JPS61275266A - Retinoid derivative - Google Patents
Retinoid derivativeInfo
- Publication number
- JPS61275266A JPS61275266A JP60115141A JP11514185A JPS61275266A JP S61275266 A JPS61275266 A JP S61275266A JP 60115141 A JP60115141 A JP 60115141A JP 11514185 A JP11514185 A JP 11514185A JP S61275266 A JPS61275266 A JP S61275266A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- derivative
- compound
- expressed
- reaction
- 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
- 150000004492 retinoid derivatives Chemical class 0.000 title description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 150000001298 alcohols Chemical class 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- -1 n-amyl Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical group [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- QQFBQBDINHJDMN-UHFFFAOYSA-N ethyl 2-trimethylsilylacetate Chemical compound CCOC(=O)C[Si](C)(C)C QQFBQBDINHJDMN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
Ｌｌ上立上Ｊｌｊ？
本発明はレチノイド誘導体に関し、更に詳しくｔｆ腫Ｊ
１１ＨＩＩ剤ト１．テ有用す１１Ｚ、１３２−２０．２
０．２０−トリフルオロレチノイド誘導体に関する。[Detailed Description of the Invention] Ll rise Jlj? The present invention relates to retinoid derivatives, and more specifically to TF tumor J.
11HII agent 1. Te useful 11Z, 132-20.2
0.20-Trifluororetinoid derivatives.
Ｉ び 。 占レチノイド（
ビタミンＡおよびその類縁体）に抗腫瘍作用がある番は
、既に知られている。I bi. Zhan retinoid (
It is already known that vitamin A and its analogues have antitumor effects.
しかしながら肝要性などの種々の問題点も指摘されてい
る。However, various problems have been pointed out, such as the lack of vitality.
近時、それ等問題点の改善を計る為、また効力の増強拡
大を目的に種々の非天然型レチノイド誘導体の探索が続
けられている〔キャンサーリサーチ ４０巻 ３４Ｉ３
頁（ｔｓｓｏ年）など〕。Recently, the search for various non-natural retinoid derivatives has continued with the aim of improving these problems and increasing and expanding efficacy [Cancer Research Vol. 40, 34I3
page (tsso year) etc.].
お古
本発明者らは、副作用を軽減させる一方で抗腫瘍効果を
増強する、すなわち治療係数の良い合成レチノイド誘導
体を探索する事を目的に１種々の含フツ素レチノイド誘
導体について鋭意検討した。The present inventors have conducted intensive studies on various fluorine-containing retinoid derivatives with the aim of searching for synthetic retinoid derivatives that reduce side effects while enhancing antitumor effects, that is, have a good therapeutic index.
その結果１本発明の一般式
〔式中、又は水素原子または炭素数１〜６個のフルキル
オキシ基を示す、〕で表わされる新規な１１２．１３２
−２０．２０．２０− ） ＩＪ フルー１ｒロレチ／
イ）’Ｍ誘導体優れた抗腫瘍作用を有している事を見
い出し１本発明を完成した。As a result 1, the novel 112.132 represented by the general formula [in the formula, or representing a hydrogen atom or a fulkyloxy group having 1 to 6 carbon atoms] of the present invention
-20.20.20-) IJ Flu 1r Lorechi/
b) The present invention was completed after discovering that 'M derivatives have excellent antitumor effects.
一般式（１）で表わされる本発明の化合物は、例えば以
下の製造法により得られる。The compound of the present invention represented by general formula (1) can be obtained, for example, by the following production method.
即ち、一般式（■）〔式中Ｒは炭素数１〜６個のアルキ
ル基を示す、〕で表わされる１３２−１１．１２−デヒ
ドロレチノイン酸誘導体に、接触還元触媒の存在下に接
触還元反応を行ない、一般式（ＩＩＩ）〔式中、Ｒは前
記と同じ意味を示す、〕で表わされる本発明化合物の一
つである１１２．１３２−２０．２０゜２０−トリフル
オロレチノイン酸エステル誘導体を得る。更に一般式（
ｍ）で表わされる化合物をハイドライド系還元剤にて還
元し、相当するアルコール体とした後、二酸化マンガン
等の酸化剤を用い酸化する事により、式（ｆｆ）で表わ
される本発明のもう一つの化合物である１１２，１３２
−２０．２０．２０−トリフルオロレチナール誘導体を
得る。That is, a 132-11.12-dehydroretinoic acid derivative represented by the general formula (■) [wherein R represents an alkyl group having 1 to 6 carbon atoms] is subjected to a catalytic reduction reaction in the presence of a catalytic reduction catalyst. to obtain a 112.132-20.20°20-trifluororetinoic acid ester derivative, which is one of the compounds of the present invention represented by the general formula (III) [wherein R has the same meaning as above]. obtain. Furthermore, the general formula (
Another compound of the present invention represented by formula (ff) is obtained by reducing the compound represented by m) with a hydride reducing agent to obtain the corresponding alcohol, and then oxidizing it with an oxidizing agent such as manganese dioxide. 112,132 which is a compound
-20.20.20-Trifluororetinal derivative is obtained.
更に詳述すれば、一般式（ＩＩ）および（ｍ）における
Ｒは炭素数１〜６個のアルキル基を表わし、直鎖１分枝
または環状のいずれをも含む０例えばメチル、エチル、
ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル
、ｔ−ブチル、ｎ−アミル、イソアミル、ｎ−ヘキシル
、シクロヘキシル基などである。More specifically, R in the general formulas (II) and (m) represents an alkyl group having 1 to 6 carbon atoms, including either a linear branched or cyclic group, such as methyl, ethyl,
Examples include n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-amyl, isoamyl, n-hexyl, and cyclohexyl groups.
化合物（■）から（ｍ）へ導く接触還元反応で用いられ
る触媒とは、白金系、パラジウム系、ロジウム系、ニッ
ケル系のいずれでも良いが、好ましくはパラジウム系の
触媒、例えばパラジウム−硫酸バリウム触媒等である。The catalyst used in the catalytic reduction reaction leading to compound (■) to (m) may be platinum-based, palladium-based, rhodium-based, or nickel-based, but is preferably a palladium-based catalyst, such as a palladium-barium sulfate catalyst. etc.
この反応に使用される溶媒は、反応に関与しないもので
あれば、特に制限は無いが、メタノール、エタノール等
のアルコール系溶媒が好ましい０反応温度は室温で良く
１反応時間は原料化合物により異なるが、１０分間から
２４時間である。The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction, but alcoholic solvents such as methanol and ethanol are preferable.The reaction temperature may be room temperature, and the reaction time varies depending on the raw material compound. , for 10 minutes to 24 hours.
化合物（ＩＩＩ）から（ｆｆ）を得る反応の第１工程で
用いられるハイドライド系還元剤とは、例えばリチウム
アルミニウムハイドライド、ジイソブチルアルミニウム
ハイドライド、ナトリウムボロハイドライド、ナトリウ
ムシアノボロハイドライド等であり、好ましくは、ジイ
ソブチルアルミニウムハイドライドである。この反応に
用いる溶媒は、特に制限は無いが、石油エーテル、ヘキ
サン等が好ましい０反応温度は一り８℃〜室温である０
反応時間は原料化合物により異なるが５分間〜２４時間
である。The hydride reducing agent used in the first step of the reaction to obtain (ff) from compound (III) is, for example, lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc., and preferably diisobutyl It is aluminum hydride. The solvent used in this reaction is not particularly limited, but petroleum ether, hexane, etc. are preferred.The reaction temperature is 8°C to room temperature.
The reaction time varies depending on the raw material compound, but is 5 minutes to 24 hours.
第二工程の酸化反応に用いられる酸化剤には、Ｈえば、
二酸化マンガン、過マンガン酸、カリウム、酸化銀、四
酢酸鉛、クロム酸、ジメチルスルホキシド−Ｎ、Ｎ−ジ
シクロへキシルカルボジイミド等があげられるが、好ま
しくは、二酸化マンガンである。The oxidizing agent used in the oxidation reaction in the second step includes, for example,
Examples include manganese dioxide, permanganic acid, potassium, silver oxide, lead tetraacetate, chromic acid, dimethylsulfoxide-N, N-dicyclohexylcarbodiimide, and preferably manganese dioxide.
この反応に用いられる溶媒は特に制限は無いが、ヘキサ
ン、石油エーテル等が好ましい。The solvent used in this reaction is not particularly limited, but hexane, petroleum ether, etc. are preferred.
反応温度θ℃〜５０℃である０反応時間は原料化合物に
より異なるが５分間〜２４時間である。The zero reaction time at which the reaction temperature is θ°C to 50°C varies depending on the raw material compound, but is 5 minutes to 24 hours.
反応で得られる一般式１）および（ｆｆ）で表わされる
化合物は、再結晶、カラムクロマトグラフィー操作等常
法により単離、精・製する事が出来る。The compounds represented by the general formulas 1) and (ff) obtained by the reaction can be isolated and purified by conventional methods such as recrystallization and column chromatography.
尚、一般式（ＩＩ）で表わされる出発原料は、それ自身
新規な物質であり、以下の反応式により製造する事が出
来る。Incidentally, the starting material represented by the general formula (II) is itself a novel substance, and can be produced according to the following reaction formula.
詳しくは参考例において説明する。Details will be explained in reference examples.
（反応式）
〔一般式（ｎ）、ｌ）および（■）におけるＲは前記と
同じ意味を表わす、〕
ｉ豆ゑ皇１
一般式（Ｉ）で表わされる化合物はすぐれた腫瘍抑制作
用を有し、医薬として使用することができる。(Reaction formula) [R in general formulas (n), l) and (■) represents the same meaning as above] and can be used as a medicine.
１施ｌ
以下に参考例、および実施例をあげて本発明を具体的に
説明するが、これ等は本発明を限定するものではない。EXAMPLES The present invention will be specifically explained below with reference to reference examples and examples, but these are not intended to limit the present invention.
参考例
工 十
工
ｌ）アルゴン気流下、リチウムインプロピルシクロヘキ
シルアミド（２２８■ｇ、１．５５■會ｏ １’）のテ
トラヒドロフラン（１０ｍｌり溶液に、トリメチルシリ
ル酢酸エチル（２４８■ｇ 、１．５５ｍｍｏｌ）を−
７８℃にて加え、更に同温度にて１０分間攪拌した。こ
れに１１．１２−デヒドロ体１ （４８０曹ｇ 、 １
．５５層■ｏｌ）のテトラヒドロフラン（３ｗｊｌ）溶
液を一７８℃にて加え、２０分間攪拌した後、更に一２
３℃で３０分反応させた０反応後、反応液に３％塩酸水
（１５−）を加え、ジエチルエーテルで３回抽出した。Reference Example 1) Under an argon atmosphere, ethyl trimethylsilylacetate (248 g, 1.55 mmol) was added to a 10 ml solution of lithium inpropylcyclohexylamide (228 g, 1.55 mmol) in tetrahydrofuran. -
The mixture was added at 78°C and further stirred at the same temperature for 10 minutes. To this, 11.12-dehydro form 1 (480 soda g, 1
．． A solution of 55 layers (1 ol) in tetrahydrofuran (3 wjl) was added at -78°C, stirred for 20 minutes, and then
After 30 minutes of reaction at 3°C, 3% aqueous hydrochloric acid (15-) was added to the reaction mixture, and the mixture was extracted three times with diethyl ether.
抽出液を５％重曹水、飽和食塩水で順次洗浄した後、無
水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、溶媒
を溜去して得られた油状物をシリカゲルフラッシュカラ
ムクロマトグラフィー（ヘキサン：メチレンクロリ）’
＝４：ｌ）、ついで、中圧シリカゲルカラムクロマトグ
ラフィー（ヘキサン：酢酸エチル＝−４０：ｌ）で分離
精製し、フラクションｌとして１３Ｅ −１１，１２−
デヒドロ−２０゜２０．２０−トリフルオロレチノイン
酸エチルエステル± （油状物）１７５■ｇを得た。The extract was washed successively with 5% aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off, and the resulting oil was subjected to silica gel flash column chromatography (hexane: methylene chloride).
= 4:l), and then separated and purified by medium pressure silica gel column chromatography (hexane:ethyl acetate = -40:l) to obtain 13E-11,12- as fraction 1.
175 g of dehydro-20.20-trifluororetinoic acid ethyl ester (oil) was obtained.
１Ｈ＝ＮＭＲδ（ＣＤＣｊＬ ３） ：８．５３（ｓ、
ＩＨ，）Ｉｌｏ）
ｆｌ、４３（ｄ、１８．Ｊ−１８，５Ｈｚ、Ｈ７）６．
１７（ｄ、ＩＨ，Ｊ雪ＩＥ１．５Ｈｚ、Ｈｓ）５．８８
（ｇ、１Ｍ、 ＨＩ３）
４．２５ （ｑ、２Ｈ，Ｊ＝ ７Ｈ２，ＯＣＲ２ＣＨ３
）２．１８（３，３）１，９−ＣＩ（３）１．８９（ｓ
、３Ｈ，５−０８３）
１．３０（ｔ 、３）１．Ｊ＝ ７Ｍ２．０ＣＨ２Ｃ’
Ｈ３）！、（１１（ｓ、８）１，１−ＣＤ５ｘ２）１９
Ｆ −ＮＭＲ（ＣＤＣｆＬ３） ： ＋ ２．９７ｐｐ
ｍ （ｓ）外部標準物質：ベンゾトリフルオライドに比
べ高磁場側を（＋）、低磁場側を（−）表示する。1H=NMRδ(CDCjL3):8.53(s,
IH,)Ilo) fl, 43(d, 18.J-18,5Hz, H7)6.
17 (d, IH, J snow IE1.5Hz, Hs) 5.88
(g, 1M, HI3) 4.25 (q, 2H, J= 7H2, OCR2CH3
)2.18(3,3)1,9-CI(3)1.89(s
, 3H, 5-083) 1.30 (t, 3) 1. J= 7M2.0CH2C'
H3)! , (11(s,8)1,1-CD5x2)19
F-NMR (CDCfL3): +2.97pp
m (s) External standard substance: Compared to benzotrifluoride, the higher magnetic field side is shown as (+) and the lower magnetic field side is shown as (-).
２） 更ニ７ラクシ、７２トＬテ１３Ｚ −１１，１２
−デヒドロ−２０，２０，２０−）リフルオロレチノイ
ン酸エチルエステル■油状物１８８．５１ｇを得た。2) Sarani 7 Rakshi, 72 ToL Te 13Z -11,12
-dehydro-20,20,20-)rifluororetinoic acid ethyl ester (1) 188.51 g of an oily substance was obtained.
高分解能質量分析：Ｃ２２Ｈ２□Ｆ３０２として計算値
： ３８０．１１１６２
実測値： ３８０．１９８１
１Ｒ（ＣＨＣｌ ） ｃｌ ： ２１８０（
ν 、 −Ｃｉｉ−Ｃ−）１７３５（ν、ＸＯ）
’ＨＮＭＲδ（ＣＤＣ１３） ：
８．４１（ｓ、１１．Ｈｌｇ ）
８．４１（ｄ、ＩＨ，Ｊ−１８，５）＋２． ＋７）８
．１３（ｃｌ、１）１．Ｊ＝ １８．５Ｈｚ、 ＋５）
５．５８（ｇ、ＩＨ，ｌ（，４）
４−２３（ｑ、２Ｈ，Ｊ ＝ ７Ｈｚ、ＱＣ：Ｈ２ＣＨ
３）２．０７（ｓ、３Ｈ，θ−ＣＨ５）
１．７０（ｇ、３Ｈ，５−ＣＤ５）
１．３１（ｔ、３Ｂ、Ｊ −７Ｈｚ、ＯＣＨ，、ＣＨ３
）１．０８（ｓ、８Ｈ，１−ＣＨ３ｘ２）”Ｆ −ＮＮ
Ｒ（ＣＤＣｆＬ３） ： −２，８７ｐｐｍ（ｇ）−実
施・例
参考例１で得た１３２−１１．１２−デヒドロ休出１８
０ ｍｇ（０，５８ｍｍｏｌ）をメタノール（３ｄ）に
溶解し。High-resolution mass spectrometry: Calculated value as C22H2□F302: 380.11162 Actual value: 380.1981 1R(CHCl) cl: 2180(
ν, -Cii-C-)1735(ν,XO)'HNMRδ(CDC13): 8.41(s, 11.Hlg) 8.41(d, IH, J-18,5)+2. +7)8
．． 13 (cl, 1)1. J = 18.5Hz, +5)
5.58(g, IH, l(,4) 4-23(q, 2H, J = 7Hz, QC:H2CH
3) 2.07 (s, 3H, θ-CH5) 1.70 (g, 3H, 5-CD5) 1.31 (t, 3B, J -7Hz, OCH,, CH3
)1.08(s, 8H, 1-CH3x2)”F-NN
R (CDCfL3): -2,87 ppm (g) - 132-11.12-dehydrolysis 18 obtained in Reference Example 1
0 mg (0.58 mmol) was dissolved in methanol (3d).
これに触媒量のパラジウム−硫酸バリウムおよびＩｔｈ
最のキノリンを加え、水素雰囲気下で攪拌した。相当量
の水素の吸収後、触媒を濾別し、濾液を濃縮し得られた
油状物を中圧シリカゲルカラムクロマトグラフィー（ヘ
キサン：酢酸エチル＝７０：ｌ）で精製り、 １１２，
１３２−２０．２０．２０− ト！Ｊフルオロレチノイ
ン酸エチルエステル国（油状）５８１ｇを得た。This is combined with a catalytic amount of palladium-barium sulfate and Ith
The first portion of quinoline was added and stirred under a hydrogen atmosphere. After absorbing a considerable amount of hydrogen, the catalyst was filtered off, the filtrate was concentrated, and the resulting oil was purified by medium pressure silica gel column chromatography (hexane:ethyl acetate = 70:l), 112,
132-20.20.20- To! 581 g of J fluororetinoic acid ethyl ester (oil) was obtained.
’Ｈ−ＮＭＲδ（ｃｏｃ見。）：
８．８０（ｔ、ＩＨ，Ｊ −１１，７Ｈ２，Ｈｌｌ）８
．３９（ｄ、１）１．Ｊ −１１，７Ｈ２，Ｈｌｏ）８
．３１（ｄ、１）１．Ｊ −１５，８Ｈｚ、８７）８．
２７（ｇ、ＩＨ，）！、、）
８．１３（ｄ、ＩＨ，Ｊ ｓ１５．８Ｈｚ、Ｈａ）５．
８９（ｄ、ＩＩ、Ｊ −１１，７Ｈ２，Ｈ，２）４．２
７（ｑ、２Ｈ，Ｊ ＠ ７．３Ｈｚ、０ＣＨ２ＣＨ３７
１−９９（Ｓ、３）１．９−ＣＨａ）
１．７１（ｓ、３８．５−ＣＤ５）
１．３２（ｔ 、３Ｈ，Ｊ−７，３Ｈｚ、０ＣＨ２ＣＨ
３）１−０２ （ｓ 、８Ｈ１１−ＣＨ３Ｘ ２）１９
Ｆ−ＮＭＲＣＣＤＣｌ５） ： −１，３ＰＰ＠（Ｓ）
前項１）で得られた化合物±３８■ｇ（０，０９ｍｍｏ
ｌ ）をアルゴン気流下、ｎ−へキサンｌｌ＋１に溶解
し、これにジイソブチルアルミニウムへイドライド（３
当量）を−７８℃で加え、更に同温度、にて５分間反応
させた。'H-NMRδ (see coc): 8.80 (t, IH, J -11,7H2, Hll) 8
．． 39(d,1)1. J-11,7H2,Hlo)8
．． 31(d,1)1. J-15.8Hz, 87)8.
27 (g, IH,)! ,,) 8.13 (d, IH, J s15.8Hz, Ha)5.
89(d, II, J-11,7H2,H,2)4.2
7 (q, 2H, J @ 7.3Hz, 0CH2CH37
1-99 (S, 3) 1.9-CHa) 1.71 (s, 38.5-CD5) 1.32 (t, 3H, J-7, 3Hz, 0CH2CH
3) 1-02 (s, 8H11-CH3X 2) 19
F-NMRCCDCl5): -1,3PP@(S)
±38 g (0.09 mmo) of the compound obtained in the previous section 1)
1) was dissolved in n-hexane 11+1 under an argon atmosphere, and diisobutylaluminum hydride (3
equivalent amount) was added at -78°C, and the mixture was further reacted at the same temperature for 5 minutes.
反応後、反応液にメタノール１ｍｌと３％硫酸５−を加
えた後、ジエチルエーテルで３回抽出した。抽出液を合
せ、飽和重曹水、飽和食塩水で順次洗浄し、無水硫酸マ
グネシウムで乾燥した。乾燥剤を濾別し、濾液を濃縮し
得られた油状物を中圧シリカゲルカラムクロマトグラフ
ィー処理（ｎ−ヘキサン：酢酸エチル＝＝１０：ｌ）ｔ
、、相当するアルコール体を１４．８ｍｇ得た。ひきつ
づきこのアルコール体をｎ−ヘキサンに溶解し、大過剰
（′！０当量）の二酸化マンガンを加え、室温で５分間
反応させた０反応後、不溶物を濾別し、濾液を濃縮する
事ニヨリ１１２，１３２−２０．２０．２０−） ＩＪ
ｙ ルオロレチナール山をｌＯ鵬ｇ得た。After the reaction, 1 ml of methanol and 3% sulfuric acid 5- were added to the reaction solution, followed by extraction three times with diethyl ether. The extracts were combined, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the resulting oil was treated with medium pressure silica gel column chromatography (n-hexane:ethyl acetate==10:l).
, 14.8 mg of the corresponding alcohol was obtained. Subsequently, this alcohol was dissolved in n-hexane, a large excess (0 equivalent) of manganese dioxide was added, and the reaction was allowed to proceed for 5 minutes at room temperature. After the reaction, insoluble matter was filtered off and the filtrate was concentrated. 112,132-20.20.20-) IJ
y fluororetinal mountain was obtained.
Claims (1)
オキシ基を示す。〕で表わされる１１Ｚ，１３Ｚ−２０
，２０，２０−トリフルオロレチノイド誘導体。[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X represents a hydrogen atom or a carbon number or an alkyloxy group having 1 to 6 carbon atoms. ] 11Z, 13Z-20 represented by
,20,20-trifluororetinoid derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60115141A JPS61275266A (en) | 1985-05-28 | 1985-05-28 | Retinoid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60115141A JPS61275266A (en) | 1985-05-28 | 1985-05-28 | Retinoid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61275266A true JPS61275266A (en) | 1986-12-05 |
Family
ID=14655306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60115141A Pending JPS61275266A (en) | 1985-05-28 | 1985-05-28 | Retinoid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61275266A (en) |
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-
1985
- 1985-05-28 JP JP60115141A patent/JPS61275266A/en active Pending
Cited By (21)
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|---|---|---|---|---|
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| US8962691B2 (en) | 2003-03-14 | 2015-02-24 | University Of Washington | Retinoid replacements and opsin agonists and methods for the use thereof |
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| US9173856B2 (en) | 2010-04-19 | 2015-11-03 | Qlt Inc. | Therapeutic regimen and methods for treating or ameliorating visual disorders associated with an endogenous retinoid deficiency |
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