JPH02255677A - 4-thiochromanone derivative - Google Patents
4-thiochromanone derivativeInfo
- Publication number
- JPH02255677A JPH02255677A JP1071790A JP7179089A JPH02255677A JP H02255677 A JPH02255677 A JP H02255677A JP 1071790 A JP1071790 A JP 1071790A JP 7179089 A JP7179089 A JP 7179089A JP H02255677 A JPH02255677 A JP H02255677A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- solvent
- compound shown
- thiochromanone
- compound
- 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
- CVQSWZMJOGOPAV-UHFFFAOYSA-N 2,3-dihydrothiochromen-4-one Chemical class C1=CC=C2C(=O)CCSC2=C1 CVQSWZMJOGOPAV-UHFFFAOYSA-N 0.000 title claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 15
- 239000002904 solvent Substances 0.000 abstract description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 8
- 239000008280 blood Substances 0.000 abstract description 8
- 210000004369 blood Anatomy 0.000 abstract description 8
- 150000002632 lipids Chemical class 0.000 abstract description 5
- 239000003524 antilipemic agent Substances 0.000 abstract description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 4
- 238000010992 reflux Methods 0.000 abstract description 4
- 241000124008 Mammalia Species 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000001603 reducing effect Effects 0.000 abstract description 3
- 239000002168 alkylating agent Substances 0.000 abstract description 2
- 229940100198 alkylating agent Drugs 0.000 abstract description 2
- 235000012000 cholesterol Nutrition 0.000 abstract description 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 abstract description 2
- 229940008406 diethyl sulfate Drugs 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 abstract 1
- 229910052939 potassium sulfate Inorganic materials 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- -1 nicotinic acid ester Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- XVOUMQNXTGKGMA-OWOJBTEDSA-N (E)-glutaconic acid Chemical compound OC(=O)C\C=C\C(O)=O XVOUMQNXTGKGMA-OWOJBTEDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ISTQHYXQWBAYOV-UHFFFAOYSA-N 4-(4-bromophenoxy)benzenethiol Chemical compound C1=CC(S)=CC=C1OC1=CC=C(Br)C=C1 ISTQHYXQWBAYOV-UHFFFAOYSA-N 0.000 description 1
- AFXSLKKTDUYDIR-UHFFFAOYSA-N 4-(4-chlorophenoxy)benzenethiol Chemical compound C1=CC(S)=CC=C1OC1=CC=C(Cl)C=C1 AFXSLKKTDUYDIR-UHFFFAOYSA-N 0.000 description 1
- VUFOTXYLUWEYFC-UHFFFAOYSA-N 4-phenoxybenzenethiol Chemical compound C1=CC(S)=CC=C1OC1=CC=CC=C1 VUFOTXYLUWEYFC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FLGZHHJNRZUPIL-UHFFFAOYSA-N chromene-4-thione Chemical class C1=CC=C2C(=S)C=COC2=C1 FLGZHHJNRZUPIL-UHFFFAOYSA-N 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005843 halogen group Chemical group 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は新規なチオクロマノン誘導体に関し、更に詳し
くは哺乳動物の血中における総コレステロール、トリグ
リセリドなどの脂質を減少させる作用を有するチオクロ
モン誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel thiochromanone derivative, and more particularly to a thiochromone derivative having the effect of reducing lipids such as total cholesterol and triglycerides in the blood of mammals.
え未疫弦オ
一般に、アテローム性動脈硬化症などの動脈硬化症は血
中の過剰脂質の沈着がその原因の一つであると考えられ
ている。従って、血中における脂質濃度を低下きせるこ
とが、動脈硬化症およびこれに関連した疾患の治療や予
防に望ましい手段ときれている。It is generally believed that one of the causes of arteriosclerosis such as atherosclerosis is the deposition of excess lipids in the blood. Therefore, reducing the lipid concentration in the blood is considered a desirable means for treating and preventing arteriosclerosis and related diseases.
従来、血中脂質低下剤としては、クロフィブレートおよ
びその誘導体、ニコチン酸エステル誘導体、プロブフー
ルなどが知られている。しかしながら、これらの薬剤は
いずれもその作用効果、副作用および毒性の点で必ずし
も満足できるものではない。Clofibrate and its derivatives, nicotinic acid ester derivatives, probufur, and the like are conventionally known as blood lipid-lowering agents. However, none of these drugs are necessarily satisfactory in terms of their effects, side effects, and toxicity.
また、チオクロマノン誘導体に関し血中脂質低下剤とし
て知られているものはない。Furthermore, there are no thiochromanone derivatives known as blood lipid-lowering agents.
明が解 しようとする課
本発明は血中における脂質濃度を低下させ、副作用が弱
い薬剤を提供することを目的とする。The purpose of the present invention is to provide a drug that lowers the lipid concentration in the blood and has weak side effects.
を 決するための 段
本発明者は鋭意研究の結果、ある種のチオクロマノン誘
導体が上記課題を解決できることを見出して本発明を完
成した。As a result of intensive research, the present inventors have completed the present invention by discovering that a certain type of thiochromanone derivative can solve the above problems.
以下、本発明を説明する。The present invention will be explained below.
本発明は、式Ｉ
（式中、Ｘはハロゲン原子で置換されていてもよいフェ
ノキシ基または炭素数５〜７のシクロアルキル基を示し
、Ｒは水素原子または低級アルキル基を示し、ｎは０〜
３の整数を示す、）で表わされる４−チオクロマノン誘
導体である。The present invention is based on the formula I (wherein, ~
It is a 4-thiochromanone derivative represented by ), which represents an integer of 3.
本発明において、ハロゲン原子とはフ・ｙ素原子、塩素
原子、臭素原子、ヨウ素原子である。低級アルキル基と
は炭素数１〜４個のアルキル基であり、たとえば、メチ
ル基、エチル基、プロピル基、イソプロピル基、ブチル
基などである。In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. A lower alkyl group is an alkyl group having 1 to 4 carbon atoms, and includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and the like.
式！で示される化合物は、たとえば、次の方法によって
製造することができる。formula! The compound represented by can be produced, for example, by the following method.
（１）すなわち、下記式■
（式中、Ｘは前記と同意義である。）で示される化合物
を分子内アシル化反応させることにより、カルボン酸タ
イプの式■で示される化合物（式■においてＲが水素原
子である化合物）を得ることができる０本反応は通常の
フリーデル・クラフッ反応の条件で進行し、たとえば、
触媒として塩化アルミニウム、四塩化スズ、塩化亜鉛な
どの存在下、不活性溶媒（たとえば、二硫化次素、ジク
ロルメタン、ニトロベンゼンなど）中、０°Ｃないし溶
媒の還流温度で反応きせればよい。(1) That is, by performing an intramolecular acylation reaction on the compound represented by the following formula ■ (wherein, X has the same meaning as above), a carboxylic acid type compound represented by the formula ■ (in the formula The reaction that can yield a compound in which R is a hydrogen atom) proceeds under normal Friedel-Krach reaction conditions, for example,
The reaction may be carried out in the presence of aluminum chloride, tin tetrachloride, zinc chloride, etc. as a catalyst in an inert solvent (eg, hydrogen disulfide, dichloromethane, nitrobenzene, etc.) at 0° C. to the reflux temperature of the solvent.
（２）また、有機溶媒（たとえば、アセトン、ジメチル
ホルムアミド、ヘキサメチルリン酸トリアミド、ジメチ
ルスルホキシドなど）中、塩基（たとえば、炭酸ナトリ
ウム、炭酸カリウム、炭酸リチウム、水素化ナトリウム
など）の存在下に、上記（１〉で得られた化合物に常用
のアルキル化剤（たとえば、ハロゲン化アルキル、硫酸
ジアルキルなど）を作用させることにより、式Ｉにおい
てＲが低級アルキル基である化合物を製造することがで
きる。(2) Also, in the presence of a base (e.g., sodium carbonate, potassium carbonate, lithium carbonate, sodium hydride, etc.) in an organic solvent (e.g., acetone, dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc.), By reacting the compound obtained in the above (1) with a commonly used alkylating agent (e.g., alkyl halide, dialkyl sulfate, etc.), a compound in which R is a lower alkyl group in formula I can be produced.
出発化合物である式■で示きれる化合物は、たとえば、
Ｆ、 Ｂ、 Ｚｉｅｎｔｙらの方法［Ｊｏｕｒｎａｌ
ｏｆ Ｏｒｇａ−ｎｉｃ Ｃｈｅｍｉｓｔｒｙ 、第２
７巻、第３１４０頁（１９６２年）］またはそれに準じ
た方法により製造することができる。The starting compound, a compound represented by the formula ■, is, for example,
The method of F. B. Zienty et al. [Journal
of Orga-nic Chemistry, Part 2
7, p. 3140 (1962)] or a method similar thereto.
すなわち、下記式■
（式中、Ｘは前記と同意義である。）で示されるチオフ
ェノール化合物と無水マレイン酸、無水グルタコン酸な
どを有機溶媒（たとえば、ニーチル、テトラヒドロフラ
ン、ジオキサン、トルエン、ベンゼンなど）中で０．０
１〜１．５モル当量の塩基触媒（たとえば、トリエチル
アミン、炭酸ナトリウム、炭酸カリウム、水酸化カリウ
ム、ナトリウムアルコラードなど）の存在下に０℃ない
し溶媒の還流温度で反応きせることにより式■で示され
る化合物を得ることができる。That is, a thiophenol compound represented by the following formula (wherein, ) in 0.0
By reacting at 0°C to the reflux temperature of the solvent in the presence of 1 to 1.5 molar equivalents of a base catalyst (for example, triethylamine, sodium carbonate, potassium carbonate, potassium hydroxide, sodium alcoholade, etc.), can be obtained.
また、式■で示きれる化合物とマレイン酸、グルタコン
酸などを同様に塩基触媒存在下に反応きせて得られる下
記式■
（式中、Ｘは前記と同意義である。）で示されるジカル
ボン酸化合物を脱水剤と反応させることによっても式■
で示される化合物を得ることができる。In addition, a dicarboxylic acid represented by the following formula (wherein, By reacting the compound with a dehydrating agent, the formula ■
A compound represented by can be obtained.
本反応に用いられる脱水剤とは、たとえば、無水酢酸、
塩化チオニル、ｐ−トルエンスルホニルクロリドなどで
あり、反応溶媒は脱水剤自体かまたは不活性溶媒（たと
えば、ベンゼン、トルエン、キシレン、テトラヒドロフ
ラン、ジオキサンなど）を用い、２０℃ないし溶媒の還
流温度で行う。The dehydrating agent used in this reaction includes, for example, acetic anhydride,
Thionyl chloride, p-toluenesulfonyl chloride, etc. are used, and the reaction solvent is a dehydrating agent itself or an inert solvent (eg, benzene, toluene, xylene, tetrahydrofuran, dioxane, etc.), and the reaction is carried out at 20° C. to the reflux temperature of the solvent.
灸泗ノと１釆
本発明化合物は、ラット、ウサギなどの哺乳動物におい
て優れた血中脂質低下作用を示し、肝肥大作用などの毒
性も低いので、脂質低下剤として有用である。The compound of the present invention exhibits an excellent blood lipid-lowering effect in mammals such as rats and rabbits, and has low toxicity such as hepatomegaly, so it is useful as a lipid-lowering agent.
夾且泗 以下、実施例を挙げて本発明を更に具体的に説明する。夾且泗 Hereinafter, the present invention will be explained in more detail with reference to Examples.
実施例１
４−フェノキシチオフェノール２０．２ｇ、無水マレイ
ン酸９．８ｇおよびトルエン４０ｍＱの混合物を７０℃
に加熱、攪拌しながらトリエチルアミン０．１ｍｌのト
ルエン（５ｍｌｌ）溶液を滴下し、同温度で更に２０分
間攪拌した。トルエンを減圧下に留去するとガラス状の
粗（４−フェノキシチオ）コノ１り酸無水物３０ｇが得
られた。これをジクロルメタン１００ｍＱに溶かし、水
冷下撹拌しながら無水塩化アルミニウム１７ｇを徐々に
加えた後、室温で１時間攪拌した。反応液に濃塩酸と氷
の混合物を加えて攪拌し、析出した結晶を濾取し、水お
よびエーテルで洗浄後乾燥した。これをヘキサン−酢酸
エチルから再結晶し、６−フェノキシ−４−チオクロマ
ノン−２−カルボン酸１７．４ ｇを得た。Example 1 A mixture of 20.2 g of 4-phenoxythiophenol, 9.8 g of maleic anhydride and 40 mQ of toluene was heated at 70°C.
A solution of 0.1 ml of triethylamine in toluene (5 ml) was added dropwise to the mixture while heating and stirring, and the mixture was further stirred at the same temperature for 20 minutes. When toluene was distilled off under reduced pressure, 30 g of glassy crude (4-phenoxythio)conollic acid anhydride was obtained. This was dissolved in 100 mQ of dichloromethane, and while stirring under water cooling, 17 g of anhydrous aluminum chloride was gradually added, followed by stirring at room temperature for 1 hour. A mixture of concentrated hydrochloric acid and ice was added to the reaction solution and stirred, and the precipitated crystals were collected by filtration, washed with water and ether, and then dried. This was recrystallized from hexane-ethyl acetate to obtain 17.4 g of 6-phenoxy-4-thiochromanone-2-carboxylic acid.
ｍ、ｐ、 １４８〜１５２℃
それぞれ対応する出発物を用い実施例１に準じて下記の
化合物を得た。m, p, 148-152°C The following compounds were obtained according to Example 1 using the corresponding starting materials.
６−（４−クロルフェノキシ）−４−チオクロモン−２
−カルボン酸
ｍ、ｐ、 １６９〜１７０℃
６−シクロへキシル−４−チオクロモン−３−カルボン
酸
ｍ、ｐ、 １９３〜１９４℃
実施例２
６−（４−クロルフェノキシ）−４−チオクロマノン−
２−カルボン酸３３．５ｇのジメチルホルムアミド（３
００ｍ１ｌ ）溶液に硫酸ジエチル１８．２ｍ１ｌ、次
いで炭酸カリウム２７．７ ｇを加え、室温で５時間攪
拌した。反応液に氷水を加えエーテルで抽出し、抽出液
を水洗後硫酸マグネシウムで乾燥し、溶媒を留去した。6-(4-chlorophenoxy)-4-thiochromone-2
-Carboxylic acid m, p, 169-170°C 6-cyclohexyl-4-thiochromone-3-carboxylic acid m, p, 193-194°C Example 2 6-(4-chlorophenoxy)-4-thiochromanone-
33.5 g of 2-carboxylic acid in dimethylformamide (3
00ml) 18.2ml of diethyl sulfate and then 27.7g of potassium carbonate were added to the solution, and the mixture was stirred at room temperature for 5 hours. Ice water was added to the reaction mixture and extracted with ether. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off.
残渣をヘキサン−エーテルから再結晶して６−（４−ク
ロルフェノキシ）−４−チオクロマノン−２−カルボン
酸エチル２２．９ｇヲイ停た。The residue was recrystallized from hexane-ether to give 22.9 g of ethyl 6-(4-chlorophenoxy)-4-thiochromanone-2-carboxylate.
ｍ、 ｐ、 ７０〜７１℃
実施例３
４−（４−クロルフェノキシ）チオフェノール２３．７
ｇおよびグルタコン酸１３．５ ｇをテトラヒドロフラ
ン７０ｍ１に溶かし、室温攪拌下にトリエチルアミン１
０．５ｍ１ｌを滴下し、室温で更に２時間攪拌した。反
応液に希塩醜を加え酢酸エチルで抽出し、抽出液を水洗
後硫酸マグネシウムで乾燥し、溶媒を留去した。残渣を
ヘキサン−エーテルを展開溶媒としたシリカゲルカラム
クロマトグラフィーで精製し、粘性油状物として３−［
４−（４−クロルフェノキシ）フェニルチオコゲルタル
酸２４．２ｇを得た。m, p, 70-71°C Example 3 4-(4-chlorophenoxy)thiophenol 23.7
g and 13.5 g of glutaconic acid were dissolved in 70 ml of tetrahydrofuran, and 1 ml of triethylamine was added with stirring at room temperature.
0.5 ml was added dropwise, and the mixture was further stirred at room temperature for 2 hours. Dilute salts were added to the reaction mixture and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography using hexane-ether as a developing solvent to obtain 3-[
24.2 g of 4-(4-chlorophenoxy)phenylthiokogeltaric acid was obtained.
これを無水酢酸１２０ｔ＋ｔＱに溶かし、７０℃で３０
分加熱攪拌した後溶媒を留去し粗３−［４−（４−クロ
ルフェノキシ）フェニルチオコゲルタル酸無水物２３ｇ
を得た。これをジクロルメタン２００ｍ１に溶かし、水
冷攪拌下に無水塩化アルミニウム１４ｇを徐々に加えた
後、室温で３０分間攪拌した。反応液に濃塩酸と氷の混
合物を加え、ジクロルメタンを減圧下に留去した後酢酸
エチルで抽出した。抽出液を水洗後硫酸マグネシウムで
乾燥し、溶媒を留去した。残渣を酢酸エチルから再結晶
し、６−（４−クロルフェノキシ）−４−チオクロマノ
ン−２−酢酸１５．０ ｇを得た。This was dissolved in 120t+tQ of acetic anhydride and heated to 70℃ for 30 minutes.
After heating and stirring for several minutes, the solvent was distilled off and 23 g of crude 3-[4-(4-chlorophenoxy)phenylthiocogeltaric acid anhydride]
I got it. This was dissolved in 200 ml of dichloromethane, and 14 g of anhydrous aluminum chloride was gradually added while stirring with water cooling, followed by stirring at room temperature for 30 minutes. A mixture of concentrated hydrochloric acid and ice was added to the reaction solution, dichloromethane was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 15.0 g of 6-(4-chlorophenoxy)-4-thiochromanone-2-acetic acid.
ｍ、 ｐ、 １７４〜１７５℃
実施例４
出発物として４−（４−ブロムフェノキシ）チオフェノ
ールを用い、実施例３に準じて６−（４−プロムフエノ
キシ）−４−チオクロマノン−２−酢酸を得た。m, p, 174-175°C Example 4 Using 4-(4-bromphenoxy)thiophenol as a starting material, 6-(4-bromphenoxy)-4-thiochromanone-2-acetic acid was obtained according to Example 3. Ta.
ｍ、ｐ、１９０〜１９１℃
実施例５
出発物として６−（４−クロルフェノキシ〕−４−チオ
クロマノン−２−酢陛を用い、実施例２に準じて６−（
４−クロルフェノキシ）−４−チオクロマノン−２−酢
酸エチルを得り。m, p, 190-191°C Example 5 6-(
Ethyl 4-chlorophenoxy)-4-thiochromanone-2-acetate was obtained.
ｍ、 ｐ、 １０２〜１０３℃m, p, 102-103℃
Claims (1)
ノキシ基または炭素数５〜７のシクロアルキル基を示し
、Ｒは水素原子または低級アルキル基を示し、ｎは０〜
３の整数を示す。）で表わされる４−チオクロマノン誘
導体(1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Indicates an alkyl group, n is 0 to
Indicates an integer of 3. ) 4-thiochromanone derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1071790A JPH02255677A (en) | 1989-03-27 | 1989-03-27 | 4-thiochromanone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1071790A JPH02255677A (en) | 1989-03-27 | 1989-03-27 | 4-thiochromanone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02255677A true JPH02255677A (en) | 1990-10-16 |
Family
ID=13470724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1071790A Pending JPH02255677A (en) | 1989-03-27 | 1989-03-27 | 4-thiochromanone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02255677A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2053095A2 (en) | 2007-09-28 | 2009-04-29 | Fujifilm Corporation | Ink composition and inkjet recording method using the same |
| EP2145932A1 (en) | 2008-07-16 | 2010-01-20 | Fujifilm Corporation | Aqueous ink composition, aqueous ink composition for inkjet recording, and inkjet recording method |
| EP2228417A1 (en) | 2009-03-09 | 2010-09-15 | Fujifilm Corporation | Ink composition and inkjet recording method |
-
1989
- 1989-03-27 JP JP1071790A patent/JPH02255677A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2053095A2 (en) | 2007-09-28 | 2009-04-29 | Fujifilm Corporation | Ink composition and inkjet recording method using the same |
| EP2145932A1 (en) | 2008-07-16 | 2010-01-20 | Fujifilm Corporation | Aqueous ink composition, aqueous ink composition for inkjet recording, and inkjet recording method |
| EP2228417A1 (en) | 2009-03-09 | 2010-09-15 | Fujifilm Corporation | Ink composition and inkjet recording method |
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