JPS6136493B2 - - Google Patents
Info
- Publication number
- JPS6136493B2 JPS6136493B2 JP53059759A JP5975978A JPS6136493B2 JP S6136493 B2 JPS6136493 B2 JP S6136493B2 JP 53059759 A JP53059759 A JP 53059759A JP 5975978 A JP5975978 A JP 5975978A JP S6136493 B2 JPS6136493 B2 JP S6136493B2
- Authority
- JP
- Japan
- Prior art keywords
- antitumor agent
- agent according
- present
- compound
- cancer
- 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 claims description 18
- -1 Nitrofurylvinyl Chemical group 0.000 claims description 9
- 201000001441 melanoma Diseases 0.000 claims description 9
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 35
- 206010028980 Neoplasm Diseases 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229920002472 Starch Polymers 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000021050 feed intake Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- UNPLRYRWJLTVAE-UHFFFAOYSA-N Cloperastine hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 UNPLRYRWJLTVAE-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000002235 sarcomere Anatomy 0.000 description 2
- 231100000456 subacute toxicity Toxicity 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000005748 tumor development Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- IAVKWAIWFRXEGL-UHFFFAOYSA-N 2-[2-(5-nitrofuran-2-yl)ethenyl]-1,3-thiazole Chemical compound O1C([N+](=O)[O-])=CC=C1C=CC1=NC=CS1 IAVKWAIWFRXEGL-UHFFFAOYSA-N 0.000 description 1
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 235000014590 basal diet Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009535 clinical urine test Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000571 inhibitory effect on melanoma Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本発明は新規抗腫瘍剤、即わち、
一般式〔〕
（但し式中R1、R2はC1〜C4の低級アルキル基、低
級アルコキシカルボニル基又はR1、R2が共に閉
環して作るシクロアルケニル環を示す）
で示されるニトロフリルビニル化合物（以下、本
発明化合物と略称する）を有効成分として含有す
る抗腫瘍剤に関する。
今日、より優れた抗腫瘍剤の開発のために幾多
の努力が払われているが、抗腫瘍剤の有すべき重
要な薬理的特性の１つである選択毒性、即わち宿
主正常細胞に損傷を与えることなしに腫瘍細胞の
みを選択的に破壊するという薬理活性の向上とい
う点では、未だ充分満足し得るものが提供されて
いない。
本発明者等は、選択毒性のより優れた抗腫瘍剤
に付き鋭意研究の結果、上記一般式〔〕に示す
各化合物の顕著な選択的抗腫瘍効果を知見し、本
発明に到達したものである。
尚、本発明で使用する上記化合物並びにその製
法自体は、特公昭52−39033号公報に開示されて
いる通りであるが、通常、これらの化合物は相当
するチアゾールと５−ニトロフルフラールとを無
水酢酸中で縮合せしめたのち、生成した５−ニト
ロフリルビニルチアゾールを過酸化水素、過酢酸
で酸化することにより製造され、その主要化合物
の幾つかに付き物理的性状を示せば、下記第１表
の通りである。
The present invention provides a novel antitumor agent, that is, the general formula [] (However, in the formula, R 1 and R 2 represent a C 1 to C 4 lower alkyl group, a lower alkoxycarbonyl group, or a cycloalkenyl ring formed by ring-closing R 1 and R 2 together.) The present invention relates to an antitumor agent containing a compound of the present invention (hereinafter abbreviated as the compound of the present invention) as an active ingredient. Today, many efforts are being made to develop better antitumor drugs, but one of the important pharmacological properties that antitumor drugs should have is selective toxicity, that is, to the host's normal cells. In terms of improving the pharmacological activity of selectively destroying tumor cells without causing damage, no drug has yet been provided that is fully satisfactory. As a result of intensive research into antitumor agents with better selective toxicity, the present inventors discovered remarkable selective antitumor effects of each compound represented by the above general formula [], and arrived at the present invention. be. The above-mentioned compounds used in the present invention and their production methods are as disclosed in Japanese Patent Publication No. 52-39033, but these compounds are usually prepared by mixing the corresponding thiazole and 5-nitrofurfural with acetic anhydride. It is produced by condensing the resulting 5-nitrofurylvinylthiazole with hydrogen peroxide and peracetic acid.The physical properties of some of its main compounds are shown in Table 1 below. That's right.
【表】【table】
【表】
約して示す。
(1) Ｎ−メチル−N′−ニトロ−Ｎ−ニトロソグ
アニジン（略称MNNG）をラツトに連日経口
投与すると30週後には高率に胃癌が発生する
が、この実験系で本発明化合物を経口投与する
ことにより胃癌の発生は顕著に抑制される。す
なわち、ウイスター（Wister）系雄ラツト
（生後６週令）をMNNG投与群、MNNG＋本発
明化合物投与群、MNNG＋５−フルオロウラ
シル投与群に分け、30週間飼育したのち腫瘍の
有無を観察した時、後記第２表に示す結果が得
られた。同表中、MNNG50ppm含有水を30週
にわたつて経口投与したラツトには66.7％の高
率で腫瘍の発生が認められたのに対し、本発明
化合物投与群では1.5mg/Kg/day投与で腫瘍発生
率が０〜20％と著るしく低く、顕著な腫瘍抑制
効果が認められた。
比較例として、５−フルオロウラシルを1.5
mg/Kg/day投与した場合、腫瘍発生率は35.3％
であり、本発明化合物の効果には及ばなかつ
た。尚、５−フルオロウラシルの7.5mg/Kg/day
投与は毒性が強く実施が不可能であつたが、本
発明化合物の場合は、7.5mg/Kg/day投与に於い
ても1.5mg/Kg/day投与例と同様に副作用もなく
低い腫瘍発生率であつた。
(2) 本発明化合物は、人ガン（メラノーマ）に対
して顕著な抑制効果を示す。
すなわち、メラノーマ関株を培地に植え、本
発明化合物を培地中濃度が1ppmになる様に添
加し、炭酸ガスインキユベーター中で５〜６日
培養したのち細胞数を計測して後記第３表に示
す結果を得た。この結果より明らかのごとく本
発明化合物はいずれも濃度1ppmにおいて、メ
ラノーマに対して顕著な抑制効果を示す。
このように、本発明化合物の如き低毒性の物
質が1ppmの低濃度でメラノーマ細胞を破壊す
るいうことは誠に驚ろくべきことであつて、こ
の事実は本発明化合物が優れた選択毒性を有す
る物質であることを明白に立証するものという
ことができる。
因みに、現在最も広く使用されるスクリーニ
ングシステムにはＬ−1210、Ｐ−388など増殖
の早い、白血病系の動物癌がとり入れられてい
るが、こういつたシステムで選び出された物質
が現在我国での罹病頻度の最も高い胃癌、肺癌
に対して十分な治療効果をあげて得ていないこ
とは周知の通りであるが、これらの困難に対し
て近年、ルイス肺癌、メラノーマB16など発育
の遅い動物癌を用いる方法や、更には人癌を用
いる評価法などが提唱されたものであり、本発
明の上記スクリーニング方法は後者に属する方
法であつて、これにより抗腫瘍剤の選択毒性の
程度は極めて正確に検知される。
(3) 本発明化合物が、代表的なスクリーニングで
あるサルコーマー180に対するマウス動物実験
に於いても高い延命効果を有するものであるこ
とは、後記実施例３に示す通りである。尚、後
記実施例４〜５に示す通り、本発明化合物は何
等の副作用もない極めて低毒性、安全なものと
いい得る。
本発明化合物を治療薬として経口的に使用す
る際には十分に粉砕したのちでんぷん、乳糖等
通常賦形剤として用いられる物質と混合し、必
要があれば界面活性剤、分散剤、崩壊剤等の副
材料を加えて粉剤、顆粒剤、カプセル、錠剤と
して使用することが出来る。
本発明化合物の投与量は人の体重１Kg当り１
日当り0.05〜100mg、好ましくは0.1〜20mgであ
る。投与は１日１〜４回に分けて投与できる。
また、水、グリセリン、アルコール、プロピレ
ン、グリコール等の液体、希釈剤あるいは脂
肪、脂肪油、ワセリン、ラノリン、流動パラフ
イン等の軟膏基剤に分散または溶解し、必要が
あれば乳化剤、分散剤、等の副材料を加えて、
外皮適用に便なる製剤とすることが出来る。
更にまた本発明化合物の溶解性を高め、組織
浸透力を高め、あるいは血液中の安定性および
滞留性を高めるために適切な補助材料を加える
ことが出来る。
実施例において製剤処方を具体的に示すが、い
ずれも本発明の範囲を限定するものではない。
本発明化合物は胃癌、食道癌、直腸癌等消化器
系に対する安全な、長期間連用の可能な治療薬と
して有用である。
更に本発明化合物はメラノーマの治療に有用で
あり、放射線療法と併用し、あるいは外科的手術
に併用してメラノーマ細胞の根絶を期するとき、
更にその有用性が発揮されることが期待される。
更にまた本発明化合物は膀胱癌の治療の際、膀
胱洗滌液に添加する安全な抗腫瘍剤としての用途
が期待される。
次に本発明を実施例により詳細に説明する。
実施例 １
本発明化合物の胃癌抑制作用
体重200〜230ｇ、生後６週令のウイスター
（Wister）雄ラツト120匹を次の各群に分け実験
を行つた。
第１群：ラツト20匹にMNNG50ppmを含む飲料
水を自由摂取させ、基礎飼料（クレア固型飼料
CE−２）を与えて30週間飼育した。
第２群〜第６群：ラツトを20匹ずつの群に分け各
群にMNNG50ppmを含む飲料水を自由摂取さ
せ、本発明化合物10ppmを混入した固型飼料
（クレア製）を与えて30週間飼育した。
第７群：ラツト20匹にMNNG50ppmを含む飲料
水を自由摂取させ、５−フルオロウラシル
10ppmを混入した固型飼料を与えて30週間飼
育した。
第８群：ラツト20匹を基礎飼料（クレア固型飼料
CE−２）で30週間飼育した。
ラツトは金属製ケージに５匹ずつ分け、室温22
〜24℃湿度60〜70％の飼育室内で飼育し、飼料摂
取量を隔日に、体重を週一回測定した。
飼育終了後、生存したラツトを屠殺し、胃を摘
出して観察したのち、10％ホルマリンで固定し、
パラフイン包埋して組織切片を作成し、ヘマトキ
シリン−エオジン染色を行つたのち検鏡した。
結果を第２表に示す。[Table] Approximately shown. (1) When N-methyl-N'-nitro-N-nitrosoguanidine (abbreviated as MNNG) is orally administered to rats every day, gastric cancer occurs at a high rate after 30 weeks. By doing so, the occurrence of gastric cancer is significantly suppressed. That is, male Wistar rats (6 weeks old) were divided into MNNG administration group, MNNG + compound of the present invention administration group, and MNNG + 5-fluorouracil administration group, and after being kept for 30 weeks, the presence or absence of tumors was observed. The results shown in Table 2 were obtained. In the same table, tumor development was observed at a high rate of 66.7% in the rats that were orally administered water containing 50 ppm of MNNG for 30 weeks, whereas in the group administered with the compound of the present invention, 1.5 mg/Kg/day was administered. The tumor incidence was extremely low at 0-20%, and a remarkable tumor suppressing effect was observed. As a comparative example, 5-fluorouracil was 1.5
When administered mg/Kg/day, tumor incidence was 35.3%
However, the effect was not as good as that of the compound of the present invention. In addition, 7.5mg/Kg/day of 5-fluorouracil
However, in the case of the compound of the present invention, administration of 7.5 mg/Kg/day showed no side effects and low tumor incidence, similar to the case of administration of 1.5 mg/Kg/day. It was hot. (2) The compound of the present invention exhibits a remarkable suppressive effect on human cancer (melanoma). That is, a melanoma Seki strain was planted in a medium, the compound of the present invention was added to the medium at a concentration of 1 ppm, and after culturing in a carbon dioxide incubator for 5 to 6 days, the number of cells was counted and shown in Table 3 below. The results shown are obtained. As is clear from these results, all of the compounds of the present invention exhibit a remarkable inhibitory effect on melanoma at a concentration of 1 ppm. It is truly surprising that a low toxicity substance such as the compound of the present invention destroys melanoma cells at a concentration as low as 1 ppm, and this fact indicates that the compound of the present invention is a substance with excellent selective toxicity. It can be said that this clearly proves that. Incidentally, the most widely used screening system currently incorporates leukemia-type animal cancers that proliferate rapidly, such as L-1210 and P-388, and the substances selected by this system are currently not available in Japan. It is well known that sufficient treatment effects have not been obtained for gastric cancer and lung cancer, which are the most frequently affected cancers in humans. A method using human cancer and an evaluation method using human cancer have been proposed, and the above-mentioned screening method of the present invention belongs to the latter method. is detected. (3) As shown in Example 3 below, the compound of the present invention has a high life-prolonging effect even in mouse animal experiments on Sarcomer 180, which is a typical screening. As shown in Examples 4 and 5 below, the compounds of the present invention can be said to be extremely low in toxicity and safe without any side effects. When the compound of the present invention is used orally as a therapeutic agent, it is thoroughly pulverized and mixed with substances commonly used as excipients such as starch and lactose, and if necessary, surfactants, dispersants, disintegrants, etc. It can be used as powder, granules, capsules, and tablets by adding auxiliary materials. The dose of the compound of the present invention is 1 kg/kg of human body weight.
The daily dose is 0.05-100 mg, preferably 0.1-20 mg. Administration can be divided into 1 to 4 times a day.
It can also be dispersed or dissolved in liquids such as water, glycerin, alcohol, propylene, and glycol, diluents, or ointment bases such as fats, fatty oils, vaseline, lanolin, and liquid paraffin, and if necessary, emulsifiers, dispersants, etc. Add the secondary ingredients of
The formulation can be conveniently applied to the skin. Furthermore, suitable auxiliary materials can be added to increase the solubility, tissue penetration, or stability and retention in the blood of the compounds of the present invention. Although the formulations are specifically shown in the Examples, they do not limit the scope of the present invention. The compounds of the present invention are useful as safe, long-term therapeutic agents for gastric cancer, esophageal cancer, rectal cancer, and other gastrointestinal cancers. Furthermore, the compounds of the present invention are useful in the treatment of melanoma, and when used in combination with radiation therapy or surgery to eradicate melanoma cells,
It is expected that its usefulness will be further demonstrated. Furthermore, the compound of the present invention is expected to be used as a safe antitumor agent to be added to bladder washing fluid during the treatment of bladder cancer. Next, the present invention will be explained in detail with reference to examples. Example 1 Stomach cancer suppressive effect of the compound of the present invention 120 male Wistar rats, 6 weeks old and weighing 200 to 230 g, were divided into the following groups and an experiment was conducted. Group 1: 20 rats were given free access to drinking water containing 50 ppm of MNNG,
CE-2) and reared for 30 weeks. Groups 2 to 6: Rats were divided into groups of 20 rats and each group was given free access to drinking water containing 50 ppm of MNNG, and fed with solid feed (manufactured by Claire) containing 10 ppm of the compound of the present invention, and reared for 30 weeks. did. Group 7: 20 rats were given free access to drinking water containing 50 ppm of MNNG, and
They were fed solid feed mixed with 10 ppm and reared for 30 weeks. Group 8: 20 rats fed basal diet (Claire solid feed)
CE-2) for 30 weeks. Rats were divided into five rats in metal cages at room temperature 22°C.
The animals were raised in a breeding room at ~24°C and humidity of 60-70%, and feed intake was measured every other day, and body weight was measured once a week. After breeding, the surviving rats were sacrificed, their stomachs were removed and observed, and then fixed in 10% formalin.
Tissue sections were prepared by embedding in paraffin, stained with hematoxylin and eosin, and then examined under a microscope. The results are shown in Table 2.
【表】【table】
【表】
第２表より明らかな様に、MNNG50ppm含有
水を30週にわたつて経口投与した群は66.7％と高
い腫瘍発生率であつた。
しかるに、本発明化合物を1.5mg/Kg/day投与し
た群は腫瘍発生率が０〜20％であり、比較例の５
−フルオロウラシルの腫瘍発生率35.3％と対比し
ても１段と好結果であるので、本発明化合物は腫
瘍発生を抑制する顕著な効果を有するということ
ができる。
実施例 ２
本発明化合物のメラノーマに対する作用
仔牛血清−RPMI 1640（１：９）２mlを含む
3.5cmφのプラスチツクシヤーレに人メラノーマ
細胞（関株）２×104個を移えつけ、飽和水蒸
気、炭酸ガス含有空気（炭酸ガス５％）の存在
下、37℃で24〜26時間培養後、DMSO又はエタノ
ールにとかした本発明化合物を培地中濃度が
1ppmになるように添加し、更に５日間上記条件
で培養を続ける。
培養終了後、浮遊細胞及びシヤーレ底面に付着
している細胞を0.25％トリプシン処理によつては
がし、全細胞数を計算する。
尚、対照例として薬剤を含まない群、及び比較
例としての５−フルオロウラシル添加群
（1ppm）を置いた。
結果を第３表に示す。
この結果より明らからように、本発明化合物は
メラノーマ細胞の増殖を1ppmと云う低濃度で抑
制し、しかも比較例の５−フルオロウラシルより
も増殖阻止率が著るしく高い。[Table] As is clear from Table 2, the group to which water containing 50 ppm of MNNG was orally administered for 30 weeks had a high tumor incidence rate of 66.7%. However, the tumor incidence in the group to which the compound of the present invention was administered at 1.5 mg/Kg/day was 0 to 20%, which was higher than Comparative Example 5.
- This is a much better result than the tumor incidence rate of 35.3% for fluorouracil, so it can be said that the compound of the present invention has a remarkable effect of suppressing tumor development. Example 2 Effect of the compound of the present invention on melanoma Contains 2 ml of calf serum-RPMI 1640 (1:9)
Transfer 2 x 10 4 human melanoma cells (Seki strain) to a 3.5 cm diameter plastic jar and culture at 37°C for 24 to 26 hours in the presence of saturated water vapor and carbon dioxide gas-containing air (5% carbon dioxide gas). , the concentration of the compound of the present invention dissolved in DMSO or ethanol in the medium is
Add it to a concentration of 1 ppm, and continue culturing under the above conditions for an additional 5 days. After culturing, floating cells and cells attached to the bottom of the shear dish are removed by treatment with 0.25% trypsin, and the total cell number is calculated. A group containing no drug was used as a control example, and a group containing 5-fluorouracil (1 ppm) was used as a comparative example. The results are shown in Table 3. As is clear from these results, the compound of the present invention inhibits the proliferation of melanoma cells at a concentration as low as 1 ppm, and the proliferation inhibition rate is significantly higher than that of the comparative example 5-fluorouracil.
【表】【table】
【表】
実施例 ３
本発明化合物のサルコーマー（Sarcoma）−180
に対する効果
一群20匹のICR−系マウス（体重20〜24ｇ、生
後５週令）の腹腔内にサルコーマー180 １×108
ケを移植し、移植24時間後より１日１回供試化合
物の生理食塩水懸濁液を腹腔内に投与し、延命効
果を観察した。
比較薬剤としては市販制ガン剤であるマイトマ
イシンＣ（協和）を用いた。
尚、延命効果は、被験動物の半数が死亡した日
（半数死亡日）であらわした。[Table] Example 3 Sarcoma-180 of the compound of the present invention
Effect on Sarcomer 180 1×10
24 hours after transplantation, a suspension of the test compound in saline was intraperitoneally administered once a day to observe the survival effect. Mitomycin C (Kyowa), a commercially available anticancer drug, was used as a comparative drug. The life prolonging effect was expressed as the day when half of the test animals died (half death date).
【表】
実施例 ４
急性毒性試験
ICR系マウス（体重20〜24ｇの雌）を用い１群
８匹を透明なポリケージに入れ本発明化合物を
0.5〜３μに粉砕したのち、ツイン−80（キシダ
化学製）を20％含む５％デンプン液とし、金属製
ゾンデを用いて１回強制経口投与した。
１週間後、死亡率よりリツチフイルド−ウイル
コツクソン〔Litchfield−Wilcoxon〕の式より
LD50値を算出した。
結果を第５表に示す。本発明化合物の急性毒性
値LD50（p.o）は３ｇ/Kg以上で比較例の市販抗
腫瘍剤のLD50値よりはるかに大きく、極めて安
全なものである。[Table] Example 4 Acute toxicity test ICR mice (female weighing 20 to 24 g) were placed in a group of 8 mice in a transparent polycage, and the compound of the present invention was administered.
After pulverizing to 0.5 to 3μ, a 5% starch solution containing 20% of Twin-80 (manufactured by Kishida Chemical Co., Ltd.) was prepared, and the solution was forcibly administered orally once using a metal probe. After one week, the mortality rate was calculated using the Litchfield-Wilcoxon formula.
LD50 values were calculated. The results are shown in Table 5. The acute toxicity value LD 50 (po) of the compound of the present invention is 3 g/Kg or more, which is much higher than the LD 50 value of the commercially available anti-tumor agent of the comparative example, and is extremely safe.
【表】【table】
【表】
実施例 ５
亜急性毒性試験
亜急性毒性はラツト（sprague Dowley 雌体
重110〜115ｇ）を１群各10匹金網製ケージに入れ
飼育し、本発明化合物を飼料中に0.2％添加し自
由に与えた。飼料摂取量は隔日に体重は週一回測
定した。尿検査は尿糖、尿タンパク、PH、潜血に
ついて月一回行なつた。尚、無添加のものを対照
群とした。飼育終了時、血液検査を行い、屠殺し
た動物を解剖して異常の有無を観察し、臓器をホ
ルマリン固定し、パラフイン包埋して、組織切片
を作成し、ヘマトキシリン−エオジン染色後検鏡
した。飼料摂取量、体重増加、死亡率、尿検査、
血液検査において対照群との差異は認められなか
つた。
更に、病理、解剖の結果を第６表に示す。
解剖および組織学的所見においても全臓器にわ
たつて異常、障害が認められなかつた。[Table] Example 5 Subacute toxicity test Subacute toxicity was determined by raising rats (sprague Dowley females, weighing 110 to 115 g) in groups of 10 rats in wire cages, and adding 0.2% of the compound of the present invention to the feed. gave to. Feed intake was measured every other day, and body weight was measured once a week. Urinalysis was performed once a month for urine sugar, urine protein, pH, and occult blood. In addition, a control group was prepared without additives. At the end of rearing, a blood test was performed, and the sacrificed animals were dissected to observe the presence or absence of abnormalities.The organs were fixed in formalin, embedded in paraffin, and tissue sections were prepared.After being stained with hematoxylin and eosin, the animals were examined under a microscope. Feed intake, weight gain, mortality rate, urine test,
No differences from the control group were observed in blood tests. Furthermore, the results of pathology and autopsy are shown in Table 6. Anatomy and histological findings revealed no abnormalities or disorders in all organs.
【表】【table】
【表】
実施例 ６
製剤化剤
処方例 １
ニトロフリルビニルシクロヘキセノチアゾールＮ
−オキサイド 200ｇ
乳 糖 790ｇ
蔗糖脂肪酸エステル 10ｇ
上記組成の混合物を粉砕機により十分混和し、
経口投与用粉剤を製する。
処方例 ２
ニトロフリルビニルシクロヘキセノチアゾールＮ
−オキサイド 200ｇ
乳糖 590ｇ
でんぷん 100ｇ
庶糖脂肪酸エステル 10ｇ
水（CMC−Na1％含有） 100ml
あらかじめ微粉砕したニトロフリルビニルシク
ロヘキセノチアゾールＮ−オキサイドを用いて上
記組成の混合物を作り、混練したのちエツクペレ
ツターにより押しだして顆粒状とする。
これを乾燥し、ふるい（32号〜200号）で選別
して経口投与用顆粒剤を製する。
処方例 ３
ニトロフリルビニルシクロ
ヘキセノチアゾールＮ−オキサイド 200ｇ
白色ワセリン 790ｇ
ポリオキシエチレンソルビ
タンエステル 10ｇ
上記組成の混合物を50〜60℃にて混練し、外皮
用軟膏を製する。[Table] Example 6 Formulation agent formulation example 1 Nitrofuryl vinylcyclohexenothiazole N
- Oxide 200g Lactose 790g Sucrose fatty acid ester 10g The mixture of the above composition was thoroughly mixed with a pulverizer,
Prepare a powder for oral administration. Prescription example 2 Nitrofuryl vinylcyclohexenothiazole N
- Oxide 200g Lactose 590g Starch 100g Sucrose fatty acid ester 10g Water (containing 1% CMC-Na) 100ml A mixture of the above composition was prepared using finely ground nitrofurylvinylcyclohexenothiazole N-oxide, kneaded, and extruded using an Eck pelleter. Make into granules. This is dried and screened with a sieve (No. 32 to No. 200) to prepare granules for oral administration. Formulation Example 3 Nitrofuryl vinyl cyclohexenothiazole N-oxide 200g White petrolatum 790g Polyoxyethylene sorbitan ester 10g A mixture of the above composition is kneaded at 50 to 60°C to prepare an ointment for the skin.
Claims (1)
級アルコキシ−カルボニル基、又はR1、R2が共
に閉環して作るシクロアルケニル環を示す） で示されるニトロフリルビニルチアゾールＮ−オ
キサイド化合物を有効成分として含有する抗腫瘍
剤。 ２ 式〔〕においてR1＝−CH3、R2＝−CH3、
−C2H5、−C3H7及び−C4H9のいずれかである特
許請求の範囲第１項に記載の抗腫瘍剤。 ３ 式〔〕においてR1＝−CH3、R2＝−
COOC2H5である特許請求の範囲第１項に記載の
抗腫瘍剤。 ４ 式〔〕においてR1、R2が共に閉環してシ
クロヘキセン環を形成している特許請求の範囲第
１項に記載の抗腫瘍剤。 ５ 消化器系の癌に使用することを特徴とする特
許請求の範囲第１項に記載の抗腫瘍剤。 ６ 消化器系の癌が、胃癌、食道癌又は直腸癌で
ある特許請求の範囲第５項記載の抗腫瘍剤。 ７ メラノーマに使用することを特徴とする特許
請求の範囲第１項に記載の抗腫瘍剤。 ８ 経口投与形態にある特許請求の範囲第１項に
記載の抗腫瘍剤。 ９ 経口投与形態が、粉剤、顆粒剤、錠剤、カプ
セルである特許請求の範囲第８項に記載の抗腫瘍
剤。 １０ 軟膏形態にある特許請求の範囲第１項に記
載の抗腫瘍剤。[Claims] 1 General formula, (However, in the formula, R 1 and R 2 represent a C 1 to C 4 lower alkyl group, a lower alkoxy-carbonyl group, or a cycloalkenyl ring formed by ring-closing R 1 and R 2 together.) Nitrofurylvinyl represented by An antitumor agent containing a thiazole N-oxide compound as an active ingredient. 2 In formula [], R 1 =-CH 3 , R 2 =-CH 3 ,
The antitumor agent according to claim 1 , which is any one of -C2H5 , -C3H7 and -C4H9 . 3 In formula [], R 1 =-CH 3 , R 2 =-
The antitumor agent according to claim 1, which is COOC 2 H 5 . 4. The antitumor agent according to claim 1, wherein in formula [], R 1 and R 2 are both ring-closed to form a cyclohexene ring. 5. The antitumor agent according to claim 1, which is used for cancer of the digestive system. 6. The antitumor agent according to claim 5, wherein the cancer of the digestive system is gastric cancer, esophageal cancer, or rectal cancer. 7. The antitumor agent according to claim 1, which is used for melanoma. 8. The antitumor agent according to claim 1, which is in an oral administration form. 9. The antitumor agent according to claim 8, wherein the oral administration form is a powder, granule, tablet, or capsule. 10. The antitumor agent according to claim 1, which is in the form of an ointment.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5975978A JPS54151134A (en) | 1978-05-19 | 1978-05-19 | Antitumorigenic agent |
| IT22723/79A IT1114243B (en) | 1978-05-19 | 1979-05-16 | ANTI-TUMORAL AGENT BASED ON THIAZOLIC DERIVATIVES |
| CH454979A CH640850A5 (en) | 1978-05-19 | 1979-05-16 | NITROFURYLVINYLTHIAZOLE-N-OXIDE COMPOUNDS AS AN ANTITUARY AGENT. |
| FR7912549A FR2426052A1 (en) | 1978-05-19 | 1979-05-17 | NITROFURYL-VINYLENIC COMPOUNDS, NEW ANTITUMOR DRUGS |
| DE2920247A DE2920247C2 (en) | 1978-05-19 | 1979-05-18 | Use of a nitrofuryl-vinylene-thiazole-N-oxide compound for the preparation of anti-tumor agents |
| GB7917473A GB2021111B (en) | 1978-05-19 | 1979-05-18 | Nitro - furyl - vinylene - thiazole n-oxides as antitumour agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5975978A JPS54151134A (en) | 1978-05-19 | 1978-05-19 | Antitumorigenic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54151134A JPS54151134A (en) | 1979-11-28 |
| JPS6136493B2 true JPS6136493B2 (en) | 1986-08-19 |
Family
ID=13122504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5975978A Granted JPS54151134A (en) | 1978-05-19 | 1978-05-19 | Antitumorigenic agent |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS54151134A (en) |
| CH (1) | CH640850A5 (en) |
| DE (1) | DE2920247C2 (en) |
| FR (1) | FR2426052A1 (en) |
| GB (1) | GB2021111B (en) |
| IT (1) | IT1114243B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0413498U (en) * | 1990-05-24 | 1992-02-03 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1864660T3 (en) | 2001-11-01 | 2011-02-21 | Spectrum Pharmaceuticals Inc | Medical compositions for intravesical treatment of bladder cancer |
| US8563592B2 (en) | 2001-11-01 | 2013-10-22 | Spectrum Pharmaceuticals, Inc. | Bladder cancer treatment and methods |
| CN101500557B (en) * | 2006-03-16 | 2012-10-31 | 罗得岛妇幼医院 | Nitrofuran compounds for the treatment of cancer and angiogenesis |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1545606A1 (en) * | 1965-07-29 | 1969-08-07 | Boehringer Mannheim Gmbh | Process for the preparation of new 5-nitrofuran derivatives |
| JPS5239033B1 (en) * | 1971-05-04 | 1977-10-03 | ||
| JPS5239033A (en) * | 1975-09-22 | 1977-03-26 | Meidensha Electric Mfg Co Ltd | An engine controlling device |
| GB2079568A (en) * | 1980-07-02 | 1982-01-20 | Hewlett Packard Co | Data compression apparatus and method |
| JPS5742662A (en) * | 1980-08-29 | 1982-03-10 | Chugai Pharmaceut Co Ltd | Benzoic acid amide derivative |
-
1978
- 1978-05-19 JP JP5975978A patent/JPS54151134A/en active Granted
-
1979
- 1979-05-16 CH CH454979A patent/CH640850A5/en not_active IP Right Cessation
- 1979-05-16 IT IT22723/79A patent/IT1114243B/en active
- 1979-05-17 FR FR7912549A patent/FR2426052A1/en active Granted
- 1979-05-18 DE DE2920247A patent/DE2920247C2/en not_active Expired
- 1979-05-18 GB GB7917473A patent/GB2021111B/en not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| ARZNEIM.FORSCH=1967 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0413498U (en) * | 1990-05-24 | 1992-02-03 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54151134A (en) | 1979-11-28 |
| DE2920247A1 (en) | 1979-11-22 |
| GB2021111B (en) | 1982-11-03 |
| IT1114243B (en) | 1986-01-27 |
| IT7922723A0 (en) | 1979-05-16 |
| FR2426052A1 (en) | 1979-12-14 |
| DE2920247C2 (en) | 1985-09-19 |
| GB2021111A (en) | 1979-11-28 |
| FR2426052B1 (en) | 1983-04-08 |
| CH640850A5 (en) | 1984-01-31 |
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