JPS631284B2 - - Google Patents
Info
- Publication number
- JPS631284B2 JPS631284B2 JP6611478A JP6611478A JPS631284B2 JP S631284 B2 JPS631284 B2 JP S631284B2 JP 6611478 A JP6611478 A JP 6611478A JP 6611478 A JP6611478 A JP 6611478A JP S631284 B2 JPS631284 B2 JP S631284B2
- Authority
- JP
- Japan
- Prior art keywords
- peroxide
- oxy
- bis
- compound
- octyl
- 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
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 150000002978 peroxides Chemical class 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- -1 peroxide compound Chemical class 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 2
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical group C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は一般式
を有する化合物の抗腫瘍剤としての新規な用途に
関する。
前記一般式（）において、Ｒは置換分として
カルボキシル、アルコキシカルボニル、置換アル
コキシカルボニルまたは置換カルバモイルを有す
ることある炭素数４乃至12個のアルキル基或いは
置換分として低級アルキル、カルボキシルまたは
アルコキシカルボニルを有することあるフエニル
基を示す。
本発明者等は、永年に亘り不飽和脂肪酸の自動
酸化物について研究を行い抗腫瘍性化合物を分離
した〔特開昭50−101301〕。更に研究を重ねた結
果前記一般式（）を有すパーオキサイド化合物
が著しい抗腫瘍作用を有することを見い出して本
発明を完成した。
前記一般式（）で表わされるパーオキサイド
化合物の代表例として下記の化合物があげられ
る。しかし本発明はこれによつて限定されるもの
ではない。
ビス（１−オキシ−ｎ−ペンチル）パーオキサ
イド（m.p.54℃）、
ビス（１−オキシ−ｎ−ヘキシル）パーオキサ
イド（m.p.50.5℃）、
ビス（１−オキシ−ｎ−ヘプチル）パーオキサ
イド（m.p.69℃）、
ビス（１−オキシ−ｎ−オクチル）パーオキサ
イド（m.p.71℃）、
ビス（１−オキシ−ｎ−ノニル）パーオキサイ
ド（m.p.72℃）、
ビス（１−オキシ−ｎ−デシル）パーオキサイ
ド（m.p.76℃）、
ビス（１−オキシ−ｎ−ウンデシル）パーオキ
サイド（m.p.78℃）、
ビス（１−オキシ−ｎ−ドデシル）パーオキサ
イド（m.p.82℃）、
ビス（１−オキシ−８−カルボキシ−ｎ−オク
チル）パーオキサイド（m.p.104〜107℃）
そのジナトリウム塩（300℃以上でもとけず）、
ビス（１−オキシ−８−メトキシカルボニル−
ｎ−オクチル）パーオキサイド（m.p.72〜75℃）、
ビス（１−オキシ−８−メトキシメトキシカル
ボニル−ｎ−オクチル）パーオキサイド（m.p.72
〜76℃）、
ビス〔１−オキシ−８−（Ｎ−カルボキシメチ
ルカルバモイル）−ｎ−オクチル〕パーオキサイ
ド（m.p.102〜105℃）、
ビス（１−オキシ−１−フエニルメチル）パー
オキサイド（m.p.86.5℃）、
ビス〔１−オキシ−１−（４−カルボキシフエ
ニル）メチル〕パーオキサイド（m.p.120〜123
℃）、そのジナトリウム塩（不明確な分解）、
ビス〔１−オキシ−１−（４−メトキシカルボ
ニルフエニル）メチル〕パーオキサイド（m.p.96
℃）、
前記一般式（）を有する化合物は、一般に適
当な溶媒中で一般式
（式中Ｒは前述したものと同意義を示す。）を有
するアルデヒドを好ましくは濃度30％以上の過酸
化水素と接触させることによつて容易に製造する
ことができる。この際必要に応じて触媒量の濃硫
酸が添加される。
前記の如く、本発明に係る前記一般式（）を
有する化合物は顕著な抗腫瘍作用を有しており、
しかも極めて低毒性である。即ちラツトに対する
急性毒性はLD50が2000mg／Kg体重以上である。
本発明に係る化合物を人体に適用する場合には皮
下又は静脈内注射により投与され、投与量は病
状、年令、体重等によつても異るが通常成人一日
当り約50〜500mgが１回または数回に分けて投与
される。注射剤は、前記一般式（）を有する化
合物を水、生理食塩液、或いは溶解補助剤例えば
トリスアミノメタン等を含有する水に溶かした溶
液或いは界面活性剤例えばツイン60、ツイン80
（商品名）等を使用した懸濁液が使用される。
次に本発明に係る化合物の薬効を示す試験例、
製剤実施例および合成例を記載するが、本発明は
これによつて限定されるものではない。
試験例 １
１群５匹のICRマウスを使用し、１匹当り100
万個のエールリツヒ腹水癌細胞をマウスの腹腔内
に移植し、検体試料を移植翌日に腹腔内に１回注
射する。
検体試料は本発明の化合物をツイン80に溶か
し、これに生理食塩液を加えて乳化状にさせる。
濃度は試料１ml当り化合物40mgを含み、ツイン80
の濃度は５％である。投与量は400mg／Kgである。
試験結果を第１表に示す。
The present invention is based on the general formula The present invention relates to a novel use of a compound having the following as an antitumor agent. In the general formula (), R is an alkyl group having 4 to 12 carbon atoms which may have carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl or substituted carbamoyl as a substituent, or a lower alkyl, carboxyl or alkoxycarbonyl as a substituent. Indicates a certain phenyl group. The present inventors have conducted research on autooxidation products of unsaturated fatty acids for many years and have isolated antitumor compounds [JP-A-101301-1989]. As a result of further research, the present invention was completed by discovering that the peroxide compound having the above general formula () has a remarkable antitumor effect. The following compounds are representative examples of the peroxide compound represented by the general formula (). However, the present invention is not limited thereby. Bis(1-oxy-n-pentyl) peroxide (mp54℃), Bis(1-oxy-n-hexyl) peroxide (mp50.5℃), Bis(1-oxy-n-heptyl) peroxide (mp69 ), bis(1-oxy-n-octyl) peroxide (mp71℃), bis(1-oxy-n-nonyl) peroxide (mp72℃), bis(1-oxy-n-decyl) peroxide ( mp76℃), bis(1-oxy-n-undecyl) peroxide (mp78℃), bis(1-oxy-n-dodecyl) peroxide (mp82℃), bis(1-oxy-8-carboxy-n- Octyl) peroxide (mp104-107℃) Its disodium salt (does not melt even above 300℃), bis(1-oxy-8-methoxycarbonyl-
n-octyl) peroxide (mp72-75℃), bis(1-oxy-8-methoxymethoxycarbonyl-n-octyl) peroxide (mp72
~76℃), Bis[1-oxy-8-(N-carboxymethylcarbamoyl)-n-octyl]peroxide (mp102~105℃), Bis(1-oxy-1-phenylmethyl)peroxide (mp86.5 ℃), bis[1-oxy-1-(4-carboxyphenyl)methyl] peroxide (mp120-123
°C), its disodium salt (undefined decomposition), bis[1-oxy-1-(4-methoxycarbonylphenyl)methyl]peroxide (mp96
°C), the compound having the general formula () is generally prepared in a suitable solvent by the general formula It can be easily produced by contacting an aldehyde having the formula (wherein R has the same meaning as defined above) with hydrogen peroxide, preferably at a concentration of 30% or more. At this time, a catalytic amount of concentrated sulfuric acid is added if necessary. As mentioned above, the compound having the general formula () according to the present invention has a remarkable antitumor effect,
Moreover, it has extremely low toxicity. That is, the acute toxicity to rats has an LD 50 of 2000 mg/Kg body weight or more.
When the compound according to the present invention is applied to the human body, it is administered by subcutaneous or intravenous injection, and the dosage varies depending on the medical condition, age, body weight, etc., but is usually about 50 to 500 mg per day for adults. Or administered in several doses. Injections may be prepared by dissolving the compound having the general formula () in water, physiological saline, or water containing a solubilizing agent such as tris-aminomethane, or a surfactant such as Twin 60 or Twin 80.
(product name) etc. is used. Next, test examples showing the medicinal efficacy of the compound according to the present invention,
Although formulation examples and synthesis examples are described, the present invention is not limited thereby. Test example 1 1 group of 5 ICR mice were used, and each mouse received 100
Ten thousand Ehrlichi ascites carcinoma cells are transplanted into the peritoneal cavity of a mouse, and a specimen sample is intraperitoneally injected once on the day after transplantation. For the test sample, the compound of the present invention is dissolved in Twin 80, and physiological saline is added to the solution to form an emulsion.
Concentration is 40 mg of compound per ml of sample, Twin 80
The concentration of is 5%. The dose is 400mg/Kg. The test results are shown in Table 1.
【表】【table】
【表】
化合物１：ビス（１−オキシ−ｎ−ヘプチル）パ
ーオキサイド）
化合物２：ビス（１−オキシ−ｎ−オクチル）パ
ーオキサイド
化合物３：ビス（１−オキシ−ｎ−ノニル）パー
オキサイド
化合物４：ビス（１−オキシ−８−メトキシカル
ボニル−ｎ−オクチル）パーオキサイド
化合物５：ビス〔１−オキシ−１−（４−メトキ
シカルボニルフエニル）メチル〕パーオキサイ
ド
上記の試験結果において投与群は非投与群と比
較して顕著な延命効果を示している。
実施例 １
ビス（１−オキシ−８−カルボキシル−ｎ−オ
クチル）パーオキサイド2.0ｇをトリスアミノメ
タン10ｇを含む生理食塩液に溶かし全量を100ml
とし、５ml／管の注射用アンブル20管を製造す
る。
実施例 ２
ビス〔１−オキシ−１−（４−カルボキシフエ
ニル）メチル〕パーオキサイドジナトリウム塩
2.0ｇを生理食塩液に溶かし全量を100mlとし、５
ml／管の注射用アンプル20管を製造する。
合成例 １
４−メトキシカルボニルベンズアルデヒド16.4
ｇに30％過酸化水素水10mlを加えて激しく撹拌
し、濃硫酸0.5mlを滴加し１時間撹拌を続ける。
そのまゝ一夜放置し、反応混合物を水で稀釈して
過する。固体を洗液が酸性を示さなくなる迄水
で洗浄し、五酸化リン上で真空乾燥するとビス
〔１−オキシ−１−（４−メトキシカルボニルフエ
ニル）メチル〕パーオキサイドの結晶16ｇが得ら
れる。このものはテトラヒドロフランより再結晶
すると融点96℃を示す純品が得られる。
合成例 ２
８−（Ｎ−カルボキシメチル）カルボニルアミ
ド−ｎ−オクチルアルデヒド1.5ｇに30％過酸化
水素水４mlを滴加し室温で20時間撹拌する。反応
混合物に水10mlを加え、過する。固体を水50ml
で洗浄し、五酸化リン上真空乾燥するとビス〔１
−オキシ−８−（Ｎ−カルボキシメチルカルバモ
イル）−ｎ−オクチル〕パーオキサイド800mgが得
られる。このものはジメチルスルホキサイド−水
より再結晶すると融点102〜105℃を示す純品が得
られる。
合成例 ３
アゼラインアルデヒド酸ナトリウム１ｇに30％
過酸化水素水２mlを加えて撹拌すると約30分後に
反応液は透明になる。10時間撹拌を続け、エタノ
ール20mlを加えるとビス（１−オキシ−８−カル
ボキシ−ｎ−オクチル）パーオキサイド ジナト
リウムの結晶が析出する。このものは水−エタノ
ールより再結晶して、その純品を得ることができ
る。[Table] Compound 1: Bis(1-oxy-n-heptyl) peroxide) Compound 2: Bis(1-oxy-n-octyl) peroxide Compound 3: Bis(1-oxy-n-nonyl) peroxide compound 4: Bis(1-oxy-8-methoxycarbonyl-n-octyl) peroxide Compound 5: Bis[1-oxy-1-(4-methoxycarbonylphenyl)methyl]peroxide In the above test results, the administration group It shows a remarkable survival effect compared to the non-administered group. Example 1 Dissolve 2.0 g of bis(1-oxy-8-carboxyl-n-octyl) peroxide in a physiological saline solution containing 10 g of trisaminomethane and make a total volume of 100 ml.
Then, 20 tubes of 5 ml/tube amble for injection are manufactured. Example 2 Bis[1-oxy-1-(4-carboxyphenyl)methyl]peroxide disodium salt
Dissolve 2.0g in physiological saline to make a total volume of 100ml,
Produce 20 injection ampoules of ml/tube. Synthesis example 1 4-methoxycarbonylbenzaldehyde 16.4
Add 10 ml of 30% hydrogen peroxide solution to g and stir vigorously, add 0.5 ml of concentrated sulfuric acid dropwise, and continue stirring for 1 hour.
After standing overnight, the reaction mixture was diluted with water and filtered. The solid is washed with water until the washing liquid no longer exhibits acidity and dried under vacuum over phosphorus pentoxide to obtain 16 g of crystals of bis[1-oxy-1-(4-methoxycarbonylphenyl)methyl]peroxide. When this product is recrystallized from tetrahydrofuran, a pure product with a melting point of 96°C can be obtained. Synthesis Example 2 4 ml of 30% hydrogen peroxide solution was added dropwise to 1.5 g of 8-(N-carboxymethyl)carbonylamide-n-octylaldehyde, and the mixture was stirred at room temperature for 20 hours. Add 10 ml of water to the reaction mixture and filter. Solid in 50ml of water
After washing and drying under vacuum over phosphorus pentoxide,
800 mg of -oxy-8-(N-carboxymethylcarbamoyl)-n-octyl]peroxide are obtained. When this product is recrystallized from dimethyl sulfoxide-water, a pure product having a melting point of 102-105°C can be obtained. Synthesis example 3 30% in 1g of sodium azelainaldehyde
After adding 2 ml of hydrogen peroxide and stirring, the reaction solution becomes clear after about 30 minutes. Stirring was continued for 10 hours and 20 ml of ethanol was added to precipitate crystals of disodium bis(1-oxy-8-carboxy-n-octyl) peroxide. This product can be recrystallized from water-ethanol to obtain a pure product.
Claims (1)
キシカルボニル、置換アルコキシカルボニルまた
は置換カルバモイルを有することある炭素数４乃
至12個のアルキル基或いは置換分として低級アル
キル、カルボキシルまたはアルコキシカルボニル
を有することあるフエニル基を示す。）を有する
化合物および／またはその形成しうる塩を有効成
分とする抗腫瘍剤。[Claims] 1 formula (In the formula, R is an alkyl group having 4 to 12 carbon atoms which may have carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl or substituted carbamoyl as a substituent, or a phenyl group which may have lower alkyl, carboxyl or alkoxycarbonyl as a substituent) ) and/or a salt thereof that can be formed as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6611478A JPS54157836A (en) | 1978-06-01 | 1978-06-01 | Anti-ulcer agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6611478A JPS54157836A (en) | 1978-06-01 | 1978-06-01 | Anti-ulcer agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS54157836A JPS54157836A (en) | 1979-12-13 |
| JPS631284B2 true JPS631284B2 (en) | 1988-01-12 |
Family
ID=13306523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6611478A Granted JPS54157836A (en) | 1978-06-01 | 1978-06-01 | Anti-ulcer agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS54157836A (en) |
-
1978
- 1978-06-01 JP JP6611478A patent/JPS54157836A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54157836A (en) | 1979-12-13 |
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