JPS6123796B2 - - Google Patents
Info
- Publication number
- JPS6123796B2 JPS6123796B2 JP98879A JP98879A JPS6123796B2 JP S6123796 B2 JPS6123796 B2 JP S6123796B2 JP 98879 A JP98879 A JP 98879A JP 98879 A JP98879 A JP 98879A JP S6123796 B2 JPS6123796 B2 JP S6123796B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkyl group
- compound
- compounds
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 28
- -1 chroman compound Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000003529 anticholesteremic agent Substances 0.000 claims description 4
- 229940127226 anticholesterol agent Drugs 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 229960001214 clofibrate Drugs 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 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 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000002484 anti-cholesterolemic effect Effects 0.000 description 2
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000000871 hypocholesterolemic effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QGQLOERTCFUGJG-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methyl-2-[(2,2,5,7,8-pentamethyl-3,4-dihydrochromen-6-yl)oxy]propanoate Chemical compound O1C(C)(C)CCC2=C(C)C(OC(C)(C)C(=O)OCCN(C)C)=C(C)C(C)=C21 QGQLOERTCFUGJG-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 210000004351 coronary vessel Anatomy 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本発明は、優れた医薬作用を有する新規なクロ
マン系化合物に関する。更に詳しく述べれば一般
式（）
（式中Ｘは式−NH−で示される基、または式
−Ｏ−で示される基を意味する。R1は、低級ア
ルキル基、ハロゲン置換若しくは無置換のフエニ
ル基、シクロアルキル基、ジメチルアミノ置換低
級アルキル基、ハイドロオキシ置換低級アルキル
基、フエニルアルキル基、ピリジルアルキル基を
意味する。更に式−Ｘ−R1がモルフオリノ基を
形成してもよい。）で表わされるクロマン系化合
物およびそれを含有する医薬に関する。
上記の定義において、低級アルキル基とは、例
えばメチル、エチル、プロピル、イソプロピル、
ブチル、イソブチルなど炭素数１〜４のアルキル
基を、シクロアルキル基とは、例えばシクロペン
チル、シクロヘキシルなどを意味する。
ハロゲン置換フエニル基のハロゲンとは、塩
素、臭素、フツ素などを意味する。
降コレステロール剤としてはクロルフイブレー
ト（化学名：エチル Ｐ−クロロフエノキシイソ
ブチレート）が広く用いられているが、降コレス
テロール作用の効力及び嘔吐、肝障害、食欲不振
等の消化器系の副作用の存在に問題があつた。本
発明はこれらの欠点を改善して、降コレステロー
ル剤としてより優れた特性を有する化合物の提供
を目的とするものである。
本発明化合物（）はその化学構造上数種の方
で合成され得るが、次に述べる方法もその例であ
る。
製造方法
次の一般式（）
で表わされるカルボン酸またはその反応性誘導体
を次の一般式（）
Ｈ−Ｘ−R1
（式中ＸおよびR1は前記の意味を有する）で
表わされるアルコール体またはアミノ体を反応さ
せて目的物質（）を得る。
次に本発明化合物の降コレステロール作用につ
いて説明する。
＜薬理試験＞
試験化合物
試験化合物として本発明化合物（）より以下
の化合物を選定した。また標準化合物としてはク
ロフイブレートを用いた。
２−（Ｎ，Ｎ−ジメチルアミノ）−エチル ２−
（２，２，５，７，８−ペンタメチル−６−クロ
マニルオキシ）−イソブチレート（以下化合物Ａ
と称す）
Ｎ−（３−クロロフエニル）−２−（２，２，
５，７，８−ペンタメチル−６−クロマニルオキ
シ）−イソブチルアミド（以下化合物Ｂと称す）
実験方法
トライトン処置してコレステロール値を上昇せ
しめたマウスを試験動物とし、これに試験化合物
200mg／Kg／day（５％水性アラビアゴム溶液に
て懸濁）を２日間連続して経口投与した後の血清
コレステロールをテクニコン オートアナライザ
ー（テクニコン社）で測定した。
一方、５％水性アラビアゴム溶液のみを試験動
物に投与してブランクテストとした。ブランクテ
ストの血清中の降コレステロール値、クロフイブ
レート及び化合物Ａ，Ｂの血清中の総コレステロ
ール値よりクロフイブレート及び化合物Ａ，Ｂの
降コレステロール作用（血清中の総コレステロー
ル減少量）を算出し、標準化合物クロフイブレー
トの降コレステロール作用と化合物Ａ，Ｂの降コ
レステロール作用を対比した。
実験成績
試験化合物の抗コレステロール作用を標準化合
物クロフイブレートの降コレステロール作用と化
合物Ａ，Ｂの降コレステロール作用の対比として
以下に表示した。尚、標準化合物クロフイブレー
トの降コレステロール作用を（＋）とした。
TECHNICAL FIELD The present invention relates to novel chroman-based compounds that have excellent medicinal effects. In more detail, the general formula () (In the formula, X means a group represented by the formula -NH- or a group represented by the formula -O-. means a substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a phenyl alkyl group, a pyridyl alkyl group.Furthermore, chroman compounds represented by the formula -X-R 1 may form a morpholino group; It relates to a medicine containing. In the above definition, lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl,
The term cycloalkyl group refers to an alkyl group having 1 to 4 carbon atoms such as butyl or isobutyl, and cycloalkyl group refers to, for example, cyclopentyl or cyclohexyl. The halogen in the halogen-substituted phenyl group means chlorine, bromine, fluorine, etc. Chlorfibrate (chemical name: ethyl P-chlorophenoxy isobutyrate) is widely used as a cholesterol-lowering drug, but it has poor cholesterol-lowering efficacy and side effects on the digestive system such as vomiting, liver damage, and anorexia. There was a problem with the existence of The object of the present invention is to improve these drawbacks and provide a compound having more excellent properties as a cholesterol-lowering agent. The compound () of the present invention can be synthesized in several ways due to its chemical structure, and the following method is an example. Manufacturing method The following general formula () A carboxylic acid represented by or a reactive derivative thereof is reacted with an alcohol or amino form represented by the following general formula () H-X-R 1 (wherein X and R 1 have the above-mentioned meanings) to obtain the desired product. Get substance (). Next, the cholesterol-lowering effect of the compound of the present invention will be explained. <Pharmacological test> Test compound The following compounds were selected from the compounds of the present invention () as test compounds. In addition, clofibrate was used as a standard compound. 2-(N,N-dimethylamino)-ethyl 2-
(2,2,5,7,8-pentamethyl-6-chromanyloxy)-isobutyrate (hereinafter compound A
) N-(3-chlorophenyl)-2-(2,2,
5,7,8-Pentamethyl-6-chromanyloxy)-isobutyramide (hereinafter referred to as compound B) Experimental method Mice treated with Triton to increase cholesterol levels were used as test animals, and the test compound was administered to them.
After oral administration of 200 mg/Kg/day (suspended in a 5% aqueous gum arabic solution) for 2 consecutive days, serum cholesterol was measured using a Technicon Autoanalyzer (Technicon). On the other hand, only a 5% aqueous gum arabic solution was administered to test animals to serve as a blank test. The cholesterol-lowering effect (total cholesterol reduction in serum) of clofibrate and compounds A and B was calculated from the serum cholesterol-lowering value of the blank test and the serum total cholesterol value of clofibrate and compounds A and B. compared the cholesterol-lowering effects of the standard compound clofibrate with those of compounds A and B. Experimental Results The anticholesterolemic effects of the test compounds are shown below as a comparison between the hypocholesterolemic effects of the standard compound clofibrate and the anticholesterolemic effects of compounds A and B. Note that the hypocholesterolemic effect of the standard compound clofibrate was designated as (+).
【表】
この表より明らかなように試験化合物全にて認
められ、標準化合物クロフイブレートとの対比で
は化合物Ａ，Ｂはクロフイブレートよりも強い降
コレステロール作用を示し、特に化合物Ａは４倍
の作用があつた。
このように本発明化合物は降コレステロール剤
として優れた特性を有するものであり、更に毒性
試験においても低毒性である事が確認された。例
えば化合物ＡおよびＢでは急性毒性値〔LD50
（マウス経口）〕５ｇ／Kg以上であつた。
以上の薬理試験の結果より本発明化合物は動脈
硬化症にともなう各種症状の治療剤、例えば過コ
レステロール血症、過脂肪血症、アテローム性動
脈硬化症、脳の循環系障害、冠状動脈系、及び末
梢脈管系障害の治療剤として期待される。
本発明化合物の臨床用量は、一般に200〜2000
mg／day（経口）、好ましくは500〜1000mg／day
（経口）の量で、分割投与にて２〜３回に分服さ
れる。
本発明化合物は任意慣用の製剤方法を用いて投
与用に調製する事ができる。従つて、本発明は人
体医薬として好適な少なくとも一種の本発明の化
合物を含有する製剤組成物をも包含するものであ
る。このような組成物は任意所要の製薬用担体あ
るいは賦形剤により慣用の方法で使用に供され
る。
この組成物は消化管からの吸収に好適な形態で
提供されるのが望ましい。経口投与の錠剤および
カプセルは単位量投与形態であり、結合剤例えば
シロツプ、アラビアゴム、ゼラチン、ソルビツ
ト、トラカント、またはポリビニルピロリドン、
賦形薬例えば乳糖、とうもろこし澱粉、りん酸カ
ルシウム、ソルビツトまたはグリシン、潤滑剤例
えばステアリン酸マグネシウム、タルク、ポリエ
チレングリコールまたはシリカ、崩壊剤例えば馬
鈴薯澱粉、あるいは許容し得る湿潤剤例えばラウ
リル硫酸ナトリウムのような慣用の賦形剤を含有
していてもよい。錠剤は当業界において周知の方
法でコーテイングしてもよい。経口用液体製剤は
水性または油性懸濁剤、溶液、シロツプ、エリキ
シル剤、その他であつてもよく、あるいは使用す
る前に水または、他の適当なビヒクルで再溶解さ
せる乾燥生成物であつてもよい。このような液体
製剤は普通に用いられる添加剤例えば懸濁化剤、
例えばソルビツトシロツプ、メチルセルローズ、
グルコース／糖シロツプ、ゼラチン、ヒドロキシ
エチルセルロース、カルボキシメチルセルロー
ス、ステアリン酸アルミニウムゲルまたは水素化
食用脂、乳化剤例えばレシチン、モノオレイン酸
ソルビタン、またはアラビアゴム、非水性ビヒク
ル、例えばアーモンド油、分別ココナツト油、油
性エステル、プロピレングリコールまたはエチル
アルコール、防腐剤例えばＰ−ヒドロキシ安息香
酸メチル、Ｐ−ヒドロキシ安息香酸プロピルまた
はソルビン酸を含有してもよい。
次に実施例により本発明を説明する。
実施例 １
２−（Ｎ，Ｎ−ジメチルアミノ）−エチル ２−
（２，２，５，７，８−ペンタメチル−６−ク
ロマニルオキシ）−イソブチレート
２−（２，２，５，７，８−ペンタメチル−６
−クロマニルオキシ）−イソ酪酸4.59ｇをベンゼ
ン90mlに溶解した溶液にチオニルクロライド4.5
mlを加え、３時間撹拌下に加熱還流した。反応終
了後、溶媒及び過剰のチオニルクロライドを減圧
留去し、残留物をベンゼン60mlに溶解、これに２
−（Ｎ，Ｎ−ジメチルアミノ）−エタノール3.0ｇ
を加え1.5時間撹拌下に加熱還流した。反応終了
後、反応生成物を氷水に注ぎ入れ、５％苛性ソー
ダ水溶液でアルカリ性とし、エチルエーテルで抽
出した。エチルエーテル抽出分を水洗、次いで芒
硝にて乾燥したのち溶媒を減圧留去し、油状の目
的物5.2ｇを得た。
赤外スペクトル測定値（cm-1，ニート）：
2850，2795，1740，1170，1140
IRスペクトル測定値（δ，CDCl3）：
7.72（ｓ，6H），7.35（ｔ，2H），5.70（ｔ，
2H）
本品をエーテルに溶解し、乾燥塩酸ガスを導
入、塩酸塩とした。エタノール−アセトン混合溶
媒より再結晶した。
融点：160〜162℃
元素分析値：分子式C22H35NO4・HCl1／3H2O
として
Ｃ Ｈ Ｎ
理論値（％） 62.91 8.80 3.34
実測値（％） 62.77 8.70 3.60
赤外スペクトル測定値（cm-1，ヌジヨール）：
2700〜2200，1730，1270，1140
実施例 ２
Ｎ−（３−クロロフエニル）−２−（２，２，
５，７，８−ペンタメチル−６−クロマニルオ
キシ）−イソブチルアミド
２−（２，２，５，７，８−ペンタメチル−６
−クロマニルオキシ）−イソ酪酸4.59ｇをベンゼ
ン90mlに溶解した溶液に、チオニルクロライド
4.5mlを加え、３時間撹拌下に加熱還流した。反
応終了後、溶媒及び過剰のチオニルクロライドを
減圧留去し、残留物をベンゼン50mlに溶解、これ
にｍ−クロロアニリン3.8ｇを加え、室温にて２
時間撹拌したのち、氷水に注ぎ入れ、次いでエチ
ルエーテルにて抽出した。エチルエーテル抽出分
を水洗、希塩酸で洗滌、芒硝で乾燥後、溶媒を減
圧留去し、残留物をｎ−ヘキサン−エチルエーテ
ル混合溶媒より再結晶して目的物3.9ｇを得た。
融点：134〜136℃
元素分析値：分子式C24H30ClNO3として
Ｃ Ｈ Ｎ
理論値（％） 69.30 7.27 3.37
実測値（％） 69.15 7.30 3.18
以下、本発明化合物の実施例を表２に示す。[Table] As is clear from this table, it was observed in all of the test compounds, and when compared with the standard compound clofibrate, compounds A and B showed a stronger cholesterol-lowering effect than clofibrate, especially compound A, which was 4 times more effective. The effect was strong. As described above, the compound of the present invention has excellent properties as a cholesterol-lowering agent, and was further confirmed to have low toxicity in toxicity tests. For example, compounds A and B have acute toxicity values [LD 50
(mouse oral)] 5 g/Kg or more. The results of the above pharmacological tests indicate that the compound of the present invention can be used as a therapeutic agent for various symptoms associated with arteriosclerosis, such as hypercholesterolemia, hyperlipidemia, atherosclerosis, cerebral circulatory system disorders, coronary artery system, and It is expected to be a therapeutic agent for peripheral vascular system disorders. Clinical doses of compounds of the invention generally range from 200 to 2000
mg/day (oral), preferably 500-1000 mg/day
(oral) dose, administered in 2 to 3 divided doses. The compounds of this invention can be prepared for administration using any conventional method of formulation. Therefore, the present invention also encompasses pharmaceutical compositions containing at least one compound of the present invention suitable as a human medicine. Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients. Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract. Tablets and capsules for oral administration are in unit dosage form and include binders such as syrup, acacia, gelatin, sorbitate, tracanth, or polyvinylpyrrolidone,
Excipients such as lactose, corn starch, calcium phosphate, sorbitate or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. It may also contain conventional excipients. The tablets may be coated by methods well known in the art. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products that are redissolved in water or other suitable vehicle before use. good. Such liquid formulations contain commonly used additives such as suspending agents,
For example, sorbitol syrup, methylcellulose,
Glucose/sugar syrups, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, sorbitan monooleate, or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters. , propylene glycol or ethyl alcohol, preservatives such as methyl P-hydroxybenzoate, propyl P-hydroxybenzoate or sorbic acid. Next, the present invention will be explained with reference to examples. Example 1 2-(N,N-dimethylamino)-ethyl 2-
(2,2,5,7,8-pentamethyl-6-chromanyloxy)-isobutyrate 2-(2,2,5,7,8-pentamethyl-6
-chromanyloxy)-isobutyric acid (4.59 g) dissolved in benzene (90 ml) was added with 4.5 g of thionyl chloride.
ml and heated to reflux while stirring for 3 hours. After the reaction, the solvent and excess thionyl chloride were distilled off under reduced pressure, and the residue was dissolved in 60 ml of benzene.
-(N,N-dimethylamino)-ethanol 3.0g
was added and heated to reflux while stirring for 1.5 hours. After the reaction was completed, the reaction product was poured into ice water, made alkaline with a 5% aqueous sodium hydroxide solution, and extracted with ethyl ether. The ethyl ether extract was washed with water, then dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.2 g of the desired product as an oil. Infrared spectrum measurements (cm -1 , neat): 2850, 2795, 1740, 1170, 1140 IR spectrum measurements (δ, CDCl 3 ): 7.72 (s, 6H), 7.35 (t, 2H), 5.70 (t ，
2H) Dissolve this product in ether and introduce dry hydrochloric acid gas to make the hydrochloride. It was recrystallized from a mixed solvent of ethanol and acetone. Melting point: 160-162℃ Elemental analysis value: Molecular formula C 22 H 35 NO 4・HCl1/3H 2 O
As C H N Theoretical value (%) 62.91 8.80 3.34 Actual value (%) 62.77 8.70 3.60 Infrared spectrum measurement value (cm -1 , Nujiol): 2700-2200, 1730, 1270, 1140 Example 2 N-(3- chlorophenyl)-2-(2,2,
5,7,8-pentamethyl-6-chromanyloxy)-isobutyramide 2-(2,2,5,7,8-pentamethyl-6
-Chromanyloxy)-isobutyric acid (4.59 g) dissolved in 90 ml of benzene, add thionyl chloride.
4.5 ml was added, and the mixture was heated to reflux while stirring for 3 hours. After the reaction, the solvent and excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in 50 ml of benzene, 3.8 g of m-chloroaniline was added thereto, and the mixture was stirred at room temperature for 2 hours.
After stirring for an hour, the mixture was poured into ice water, and then extracted with ethyl ether. The ethyl ether extract was washed with water, diluted hydrochloric acid, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl ether to obtain 3.9 g of the desired product. Melting point: 134-136°C Elemental analysis value: Molecular formula C 24 H 30 ClNO 3 C H N Theoretical value (%) 69.30 7.27 3.37 Actual value (%) 69.15 7.30 3.18 Examples of the compounds of the present invention are shown in Table 2 below. .
【表】【table】
【表】
次に本発明の化合物２−（Ｎ，Ｎ−ジメチルア
ミノ）−エチル α−（２，２，５，７，８−ペン
タメチル−６−クロマニルオキシ）−イソブチレ
ート（以下主薬と称する）を活性成分とした製剤
例を実施例として記載する。
実施例 10
錠 剤
主 薬 50ｇ
コーンスターチ 72.5ｇ
カルボキシセルローズ 20ｇ
ポリビニルピロリドン 4.5ｇ
ステアリン酸カルシウム ３ｇ
全 量
常法により１錠150mgの錠剤で製造した。
錠剤１錠中主薬50mgを含有する。
実施例 11
散剤、カプセル剤
主 薬 50ｇ
結晶セルローズ 250ｇ
全 量 300ｇ
両粉末を混合して散剤とした。また、この散剤
を３号のハードカプセルに充填してカプセル剤と
した。[Table] Next, the compound of the present invention 2-(N,N-dimethylamino)-ethyl α-(2,2,5,7,8-pentamethyl-6-chromanyloxy)-isobutyrate (hereinafter referred to as the main drug) An example of a formulation containing the active ingredient as an active ingredient will be described as an example. Example 10 Tablets Main drug 50g Cornstarch 72.5g Carboxycellulose 20g Polyvinylpyrrolidone 4.5g Calcium stearate 3g Total amount Tablets each weighing 150mg were manufactured by a conventional method. One tablet contains 50mg of the active ingredient. Example 11 Powder, Capsule Main drug: 50g Crystalline cellulose: 250g Total amount: 300g Both powders were mixed to form a powder. Further, this powder was filled into No. 3 hard capsules to prepare capsules.
Claims (1)
−Ｏ−で示される基を意味する。R1は、低級ア
ルキル基、ハロゲン置換若しくは無置換のフエニ
ル基、シクロアルキル基、ジメチルアミノ置換低
級アルキル基、ハイドロオキシ置換低級アルキル
基、フエニルアルキル基、ピリジルアルキル基を
意味する。更に式−Ｘ−R1がモルフオリノ基を
形成してもよい。）で表わされるクロマン系化合
物。 ２ 化合物が２−（Ｎ，Ｎ−ジメチルアミノ）−エ
チル２−（２，２，５，７，８−ペンタメチル−
６−クロマニルオキシ）−イソブチレートである
特許請求の範囲第１項記載のクロマン系化合物。 ３ 化合物がＮ−（３−クロロフエニル）−２−
（２，２，５，７，８−ペンタメチル−６−クロ
マニルオキシ）イソブチルアミドである特許請求
の範囲第１項記載のクロマン系化合物。 ４ 一般式 （式中Ｘは式−NH−で示される基、または式
−Ｏ−で示される基を意味する。R1は、低級ア
ルキル基、ハロゲン置換若しくは無置換のフエニ
ル基、シクロアルキル基、ジメチルアミノ置換低
級アルキル基、ハイドロオキシ置換低級アルキル
基、フエニルアルキル基、ピリジルアルキル基を
意味する。更に式−Ｘ−R1がモルフオリノ基を
形成してもよい。）で表わされるクロマン系化合
物を有効成分とする降コレステロール剤。[Claims] 1. General formula (In the formula, X means a group represented by the formula -NH- or a group represented by the formula -O-. A chroman compound represented by the formula -X-R 1 which means a substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a phenyl alkyl group, or a pyridyl alkyl group. 2 The compound is 2-(N,N-dimethylamino)-ethyl 2-(2,2,5,7,8-pentamethyl-
The chroman compound according to claim 1, which is 6-chromanyloxy)-isobutyrate. 3 The compound is N-(3-chlorophenyl)-2-
The chroman compound according to claim 1, which is (2,2,5,7,8-pentamethyl-6-chromanyloxy)isobutyramide. 4 General formula (In the formula, X means a group represented by the formula -NH- or a group represented by the formula -O-. It means a substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a phenyl alkyl group, a pyridyl alkyl group.Furthermore, the formula -X-R 1 may form a morpholino group). A cholesterol-lowering agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP98879A JPS5594382A (en) | 1979-01-11 | 1979-01-11 | Chroman-based compound and cholestrol lowering drug comprising it |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP98879A JPS5594382A (en) | 1979-01-11 | 1979-01-11 | Chroman-based compound and cholestrol lowering drug comprising it |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27907085A Division JPS61143372A (en) | 1985-12-13 | 1985-12-13 | Chroman compound and cholesterol-lowering agent containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5594382A JPS5594382A (en) | 1980-07-17 |
| JPS6123796B2 true JPS6123796B2 (en) | 1986-06-07 |
Family
ID=11488971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP98879A Granted JPS5594382A (en) | 1979-01-11 | 1979-01-11 | Chroman-based compound and cholestrol lowering drug comprising it |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5594382A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4681890A (en) * | 1984-10-30 | 1987-07-21 | Kuraray Co., Ltd. | 3,4-dihydrobenzopyran compounds and pharmaceutical composition containing the same |
| DE3484473D1 (en) * | 1984-12-06 | 1991-05-23 | Kuraray Co | CHROMAN CONNECTIONS AND THEIR PRODUCTION. |
| IT1256264B (en) * | 1992-12-31 | 1995-11-29 | Lifegroup Spa | N-HYDROXYAMINE N-ACIL DERIVATIVES EQUIPPED WITH SCAVENGER ACTIVITIES AND USABLE IN ACUTE AND CHRONIC PATHOLOGIES RELATED TO PHENOMENA OF PEROXIDATION AND INFLAMMATION |
-
1979
- 1979-01-11 JP JP98879A patent/JPS5594382A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5594382A (en) | 1980-07-17 |
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