JPH01186834A - 6-substituted benzene compound and cell differentiation inducer - Google Patents
6-substituted benzene compound and cell differentiation inducerInfo
- Publication number
- JPH01186834A JPH01186834A JP685788A JP685788A JPH01186834A JP H01186834 A JPH01186834 A JP H01186834A JP 685788 A JP685788 A JP 685788A JP 685788 A JP685788 A JP 685788A JP H01186834 A JPH01186834 A JP H01186834A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- cell differentiation
- differentiation inducer
- substituted benzene
- lower alkyl
- 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
- -1 6-substituted benzene compound Chemical class 0.000 title claims abstract description 15
- 230000024245 cell differentiation Effects 0.000 title claims abstract description 8
- 239000000411 inducer Substances 0.000 title claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 24
- 150000001875 compounds Chemical class 0.000 abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 7
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 150000007944 thiolates Chemical class 0.000 abstract description 5
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 abstract description 4
- 229930002330 retinoic acid Natural products 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 229960001727 tretinoin Drugs 0.000 abstract description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 230000000737 periodic effect Effects 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- PHEDXBVPIONUQT-BJBOKCJXSA-N 12-Tetradecanoylphorbol 13-acetate Natural products O=C(O[C@H]1[C@@H](C)[C@@]2(O)[C@H]3[C@@](O)(C(=O)C(C)=C3)CC(CO)=C[C@H]2[C@H]2C(C)(C)[C@]12OC(=O)C)CCCCCCCCCCCCC PHEDXBVPIONUQT-BJBOKCJXSA-N 0.000 description 1
- UEUMAXMCCDEOIJ-XYOKQWHBSA-N 5-chloro-3-[(2e)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-methylbenzaldehyde Chemical compound CC(C)=CCC\C(C)=C\CC1=C(O)C(Cl)=C(C)C(C=O)=C1O UEUMAXMCCDEOIJ-XYOKQWHBSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 238000010817 Wright-Giemsa staining Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UEUMAXMCCDEOIJ-UHFFFAOYSA-N colletochlorin B Natural products CC(C)=CCCC(C)=CCC1=C(O)C(Cl)=C(C)C(C=O)=C1O UEUMAXMCCDEOIJ-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- LLXSTCAYPDXLJL-UHFFFAOYSA-K ethane;trichloroalumane Chemical compound [Al+3].[Cl-].[Cl-].[Cl-].CC LLXSTCAYPDXLJL-UHFFFAOYSA-K 0.000 description 1
- 239000012894 fetal calf serum Substances 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JPSNJFMTQIIVFG-UHFFFAOYSA-M lithium;ethanethiolate Chemical compound [Li+].CC[S-] JPSNJFMTQIIVFG-UHFFFAOYSA-M 0.000 description 1
- XTOPWLDTKIFTMJ-UHFFFAOYSA-L magnesium ethanethiolate bromide Chemical compound [Br-].C(C)S[Mg+] XTOPWLDTKIFTMJ-UHFFFAOYSA-L 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- VGGNVBNNVSIGKG-UHFFFAOYSA-N n,n,2-trimethylaziridine-1-carboxamide Chemical compound CC1CN1C(=O)N(C)C VGGNVBNNVSIGKG-UHFFFAOYSA-N 0.000 description 1
- ZCOGQSHZVSZAHH-UHFFFAOYSA-N n,n-dimethylaziridine-1-carboxamide Chemical compound CN(C)C(=O)N1CC1 ZCOGQSHZVSZAHH-UHFFFAOYSA-N 0.000 description 1
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- XVSFHIIADLZQJP-UHFFFAOYSA-M sodium;propane-1-thiolate Chemical compound [Na+].CCC[S-] XVSFHIIADLZQJP-UHFFFAOYSA-M 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野〕
本発明は、後記−数式〔１〕で表される６置換ベンゼン
化合物及び該化合物から成る細胞分化誘導剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a 6-substituted benzene compound represented by formula [1] below and a cell differentiation inducer comprising the compound.
従来、ガンの化学療剤として、ガン細胞を殺す作用をも
つ制ガン剤の探索が広範におこなわれ、強力なものが敗
多く見つかっている。ところが、これら強力な制ガン剤
は、しばしば正常細胞をも無差別に殺してしまう。Conventionally, there has been a wide range of searches for anticancer drugs that have the effect of killing cancer cells as chemotherapeutic agents for cancer, and many powerful drugs have been successfully discovered. However, these powerful anticancer drugs often kill normal cells indiscriminately.
最近、ガン細胞とは、正常細胞が、分化の途中で増殖を
繰り返すものであるという認識が生まれつつある。した
がって、この未分化細胞を何らかの刺部によって分化さ
せることができればガン細胞の増殖を抑えることができ
、ガン治療に利用できる。この刺激物質すなわち分化誘
導剤としていくつか知られている。なかでもレチン酸（
ｒｓｔｉｎｏｌｃ ａｃｉｄ）は指標化合物として広
く用いられているが、毒性のため、臨床への応用は困難
である（化学と生物 １工、５（１９８７）参照）。Recently, there is a growing recognition that cancer cells are normal cells that repeatedly proliferate during differentiation. Therefore, if these undifferentiated cells can be differentiated by some kind of barb, the proliferation of cancer cells can be suppressed and can be used for cancer treatment. Several stimulants or differentiation-inducing agents are known. Among them, retinoic acid (
rstinolc acid) is widely used as an indicator compound, but it is difficult to apply clinically due to its toxicity (see Chemistry and Biology 1 Engineering, 5 (1987)).
本発明者らは、鋭意検討を重ねた結果、レチン′ 酸
よりも毒性が低く、かつヒトガン細胞を正常分化させう
る細胞分化誘導剤として期待される化合物を見出し、本
発明を完成するにいたった。As a result of extensive studies, the present inventors discovered a compound that is less toxic than retinoic acid and is expected to be a cell differentiation inducer capable of normal differentiation of human cancer cells, leading to the completion of the present invention. .
本発明は下記−数式（１）で表される６置換ベンゼン
（式中、Ｒ１及びＲ１は相異なって、水素原子または低
級アルキル基である。）化合物及び該化合物から成る細
胞分化誘導剤である。前記−数式ｃ目で表される化合物
は一般式（Ｕ）で表されるエーテル化合物
（式中、Ｒは低級アルキル基である。）に−数式Ｍ ｔ
Ｉ Ｓ Ｒ” −（Ｉ）（式中、Ｍｔｌは
周期律表第１．２又は１３族元素を表し、２又は１３族
元素の場合はそれぞれハロゲンイオンを１又は２個伴う
、Ｒ３は低級アルキルＳ＞で表される金属チオラートを
作用させて得ることができる。The present invention relates to a 6-substituted benzene compound represented by the following formula (1) (wherein R1 and R1 are each a hydrogen atom or a lower alkyl group) and a cell differentiation inducer comprising the compound. . The compound represented by formula c is an ether compound represented by general formula (U) (wherein R is a lower alkyl group) - formula M t
I S R" - (I) (wherein, Mtl represents an element of group 1.2 or 13 of the periodic table, and in the case of an element of group 2 or 13, it is accompanied by one or two halogen ions, R3 is a lower alkyl It can be obtained by reacting with a metal thiolate represented by S>.
前記−数式（ＩＩ）で表されるエーテル化合物としては
３−クロロ−４，６−ジェトキシ−２−メチル−５−（
３，７−シメチルー２．６−オクタジェニル）ベンゼン
−１−カルボアルデヒド、３−クロロ−４，６−シメト
キシー２−メチル−５−（３，７−シメチルー２．６−
オクタジェニル）ベンゼン−１−カルボアルデヒド、３
−クロｍ−４，ｓ−ジ（ｔ−ブトキシ）−２−メチル−
５−（３，７−シメチルー２．６−オクタジェニル）ベ
ンゼン−１−カルボアルデヒドなどを例示することがで
きる。The ether compound represented by formula (II) is 3-chloro-4,6-jethoxy-2-methyl-5-(
3,7-dimethyl-2,6-octagenyl)benzene-1-carbaldehyde, 3-chloro-4,6-simethoxy2-methyl-5-(3,7-dimethyl-2,6-
octagenyl)benzene-1-carbaldehyde, 3
-Chromo-4,s-di(t-butoxy)-2-methyl-
Examples include 5-(3,7-dimethyl-2,6-octagenyl)benzene-1-carbaldehyde.
前記−数式（１）で表される金属チオラートとしてはナ
トリウムエタンチオラート、ナトリウムメタンチオラー
ト、ナトリウムプロパンチオラート、リチウムエタンチ
オラート、臭化マグネシウムエタンチオラート、塩化マ
グネシウムエタンチオラート、臭化マグネシウムメタン
チオラート、塩化アルミニウムエタンチオラート、塩化
ホウ素エタンチオラートなどをあげることができる。The metal thiolate represented by formula (1) includes sodium ethanethiolate, sodium methanethiolate, sodium propanethiolate, lithium ethanethiolate, magnesium bromide ethanethiolate, magnesium chloride ethanethiolate, magnesium bromide methanethiolate, and aluminum chloride ethane. Examples include thiolate, boron chloride ethanethiolate, and the like.
−数式（１）で表される金属チオラートを一数式ＣＩ＋
）で表されるエーテル化合物に作用させる際、有機溶媒
中でおこなうことが望ましい、用いる溶媒としてはジメ
チルホルムアミド（ＤＭＦ）、ヘキサメチルリン酸トリ
アミド、Ｎ−メチルピロリドン、Ｎ、Ｎ−ジメチルプロ
ピレンウレア、Ｎ、Ｎ−ジメチルエチレンウレア、テト
ラヒドロフランなどをあげることができる０反応温度は
０℃から２００℃の範囲、望ましくは室温から１５０℃
の範囲がよい、−数式（ＩＩ）で表される反応剤の使用
量は一般式（ＩＩ）で表されるエーテル化合物に対し１
当量ないし大過剰の範囲で使用できるが望ましくは５な
いし１５当量である。金属に応じて一般式（ＩＩ）のＯ
Ｒ基二つのいずれかを選択的にＯＨ基に変換することが
できる。- a metal thiolate represented by the formula (1) with the formula CI+
) When acting on the ether compound represented by (), it is preferable to carry out the reaction in an organic solvent. Examples of solvents used include dimethylformamide (DMF), hexamethylphosphoric acid triamide, N-methylpyrrolidone, N,N-dimethylpropylene urea, Examples include N,N-dimethylethyleneurea, tetrahydrofuran, etc.The reaction temperature is in the range of 0°C to 200°C, preferably room temperature to 150°C.
- The amount of the reactant represented by formula (II) to be used is preferably within the range of 1 to 1 per ether compound represented by general formula (II).
It can be used in an equivalent to a large excess, but preferably 5 to 15 equivalents. O of general formula (II) depending on the metal
Either of the two R groups can be selectively converted to an OH group.
以上の如くして得られる本発明化合物について活性試験
を行い、細胞分化誘導剤としての育用性を確認した。An activity test was conducted on the compound of the present invention obtained as described above, and its applicability as a cell differentiation inducer was confirmed.
実施例１ 水素化ナトリウム（５０％オイル、４５ｗ。Example 1 Sodium hydride (50% oil, 45w.
０．９４ｍｍｏｌ）をＤＭＦ （３ｍｌ）で２回洗浄し
、ＤＭＦ（２ｍｌ）に懸濁させた。ここへエタンチオー
ル（５３ｗ、０．８６ｍｍｏ ｌ）を加え、２０分間攪
拌してＮａ５Ｅｔを調整した。ここへ３−クロロ−４，
６−シメトキシー２−メチル−５−（３，７−シメチル
ー２．６−オクタジェニル）ベンゼンカルボアルデヒド
（Ｔｅｔｒａｈｅｄｒｏａ Ｌ＠ｔｔ。0.94 mmol) was washed twice with DMF (3 ml) and suspended in DMF (2 ml). Ethanethiol (53w, 0.86mmol) was added thereto and stirred for 20 minutes to adjust Na5Et. here 3-chloro-4,
6-Simethoxy2-methyl-5-(3,7-dimethyl-2,6-octagenyl)benzenecarbaldehyde (Tetrahedroa L@tt.
２７．５９７ （１９８６））（３０曜、０．０８６ｍ
ｍｏｌ）のＤＭＦ （１ｍｌ）ｍ液を加え、１００℃で
１５分、１２０℃で１．１時間攪拌した。室温に冷やし
、ジクロロメタン（３０ｍｌ）および飽和食塩水（５ｍ
ｌ ）を加えて有機層を分離し、水層は１Ｍ塩酸でｐ
Ｈ１としてジクロロメタン（５ｍｌＸ３）で抽出した。27.597 (1986)) (30th day, 0.086m
mol) of DMF (1 ml) was added thereto, and the mixture was stirred at 100°C for 15 minutes and at 120°C for 1.1 hours. Cool to room temperature and add dichloromethane (30 ml) and saturated brine (5 ml).
l) to separate the organic layer, and the aqueous layer was diluted with 1M hydrochloric acid.
Extracted with dichloromethane (5ml x 3) as H1.
゛有機層を合わせ、乾燥（無水硫酸ナトリウム）したの
ち濃縮してオイル（３３＊）を得た。ＴＬＣで精製して
（シリカゲル、ジクロロメタン−ヘキサン３：１）３−
クロロ−４−ヒドロキシ−６−メドキシー２−メチル−
５−（３，７−シメチルー２．６−オクタジェニル）ベ
ンゼン−１−カルボアルデヒド
（Ｒｒｏ、３７−０．４７．５．Ｏｗ、収率１７％）を
得た。``The organic layers were combined, dried (anhydrous sodium sulfate), and concentrated to obtain an oil (33*). Purified by TLC (silica gel, dichloromethane-hexane 3:1) 3-
Chloro-4-hydroxy-6-medoxy-2-methyl-
5-(3,7-dimethyl-2.6-octagenyl)benzene-1-carbaldehyde (Rro, 37-0.47.5.Ow, yield 17%) was obtained.
ＩＲ（ＫＢｒ）３４５０．１６７０，１５９０゜１５６
３．１３１１．１２３２゜
１０９９ ｃｍ−’。IR(KBr)3450.1670,1590°156
3.1311.1232°1099 cm-'.
’Ｈ−ＮＭＲ（ＣＤＣＩｍ）６１．５７ （ｓ、３Ｈ
）。'H-NMR (CDCIm) 61.57 (s, 3H
).
１．６４ （ｓ、３１（）、１．７８ （ｓ、３Ｈ）
。1.64 (s, 31(), 1.78 (s, 3H)
.
１．９−２．２ （ｍ、４Ｈ）、２．６５（富＋ ３
ＨＬ３．４１ （ｄ、Ｊｍ６．８Ｈｚ。1.9-2.2 (m, 4H), 2.65 (wealth + 3
HL3.41 (d, Jm6.8Hz.
２Ｈ）、３．８０ （ｓ、 ３Ｈ）、４．９−５．
３（ｍａｔ（δ５．１９． Ｊ−６，８Ｈり 。2H), 3.80 (s, 3H), 4.9-5.
3(mat(δ5.19.J-6,8Hri.
２Ｈ）、６．２８ （ｂｒａ、 ＩＨ）。2H), 6.28 (bra, IH).
１０．３８ （ｓ、 ＩＨ）。10.38 (s, IH).
ＭＳｍ／ｇ（相対強度）３３ｇ（Ｍ’″＋２゜４）、
３３６ （Ｍ”、 １０）、 ３０４（１Ｇ）
、 ２６７ （３９）、 ２５３（１６）、２３
７ （２３）、２１５（１９）、 ２１３ （５
９）、 ２１１（２４）、 １９９ （４２）、
１２’３（１００）、 １２２ （１８）、６
９（５１）、 ４１ （４６）。MSm/g (relative strength) 33g (M'″+2°4),
336 (M”, 10), 304 (1G)
, 267 (39), 253 (16), 23
7 (23), 215 (19), 213 (5
9), 211 (24), 199 (42),
12'3 (100), 122 (18), 6
9(51), 41(46).
ほかにコレトクロリンＢ （Ｒｆｏ、６３−０．７１゜
１２．５ｍ、収率４５％）を得た。In addition, colletochlorin B (Rfo, 63-0.71°12.5m, yield 45%) was obtained.
実施例２
エタンチオール（Ｓ ３ｗ、０．８６ｍｍｏ １）のエ
ーテル（０，５ｍ１）１液に０℃にて臭化エチルマグネ
シウム（２，０Ｍエーテル溶液０．４２８ｍ１゜０．８
６ｍｍｏｌ）を加え１０分間攪拌ののちエーテルを減圧
下に留去した。残渣をＤＭＦ （１ｍｌ）に溶かし、こ
こへ３−クロロ−４，６〜ジメトキシ−２−メチル−５
−（３，７−シメチルー２．６−オクタジエニノリベン
ゼンー１−カルボアルデヒド（３：ＪＫ、０．０９４ｍ
ｍｏ１）のＤＭＦ （１，５ｍ１）を加え１００℃にて
１０分間攪拌した。実施例１と同様の後処理を行い、Ｔ
ＬＣで精製して３−クロロ−６−ヒドロキシ−４−メト
キシ−２−メチル−５−（３，７−シメチルー２．６−
オクタジェニル）ベンゼン−１−カルボアルデヒド（８
，６■。Example 2 Ethylmagnesium bromide (2.0M solution in ether 0.428ml 0.8
After stirring for 10 minutes, the ether was distilled off under reduced pressure. The residue was dissolved in DMF (1 ml) and 3-chloro-4,6-dimethoxy-2-methyl-5 was added thereto.
-(3,7-dimethyl-2,6-octadienylinobenzene-1-carbaldehyde (3:JK, 0.094m
mol of DMF (1.5 ml) was added and stirred at 100°C for 10 minutes. The same post-processing as in Example 1 was performed, and T
Purified by LC to give 3-chloro-6-hydroxy-4-methoxy-2-methyl-5-(3,7-dimethyl-2,6-
octagenyl)benzene-1-carbaldehyde (8
,6■.
収率２７％）を得た。A yield of 27% was obtained.
ＩＲ（ｎｅａｔ）３４２５．３２６５．１６３Ｂ。IR(neat)3425.3265.163B.
１６０８．１４０１．１２４６，１１０９゜７９６ａａ
−’。1608.1401.1246, 1109°796aa
-'.
’Ｈ−ＮＭＲ（ＣＤＣＩｓ）６１．５７ （ｓ、３）１
）。'H-NMR (CDCIs) 61.57 (s, 3) 1
).
−１，６４（ｓ、３Ｈ）、１．７８ （ｓ、３８）。-1,64 (s, 3H), 1.78 (s, 38).
１．９−２．２ （ｍ、４Ｈ）、２．６２←ｓ、３Ｈ）
、３．３９ （ｄ、Ｊ＝６．６Ｈｚ。1.9-2.2 (m, 4H), 2.62←s, 3H)
, 3.39 (d, J=6.6Hz.
２Ｈ）、３．８５ （ａ、３Ｈ）、４．９−５．３（ｍ
＋ｔ（δ５．１〕、Ｊ”６．６）１！１２Ｈ）、１Ｇ、
２６ （ｓ、ＩＨ）、１２．５１３３６ （Ｍ”、１９
）、２９３ （２１）。2H), 3.85 (a, 3H), 4.9-5.3 (m
+t(δ5.1], J"6.6)1!12H), 1G,
26 (s, IH), 12.51336 (M”, 19
), 293 (21).
２６９ （２２）、２６７ （６６）、２２５（２４）
、 ２１５ （３２）、２１３（９０）、 １９
９ （２３）、 １２３（１００）、 １２２
（３４）、 ６９（６２）、 ４１ （８Ｇ）
。269 (22), 267 (66), 225 (24)
, 215 (32), 213 (90), 19
9 (23), 123 (100), 122
(34), 69 (62), 41 (8G)
.
分化誘導活性試験 １、化合物の調製 各化合物をエタノールに溶解し５ｍＭ濃度に調製した。Differentiation induction activity test 1. Preparation of compounds Each compound was dissolved in ethanol to a concentration of 5mM.
これをＲＰＭＩ培養液を用い各濃度に希釈した。This was diluted to various concentrations using RPMI culture medium.
２、ＭＬ−６０細胞の調製
液体窒素中に保存したＨＬ−６０細胞を溶解し、５％胎
仔牛血清（Ｆｅ２） 、０．５％ペニシリン・ストレプ
トマイシンを含むＲＰＭＩ培養液で培養後血球針算盤で
細胞数を算出し、Ｆｅ２．ペニシリン・ストレプトマイ
シンを含まない培養液で細胞を洗浄、遠心しインシュリ
ン（５Ｈｓ／ｍｌ）トランスフェリン（５Ｈｇ ／ ｍ
１ ）を含む培養液に懸濁した。最終細胞濃度を３
Ｘ １ Ｇ ’ｃｅｌｌｓ／ｍｌに調製した。2. Preparation of ML-60 cells The HL-60 cells stored in liquid nitrogen were lysed, cultured in RPMI medium containing 5% fetal calf serum (Fe2) and 0.5% penicillin/streptomycin, and then cultured using a hemocytometer. Calculate the number of cells and Fe2. Cells were washed with penicillin/streptomycin-free culture medium, centrifuged, and treated with insulin (5Hs/ml) and transferrin (5Hg/ml).
1) was suspended in a culture solution containing the following. Reduce the final cell concentration to 3
The concentration was adjusted to X 1 G' cells/ml.
３、活性測定
培養器として９６ウエルカルチヤーデイツシエを用い、
これに上記のＨＬ−６０細胞（１００，ｕｊ）と各濃度
の化合物（１００μｍ）を入れ、５％ＣＯ，存在下３７
℃で４日間培養した０反応前の最終細胞濃度は２ Ｘ
１ Ｇ ’ｃｅｌｌｓ／ｍｌで反応液中のエタノール濃
度は０．１Ｍ以下にした。４日間培養後の反応液を反応
細胞液と略し以下用いる。3. Using a 96-well culture dish as a culture vessel for activity measurement,
The above HL-60 cells (100, uj) and each concentration of compound (100 μm) were added to this, and the mixture was heated at 37° C. in the presence of 5% CO.
The final cell concentration before the 0 reaction, incubated for 4 days at °C, was 2X
The ethanol concentration in the reaction solution was adjusted to 0.1 M or less at 1 G' cells/ml. The reaction solution after 4 days of culture is abbreviated as reaction cell solution and will be used below.
４、殺細胞活性
細胞数はｌ１ｌｉ徽鏡とコールタ−カウンターを用いて
測定した。細胞パイアビリティ（ＶＤｓｓ）はトリバン
プルーで細胞を染色後、顕微鏡を用いて測定した。細胞
形態は顕微鏡で観察し、考察した。4. The number of cells with active cell killing was measured using a 11li mirror and a Coulter counter. Cell viability (VDss) was measured using a microscope after staining cells with trivan blue. Cell morphology was observed under a microscope and discussed.
５、分化誘導活性（ＥＤｓｅ）。5. Differentiation-inducing activity (EDse).
反応細胞液１００．ｕｊを９６ウエルカルチヤーデイツ
シエに入れ、遠心後上滑を除去し２０％ＦＣ３含有ＲＰ
ＭＩ墳養液（１００ｕｊ）とＮＢＴｔｌｌ液 （ｌ ０
０ μ １） （１１■／５ｌＮＢＴ”＋３．２４
μＭ ＴＰＡ”）を加え、５％Ｃ０３゜３７℃、２５
分間培養を行った０次に氷で冷却、遠心し上清を除去し
た後、ライト・ギムザ染色液を加え染色し、顕微鏡下、
黒く染色した細胞を数える。Reaction cell solution 100. Place the uj in a 96-well culture dish, remove the supernatant after centrifugation, and add 20% FC3-containing RP.
MI culture solution (100uj) and NBTtll solution (l 0
0 μ 1) (11■/5lNBT”+3.24
μM TPA”) and 5% C03°37°C, 25
After incubation for 0 minutes, cool on ice, centrifuge, remove the supernatant, add Wright-Giemsa staining solution, and stain under a microscope.
Count the cells stained black.
巖ＮＴＢ ：ニトロブルーテトラゾリウム＊ＴＰＡ ：
１２−テトラデカノイル−フォルボール−１３−アセ
タート
表 １ 活性試験測定値
ａｌｌ ｔｒａｎｓ ｒｅｔｉｎｏｉｃ ａｃｉｄ（Ｒ
Ａ）ａ： 細胞パイアビリティ
ｂ： 分化誘導活性
手続補正書（方式）
％式％
１、事件の表示
昭和６３年特許願第 ００６８５７ 号３、補正をす
る者
４、補正命令の日付（発送臼）
昭和６３年 ４月２６日
５、補正の対象
明細書の「発明の名称」の欄
６、補正の内容
本願明細書第１頁３行目の「６置換ベンゼン・・・」を
ｒ６−置換ベンゼン・・・ｊに訂正する。Iwao NTB: Nitro blue tetrazolium *TPA:
12-tetradecanoyl-phorbol-13-acetate Table 1 Activity test measurement values all trans retinoic acid (R
A) a: Cell pyability b: Differentiation induction activity procedure amendment (method) % formula % 1. Indication of the case Patent Application No. 006857 of 1988 3. Person making the amendment 4. Date of amendment order (dispatch mortar) April 26, 1988, 5, Column 6 of "Title of the Invention" of the specification to be amended, contents of the amendment "6-substituted benzene..." on page 1, line 3 of the specification of the present application was changed to r6-substituted benzene. ...Correct to j.
′以 上'that's all
Claims (2)
は低級アルキル基である。）で表される６置換ベンゼン
化合物。(1) A 6-substituted benzene compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 are different and each is a hydrogen atom or a lower alkyl group.)
合物から成る細胞分化誘導剤。(2) A cell differentiation inducer comprising a 6-substituted benzene compound represented by the general formula described in item 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP685788A JPH01186834A (en) | 1988-01-18 | 1988-01-18 | 6-substituted benzene compound and cell differentiation inducer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP685788A JPH01186834A (en) | 1988-01-18 | 1988-01-18 | 6-substituted benzene compound and cell differentiation inducer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01186834A true JPH01186834A (en) | 1989-07-26 |
Family
ID=11649906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP685788A Pending JPH01186834A (en) | 1988-01-18 | 1988-01-18 | 6-substituted benzene compound and cell differentiation inducer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01186834A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015521163A (en) * | 2012-04-25 | 2015-07-27 | ザ ユニバーシティー オブ サセックス | Compounds for use as inhibitors of alternative oxidase or cytochrome BC1 complex |
-
1988
- 1988-01-18 JP JP685788A patent/JPH01186834A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015521163A (en) * | 2012-04-25 | 2015-07-27 | ザ ユニバーシティー オブ サセックス | Compounds for use as inhibitors of alternative oxidase or cytochrome BC1 complex |
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