invention was completed based on the above findings. be.
即ち、本発明はブチルシクロヘプチルプロディギニン又
はその薬理上許容される塩を有効成分とする免疫抑制剤
に関する。That is, the present invention relates to an immunosuppressant containing butylcycloheptylprodiginine or a pharmacologically acceptable salt thereof as an active ingredient.
本発明で使用される式（１）のブチルシクロヘプチルプ
ロディギニンは、ジャーナル・オブ・アンチバイオティ
クス（Ｊｏｕｒｎａｌ ｏｆ Ａｎｔｉｂｉｏｔｉｃｓ
）２８４１９４ページ、１９７５年に記載されている公
知化合物である。（以下本発明の上記式（１）で示され
る化合物を「本化合物」という。）
本化合物は酸と塩を形成するが、塩を形成するための酸
としては、例えば、薬理学上許容される酸であればよく
、例えば、塩酸、硫酸、硝酸、リン酸などが好ましい。Butylcycloheptylprodiginine of formula (1) used in the present invention is described in the Journal of Antibiotics.
) 284194, 1975. (Hereinafter, the compound represented by the above formula (1) of the present invention will be referred to as "the present compound".) The present compound forms a salt with an acid, and as an acid for forming a salt, for example, a pharmacologically acceptable acid is used. For example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. are preferable.
本化合物が免疫抑制剤として用いられる場合は、単独ま
たは賦形剤あるいは担体と混合して注射剤、経口剤、ま
たは坐剤などとして投与される。賦形剤及び担体として
は薬剤学的に許、容されるものが選ばれ、その種類及び
組成は投与経路や投与方法によって決まる０例えば液状
担体として水、アルコール類もしくは大豆油、ピーナツ
油、ゴマ油、ミネラル油等の動植物油、または合成油が
用いられる固体担体としてマルトース、シェフロースな
どの糖類、アミノ酸類、ヒドロキシプロピルセルロース
などセルロース誘導体、ステアリン酸マグネシウムなど
の有機酸塩などが使用される。注射剤の場合一般には生
理食塩水、各種緩衝液、グルコース、イノシトール、マ
ンニトール等の糖類溶液、エチレングリコール、プロピ
レングリコール、ポリエチレングリコール等のグリコー
ル類が望ましい、また、イノシトール、マンニトール、
グルコース、マンノース、マルトース、シュークロース
等のａｍ、フェニルアラニン等のアミノ酸等の賦形剤と
共に凍結乾燥製剤とし、それを投与時に注射用の適当な
溶剤、例えば滅菌水、生理食塩水、ブドウ糖液、電解質
溶液、アミノ酸液等静脈投与用液体に溶解して投与する
こともできる。When the present compound is used as an immunosuppressant, it is administered alone or mixed with an excipient or carrier as an injection, oral preparation, or suppository. Pharmaceutically acceptable excipients and carriers are selected, and their type and composition depend on the route and method of administration. For example, liquid carriers include water, alcohol, soybean oil, peanut oil, and sesame oil. , animal and vegetable oils such as mineral oil, or synthetic oils are used.Saccharides such as maltose and shefrose, amino acids, cellulose derivatives such as hydroxypropylcellulose, and organic acid salts such as magnesium stearate are used as solid carriers. In the case of injections, physiological saline, various buffer solutions, saccharide solutions such as glucose, inositol, and mannitol, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are generally preferred;
It is made into a lyophilized preparation together with excipients such as amino acids such as glucose, mannose, maltose, and sucrose, and amino acids such as phenylalanine, and is then administered in a suitable solvent for injection, such as sterile water, physiological saline, glucose solution, and electrolyte. It can also be administered by dissolving it in a liquid for intravenous administration, such as a solution or an amino acid solution.
製剤中における本化合物の含量は製剤により種々異なる
が通常０．１〜１００重量％好ましくは１〜９８重量％
である１９１えば注射液の場合には、通常０．１〜３０
重量％、好ましくは１〜１０重量％の有効成分を含むよ
うにすることがよい、経口投与する場合には、前記固体
担体もしくは液状担体とともに錠剤、カプセル剤、粉剤
、顆粒剤、液剤、ドライシロップ剤等の形態で、用いら
れる。カプセル、錠剤、顆粒、粉剤は一般に５〜１００
重量％、好ましくは２５〜９８重量％の有効成分を含む
。The content of this compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight.
191 For example, in the case of injection solutions, it is usually 0.1 to 30
When administered orally, tablets, capsules, powders, granules, liquids, and dry syrups may be prepared together with the solid or liquid carrier, preferably containing 1 to 10% by weight of the active ingredient. It is used in the form of Capsules, tablets, granules, and powders are generally 5 to 100
% by weight of active ingredient, preferably 25-98% by weight.
投与量は、患者の年令、体重、症状、治療目的等により
決定されるが、治療量は一般に、非経口投与で１〜１０
０ｍｇ／ ｋｇ ・日、経口投与で５〜５００Ｉ１ｇ／
ｋｇ・口である。The dose is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally 1 to 10 mg for parenteral administration.
0mg/kg/day, 5-500I1g/day by oral administration
kg/mouth.
本化合物は免疫担当細胞であるマウスリンパ球の機能に
抑制作用を及ぼす。即ち、Ｗａｉｔｈｅ等による方法（
Ｗａｉｔｈｅ ｅｔａｌ、、 ｌ１ａｎｄｂｏｏｋ ｏ
ｆ ＥＸｐｅｒｉｍｅ−ｎｔａｌ Ｉｍｍｕｎｏｌｏｇ
ｙ 頁２６． １ 、１９７８） に準じ、リンパ球
幼若化反応に対する作用を調べたところ本化合物はＣｏ
ｎ Ａ（コンカナバリンＡ）で刺激を受けたＴリンパ球
の幼若化と、ＬＰＳ （リポポリサッカライド）で刺激
を受けた８９７８球の幼若化反応を著しく抑制した。This compound exerts a suppressive effect on the function of mouse lymphocytes, which are immunocompetent cells. That is, the method by Waithe et al.
Waithe etal,, l1andbook o
f EXperime-ntal Immunolog
y page 26. 1, 1978), the effect of this compound on lymphocyte blastogenesis was investigated.
It significantly suppressed the juvenileization of T lymphocytes stimulated with nA (concanavalin A) and the juvenileization response of 8978 cells stimulated with LPS (lipopolysaccharide).
そこで、８９７８球に対する作用をインビボ（ｉｎｖ
ｉ ｖｏ） で調べた。ｒｘＪち、Ｊｅｒｎｅ等の方法
（Ｊｅｒｎｅ ｅｔａｌ ’Ｃｅ１ｌ−ｂｏｕｎｄ
Ａｎｔｉｂｏｄｉｅｓ Ｊ頁１０９〜１２２１９６３）
に準じて、羊赤血球を抗原としたマウス牌細胞のプラ
ーク形成能に与える影響を調べたところ、本化合物の抑
制効果が認められた。これは、本化合物が８９７８球に
よる抗体産生に抑制的作用することを意味する。Therefore, we investigated the effect on 8978 balls in vivo.
i vo). Jerne et al 'Cel-bound
Antibodies J pages 109-1221963)
When we investigated the effect of using sheep red blood cells as an antigen on the plaque formation ability of mouse tile cells, we found that this compound had an inhibitory effect. This means that the present compound has an inhibitory effect on antibody production by 8978 cells.
以上に記載した本化合物の薬理作用を試験例により具体
的に説明する。The pharmacological action of the present compound described above will be specifically explained using test examples.
試験例１゜
Ｃｏｎ ＡによるＴ ＩＪンパ球幼若化反応の抑制ＢＡ
ＬＢ／■マウスの牌細胞をマイクロプレートに２Ｘ１０
’個１０．２ｍｌ／ウェルになるように分注し、対照群
以外の各ウェルに各濃度の被試化合物を添加し、さらに
すべてのウェルにＣｏｎ Ａを５μｇｏｄになるよう加
えたのち、この細胞浮遊液を３７℃で５％の炭酸ガス培
＃器で７２時間培養した。リンパ球幼若化反応は、培養
終了の８時間前にＪｌ−チミジンをｌμＣｉ／ウェル添
加し、培＃細胞への取込み量を液体シンチレーシタンカ
ウンターで測定した。 Ｃｏ口Ａのみを添加したときの
取込みカウントをＡｄｐｍ、 Ｃｏｎ Ａ及び薬物を加
えたときのカウントをｌ１ｄｌ）−として、（１−Ｂｄ
ｐｍ／ Ａｄｐｓ） Ｘ １００の数値を、幼若化に対
する各薬物の抑制率とした。その結果を表１に示す。Test Example 1゜Inhibition of T IJ lymphocyte blastogenesis reaction by Con A BA
2x10 LB/■ mouse tile cells in a microplate
The test compound at each concentration was added to each well except for the control group, and Con A was added to all wells at a concentration of 5 μg. The suspension was cultured at 37° C. in a 5% carbon dioxide culture medium for 72 hours. For the lymphocyte rejuvenation reaction, 1 μCi/well of Jl-thymidine was added 8 hours before the end of the culture, and the amount taken into the cells in the culture medium was measured using a liquid scintillation counter. The uptake count when only Co A is added is Adpm, and the count when Con A and the drug are added is l1dl)-, (1-Bd
The value of pm/Adps) x 100 was taken as the inhibition rate of each drug against juvenile development. The results are shown in Table 1.
表１
本化合物のＣｏｎ ＡによるＴリンパ球幼若化反応の抑
制
試験例１の方法に準じ（ただし、Ｃｏｎ Ａの代りに、
大腸菌のＬＰＳＪＩｒ１００μ５ｌｙｄになるよう加え
た）、幼若化ＢＩ１１１＋に取りこまれた３トチミジン
／量を測定した。被験化合物による抑制率を同様に求め
た。Table 1 Inhibition of T lymphocyte blastogenesis by Con A of the present compound According to the method of Test Example 1 (however, instead of Con A,
LPSJIr of E. coli was added to 100 μ5 lyd), and the amount of 3 tothymidine incorporated into the immature BI111+ was measured. The inhibition rate by the test compound was determined in the same manner.
表２に示すように、本化合物はＬＰＳによる８９７８球
幼若化を著しく抑制した。As shown in Table 2, the present compound significantly inhibited LPS-induced 8978 sphere juvenile development.
表２ 本化合物のＬＰＳによる８９７８球幼若化の抑制。Table 2 Suppression of 8978 bulb blastogenesis by LPS of this compound.
上表から明らかなように本化合物は、Ｔリンパ球幼若化
反応を強く抑制した。As is clear from the above table, this compound strongly suppressed the T lymphocyte priming reaction.
試験例２゜
ＬＰＳ （リポポリサッカライド）による８９７８球幼
若化反応の抑制。Test Example 2 Suppression of 8978 bulb juvenileization reaction by LPS (lipopolysaccharide).
試験例３
ＣＤＦ １マウス（６週齢、雌性）に羊赤血球１×１０
−個を静脈内注射し免疫を施した。その当０１時間後よ
り４日間、被験化合物０．０４．０．０２及び０．１０
＋ａｇ ／ ｍｏｕｓｅ／日をマウス腹腔内に投与した
。Test Example 3 CDF 1 mouse (6 weeks old, female) with 1 x 10 sheep red blood cells
- Immunization was administered by intravenous injection. 0.04, 0.02 and 0.10 of the test compound for 4 days from 1 hour later.
+ag/mouse/day was administered intraperitoneally to mice.
４日後に牌細胞を分離しそのプラーク形成細胞を計数し
た。対照群（生理食塩水投与群）の測定値Ａとし、溶剤
投与群における測定をＢとして、（ｌＢ／＾） Ｘ １
００の数値を、抗体産生能の迎抑率とした。After 4 days, the tile cells were separated and the plaque-forming cells were counted. The measurement value of the control group (physiological saline administration group) is taken as A, and the measurement value of the solvent administration group is taken as B, (lB/^) X 1
The value of 00 was taken as the inhibition rate of antibody production ability.
表３
本化合物の羊赤血球に対する抗体産生能の抑制投与量（
ｍｇ／マウス） 抑制率（％）０．０４
０．０２
０．１０
１６．０
９６．２
本化合物は表３に示すように比較的低い投与量で抗体産
生能の抑制を示した。Table 3 Dose of this compound for suppressing antibody production ability against sheep erythrocytes (
mg/mouse) Inhibition rate (%) 0.04 0.02 0.10 16.0 96.2 As shown in Table 3, this compound showed inhibition of antibody production ability at a relatively low dose.
以上の結果は、本化合物がＢリンパ球及び１９７８球の
機能を抑制することを示す、この抑制作用は、それぞれ
体液性免疫及び細胞性免疫の抑制を意味するので、その
異常亢進が原因と考えられる臓器移植あるいは皮膚移植
における拒絶反応の抑制、各種の自己免疫が主たる原因
と考えられる自己免疫病例えば多発性硬化症、溶血性貧
血、Ｉ型糖尿病、重症筋無力症、橋本甲状腺炎、ベーチ
ェット症候群リウマチの治療またアレルギー疾患の治療
に対する本化合物の有用性を強く示唆する又本化合物は
従来の免疫抑制剤と異なる作用機作が考えられるので、
細胞毒性物質に属する抑制剤に共通に認められる造血器
障害等、またステロイドホルモンで認められる胃潰瘍、
白内障等の重篤な副作用はないと考えられる。The above results indicate that this compound suppresses the functions of B lymphocytes and 1978 cells. This suppressive effect means suppression of humoral immunity and cell-mediated immunity, respectively, and is thought to be caused by their abnormal enhancement. Suppression of rejection reactions in organ transplants or skin transplants, various autoimmune diseases thought to be primarily caused by autoimmunity, such as multiple sclerosis, hemolytic anemia, type I diabetes, myasthenia gravis, Hashimoto's thyroiditis, Behcet's syndrome This strongly suggests the usefulness of this compound for the treatment of rheumatism and allergic diseases, and the mechanism of action of this compound is thought to be different from that of conventional immunosuppressants.
Hematopoietic organ disorders commonly observed with inhibitors belonging to cytotoxic substances, gastric ulcers observed with steroid hormones, etc.
It is thought that there are no serious side effects such as cataracts.
上記したことから明らかなように本化合物は、１９７８
球、およびＢリンパ球の機能抑制作用、羊赤血球に対す
る抗体産生能の抑制作用等の優れた免疫抑制作用を示し
、従来の免疫抑制剤と作用機作が異なると考えられ、副
作用の少ない免疫抑制剤として期待される。As is clear from the above, this compound was developed in 1978.
It exhibits excellent immunosuppressive effects, such as suppressing the function of B cells and B lymphocytes, and suppressing the ability to produce antibodies against sheep red blood cells.It is thought to have a different mechanism of action from conventional immunosuppressants, and has fewer side effects. It is expected to be used as a drug.
以下本発明を実施例により具体的に説明する。The present invention will be specifically explained below using examples.
実施例１
本化合物の塩酸塩３０重量部に対し蒸留水を加え全量を
２０００部としてこれを溶解後ミリポアフィルターＧＳ
タイプを用いて除菌濾過する。Example 1 Distilled water was added to 30 parts by weight of the hydrochloride of the present compound to make a total of 2000 parts, and the mixture was dissolved and filtered using a Millipore filter GS.
Filter to sterilize using a type.
この濾液２ｇを１０艷のバイアルビンにとり凍結乾燥し
、１バイアルに化合物＋１１の塩酸塩３ｏｓｇを含むむ
凍結乾燥注射剤を得た。2 g of this filtrate was placed in a 10-bar vial and lyophilized to obtain a lyophilized injection containing 3 osg of compound +11 hydrochloride per vial.
実施例２
顆粒剤
本化合物の塩酸塩５０重１ｇｊ、乳糖６００部、結晶セ
ルロース３３０部及びヒドロキシプロピルセルロース２
０部をよく混和し、ロール型圧縮機（ローラーコンバク
ターＯ）を用いて圧縮し、破砕して１６メツシユと６０
メツシエの間に入るよう篩遇し、顆粒とした。Example 2 Granules Hydrochloride of the present compound 50 weight 1 gj, lactose 600 parts, crystalline cellulose 330 parts and hydroxypropylcellulose 2
Mix 0 parts well, compress using a roll compressor (roller condenser O), and crush to make 16 mesh and 60 mesh.
It was sieved so that it could get into the mesh, and it was made into granules.
実施例３
錠 剤
本化合物の塩酸塩３０ｆｆｉ量部、結晶乳糖１２０部、
結晶セルロース１４７部及びステアリン酸マグネシウム
３部を■型混合機で打錠し、１錠３００ｍｇの錠剤を得
た。Example 3 Tablet 30ffi parts of the hydrochloride of the present compound, 120 parts of crystalline lactose,
147 parts of crystalline cellulose and 3 parts of magnesium stearate were compressed into tablets using a ■-type mixer to obtain tablets each weighing 300 mg.
Claims (1)
上許容される塩を有効成分とする新規免疫抑制剤。A novel immunosuppressant containing butylcycloheptylprodiginine or a pharmacologically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6934689A JPH02250828A (en) | 1989-03-23 | 1989-03-23 | New immunosuppressive agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6934689A JPH02250828A (en) | 1989-03-23 | 1989-03-23 | New immunosuppressive agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02250828A true JPH02250828A (en) | 1990-10-08 |
Family
ID=13399895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6934689A Pending JPH02250828A (en) | 1989-03-23 | 1989-03-23 | New immunosuppressive agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02250828A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6407244B1 (en) | 2000-01-26 | 2002-06-18 | Gemin X Biotechnologies Inc. | Pyrrole-type compounds, compositions, and methods for treating cancer or viral diseases |
| EP1241162A1 (en) * | 1993-12-23 | 2002-09-18 | Pharmacia Italia S.p.A. | 2,2'-bi-1H-pyrrole derivatives with immunosuppressant activity |
| US6645962B1 (en) * | 1997-09-20 | 2003-11-11 | Korea Research Institute Of Bioscience And Biotechnology | Process of using prodigiosin as an immunosuppressive |
| US7144912B2 (en) | 2001-07-18 | 2006-12-05 | Gemin X Biotechnologies Inc. | Pyrrole-type compounds, compositions, and methods for treating cancer, treating viral diseases and causing immunosuppression |
| US7491745B2 (en) | 2000-01-26 | 2009-02-17 | Gemin X Pharmaceuticals Canada Inc. | Pyrrole-Type compounds, compositions and methods for treating cancer or viral disease |
-
1989
- 1989-03-23 JP JP6934689A patent/JPH02250828A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1241162A1 (en) * | 1993-12-23 | 2002-09-18 | Pharmacia Italia S.p.A. | 2,2'-bi-1H-pyrrole derivatives with immunosuppressant activity |
| EP0686147B1 (en) * | 1993-12-23 | 2002-09-25 | Pharmacia Italia S.p.A. | Novel 2,2'-bi-1h-pyrrole derivatives with immunosuppressant activity |
| US6645962B1 (en) * | 1997-09-20 | 2003-11-11 | Korea Research Institute Of Bioscience And Biotechnology | Process of using prodigiosin as an immunosuppressive |
| US6407244B1 (en) | 2000-01-26 | 2002-06-18 | Gemin X Biotechnologies Inc. | Pyrrole-type compounds, compositions, and methods for treating cancer or viral diseases |
| US6602879B2 (en) | 2000-01-26 | 2003-08-05 | Gemin X Biotechnologies Inc. | Pyrrole-type compounds, compositions, and methods for treating cancer or viral diseases |
| US7491745B2 (en) | 2000-01-26 | 2009-02-17 | Gemin X Pharmaceuticals Canada Inc. | Pyrrole-Type compounds, compositions and methods for treating cancer or viral disease |
| US7144912B2 (en) | 2001-07-18 | 2006-12-05 | Gemin X Biotechnologies Inc. | Pyrrole-type compounds, compositions, and methods for treating cancer, treating viral diseases and causing immunosuppression |
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