JPH08319235A - Carcinostatic action inducer - Google Patents
Carcinostatic action inducerInfo
- Publication number
- JPH08319235A JPH08319235A JP12405895A JP12405895A JPH08319235A JP H08319235 A JPH08319235 A JP H08319235A JP 12405895 A JP12405895 A JP 12405895A JP 12405895 A JP12405895 A JP 12405895A JP H08319235 A JPH08319235 A JP H08319235A
- Authority
- JP
- Japan
- Prior art keywords
- nitro
- triazolyl
- formula
- integer
- body weight
- 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
- 230000003327 cancerostatic effect Effects 0.000 title abstract description 8
- 239000000411 inducer Substances 0.000 title abstract description 4
- YXFWFUSVDJIVIV-UHFFFAOYSA-N 4-nitro-2h-triazole Chemical class [O-][N+](=O)C=1C=NNN=1 YXFWFUSVDJIVIV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000037396 body weight Effects 0.000 claims abstract description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims abstract description 4
- 230000001939 inductive effect Effects 0.000 claims description 5
- 230000000711 cancerogenic effect Effects 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 238000002512 chemotherapy Methods 0.000 abstract description 3
- 208000032839 leukemia Diseases 0.000 abstract description 3
- 238000001959 radiotherapy Methods 0.000 abstract description 3
- 238000000015 thermotherapy Methods 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 13
- 210000004072 lung Anatomy 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010020843 Hyperthermia Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000036031 hyperthermia Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- -1 methoxyethyl Chemical group 0.000 description 2
- 230000000637 radiosensitizating effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 208000007596 Byssinosis Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002295 alkylating antineoplastic agent Substances 0.000 description 1
- 239000002839 antibiotic anticancer agent Substances 0.000 description 1
- 239000002814 antineoplastic antimetabolite Substances 0.000 description 1
- 125000006226 butoxyethyl group Chemical group 0.000 description 1
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- QSCNLGHKALSYKF-UHFFFAOYSA-N ethoxymethanamine Chemical compound CCOCN QSCNLGHKALSYKF-UHFFFAOYSA-N 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 201000003456 pulmonary hemosiderosis Diseases 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、生体のもつ制癌作用を
誘発することができる制癌作用誘発剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a carcinostatic agent capable of inducing a carcinostatic effect of a living body.
【０００２】[0002]
【従来の技術】細胞障害性制癌剤を用いる、いわゆる癌
の化学治療法は、人体の複数の個所および白血病などの
全身に分布する癌の治療法である。そうした細胞障害性
制癌剤としてアルキル化剤系制癌剤、抗生物質系制癌
剤、代謝拮抗性制癌剤などが知られている。しかし、細
胞障害性制癌剤は正常組織に対しても障害を与えるため
体重減少などの副作用が激しく、治療に必要な量を投与
することができないことが致命的な欠点とされている。2. Description of the Related Art A so-called chemotherapeutic method for cancer using a cytotoxic anticancer agent is a method for treating cancer that is distributed in multiple parts of the human body and in the whole body such as leukemia. As such cytotoxic anticancer agents, alkylating anticancer agents, antibiotic anticancer agents, antimetabolite anticancer agents and the like are known. However, the cytotoxic anti-cancer agent causes a serious side effect such as weight loss because it also damages normal tissues, and it is a fatal drawback that it cannot administer an amount necessary for treatment.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、生体のもつ
制癌作用を誘発させる制癌作用誘発剤を提供することを
目的とする。SUMMARY OF THE INVENTION It is an object of the present invention to provide a carcinostatic effect-inducing agent for inducing a carcinostatic effect of a living body.
【０００４】[0004]
【課題を解決するための手段】本発明は、１ｍｇ／ｋｇ
体重／回以下の量の継続投与用の式（Ｉ）：The present invention provides 1 mg / kg.
Formula (I) for continuous administration of body weight / dose or less:
【０００５】[0005]
【化２】 Embedded image
【０００６】（式中のＲは、Ｈ、（ＣＨ2）aＲ1（ａは
１〜８の整数、Ｒ1はＨまたはＯ（ＣＨ2）mＨ（ｍは０
または１〜２の整数））、（ＣＨ2）cＣＯＯ（ＣＨ2）d
Ｈ（ｃは１〜３の整数、ｄは０または１〜２の整数）、
または（ＣＨ2）eＣＯＮＨ（ＣＨ2）fＯ（ＣＨ2）gＨ
（ｅは１〜３の整数、ｆは０または１〜６の整数、ｇは
０または１〜２の整数））で表わされるニトロトリアゾ
ール誘導体を有効成分とする生体の制癌作用の誘発剤に
関する。(Wherein R is H, (CH 2 ) a R 1 (a is an integer of 1 to 8, R 1 is H or O (CH 2 ) m H (m is 0
Or an integer of 1 to 2)), (CH 2 ) c COO (CH 2 ) d
H (c is an integer of 1-3, d is 0 or an integer of 1-2),
Or (CH 2) e CONH (CH 2) f O (CH 2) g H
(E is an integer of 1 to 3, f is 0 or an integer of 1 to 6, and g is an integer of 0 or 1 to 2)) .
【０００７】[0007]
【作用】ニトロトリアゾール誘導体（Ｉ）は公知の化合
物であり、それ自体には制癌作用はないが、該トリアゾ
ール誘導体が単独投与（２００〜５００ｍｇ／ｋｇ体重
／回）でマウスの固型腫瘍内に存在する放射線抵抗性の
低酸素細胞に対する放射線感受性を高める作用を有する
ことが本発明者の一人により見出されている（特開昭61
-194019 号公報）。また、オシンスキーらによって、該
誘導体を２００ｍｇ／ｋｇ体重／回投与すると動物（ラ
ット）の固型腫瘍内の生理系に異常が生じて腫瘍内の酸
性が増大し、癌の温熱治療効果が高められることが明ら
かにされている（ラジオセンシティゼイション ニュー
ズレター(Radiosensitization Newsletter) 、Vol.９、
No. ３、12〜14（1990））。さらに、投与量１００〜５
００ｍｇ／ｋｇ体重／回で細胞障害性制癌剤と併用する
とその制癌作用を増強することも本発明者らによって見
出されている（特願平３−１８７４２７、特願平４−１
９３９１６号）。[Function] The nitrotriazole derivative (I) is a known compound and has no antitumor effect by itself, but when the triazole derivative is administered alone (200 to 500 mg / kg body weight / dose), it is in a solid tumor in mice. It has been found by one of the present inventors that it has the effect of increasing the radiosensitivity to the radiation-resistant hypoxic cells present in A.
-194019). Further, by Oshinsky et al., When the derivative is administered at 200 mg / kg body weight / dose, abnormalities occur in the physiological system in solid tumors of animals (rats), the acidity in the tumors increases, and the thermotherapy effect of cancer is enhanced. Has been clarified (Radiosensitization Newsletter, Vol. 9,
No. 3, 12-14 (1990)). Furthermore, the dose is 100 to 5
It has also been found by the present inventors that, when used in combination with a cytotoxic anti-cancer agent at a dose of 00 mg / kg body weight / dose, the anti-cancer effect thereof is enhanced (Japanese Patent Application No. 3-187427, Japanese Patent Application No. 4-1427).
93916).
【０００８】これらの先行技術はいずれも、ニトロトリ
アゾール誘導体（Ｉ）による放射線治療法、温熱治療や
化学治療法の治療効果を増強させるものであり、単独の
腫瘍治療効果については記載されていない。[0008] None of these prior arts enhances the therapeutic effect of the radiotherapy, hyperthermia or chemotherapeutic method with the nitrotriazole derivative (I), and does not describe the effect of treating a single tumor.
【０００９】本発明者らは、ニトロトリアゾール誘導体
（Ｉ）の癌治療に関する研究を進めた結果、１ｍｇ／ｋ
ｇ体重／回という微量の該誘導体（Ｉ）を１日１回、少
なくとも週２日以上継続的に投与することによって、生
体のもつ制癌作用を著しく誘発することを見出した。微
量のニトロトリアゾール誘導体（Ｉ）の継続投与がかか
る制癌作用誘発効果を奏する作用機序の詳細は不明で、
現在検討中であるが、該誘導体（Ｉ）が生体内で、癌免
疫活性を誘発しているものと推察される。The present inventors have conducted research on cancer treatment of nitrotriazole derivative (I), and as a result, 1 mg / k
It has been found that by continuously administering a small amount of the derivative (I) of g body weight / dose once a day for at least 2 days a week, the carcinogenic effect of the living body is significantly induced. The details of the mechanism of action that induces the anti-cancer effect by continuous administration of a small amount of nitrotriazole derivative (I) is unknown,
Although currently under study, it is speculated that the derivative (I) induces cancer immunoreactivity in vivo.
【００１０】[0010]
【試験例】本発明の有効成分である式（Ｉ）で表わされ
るニトロトリアゾール誘導体のうちＲがＨまたは（ＣＨ
2）aＲ1であるものとしては、２−（３′−ニトロ−
１′−トリアゾール）、２−（３′−ニトロ−１′−ト
リアゾリル）メタノール、２−（３′−ニトロ−１′−
トリアゾリル）メトキシメチル、２−（３′−ニトロ−
１′−トリアゾリル）メトキシエチル、２−（３′−ニ
トロ−１′−トリアゾリル）エタノール、２−（３′−
ニトロ−１′−トリアゾリル）エトキシメチル、２−
（３′−ニトロ−１′−トリアゾリル）エトキシエチ
ル、２−（３′−ニトロ−１′−トリアゾリル）プロパ
ノール、２−（３′−ニトロ−１′−トリアゾリル）プ
ロポキシメチル、２−（３′−ニトロ−１′−トリアゾ
リル）プロポキシエチル、２−（３′−ニトロ−１′−
トリアゾリル）ブタノール、２−（３′−ニトロ−１′
−トリアゾリル）ブトキシメチル、２−（３′−ニトロ
−１′−トリアゾリル）ブトキシエチル、２−（３′−
ニトロ−１′−トリアゾリル）ヘキサル、２−（３′−
ニトロ−１′−トリアゾリル）ヘキサオキシメチル、２
−（３′−ニトロ−１′−トリアゾリル）ヘキサオキシ
エチル、２−（３′−ニトロ−１′−トリアゾリル）−
オクタノール、２−（３′−ニトロ−１′−トリアゾリ
ル）−オクタオキシメチル、２−（３′−ニトロ−１′
−トリアゾリル）−オクタオキシエチルなどがあげられ
る。Test Example In the nitrotriazole derivative represented by the formula (I), which is the active ingredient of the present invention, R is H or (CH
2 ) a R 1 includes 2- (3′-nitro-
1'-triazole), 2- (3'-nitro-1'-triazolyl) methanol, 2- (3'-nitro-1'-
Triazolyl) methoxymethyl, 2- (3'-nitro-
1'-triazolyl) methoxyethyl, 2- (3'-nitro-1'-triazolyl) ethanol, 2- (3'-
Nitro-1'-triazolyl) ethoxymethyl, 2-
(3'-Nitro-1'-triazolyl) ethoxyethyl, 2- (3'-nitro-1'-triazolyl) propanol, 2- (3'-nitro-1'-triazolyl) propoxymethyl, 2- (3 '-Nitro-1'-triazolyl) propoxyethyl, 2- (3'-nitro-1'-
Triazolyl) butanol, 2- (3'-nitro-1 '
-Triazolyl) butoxymethyl, 2- (3'-nitro-1'-triazolyl) butoxyethyl, 2- (3'-
Nitro-1'-triazolyl) hexal, 2- (3'-
Nitro-1'-triazolyl) hexaoxymethyl, 2
-(3'-Nitro-1'-triazolyl) hexaoxyethyl, 2- (3'-nitro-1'-triazolyl)-
Octanol, 2- (3'-nitro-1'-triazolyl) -octaoxymethyl, 2- (3'-nitro-1 '
-Triazolyl) -octaoxyethyl and the like.
【００１１】さらに、本発明の有効成分である式（Ｉ）
で表わされるニトロトリアゾール誘導体のうちＲが（Ｃ
Ｈ2）cＣＯＯ（ＣＨ2）dＨであるものとしては、２−
（３′−ニトロ−１′−トリアゾリル）酢酸、２−
（３′−ニトロ−１′−トリアゾリル）酢酸メチル、２
−（３′−ニトロ−１′−トリアゾリル）酢酸エチル、
２−（３′−ニトロ−１′−トリアゾリル）プロピオン
酸、２−（３′−ニトロ−１′−トリアゾリル）プロピ
オン酸メチル、２−（３′−ニトロ−１′−トリアゾリ
ル）プロピオン酸エチルなどがあげられる。Further, the formula (I) which is the active ingredient of the present invention
In the nitrotriazole derivative represented by, R is (C
H 2 ) c COO (CH 2 ) d H includes 2-
(3'-nitro-1'-triazolyl) acetic acid, 2-
Methyl (3'-nitro-1'-triazolyl) acetate, 2
Ethyl-(3'-nitro-1'-triazolyl) acetate,
2- (3'-nitro-1'-triazolyl) propionic acid, methyl 2- (3'-nitro-1'-triazolyl) propionate, ethyl 2- (3'-nitro-1'-triazolyl) propionate, etc. Can be given.
【００１２】さらに、本発明の有効成分である式（Ｉ）
で表わされるニトロトリアゾール誘導体のうちＲが（Ｃ
Ｈ2）eＣＯＮＨ（ＣＨ2）fＯ（ＣＨ2）gＨのものとして
は、２−（３′−ニトロ−１′−トリアゾリル）酢酸ア
ミド、２−（３′−ニトロ−１′−トリアゾリル）酢酸
メタノールアミド、２−（３′−ニトロ−１′−トリア
ゾリル）酢酸−１″−メトキシメチルアミド、２−
（３′−ニトロ−１′−トリアゾリル）酢酸−１″−エ
トキシメチルアミド、２−（３′−ニトロ−１′−トリ
アゾリル）酢酸−２″−プロポキシメチルアミド、２−
（３′−ニトロ−１′−トリアゾリル）酢酸エタノール
アミド、２−（３′−ニトロ−１′−トリアゾリル）酢
酸−２″−メトキシエチルアミド、２−（３′−ニトロ
−１′−トリアゾリル）酢酸−２″−エトキシエチルア
ミド、２−（３′−ニトロ−１′−トリアゾリル）酢酸
−２″−プロポキシエチルアミド、２−（３′−ニトロ
−１′−トリアゾリル）プロピオン酸アミド、２−
（３′−ニトロ−１′−トリアゾリル）プロピオン酸メ
タノールアミド、２−（３′−ニトロ−１′−トリアゾ
リル）プロピオン酸−１″−メトキシメチルアミド、２
−（３′−ニトロ−１′−トリアゾリル）プロピオン酸
−１″−エトキシメチルアミド、２−（３′−ニトロ−
１′−トリアゾリル）プロピオン酸−１″−プロポキシ
メチルアミド、２−（３′−ニトロ−１′−トリアゾリ
ル）プロピオン酸エタノールアミド、２−（３′−ニト
ロ−１′−トリアゾリル）プロピオン酸−２″−メトキ
シエチルアミド、２−（３′−ニトロ−１′−トリアゾ
リル）プロピオン酸−２″−エトキシエチルアミド、２
−（３′−ニトロ−１′−トリアゾリル）プロピオン酸
−２″−プロポキシエチルアミド、２−（３′−ニトロ
−１′−トリアゾリル）プロピオン酸プロパノールアミ
ド、２−（３′−ニトロ−１′−トリアゾリル）プロピ
オン酸−３″−メトキシプロピルアミド、２−（３′−
ニトロ−１′−トリアゾリル）プロピオン酸−３″−エ
トキシプロピルアミド、２−（３′−ニトロ−１′−ト
リアゾリル）プロピオン酸−３″−プロポキシプロピル
アミドなどがあげられる。Furthermore, the formula (I) which is the active ingredient of the present invention is
In the nitrotriazole derivative represented by, R is (C
H 2 ) e CONH (CH 2 ) f O (CH 2 ) g H includes 2- (3′-nitro-1′-triazolyl) acetic acid amide and 2- (3′-nitro-1′-triazolyl). ) Acetic acid methanolamide, 2- (3'-nitro-1'-triazolyl) acetic acid-1 "-methoxymethylamide, 2-
(3'-Nitro-1'-triazolyl) acetic acid-1 "-ethoxymethylamide, 2- (3'-nitro-1'-triazolyl) acetic acid-2" -propoxymethylamide, 2-
(3'-Nitro-1'-triazolyl) acetic acid ethanolamide, 2- (3'-nitro-1'-triazolyl) acetic acid-2 "-methoxyethylamide, 2- (3'-nitro-1'-triazolyl) Acetic acid-2 "-ethoxyethylamide, 2- (3'-nitro-1'-triazolyl) acetic acid-2" -propoxyethylamide, 2- (3'-nitro-1'-triazolyl) propionic acid amide, 2-
(3′-Nitro-1′-triazolyl) propionic acid methanolamide, 2- (3′-nitro-1′-triazolyl) propionic acid-1 ″ -methoxymethylamide, 2
-(3'-Nitro-1'-triazolyl) propionic acid-1 "-ethoxymethylamide, 2- (3'-nitro-
1'-triazolyl) propionic acid-1 "-propoxymethylamide, 2- (3'-nitro-1'-triazolyl) propionic acid ethanolamide, 2- (3'-nitro-1'-triazolyl) propionic acid-2 "-Methoxyethylamide, 2- (3'-nitro-1'-triazolyl) propionic acid-2" -ethoxyethylamide, 2
-(3'-Nitro-1'-triazolyl) propionic acid-2 "-propoxyethylamide, 2- (3'-nitro-1'-triazolyl) propionic acid propanolamide, 2- (3'-nitro-1 ' -Triazolyl) propionic acid-3 "-methoxypropylamide, 2- (3'-
Examples thereof include nitro-1'-triazolyl) propionic acid-3 "-ethoxypropylamide and 2- (3'-nitro-1'-triazolyl) propionic acid-3" -propoxypropylamide.
【００１３】本発明で用いるニトロトリアゾール誘導体
（Ｉ）は前記のとおり公知の化合物であり、ヒトに１．
０ｇ／ｍ2表面積（約３０ｍｇ／ｋｇ体重）／回投与し
ても重篤な副作用が発現しないことが知られている（前
記刊行物、ラジオセンシティゼイション ニューズレタ
ー、Ｖｏｌ．１０、Ｎｏ．２．１（１９９１））。本発
明における誘導体（Ｉ）の有効量は毎回、１日あたり１
ｍｇ／ｋｇ体重以下、好ましくは１０-1〜１０-5ｍｇ／
ｋｇ体重である。投与方法は経口投与、静脈内投与、動
脈内投与、腹腔内投与あるいは局所投与などが採用さ
れ、投与方法に応じて錠剤、カプセル剤、注射剤など通
常の剤形で使用される。また、毎回の投与量が微量であ
るので、食品や飲料に添加して投与することもできる。
また投与の頻度および回数は癌の種類および大きさによ
って異なるが、頻度は１日に１回、少なくとも週２日以
上であるのが望ましい。適用可能な癌の種類としては、
特に制限はないが、たとえば各種の固型腫瘍や白血病な
どがあげられる。The nitrotriazole derivative (I) used in the present invention is a known compound as described above.
It is known that serious side effects do not occur even after administration of 0 g / m 2 surface area (about 30 mg / kg body weight) / dose (said publication, Radio Sensitization Newsletter, Vol. 10, No. 2). 1 (1991)). An effective amount of derivative (I) in the present invention is 1 per day
mg / kg body weight or less, preferably 10 -1 to 10 -5 mg /
It is kg body weight. The administration method may be oral administration, intravenous administration, intraarterial administration, intraperitoneal administration, local administration or the like, and it may be used in a usual dosage form such as tablets, capsules and injections depending on the administration method. Further, since the dose for each administration is very small, it can be added to foods and drinks for administration.
The frequency and frequency of administration depend on the type and size of cancer, but the frequency is preferably once a day and at least 2 days a week. Applicable types of cancer include
Although not particularly limited, examples thereof include various solid tumors and leukemias.
【００１４】本発明の制癌作用誘発剤は、１ｍｇ／ｋｇ
／回以下という微量の継続的な投与によって、生体のも
つ制癌作用を誘発するから、細胞障害制癌剤を用いる、
いわゆる癌の化学療法とは本質的に異なるメカニズムに
よって癌細胞を不活性化すると考えられる。なお、従来
の各種化学治療、放射線治療や温熱治療などの治療法と
併用することができる。The antitumor agent of the present invention is 1 mg / kg
A cytotoxic anti-cancer agent is used because the anti-tumor effect of the living body is induced by the continuous administration of a minute amount or less
It is believed that cancer cells are inactivated by a mechanism that is essentially different from so-called cancer chemotherapy. In addition, it can be used in combination with various conventional therapeutic methods such as chemotherapy, radiation therapy and hyperthermia.
【００１５】また、本発明の制癌作用誘発剤は１０ｍｇ
／ｋｇ／回以上の多量を継続的に投与した場合には、制
癌作用誘発効果は少なく、嘔吐などの副作用が発現す
る。The antitumor agent of the present invention is 10 mg.
When continuously administered in a large amount of not less than / kg / dose, the carcinostatic effect is small and side effects such as vomiting occur.
【００１６】つぎに本発明の制癌作用誘発剤を試験例に
基づいて説明するが、本発明はかかる試験例のみに限定
されるものではない。Next, the antitumor action inducer of the present invention will be explained based on test examples, but the present invention is not limited to such test examples.
【００１７】試験例１〜８ 体重２２〜２９ｇ（８週令）のＢＤＦ1雌性マウスの腹
腔に、表１に示した量の２−（３′−ニトロ−１′−ト
リアゾリル）酢酸−１″−エトキシメチルアミドを含有
する蒸留水０．２ｍｌを毎日１回注入した。１０日間の
連日投与の後、マウスの脚部の皮下に５×１０6箇のＢ
１６メラノーマ細胞を移植した。Test Examples 1-8 The amount of 2- (3'-nitro-1'-triazolyl) acetic acid-1 "shown in Table 1 was intraperitoneally injected into the abdominal cavity of BDF 1 female mice weighing 22 to 29 g (8 weeks old). -0.2 ml of distilled water containing ethoxymethylamide was injected once a day, and after daily administration for 10 days, 5 x 10 6 B were subcutaneously injected into the leg of mice.
16 melanoma cells were transplanted.
【００１８】試験例１〜６においては、その後引き続い
て、該化合物を毎日１回、１０日間連日投与した。該細
胞移植の２８日後に、腫瘍重量、腫瘍細胞が肺に転移し
たマウスの匹数および肺転移マウスの肺に生じた腫瘍コ
ロニーの平均数（平均肺コロニー数）をつぎの要領で測
定した。In Test Examples 1 to 6, subsequently, the compound was administered once daily for 10 consecutive days. Twenty-eight days after the cell transplantation, the tumor weight, the number of mice in which tumor cells had metastasized to the lungs, and the average number of tumor colonies formed in the lungs of lung metastasized mice (average number of lung colonies) were measured as follows.
【００１９】腫瘍細胞の移植２８日後に測定する。ま
ず、全マウス（１０匹）を屠殺し、固型腫瘍を摘出して
重量を測定し、その平均値をもって腫瘍重量とする。ま
た、マウスの肺を調べると平滑する赤褐色の肺の表面に
１〜２ｍｍの白黄色の粒（いぼ）（コロニー）が観測さ
れる。このようなマウスを肺転移マウスと呼び、その数
を肺に転移したマウスの数とした。また、肺に転移した
マウスの肺に生じたコロニー数を数え、それを平均して
平均肺コロニーとする。It is measured 28 days after the implantation of tumor cells. First, all mice (10 mice) are sacrificed, solid tumors are excised, their weights are measured, and the average value thereof is taken as the tumor weight. In addition, when the mouse lung is examined, white-yellow particles (warts) (colony) of 1 to 2 mm are observed on the surface of the smooth reddish brown lung. Such mice were called lung metastases mice, and the number was defined as the number of mice metastasized to the lungs. In addition, the number of colonies generated in the lungs of mice that have metastasized to the lungs is counted and averaged to obtain the average lung colony.
【００２０】また、該化合物を投与しなかった場合（試
験例７）および該化合物を含まない蒸留水のみを上記と
同じ頻度で同一回数投与した場合（試験例８）にも同様
の事項を測定した。以上の結果を表１に示す。なお１回
の実験に使用したマウスの数は各試験例につき１０匹で
ある。The same items are measured when the compound is not administered (Test Example 7) and when only distilled water not containing the compound is administered at the same frequency and the same number of times (Test Example 8). did. Table 1 shows the above results. The number of mice used in one experiment was 10 in each test example.
【００２１】[0021]
【表１】 [Table 1]
【００２２】以上の結果から腫瘍細胞移植の１０日前か
ら１０日後まで、毎日１回微量の本発明のニトロトリア
ゾール誘導体を継続投与することによって、移植２８日
後の腫瘍重量は比較例の約１／２〜１／３に、肺転移率
は約１／２〜１／５に、肺転移したマウスの平均肺コロ
ニー数は約１／６〜１／１３に抑制されることが示され
た。From the above results, by continuously administering a small amount of the nitrotriazole derivative of the present invention once a day from 10 days before to 10 days after the tumor cell transplantation, the tumor weight 28 days after the transplantation was about 1/2 of that of the comparative example. It was shown that the lung metastasis rate was suppressed to about 1/2 to 1/5, and the average number of lung colonies of the mice with lung metastasis was suppressed to about 1/6 to 1/13.
【００２３】[0023]
【発明の効果】本発明の制癌作用誘発剤により、生体の
制癌作用を著るしく誘発させることができる。INDUSTRIAL APPLICABILITY The antitumor effect-inducing agent of the present invention can significantly induce the carcinogenic effect of a living body.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 コノバリョバ ニイナ ペトロブナ ロシア連邦、242432 チェルノゴロブカ、 モスコフスコイ オブラスチ、３ ウリ ツ、３−１ ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Konova Lova Niina Petrovna Russian Federation, 242432 Chernogolovka, Moskovskoy Obrast, 3 Urits, 3-1
Claims (1)
与用の式（Ｉ）： 【化１】 （式中Ｒは、Ｈ、（ＣＨ2）aＲ1（ａは１〜８の整数、
Ｒ1はＨまたはＯ（ＣＨ2）mＨ（ｍは０または１〜２の
整数））、（ＣＨ2）cＣＯＯ（ＣＨ2）dＨ（ｃは１〜３
の整数、ｄは０または１〜２の整数）、または（Ｃ
Ｈ2）eＣＯＮＨ（ＣＨ2）fＯ（ＣＨ2）gＨ（ｅは１〜３
の整数、ｆは０または１〜６の整数、ｇは０または１〜
２の整数））で表わされるニトロトリアゾール誘導体を
有効成分とする生体の制癌作用の誘発剤。1. A formula (I) for continuous administration of an amount of 1 mg / kg body weight / dose or less: (In the formula, R is H, (CH 2 ) a R 1 (a is an integer of 1 to 8,
R 1 is H or O (CH 2 ) m H (m is 0 or an integer of 1 to 2), (CH 2 ) c COO (CH 2 ) d H (c is 1 to 3).
, D is 0 or an integer of 1-2), or (C
H 2) e CONH (CH 2 ) f O (CH 2) g H (e 1-3
Is an integer, f is 0 or an integer of 1 to 6, g is 0 or 1
(Integer of 2)) An agent for inducing a carcinogenic effect on a living body, which comprises a nitrotriazole derivative represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12405895A JPH08319235A (en) | 1995-05-23 | 1995-05-23 | Carcinostatic action inducer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12405895A JPH08319235A (en) | 1995-05-23 | 1995-05-23 | Carcinostatic action inducer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH08319235A true JPH08319235A (en) | 1996-12-03 |
Family
ID=14875931
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12405895A Pending JPH08319235A (en) | 1995-05-23 | 1995-05-23 | Carcinostatic action inducer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH08319235A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000051601A1 (en) * | 1999-02-26 | 2000-09-08 | Tsutomu Kagiya | Immunopotentiators |
-
1995
- 1995-05-23 JP JP12405895A patent/JPH08319235A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000051601A1 (en) * | 1999-02-26 | 2000-09-08 | Tsutomu Kagiya | Immunopotentiators |
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