JPS6350348B2 - - Google Patents
Info
- Publication number
- JPS6350348B2 JPS6350348B2 JP4628186A JP4628186A JPS6350348B2 JP S6350348 B2 JPS6350348 B2 JP S6350348B2 JP 4628186 A JP4628186 A JP 4628186A JP 4628186 A JP4628186 A JP 4628186A JP S6350348 B2 JPS6350348 B2 JP S6350348B2
- Authority
- JP
- Japan
- Prior art keywords
- halogen atom
- group
- formula
- chloro
- toluene
- 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
- 125000005843 halogen group Chemical group 0.000 claims description 11
- -1 benzoyl urea compound Chemical class 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 230000001093 anti-cancer Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UPWAAFFFSGQECJ-UHFFFAOYSA-N 2,6-dichloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1Cl UPWAAFFFSGQECJ-UHFFFAOYSA-N 0.000 description 1
- MCVFKLFXNAUKTG-UHFFFAOYSA-N 2-bromo-n-[[3-chloro-4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]carbamoyl]benzamide Chemical compound N1=C(Cl)C(C(F)(F)F)=CC=C1OC(C(=C1)Cl)=CC=C1NC(=O)NC(=O)C1=CC=CC=C1Br MCVFKLFXNAUKTG-UHFFFAOYSA-N 0.000 description 1
- NHNAEZDWNCRWRW-UHFFFAOYSA-N 2-bromobenzamide Chemical compound NC(=O)C1=CC=CC=C1Br NHNAEZDWNCRWRW-UHFFFAOYSA-N 0.000 description 1
- UWOFDONFTURSKL-UHFFFAOYSA-N 2-chloro-6-(2-chloro-4-isocyanatophenoxy)-3-(trifluoromethyl)pyridine Chemical compound N1=C(Cl)C(C(F)(F)F)=CC=C1OC1=CC=C(N=C=O)C=C1Cl UWOFDONFTURSKL-UHFFFAOYSA-N 0.000 description 1
- XQIGAUXIAKZAAF-UHFFFAOYSA-N 3-chloro-4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]oxyaniline Chemical compound ClC1=CC(N)=CC=C1OC1=CC=C(C(F)(F)F)C(Cl)=N1 XQIGAUXIAKZAAF-UHFFFAOYSA-N 0.000 description 1
- ZYZQSCWSPFLAFM-UHFFFAOYSA-N 4-amino-2-chlorophenol Chemical compound NC1=CC=C(O)C(Cl)=C1 ZYZQSCWSPFLAFM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 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
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 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 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HRYILSDLIGTCOP-UHFFFAOYSA-N N-benzoylurea Chemical class NC(=O)NC(=O)C1=CC=CC=C1 HRYILSDLIGTCOP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はベンゾイルウレア系化合物の製造方法
に関するものである。
更に詳しくは、一般式（）
（式中Ｘはハロゲン原子、ニトロ基又はトリフル
オロメチル基であり、Ｙ及びZ2は水素原子又はハ
ロゲン原子であり、Z1はハロゲン原子又はトリフ
ルオロメチル基であり、Ａは基＝CH−又は＝Ｎ
−である。但しＸがハロゲン原子でかつＡが基＝
CH−のときZ2はハロゲン原子である）で表わさ
れるベンゾイルウレア系化合物の製造法に関す
る。
前記ハロゲン原子としては弗素、塩素、臭素、
沃素があげられる。
従来、抗癌剤として数多くの抗生物質、各種植
物体などからの抽出物質或は合成物質が用いられ
ている。例えば、マイトマイシン、アドリアマイ
シン、ブレオマイシン、ビンクリスチン、PSK、
ナイトロジエンマスタード類、５−フルオロウラ
シル等が挙げられる。
本発明者らは、数多くの合成物質について鋭意
研究の結果、前記一般式（）で表わされるベン
ゾイルウレア系化合物が、癌の治療に効果をもた
らすことの新規な知見を得、本発明の製造方法を
提案するに至つた。
本発明に係るベンゾイルウレア系化合物は、例
えば次の様な方法で製造できる。
（式中Ｘ、Ｙ、Z1、Z2及びＡは前述の通りであ
る）
上記反応で使用される溶媒としては、トルエ
ン、キシレン、モノクロロベンゼン、酢酸エチ
ル、ジオキサン、１，２−ジクロロエタン、クロ
ロホルム、四塩化炭素などが挙げられる。
また、上記各反応で用いられる原料のフエニル
イソシアネート系化合物は、例えば次の様な方法
で製造される。
（式中Ｙ、Z1、Z2及びＡは前述の通りである）
使用するアルカリ性物質としては、水酸化ナト
リウム、水酸化カリウム、炭酸ナトリウム、炭酸
カリウムなどが挙げられ、溶媒としては、ジメチ
ルスルホキシド、ジメチルホルムアミド、ヘキサ
メチルホスホロアミドなどの非プロトン性極性溶
媒、アセトン、メチルエチルケトン、メチルイソ
ブチルケトンなどのケトン類、ジエチルエーテ
ル、ジオキサンなどのエーテル類、トルエン、キ
シレンなどの芳香族炭化水素類などが挙げられ
る。また、この縮合反応を窒素ガスの存在下で行
なうことは、望ましい方法である。
（式中Ｙ、Z1、Z2及びＡは前述の通りである）
使用する溶媒としては、ホスゲンに不活性なも
のであつて、例えばトルエン、キシレン、モノク
ロロベンゼン、酢酸エチル、ジオキサンなどが挙
げられる。
合成例
Ｎ−（２−ブロモベンゾイル）−N′−〔３−クロ
ロ−４−（５−トリフルオロメチル−６−クロ
ロ−２−ピリジルオキシ）フエニル〕ウレアの
合成
アニリン系化合物の合成：
フラスコに、予め２−クロロ−４−アミノフエ
ノール1.43ｇをジメチルスルホキシド20mlに溶解
した溶液及び水酸化カリウム1.12ｇを入れ、140
℃で１時間加熱してカリウム塩を生成させた。こ
れを常温にまで冷却し、そこへ２，６−ジクロロ
−３−トリフルオロメチルピリジン2.16ｇをジメ
チルスルホキシド10mlに溶解させた溶液を10分間
にわたつて滴下して、100℃で２時間反応させた。
反応終了後、生成物を水に投入し、塩化メチレン
で抽出した。抽出物を水洗し、無水芒硝で乾燥
し、塩化メチレンを留去して、３−クロロ−４−
（５−トリフルオロメチル−６−クロロ−２−ピ
リジルオキシ）アニリン（融点76〜78℃）2.16ｇ
を得た。
フラスコにトルエン75mlを入れ、乾燥ホスゲン
ガスを吹込んで飽和させた後、前記アニリン系化
合物の合成方法と同じ方法で得られた３−クロロ
−４−（５−トリフルオロメチル−６−クロロ−
２−ピリジルオキシ）アニリン９ｇをトルエン75
mlに溶解させた溶液を、反応温度が80℃で、系内
がホスゲン過剰になるようにホスゲンを通じなが
ら、滴下した。滴下終了後、さらに５〜10分間ホ
スゲンを通じてから、温度を上げて過剰のホスゲ
ンを留去すると、定量的に３−クロロ−４−（５
−トリフルオロメチル−６−クロロ−２−ピリジ
ルオキシ）フエニルイソシアネートが得られた。
更に、２−ブロモベンズアミドのトルエン溶液30
mlを加えて昇温し、還流下（110℃）に20時間反
応させた。
反応生成物を200mlの水中に投入し、酢酸エチ
ル100mlを加えて抽出、有機層を芒硝で乾燥した
後、溶媒を留去した。少量のトルエンで洗浄して
融点168〜171℃の目的物10.5ｇを得た。
前記製造法或は合成例に準じて合成した、本発
明に係る化合物の代表例を第１表に示す。
The present invention relates to a method for producing benzoyl urea compounds. For more details, see the general formula () (In the formula, X is a halogen atom, a nitro group or a trifluoromethyl group, Y and Z 2 are a hydrogen atom or a halogen atom, Z 1 is a halogen atom or a trifluoromethyl group, and A is a group =CH- or=N
− is. However, X is a halogen atom and A is a group =
The present invention relates to a method for producing a benzoyl urea compound represented by (when CH-, Z 2 is a halogen atom). The halogen atoms include fluorine, chlorine, bromine,
Iodine can be given. Conventionally, many antibiotics, substances extracted from various plants, or synthetic substances have been used as anticancer agents. For example, mitomycin, adriamycin, bleomycin, vincristine, PSK,
Examples include nitrogen mustards, 5-fluorouracil, and the like. As a result of intensive research on a large number of synthetic substances, the present inventors have obtained the novel finding that the benzoylurea compound represented by the general formula () above is effective in cancer treatment, and the production method of the present invention I have come to propose this. The benzoyl urea compound according to the present invention can be produced, for example, by the following method. (In the formula, X, Y, Z 1 , Z 2 and A are as described above) Solvents used in the above reaction include toluene, xylene, monochlorobenzene, ethyl acetate, dioxane, 1,2-dichloroethane, chloroform , carbon tetrachloride, etc. Further, the phenyl isocyanate compound used as a raw material in each of the above reactions is produced, for example, by the following method. (In the formula, Y, Z 1 , Z 2 and A are as described above.) Examples of the alkaline substance used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and the solvent includes dimethyl sulfoxide. , aprotic polar solvents such as dimethylformamide and hexamethylphosphoramide, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ethers such as diethyl ether and dioxane, and aromatic hydrocarbons such as toluene and xylene. Can be mentioned. It is also desirable to carry out this condensation reaction in the presence of nitrogen gas. (In the formula, Y, Z 1 , Z 2 and A are as described above.) Examples of the solvent used include those inert to phosgene, such as toluene, xylene, monochlorobenzene, ethyl acetate, and dioxane. It will be done. Synthesis Example Synthesis of N-(2-bromobenzoyl)-N'-[3-chloro-4-(5-trifluoromethyl-6-chloro-2-pyridyloxy)phenyl]urea Synthesis of aniline compound: In a flask , add a solution prepared by dissolving 1.43 g of 2-chloro-4-aminophenol in 20 ml of dimethyl sulfoxide and 1.12 g of potassium hydroxide,
The potassium salt was formed by heating at 0C for 1 hour. This was cooled to room temperature, and a solution of 2.16 g of 2,6-dichloro-3-trifluoromethylpyridine dissolved in 10 ml of dimethyl sulfoxide was added dropwise over 10 minutes to react at 100°C for 2 hours. Ta.
After the reaction was completed, the product was poured into water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, methylene chloride was distilled off, and 3-chloro-4-
(5-trifluoromethyl-6-chloro-2-pyridyloxy)aniline (melting point 76-78℃) 2.16g
I got it. After putting 75 ml of toluene into a flask and saturating it by blowing in dry phosgene gas, 3-chloro-4-(5-trifluoromethyl-6-chloro-
9 g of 2-pyridyloxy)aniline to 75 g of toluene
ml of the solution was added dropwise at a reaction temperature of 80° C. while passing phosgene into the system so that there was an excess of phosgene. After the dropwise addition, phosgene is passed through for another 5 to 10 minutes, and then the temperature is raised to distill off excess phosgene, quantitatively converting 3-chloro-4-(5
-trifluoromethyl-6-chloro-2-pyridyloxy)phenyl isocyanate was obtained.
Furthermore, a toluene solution of 2-bromobenzamide 30
ml was added, the temperature was raised, and the reaction was carried out under reflux (110°C) for 20 hours. The reaction product was poured into 200 ml of water, extracted with 100 ml of ethyl acetate, and the organic layer was dried with Glauber's salt, and then the solvent was distilled off. Washing with a small amount of toluene gave 10.5 g of the desired product with a melting point of 168-171°C. Table 1 shows representative examples of compounds according to the present invention synthesized according to the above-mentioned production method or synthesis example.
【表】
次に、本発明に係るベンゾイルウレア系化合物
の抗癌活性、急性毒性、投与量及び投与方法につ
いて記載する。
(1) 抗癌活性
試験例 １
CDF1マウスに、ｐ−388白血病細胞を１×
106ケ／マウスの割合で腹腔内移植し、供試薬
剤を移植後、１日目と４日目の２回に亘つて腹
腔内へ投与した。30日間マウスの生死を観察
し、生理食塩水を投与した対照群のマウスの生
存日数を100として、各処理区の延命率（％）
を求めた。なお、薬剤は供試化合物に少量の界
面活性剤（例えばTween−80）を添加した懸
濁剤である。[Table] Next, the anticancer activity, acute toxicity, dosage, and administration method of the benzoyl urea compound according to the present invention will be described. (1) Anticancer activity test example 1 p-388 leukemia cells were injected 1x into CDF 1 mice.
The mice were intraperitoneally transplanted at a rate of 10 6 mice/mouse, and the test drug was intraperitoneally administered twice on the 1st and 4th day after transplantation. The survival rate (%) of each treatment group was determined by observing the survival of mice for 30 days and taking the number of survival days of mice in the control group administered with physiological saline as 100.
I asked for The drug is a suspension prepared by adding a small amount of a surfactant (for example, Tween-80) to the test compound.
【表】
(2) 急性毒性
腹腔内投与によるLD50値は、化合物No.１〜
11、13及び14のいずれも500mg／Kg以上であつ
た。また、化合物No.12のLD50値は、100〜200
mg／Kgであつた。
(3) 投与量及び投与法
本発明に係る抗癌剤の投与量は、投与条件の
違いにより一概に規定できないが、普通有効成
分について、１日当り体重１Kg当り約１〜約
2000mg、好ましくは約５〜約1000mg、更に好ま
しくは約５〜約500mgである。
薬剤投与に当り、前記投与量を一時に乃至分
割で投与してもよく、或は治療状態の緊急状態
によつて増減してもよい。
また、薬剤投与は経口、静脈内、筋肉内、皮
下径路などの方法で行なうことができる。本発
明に係る抗癌剤は通常の医薬の場合と同様に製
剤され、例えば、活性成分と薬理上許容される
各種担体、例えば不活性希釈剤又は同化性食用
担体とから製剤され、これらを経口的に投与す
ることが最も適当である。この場合、硬質又は
軟質のゼラチンカプセル中に封入してもよく、
錠剤に圧縮してもよく、或は油性懸濁液とする
こともできる。
次に、本発明に係る抗癌剤の製剤例を挙げる。
製剤例 １
前記化合物No.10の非結晶性粉末85重量部を、ブ
ドウ糖１重量部、コーンスターチ10重量部及び５
％コーンスターチ糊液1.5重量部と均一に混合し、
湿式法によつて顆粒状としたのち、ステアリン酸
マグネシウム１重量部を加えて圧縮打錠し、経口
用錠剤とした。
製剤例 ２
前記化合物No.１の５ｇを、ジメチルアセトアミ
ド５mlに溶解したのち、ヤシ油25ml、ペグノール
HC−17（東邦化学製）７ｇ及びHO−10M（東邦
化学製）６ｇを加えて乳剤とした。この乳剤に同
量の殺菌蒸留水を加えて、20〜30秒間超音波処理
をして油性懸濁液とした。[Table] (2) Acute toxicity The LD 50 value after intraperitoneal administration is
All of No. 11, 13, and 14 were 500 mg/Kg or more. In addition, the LD 50 value of compound No. 12 is 100 to 200
It was mg/Kg. (3) Dosage and administration method Although the dose of the anticancer agent according to the present invention cannot be absolutely defined due to differences in administration conditions, it is usually about 1 to about 1 to 1 kg per 1 kg of body weight per day for the active ingredient.
2000 mg, preferably about 5 to about 1000 mg, more preferably about 5 to about 500 mg. When administering the drug, the dosage may be administered all at once or in divided doses, or may be increased or decreased depending on the exigencies of the therapeutic condition. Moreover, drug administration can be carried out by oral, intravenous, intramuscular, subcutaneous routes, and the like. The anticancer agent according to the present invention is formulated in the same manner as ordinary pharmaceuticals, for example, it is formulated from an active ingredient and various pharmacologically acceptable carriers, such as an inert diluent or an assimilable edible carrier, and these are administered orally. It is most appropriate to administer In this case, it may be enclosed in a hard or soft gelatin capsule,
It may be compressed into tablets or it may be an oily suspension. Next, examples of formulations of the anticancer agent according to the present invention will be given. Formulation Example 1 85 parts by weight of the amorphous powder of Compound No. 10 was mixed with 1 part by weight of glucose, 10 parts by weight of corn starch, and 5 parts by weight of corn starch.
% corn starch paste liquid and 1.5 parts by weight,
After the mixture was made into granules by a wet method, 1 part by weight of magnesium stearate was added and compressed into tablets for oral use. Formulation Example 2 After dissolving 5 g of the above compound No. 1 in 5 ml of dimethylacetamide, 25 ml of coconut oil and pegnol were added.
An emulsion was prepared by adding 7 g of HC-17 (manufactured by Toho Chemical Co., Ltd.) and 6 g of HO-10M (manufactured by Toho Chemical Co., Ltd.). The same amount of sterilized distilled water was added to this emulsion and subjected to ultrasonication for 20 to 30 seconds to obtain an oily suspension.
Claims (1)
オロメチル基である）で表わされる化合物と一般
式（） （式中Ｙ及びZ2は水素原子又はハロゲン原子であ
り、Z1はハロゲン原子又はトリフルオロメチル基
であり、Ａは基＝CH−又は＝Ｎ−である）で表
わされる化合物とを反応させて一般式（） （式中Ｘ、Ｙ、Z1、Z2及びＡは前述の通りであ
る。但しＸがハロゲン原子でかつＡが基＝CH−
のときZ2はハロゲン原子である）で表わされるベ
ンゾイルウレア系化合物を製造することを特徴と
するベンゾイルウレア系化合物の製造方法。[Claims] 1 General formula () (In the formula, X is a halogen atom, a nitro group, or a trifluoromethyl group) and a compound represented by the general formula () (In the formula, Y and Z 2 are a hydrogen atom or a halogen atom, Z 1 is a halogen atom or a trifluoromethyl group, and A is a group =CH- or =N-). General formula () (In the formula, X, Y, Z 1 , Z 2 and A are as described above. However, X is a halogen atom and A is a group =CH-
1. A method for producing a benzoyl urea compound, the method comprising producing a benzoyl urea compound represented by (where Z 2 is a halogen atom).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61046281A JPS625960A (en) | 1986-03-05 | 1986-03-05 | Production of benzoylurea compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61046281A JPS625960A (en) | 1986-03-05 | 1986-03-05 | Production of benzoylurea compound |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18545180A Division JPS57109721A (en) | 1980-12-27 | 1980-12-27 | Carcinostatic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS625960A JPS625960A (en) | 1987-01-12 |
| JPS6350348B2 true JPS6350348B2 (en) | 1988-10-07 |
Family
ID=12742844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61046281A Granted JPS625960A (en) | 1986-03-05 | 1986-03-05 | Production of benzoylurea compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS625960A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
| TW200538453A (en) | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
| US7432373B2 (en) | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
| US7173031B2 (en) | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US7439246B2 (en) | 2004-06-28 | 2008-10-21 | Bristol-Myers Squibb Company | Fused heterocyclic kinase inhibitors |
-
1986
- 1986-03-05 JP JP61046281A patent/JPS625960A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS625960A (en) | 1987-01-12 |
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