JPS604802B2 - anticancer drug - Google Patents
anticancer drugInfo
- Publication number
- JPS604802B2 JPS604802B2 JP51107520A JP10752076A JPS604802B2 JP S604802 B2 JPS604802 B2 JP S604802B2 JP 51107520 A JP51107520 A JP 51107520A JP 10752076 A JP10752076 A JP 10752076A JP S604802 B2 JPS604802 B2 JP S604802B2
- Authority
- JP
- Japan
- Prior art keywords
- anticancer
- carbamoyl
- injection
- compound
- administration
- 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.)
- Expired
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims description 8
- 229940041181 antineoplastic drug Drugs 0.000 title description 2
- UEWSIIBPZOBMBL-UHFFFAOYSA-N 5-hydroxyimidazole-4-carboxamide Chemical compound NC(=O)C1=C([O-])[NH2+]C=N1 UEWSIIBPZOBMBL-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000000203 mixture Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 230000001093 anti-cancer Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000005856 abnormality Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 206010028980 Neoplasm Diseases 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- -1 sorbit Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000009535 clinical urine test Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- DXMFNIAOLDXICA-UHFFFAOYSA-N 4-hydroxy-1h-imidazole-5-carboxamide;hydrochloride Chemical compound Cl.NC(=O)C=1N=CNC=1O DXMFNIAOLDXICA-UHFFFAOYSA-N 0.000 description 1
- 206010000188 Abnormal weight gain Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920002261 Corn starch Polymers 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
- 239000001263 FEMA 3042 Substances 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 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
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000008168 almond oil 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
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001223 polyethylene glycol 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
- 239000000843 powder Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 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 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
【発明の詳細な説明】
この発明は、一般式
で示される４−カルバモイルー５ーハイドロキシーィミ
ダゾール又はその塩を主成分とする制癌剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anticancer agent containing 4-carbamoyl-5-hydroxyimidazole represented by the general formula or a salt thereof as a main component.
この一般式〔１〕で示される化合物は公知化合物であり
、例えばジャーナル オブ ジ アメリカン ケミカル
ソサエテイ（Ｊ．Ａｍ．Ｃｈｅｍ．ＳＭ），７年萱（
１９５２年），２８班ページ記載の方法によつて合成さ
れ得る。The compound represented by the general formula [1] is a known compound, for example, as described in Journal of the American Chemical Society (J. Am. Chem. SM),
(1952), page 28.
一般式〔１〕で示される化合物は、従来、単にＬ‐５１
７８Ｙ細胞に対する細胞毒性が知られていたにすぎず、
それが強力なる制漣作用を有することは全く知られてい
なかったが、当該発明者らは各種瞳湯、例えばザルコー
マ１８０、ェーリツヒ樺、ＭＨＩ私へパトーマなどを用
いて該化合物の制癌活性を詳細に検討し、該化合物に署
しい制類作用、殊に従来治療困難とされている園型癌に
対してもきわめて強い制癌作用があり、尚かつ経口投与
によってもその作用が十分に発現されることを証明し、
該化合物が臨床的にきわめて有用な制癌剤であることを
始めて見し、出した。Conventionally, the compound represented by the general formula [1] is simply L-51
Cytotoxicity against 78Y cells was only known;
Although it was not known at all that it had a strong anti-nasal effect, the inventors investigated the anticancer activity of the compound using various Hitomitos, such as Sarcoma 180, Ehritz-Kaba, and MHI Patoma. A detailed study revealed that this compound has a significant anticancer effect, especially against cancerous cancer, which is conventionally considered difficult to treat, and that the effect is sufficiently expressed even when administered orally. prove that
It was discovered for the first time that this compound was a clinically extremely useful anticancer agent.
以下、本化合物の制癌作用、毒性等を示す。The anticancer effect, toxicity, etc. of this compound are shown below.
【１’制糠作用本化合物の各種実験腫湯に対する制癌作
用を、応用薬理、４巻（１９７０Ｅ），５２１ページに
記載された方法に従って調べた。[1' Anticancer effect] The anticancer effect of the present compound on various experimental tumors was investigated according to the method described in Applied Pharmacology, Vol. 4 (1970E), page 521.
結果を表１および表２に示す。１ マウスの ・
に・ 、
表２ マウスの実験的移植瞳傷Ｋ対する制癌効果‘２）
急性毒性使用動物：マウスＩＣＲ−ＪＣＬ系、雄、体
重２２〜２５夕（ｎ＝１０）。The results are shown in Tables 1 and 2. 1 Mouse
, Table 2: Anticancer effect on experimental mouse transplant pupil scar K'2)
Acute toxicity Animals used: Mouse ICR-JCL strain, male, body weight 22-25 mm (n=10).
但し、動物は投与後５日間観察した。However, animals were observed for 5 days after administration.
結果を表３に示す。表３ マウスに対する急性毒性値
（３ー 亜急性毒性試験
マウスＩＣＲ−ＪＣＬ系、雄、２５タ前後（ｎ＝１０）
を使用し、被験動物は金網製のケージで個別飼育し、試
料は１００ｍ９／ｋ９を連日２１日間強制経口投与した
。The results are shown in Table 3. Table 3 Acute toxicity value for mice (3- Subacute toxicity test mouse ICR-JCL strain, male, around 25 ta (n=10)
The test animals were individually housed in cages made of wire mesh, and 100 m9/k9 was orally administered by force every day for 21 days.
２１回投与後２独時間目に屠殺し、血液検査、尿検査、
解剖所見、臓器重量、病理組織学的検査に供した。Animals were sacrificed at 2 hours after the 21st administration, blood test, urine test,
The animals were subjected to anatomical findings, organ weights, and histopathological examination.
尚飼育飼料は園型飼料とし、４〜５日に１回摂取量を測
定し、飲料水はガラス給水瓶にて自由摂取させた。体重
は投与期間中連日測定を行った。結果を以下に示す。【
１｝ 体重増加量および飼料摂取量
異常をめない。The breeding feed was a garden type feed, the intake was measured once every 4 to 5 days, and drinking water was provided ad libitum from a glass water bottle. Body weight was measured every day during the administration period. The results are shown below. [
1} Avoid abnormal weight gain and feed intake.
｛２｝ 血液検査結果
白血球数（平均）６５００個／燐
赤血球数（ ″ ） ６．０×１０５個／松Ｈｂ量（
″ ）１５．１夕／ｄ〃へマトクリット値（ ″ ）
３５％
ＧＯＴ活性値（ ″ ） ５４．４ｋａｒｍｅｎ単位上
記の通りであって異常を認めない。{2} Blood test results White blood cell count (average) 6,500 cells/Phosphorocyte count ('') 6.0 x 105 cells/pine Hb amount (
″ ) 15.1 evening/d〃 matocrit value ( ″ )
35% GOT activity value ('') 54.4 karmen units As above, no abnormalities were observed.
｛３｝ 尿検査 蛋白 ３０〜１００の９／ｄｌ 裏 潜血 陰性 ｐＨ ６．０〜６．５ 上記の通りであって異常を認めない。{3} Urine test Protein 30-100 9/dl back Occult blood negative pH 6.0-6.5 As above, no abnormality detected.
‘４｝ 解剖所見 異常を認めない。‘4} Anatomical findings No abnormality detected.
【５）臓器重量（体重比％） 肝 （平均） ６．２４ 腎 （ ″ ） １．５０ 胴 （ ″ ） ０．３０ 胸腺（ ″ ） ０．２０ 心臓（ ″ ） ０．４９ 軍丸（ ″ ） ０．３８ 肺 （ ″ ） ０．８１ 上記の逸りであって隅糠が若干萎縮す る煩向が見られた以外には異常を認めなかった。[5) Organ weight (% of body weight) Liver (average) 6.24 Kidney (″) 1.50 Torso (″) 0.30 Thymus (″) 0.20 Heart (″) 0.49 Gunmaru (″) 0.38 Lungs (″) 0.81 Due to the above deviation, the corner bran will shrink slightly. No abnormalities were observed other than the presence of a feeling of discomfort.
（６｝ 病理組織学的検討
肝、腎、勝、胸腺、リンパ、肺、心臓、幸丸について検
討したが勝糠がわずかに萎縮する頬向にある以外には異
常を認めなかった。(6) Histopathological examination The liver, kidneys, bran, thymus, lymph, lungs, heart, and Yukimaru were examined, but no abnormalities were found except for the bran on the buccal side, where the bran was slightly atrophied.
以上の実験例から明らかなように、一般式〔１〕で示さ
れる４−カルバモイル−５−ハイドロキシーィミダゾー
ルは制梶活性が強く、また副作用等が少し、安全性の高
い制癌剤である。As is clear from the above experimental examples, 4-carbamoyl-5-hydroxyimidazole represented by the general formula [1] is a highly safe anticancer agent with strong anti-caking activity and few side effects.
特に従来イｂ学的治療が困難とされた固型癌に対し、上
記の如き強力な効果を発揮し、尚かつ経口投与可能な制
癌剤が少し、現状において、上記のように経口投与によ
ってすぐれた制癌効果を示す本剤は、きわめて有用かつ
画期的な制癌剤として、人癌の治療にも用いられ得る。
本剤は静脈内注射、皮下注射、経口等の方法で投与され
、成人の治療に用いられる場合の投与量は、投与経路お
よび投与回数により、１印こ３〜１０夕の範囲が好まし
い。In particular, there are only a few anticancer drugs that can be administered orally and have the above-mentioned strong effects on solid cancers, which have traditionally been difficult to treat clinically. This drug, which exhibits anticancer effects, can also be used in the treatment of human cancer as an extremely useful and innovative anticancer agent.
This drug is administered by intravenous injection, subcutaneous injection, orally, etc., and when used for treatment of adults, the dosage is preferably in the range of 3 to 10 days per day, depending on the route of administration and the number of administrations.
一般式〔１〕で示される４−カルバモイル−５−ハイド
ロキシ−イミダゾールは他の経口投与可能の制癌剤、た
とえばフトラフールから類推して任意慣用の方法で投与
用に調製することができる。4-Carbamoyl-5-hydroxy-imidazole represented by the general formula [1] can be prepared for administration by any conventional method by analogy with other orally administrable anticancer agents, such as ftorafur.
従ってこの発明は人体用医薬として好適な、少くとも一
般式〔１〕で表わされる化合物または製薬上許容し得る
塩を含有する製剤組成物をも包含するものである。この
ような組成物は任意所要の製薬用担体あるし、は賦形剤
により慣用の方法で使用に供される。この組成物は胃腸
管からの吸収に好適な形態で提供されるのが望ましい。Therefore, the present invention also includes a pharmaceutical composition containing at least a compound represented by formula [1] or a pharmaceutically acceptable salt, which is suitable as a human medicine. Such compositions are prepared for use in a conventional manner with any required pharmaceutical carriers or excipients. Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract.
経口投与用の錠剤およびカプセルは一定量投与形態であ
り、結合剤例えばシロップ、アラビアゴム、ゼラチン、
ソルビツト、トラガカント、またはポリビニルピロリド
ン、賦形薬例えば乳糖、砂糖、とうもろこし澱粉、りん
酸カルシウム、ソルビツトまたはグリシン、潤滑剤例え
ばステアリン酸マグネシウム、タルク、ポリエチレング
リコールまたはシリカ、崩壊剤例えば馬鈴薯澱粉あるい
は許容し得る湿潤剤例えばラウリル硫酸ナトリウムのよ
うな賦形剤を含有していてもよい。錠剤は当業界で周知
の方法でコーティングしてもよく、必要に応じて着色剤
、橋味剤などを加えることができる。経口用液体製剤は
水性または油性懸濁液、溶液、シロップ、ェリキシル剤
その他であってもよく、あるいは使用する前に水または
他のビヒクルで再溶解させる乾燥生成物であってもよい
。このような液体製剤は普通に用いられる添加剤例えば
懸濁化剤例えばソルビツトシロツプ、メチルセルロース
、グルコース／糠シロップ、ゼラチン、ヒドロキシェチ
ルセルロース、力ルボキシメチルセルロース、ステァリ
ン酸アルミニウムゲルまたは水素化食用脂、乳化剤例え
ばレシチン、モノオレイン酸ソルビタンまたはアラビア
ゴム、非水性ピヒクル例えばアーモンド油、分別ココナ
ット油、油性ェステル、プロピレングリコールまたはエ
チルアルコール、防腐剤例えばｐーハィドロキシ安息香
酸メチル、ｐーハィドロキシ安息香酸プロピルまたはソ
ルビン酸、場合によっては色素、香料を含有してもよい
。注射用組成物は一定投与量アンプルあるし、は添加防
腐剤、適当な溶解補助剤と共に多投与量容器中に提供さ
れる。Tablets and capsules for oral administration are metered dosage forms and may contain binders such as syrup, acacia, gelatin,
sorbit, tragacanth, or polyvinylpyrrolidone, excipients such as lactose, sugar, corn starch, calcium phosphate, sorbit or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch or as may be acceptable. Excipients such as wetting agents such as sodium lauryl sulfate may also be included. The tablets may be coated by methods well known in the art, and coloring agents, crosslinking agents, etc. may be added as necessary. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products that are redissolved in water or other vehicle before use. Such liquid preparations may contain commonly used excipients such as suspending agents such as sorbitol syrup, methylcellulose, glucose/bran syrup, gelatin, hydroxyethylcellulose, hydroxymethylcellulose, aluminum stearate gel or hydrogenated Edible fats, emulsifiers such as lecithin, sorbitan monooleate or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or It may also contain sorbic acid and optionally a dye and fragrance. Compositions for injection may be presented in fixed-dose ampoules or in multi-dose containers with added preservatives and suitable solubility aids.
組成物は懸濁液、溶液、油性または水性ビヒクル中の乳
液のような形態であってもよく、懸濁化剤、安定化剤お
よび（または）分散剤のような処方剤を含んでいてもよ
い。一方、活性成分は使用する前に適当なピヒクル例え
ば発熱物質不含の滅菌した水で再溶解させる粉末であっ
てもよい。これら組成物およびその可溶性塩は投与方法
により０．１％以上、好ましくは１０〜６０％の活性物
質を含有することができる。The compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and/or dispersing agents. good. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use. These compositions and their soluble salts can contain 0.1% or more of active substance, preferably 10-60%, depending on the method of administration.
組成物が一定投与量からなる場合には５０〜２０００の
９の活性成分を含有するのが好ましい。一般式〔１〕で
示される４−カルバモィル−５−ハイドロキシーイミダ
ゾールを静脈内投与しようとする場合には、該化合物を
塩の形、例えばナトリウム塩あるいは塩酸塩とするのが
好ましい。When the composition consists of a fixed dosage, it is preferred to contain from 50 to 2000 9 active ingredients. When 4-carbamoyl-5-hydroxyimidazole represented by general formula [1] is to be administered intravenously, it is preferable to form the compound into a salt form, such as a sodium salt or a hydrochloride.
この発明の製剤例をいくつかあげる。製剤例 １
注射剤
滅菌４−カルバモィルー５−ハイドロキシーィミダゾー
ル・ナトリウム塩２５０雌を含有するようにバィアルに
無菌的に分配し、密封して水分およびバクテリアを除去
した。Some examples of formulations of this invention are listed below. Formulation Example 1 Injection Sterile 4-Carbamoyl-5-Hydroxyimidazole Sodium Salt 250ml was aseptically dispensed into vials and sealed to remove moisture and bacteria.
伊用前にリドカィン０．５％注射液２の‘を添加して注
射剤とする。製剤例 ２注射剤
滅菌４−カルバモィル−５−ハイドロキシ−ィミダゾー
ル塩酸塩２５０の９を含有するようにバィアルに無菌的
に分配し、密封して水分およびバクテリアを除去した。Before administration, add Lidocaine 0.5% Injection 2' to prepare an injection. Formulation Example 2 Injection Sterile 4-Carbamoyl-5-Hydroxy-imidazole Hydrochloride 250 parts were aseptically dispensed into vials containing 9 parts and sealed to remove moisture and bacteria.
使用前にリドカィン０．５％注射液２の‘を添加して注
射剤とする。製剤例 ３
経口用錠剤
１．４ーカルバモイル−５ーハイドロキシーイミダゾー
ル ２５０の９
２．マンニツト
２００の夕３り馬鈴薯でんぷん
４７の９４．ステアリン酸マグネシウム
３の９１および２を混合し、３を１０％でんぷん糊
として加えて粒状化した。Before use, add Lidocaine 0.5% Injection 2' to prepare an injection. Formulation example 3 Oral tablet 1.4-carbamoyl-5-hydroxyimidazole 250/9
2. mannit
200 servings of potato starch
94 of 47. Magnesium stearate
91 of 3 and 2 were mixed, 3 was added as a 10% starch paste and granulated.
この粒子を蛇．６０メッシュ（Ｂ．Ｓ．）ふるいを通し
、乾燥して一定の重量とし、紬．１６メッシュ（Ｂ．Ｓ
．）のふるいでふるった。次にこの粒子を４と混合して
なめらかにし、７／Ｉ６″パンチで圧縮して各錠５００
の９の錠剤とした。製剤例 ４坐剤
１．４ーカルバモイルー５−ハイドロキシーイミダゾー
ル ５００雌２．タン
ニン酸 ３０雌３．ロートエ
キス ２０雌４．イクタ
モール ２００雌５．ァミ
／安息香酸エチル １００の９６．カカ
オ脂 １５００の９１〜５
と１／乳量の６を研和して坐剤塊とし、次に２／３量の
６を熔融したもの（３０〜３５℃）を加え、かきまぜな
がら放袷固化する直前、粘稲となった時速かに坐剤型に
注入して冷却した。This particle is called a snake. Pass through a 60 mesh (B.S.) sieve and dry to a constant weight. 16 mesh (B.S.
．． ) was sifted with a sieve. The particles were then mixed with 4 to make it smooth and compressed with a 7/I6'' punch to form 500 tablets each.
It was made into 9 tablets. Formulation example 4 Suppositories 1.4-carbamoyl-5-hydroxyimidazole 500 females 2. Tannic acid 30 females 3. Roto extract 20 females 4. Iktamor 200 female 5. ethyl benzoate 96 of 100. Cocoa butter 1500-91-5
and 1/milk volume of 6 to make a suppository mass, then add 2/3 of the amount of 6 melted (at 30-35°C) and stir while stirring just before it solidifies until it becomes sticky rice. The mixture was immediately poured into crab suppository molds and cooled.
Claims (1)
ル又はその塩を主成分とする制癌剤。1 An anticancer agent containing 4-carbamoyl-5-hydroxy-imidazole or a salt thereof as a main component.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP51107520A JPS604802B2 (en) | 1976-09-07 | 1976-09-07 | anticancer drug |
| NL7709853A NL7709853A (en) | 1976-09-07 | 1977-09-07 | NEW PHARMACEUTICAL APPLICATION OF 4-CARBAMOYL-5-HYDROXYIMIDAZOL. |
| CA286,281A CA1078736A (en) | 1976-09-07 | 1977-09-07 | Therapeutic application of 4-carbamoyl-5-hydroxyimidazole |
| FR7727134A FR2363329A1 (en) | 1976-09-07 | 1977-09-07 | 4-Carbamoyl-5-hydroxy-imidazole - used to treat cancer, nephritis and rheumatism |
| DE19772740281 DE2740281A1 (en) | 1976-09-07 | 1977-09-07 | USE OF 4-CARBAMOYL-5-HYDROXYIMIDAZOLE IN THE TREATMENT OF CANCER, RHEUMATISM AND NEPHRITIS |
| AU28619/77A AU509455B2 (en) | 1976-09-07 | 1977-09-07 | 4-carbamoy-5-hydroxyimdazole to treat cancer |
| US05/918,074 US4181731A (en) | 1976-09-07 | 1978-06-22 | Novel therapeutic application of 4-carbamoyl-5-hydroxyimidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP51107520A JPS604802B2 (en) | 1976-09-07 | 1976-09-07 | anticancer drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5332124A JPS5332124A (en) | 1978-03-27 |
| JPS604802B2 true JPS604802B2 (en) | 1985-02-06 |
Family
ID=14461270
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51107520A Expired JPS604802B2 (en) | 1976-09-07 | 1976-09-07 | anticancer drug |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS604802B2 (en) |
| AU (1) | AU509455B2 (en) |
| CA (1) | CA1078736A (en) |
| DE (1) | DE2740281A1 (en) |
| FR (1) | FR2363329A1 (en) |
| NL (1) | NL7709853A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU507066B1 (en) * | 1977-09-06 | 1980-01-31 | Sumitomo Chemical Company, Limited | 2-Substituted-5-Hydroxy-1h-Imidazole 4-Carbozamide Derivatives |
| JPS5495568A (en) * | 1978-01-06 | 1979-07-28 | Sumitomo Chem Co Ltd | Novel imidazoleacetic acid derivative |
| AU530916B2 (en) * | 1979-08-08 | 1983-08-04 | Sumitomo Chemical Company, Limited | 4-carbamoyl imidazolium-5-olate derivatives |
| JPS5780317A (en) * | 1980-11-05 | 1982-05-19 | Sumitomo Chem Co Ltd | Preparation of pharmaceutical composition for injection |
| EP0051962B1 (en) * | 1980-11-05 | 1988-08-24 | Sumitomo Chemical Company, Limited | Pharmaceutical composition comprising 4-carbamoyl-imidazolium-5-olate |
| US4464531A (en) * | 1981-04-20 | 1984-08-07 | Sumitomo Chemical Company, Limited | 4-Carbamoylimidazolium-5-olate derivatives |
| JPS6089418A (en) * | 1983-10-20 | 1985-05-20 | Sumitomo Chem Co Ltd | Sustained release carcinostatic agent |
| JPS60193997A (en) * | 1984-03-14 | 1985-10-02 | Sumitomo Chem Co Ltd | New cyanoimidazole ribonucleoside derivative and its preparation |
| JP4574856B2 (en) * | 1998-11-13 | 2010-11-04 | エルパトローニク アクチエンゲゼルシヤフト | Method for welding tubes and apparatus for carrying out the method |
| JP5266010B2 (en) | 2007-09-14 | 2013-08-21 | 富士フイルム株式会社 | 4-Carbamoyl-5-hydroxy-imidazole derivative sulfonate compound |
| JP6001684B2 (en) * | 2013-01-15 | 2016-10-05 | 富士フイルム株式会社 | 5-hydroxy-1H-imidazole-4-carboxamide sulfate |
| RS56032B1 (en) | 2013-01-15 | 2017-09-29 | Fujifilm Corp | Tablet containing 5-hydroxy-1h-imidazole-4-carboxamide |
| BR112014026250A2 (en) | 2013-01-15 | 2017-06-27 | Fujifilm Corp | preparation of packed solid product containing 5-hydroxy-1h-imidazole-4-carboxamide or salt thereof, or hydrate thereof |
| CA2935905C (en) | 2014-01-10 | 2019-02-05 | Fujifilm Corporation | Method and apparatus for predicting effective dose or sensitivity of 5-hydroxy-1h-imidazole-4-carboxamide, method for determining amount of xanthosine monophosphate, and treatmentagent and method for treating myelodysplastic syndrome |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52101855A (en) * | 1976-02-21 | 1977-08-26 | Toyo Seisakusho Kk | Air moistener |
-
1976
- 1976-09-07 JP JP51107520A patent/JPS604802B2/en not_active Expired
-
1977
- 1977-09-07 FR FR7727134A patent/FR2363329A1/en active Granted
- 1977-09-07 NL NL7709853A patent/NL7709853A/en not_active Application Discontinuation
- 1977-09-07 CA CA286,281A patent/CA1078736A/en not_active Expired
- 1977-09-07 DE DE19772740281 patent/DE2740281A1/en not_active Ceased
- 1977-09-07 AU AU28619/77A patent/AU509455B2/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52101855A (en) * | 1976-02-21 | 1977-08-26 | Toyo Seisakusho Kk | Air moistener |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2740281A1 (en) | 1978-03-09 |
| AU2861977A (en) | 1979-03-15 |
| AU509455B2 (en) | 1980-05-15 |
| CA1078736A (en) | 1980-06-03 |
| JPS5332124A (en) | 1978-03-27 |
| FR2363329B1 (en) | 1981-01-23 |
| NL7709853A (en) | 1978-03-09 |
| FR2363329A1 (en) | 1978-03-31 |
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