JPS642087B2 - - Google Patents
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- Publication number
- JPS642087B2 JPS642087B2 JP2855181A JP2855181A JPS642087B2 JP S642087 B2 JPS642087 B2 JP S642087B2 JP 2855181 A JP2855181 A JP 2855181A JP 2855181 A JP2855181 A JP 2855181A JP S642087 B2 JPS642087 B2 JP S642087B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- group
- compound
- represented
- acid residue
- 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
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- -1 sulfonium compound Chemical class 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 150000007524 organic acids Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000007522 mineralic acids Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- XJWWFLIOOJIBFD-UHFFFAOYSA-M [I-].C[S+](C)CCOC(=O)C1=CC=CC=C1 Chemical compound [I-].C[S+](C)CCOC(=O)C1=CC=CC=C1 XJWWFLIOOJIBFD-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006215 rectal suppository Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical class CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000843 powder Substances 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- FFPKDYGMQUWLOG-UHFFFAOYSA-M silver;2-methylbenzenesulfonate Chemical compound [Ag+].CC1=CC=CC=C1S([O-])(=O)=O FFPKDYGMQUWLOG-UHFFFAOYSA-M 0.000 description 1
- AJVTWWKCZSXDMP-UHFFFAOYSA-M silver;n-cyclohexylsulfamate Chemical compound [Ag+].[O-]S(=O)(=O)NC1CCCCC1 AJVTWWKCZSXDMP-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は抗腫瘍剤に関する。
本発明の抗腫瘍剤は、下記一般式()で表わ
されるスルホニウム化合物を有効成分として含有
する点において特徴付けられる。
式中、R1、R2およびR3は同一又は相異なつて
水素原子、ハロゲン原子、アルキル基、アルコキ
シ基、アシル基およびアミノ基を、Aは一般式
CnH2o(nは2〜5の整数を示す。)で表わされる
直鎖状又は分枝状のアルキレン基を、またYは無
機酸残基または有機酸残基を意味する。
上記一般式()中R1,R2およびR3で表わさ
れるハロゲン原子としては、塩素、弗素、臭素、
沃素を、アルキル基としては、分枝状又は直鎖状
の低級アルキル基例えばメチル、エチル、n―プ
ロピル、イソプロピル基等を、アルコキシ基とし
てはメトキシ、エトキシ等の低級アルコキシ基
を、アシル基としては、アセチル、ブチリル等の
低級アルキルカルボニル基を夫々例示できる。
一般式()中Aで表わされる炭素数2〜5の
直鎖状または分枝状アルキレン基としては、エチ
レン、トリエチレン、プロピレン、テトラエチレ
ン、ペンタエチレン等を好ましく例示できる。ま
たYで表わされる無機酸残基および有機酸残基と
しては、好ましくは塩素、弗素、臭素、沃素等の
ハロゲンおよびパークロレイト、テトラフルオロ
ボレイト等の無機酸残基並びにシクロヘキシルス
ルフアメート、p―トルエンスルホネート等の有
機酸残基を例示できる。
本発明者らは、上記一般式()で表わされる
一群のスルホニウム化合物が、後述する薬理試験
例において詳述する通り、抗腫瘍作用を有するこ
とを始めて発見し、この知見に基づいて本発明を
完成した。上記一般式()で表わされるスルホ
ニウム化合物には、一部公知化合物が含まれる
が、従来之等化合物が抗腫瘍作用を有することに
ついては勿論全く知られていない。
本発明の抗腫瘍剤の有効成分とする上記一般式
()で表わされる各化合物は、例えば下記方法
A及び方法Bにより製造することができる。
<方法 A>
一般式
(式中、R1,R2、R3及びAは前記と同一の意
味を有する)で表わされる化合物と、一般式
CH3Y ()
(式中、Yは前記と同一の意味を有する)で表
わされる化合物と反応させる。
一般式()および一般式()で表わされる
化合物は公知である。本反応は無溶媒又は溶媒
中、約−20〜150℃、好ましくは約0〜100℃で行
なわれ、一般式()の化合物に対し、一般式
()の化合物を1〜4倍モル使用するのが好ま
しい。溶媒としては、反応に関与しないものであ
れば、広く使用でき、例えばメタノール、エタノ
ール等のアルコール類、アセトニトリル、ニトロ
メタン、ジメチルホルムアミド、ジメチルスルホ
キシド等の非プロトン性極性溶媒類、メチレンク
ロライド、クロロホルム等のハロゲン化炭化水
素、ベンゼン、トルエン等の芳香族炭化水素、エ
チルエーテル、プロピルエーテル類その他アセト
ン、酢酸エチル等が使用される。
<方法 B>
一般式
(式中、Xはハロゲンを、R1、R2、R3及びA
は前記と同一の意味を有する)で表わされるスル
ホニウムハライドと一般式
Y1Ag ()
(式中、Y1はXとは異なる無機酸残基又は有
機酸残基を意味する)で表わされる銀塩を反応さ
せる。
一般式()で表わされる化合物および一般式
()で表わされる化合物は公知である。本反応
は溶媒中約0〜100℃で行なわれ、一般式()
のスルホニウムハライドに対し、一般式()の
化合物を約1〜4倍モル使用するのが好ましい。
溶媒としては、<方法A>と同じものを使用でき
る。
上記二種の方法に従い得られるスルホニウム化
合物は通常の単離方法、例えば再結晶、カラムク
ロマトグラフイー等により容易に単離できる。
本発明の抗腫瘍剤の投与形態としては、特に制
限はなく、通常採用される例えば経口剤、注射
剤、直腸坐剤等のいずれでもよく、当業者に公知
慣用の製剤方法により製造できる。経口用固型製
剤を調製する場合は上記一般式()で表わされ
るスルホニウム化合物を有効成分とし、これに賦
形剤、更に必要に応じて、結合剤、崩壊剤、滑沢
剤、着色剤、矯味剤、矯臭剤等を加えた後、常法
により、錠剤、被覆錠剤、顆粒剤、散剤、カプセ
ル剤等を作成することができる。
経口液状製剤を調製する場合には、有効成分化
合物に矯味剤、緩衝剤、安定化剤、矯臭剤等を加
えて常法により内服液剤、シロツプ剤、ドライシ
ロツプ剤等を製造することができる。注射剤を調
製する場合は有効成分化合物にPH調整剤、緩衝
剤、安定化剤、等張化剤、局所麻酔剤等を添加
し、常法により、皮下、筋肉内、静脈内用注射剤
を製造することができる。直腸坐薬製剤を調製す
る場合には有効成分化合物に賦形剤、更に必要に
応じて界面活性剤等を加えた後常法により坐剤を
製造することができる。
上記の投与単位形態中に配合されるべき、有効
成分化合物の量は症状により、或いは剤型により
一定でないが、一般に経口剤では約5〜1000mg、
注射剤では約0.1〜100mg、坐剤では約0.5〜500mg
とするのが望ましい。又1日当りの投与量も症状
等に応じ一概には決定できないが通常成人約0.1
〜5000mgとするのが好ましい。
次に本発明の有効成分化合物の製造実施例、製
剤例、抗腫瘍効果試験結果及び急性毒性試験結果
を示す。
実施例 1
2―ベンゾイロキシエチルジメチルスルホニウ
ム p―トルエンスルホネート(化合物1)の
合成
2―ベンゾイロキシエチルメチルサルフアイド
1.96gにメチル p―トルエンスルホネート3.72
gを加え、室温で12時間撹拌後、反応物にエーテ
ルを加える。析出した結晶を取し、エタノール
―エーテルより再結晶して、2―ベンゾイロキシ
エチルジメチルスルホニウム p―トルエンスル
ホネート3.72g(収率97.4%)を得る。
mp. 128―129℃
元素分析値 C18H22S2O5として
C H
計算値(%) 56.52 5.80
実測値(%) 56.31 5.80
実施例 2
実施例1と同様に操作して、下記第1表に示す
化合物4、8、9、10、11、12、13、14、15、
16、17及び18を合成した。
実施例 3
2―(2―メチルベンゾイロキシ)エチルジメ
チルスルホニウム p―トルエンスルホネート
(化合物5)の合成
2―(2―メチルベンゾイロキシ)エチルジメ
チルスルホニウム アイオダイド3.52gをジクロ
ルメタン50mlに溶解し、p―トルエンスルホン酸
銀5.58gを加え室温で4時間撹拌する。反応液を
ロ過し、ロ液に硫化水素ガスを飽和させた後、活
性炭を加え過する。ロ液を濃縮し、残渣をエタ
ノール―エーテルより再結晶し、2―(2―メチ
ルベンゾイロキシ)エチルジメチルスルホニウム
p―トルエンスルホネート3.88g(収率97.7
%)を得る。
mp. 98―100℃
元素分析値 C19H24S2O5として
C H
計算値(%) 57.55 6.10
実測値(%) 57.62 6.29
実施例 4
実施例3と同様に操作して、下記第1表に示す
化合物6及び7を合成した。
実施例 5
2―ベンゾイロキシエチルジメチルスルホニウ
ム クロライド(化合物2)の合成
2―ベンゾイロキシエチルジメチルスルホニウ
ム アイオダイド3.38gをジクロルメタン50mlに
溶解し、塩化銀2.86gを加え室温で10時間撹拌
後、過する。ロ液に硫化水素ガスを飽和し、活
性炭を加え、過する。液を濃縮し、残渣をエ
タノールより再結晶して、2―ベンゾイロキシエ
チルジメチルスルホニウム クロライド2.35g
(収率95.1%)を得る。
mp. 154―156℃
元素分析値 C11H15SO2Clとして
C H
計算値(%) 53.54 6.13
実測値(%) 53.44 6.10
実施例 6
2―ベンゾイロキシエチルジメチルスルホニウ
ム シクロヘキシルスルフアメート(化合物
3)の合成
2―ベンゾイロキシエチルジメチルスルホニウ
ム アイオダイド3.38gをエタノール100mlに溶
解し、シクロヘキシルスルフアミン酸銀4.29gを
加え室温で一夜撹拌する。反応液を過し、ロ液
に硫化水素ガスを飽和し、活性炭を加えて、過
する。ロ液を濃縮し、残渣をエタノール―エーテ
ルより再結晶して、2―ベンゾイロキシエチルジ
メチルスルホニウム シクロヘキシルスルフアメ
ート3.8g(収率97.7%)を得る。
mp. 120―122℃
元素分析値 C17H27S2O5Nとして
C H N
計算値(%) 52.42 6.99 3.60
実測値(%) 52.15 7.26 3.63
上記各実施例で得られた化合物(化合物No.1〜
18)の構造、収率(%)、mp(℃)、及び元素分析
値もしくはNMR分析値(δ、ppm)を第1表に
示す。第1表中元素分析値において( )を付し
て示す数値は計算値(%)を、また()を付しな
いで示した数値は実測値(%)を示す。また
NMRは、DMSO―d6中TMSを内部標準物質と
して測定した値である。
The present invention relates to antitumor agents. The antitumor agent of the present invention is characterized in that it contains a sulfonium compound represented by the following general formula () as an active ingredient. In the formula, R 1 , R 2 and R 3 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group and an amino group, and A represents the general formula
A linear or branched alkylene group represented by CnH 2o (n is an integer of 2 to 5), and Y means an inorganic acid residue or an organic acid residue. The halogen atoms represented by R 1 , R 2 and R 3 in the above general formula () include chlorine, fluorine, bromine,
Iodine, the alkyl group is a branched or straight-chain lower alkyl group such as methyl, ethyl, n-propyl, isopropyl group, etc., the alkoxy group is a lower alkoxy group such as methoxy, ethoxy, etc., and the acyl group is can be exemplified by lower alkylcarbonyl groups such as acetyl and butyryl. Preferred examples of the linear or branched alkylene group having 2 to 5 carbon atoms represented by A in the general formula () include ethylene, triethylene, propylene, tetraethylene, and pentaethylene. The inorganic acid residues and organic acid residues represented by Y are preferably halogens such as chlorine, fluorine, bromine, and iodine, inorganic acid residues such as perchlorate and tetrafluoroborate, and cyclohexylsulfamate, p- Examples include organic acid residues such as toluenesulfonate. The present inventors discovered for the first time that a group of sulfonium compounds represented by the above general formula () have an antitumor effect, as detailed in the pharmacological test examples described below, and based on this knowledge, the present invention was developed. completed. The sulfonium compounds represented by the above general formula () include some known compounds, but it is of course completely unknown that these compounds have antitumor effects. Each compound represented by the above general formula () used as an active ingredient of the antitumor agent of the present invention can be produced, for example, by Method A and Method B below. <Method A> General formula (wherein R 1 , R 2 , R 3 and A have the same meanings as above) and a compound represented by the general formula CH 3 Y () (wherein Y has the same meanings as above) React with the compound represented by The compounds represented by the general formula () and the general formula () are known. This reaction is carried out without a solvent or in a solvent at about -20 to 150°C, preferably about 0 to 100°C, and the compound of general formula () is used in a molar amount of 1 to 4 times that of the compound of general formula (). is preferable. A wide range of solvents can be used as long as they do not participate in the reaction, such as alcohols such as methanol and ethanol, aprotic polar solvents such as acetonitrile, nitromethane, dimethylformamide, and dimethyl sulfoxide, methylene chloride, chloroform, etc. Halogenated hydrocarbons, aromatic hydrocarbons such as benzene and toluene, ethyl ether, propyl ethers, acetone, ethyl acetate, etc. are used. <Method B> General formula (In the formula, X represents halogen, R 1 , R 2 , R 3 and A
has the same meaning as above) and a silver salt represented by the general formula Y 1 Ag () (wherein Y1 means an inorganic acid residue or an organic acid residue different from X). react. The compounds represented by the general formula () and the compounds represented by the general formula () are known. This reaction is carried out in a solvent at about 0 to 100°C, and the general formula ()
It is preferable to use the compound of general formula () in an amount of about 1 to 4 times the mole of the sulfonium halide.
As the solvent, the same solvent as in <Method A> can be used. The sulfonium compounds obtained according to the above two methods can be easily isolated by conventional isolation methods such as recrystallization and column chromatography. The administration form of the antitumor agent of the present invention is not particularly limited, and may be any of the commonly used forms such as oral preparations, injections, and rectal suppositories, and can be manufactured by conventional formulation methods known to those skilled in the art. When preparing a solid preparation for oral use, the sulfonium compound represented by the above general formula () is used as an active ingredient, and excipients are added to this, and if necessary, binders, disintegrants, lubricants, colorants, After adding a flavoring agent, flavoring agent, etc., tablets, coated tablets, granules, powders, capsules, etc. can be prepared by conventional methods. When preparing oral liquid preparations, oral liquid preparations, syrups, dry syrups, etc. can be prepared by adding flavoring agents, buffering agents, stabilizers, flavoring agents, etc. to the active ingredient compound and using conventional methods. When preparing injections, add PH regulators, buffers, stabilizers, isotonic agents, local anesthetics, etc. to the active ingredient compound, and prepare subcutaneous, intramuscular, or intravenous injections using conventional methods. can be manufactured. When preparing a rectal suppository formulation, the suppository can be manufactured by a conventional method after adding excipients and, if necessary, a surfactant and the like to the active ingredient compound. The amount of the active ingredient compound to be incorporated into the above dosage unit form varies depending on the symptoms or dosage form, but is generally about 5 to 1000 mg for oral preparations.
Approximately 0.1 to 100 mg for injections, approximately 0.5 to 500 mg for suppositories
It is desirable to do so. The daily dosage cannot be determined unconditionally depending on the symptoms, etc., but it is usually about 0.1 for adults.
It is preferable to set it as 5000 mg. Next, production examples, formulation examples, antitumor effect test results, and acute toxicity test results of the active ingredient compound of the present invention will be shown. Example 1 Synthesis of 2-benzoyloxyethyldimethylsulfonium p-toluenesulfonate (compound 1) 2-benzoyloxyethylmethylsulfonate
Methyl p-toluenesulfonate 3.72 in 1.96g
After stirring at room temperature for 12 hours, ether is added to the reaction. The precipitated crystals are collected and recrystallized from ethanol-ether to obtain 3.72 g (yield 97.4%) of 2-benzoyloxyethyldimethylsulfonium p-toluenesulfonate. mp. 128-129℃ Elemental analysis value C 18 H 22 S 2 O 5 C H Calculated value (%) 56.52 5.80 Actual value (%) 56.31 5.80 Example 2 The following procedure was carried out in the same manner as in Example 1. Compounds 4, 8, 9, 10, 11, 12, 13, 14, 15 shown in the table,
16, 17 and 18 were synthesized. Example 3 Synthesis of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium p-toluenesulfonate (compound 5) Dissolve 3.52 g of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium iodide in 50 ml of dichloromethane, - Add 5.58 g of silver toluenesulfonate and stir at room temperature for 4 hours. The reaction solution is filtered, and after the filtrate is saturated with hydrogen sulfide gas, activated carbon is added and filtered. The filtrate was concentrated, and the residue was recrystallized from ethanol-ether to produce 3.88 g of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium p-toluenesulfonate (yield 97.7).
%). mp. 98-100℃ Elemental analysis value C 1 9H 24 S 2 O 5 C H Calculated value (%) 57.55 6.10 Actual value (%) 57.62 6.29 Example 4 The following procedure was carried out in the same manner as in Example 3. Compounds 6 and 7 shown in the table were synthesized. Example 5 Synthesis of 2-benzoyloxyethyldimethylsulfonium chloride (compound 2) 3.38g of 2-benzoyloxyethyldimethylsulfonium iodide was dissolved in 50ml of dichloromethane, 2.86g of silver chloride was added thereto, stirred at room temperature for 10 hours, and then filtered. do. Saturate the filtrate with hydrogen sulfide gas, add activated carbon, and filter. Concentrate the liquid and recrystallize the residue from ethanol to obtain 2.35 g of 2-benzoyloxyethyldimethylsulfonium chloride.
(yield 95.1%). mp. 154-156℃ Elemental analysis value C 11 H 15 SO 2 As Cl C H Calculated value (%) 53.54 6.13 Actual value (%) 53.44 6.10 Example 6 2-benzoyloxyethyldimethylsulfonium cyclohexylsulfamate (compound Synthesis of 3) Dissolve 3.38 g of 2-benzoyloxyethyldimethylsulfonium iodide in 100 ml of ethanol, add 4.29 g of silver cyclohexylsulfamate, and stir overnight at room temperature. The reaction mixture is filtered, the filtrate is saturated with hydrogen sulfide gas, activated carbon is added, and the mixture is filtered. The filtrate is concentrated, and the residue is recrystallized from ethanol-ether to obtain 3.8 g of 2-benzoyloxyethyldimethylsulfonium cyclohexylsulfamate (yield: 97.7%). mp. 120-122℃ Elemental analysis value C 17 H 27 S 2 O 5 N Calculated value (%) 52.42 6.99 3.60 Actual value (%) 52.15 7.26 3.63 Compounds obtained in each of the above examples (Compound No. .1~
Table 1 shows the structure, yield (%), mp (°C), and elemental analysis value or NMR analysis value (δ, ppm) of 18). In the elemental analysis values in Table 1, numerical values shown in parentheses indicate calculated values (%), and numerical values shown without parentheses indicate measured values (%). Also
NMR is a value measured using TMS in DMSO- d6 as an internal standard.
【表】【table】
Claims (1)
て水素原子、ハロゲン原子、アルキル基、アルコ
キシ基、アシル基およびアミノ基を、Aは一般式
CnH2o(nは2〜5の整数を示す) で表わされる直鎖状又は分枝状のアルキレン基
を、またYは無機酸残基または有機酸残基を意味
する) で表わされるスルホニウム化合物を含有すること
を特徴とする抗腫瘍剤。[Claims] 1. General formula (In the formula, R 1 , R 2 and R 3 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group and an amino group, and A is a general formula
A sulfonium compound represented by a linear or branched alkylene group represented by CnH 2o (n represents an integer of 2 to 5, and Y represents an inorganic acid residue or an organic acid residue). An antitumor agent characterized by containing.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2855181A JPS57142916A (en) | 1981-02-27 | 1981-02-27 | Antitumor agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2855181A JPS57142916A (en) | 1981-02-27 | 1981-02-27 | Antitumor agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57142916A JPS57142916A (en) | 1982-09-03 |
JPS642087B2 true JPS642087B2 (en) | 1989-01-13 |
Family
ID=12251786
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2855181A Granted JPS57142916A (en) | 1981-02-27 | 1981-02-27 | Antitumor agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57142916A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6407666B2 (en) * | 2014-07-30 | 2018-10-17 | 学校法人東京理科大学 | Thermal acid generator |
-
1981
- 1981-02-27 JP JP2855181A patent/JPS57142916A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS57142916A (en) | 1982-09-03 |
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