JPS6144874B2 - - Google Patents
Info
- Publication number
- JPS6144874B2 JPS6144874B2 JP27907085A JP27907085A JPS6144874B2 JP S6144874 B2 JPS6144874 B2 JP S6144874B2 JP 27907085 A JP27907085 A JP 27907085A JP 27907085 A JP27907085 A JP 27907085A JP S6144874 B2 JPS6144874 B2 JP S6144874B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- chromanyloxy
- pentamethyl
- compounds
- cholesterol
- 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 24
- -1 phenylaminocarbonyl group Chemical group 0.000 claims description 20
- 239000003529 anticholesteremic agent Substances 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 3
- 239000011664 nicotinic acid Substances 0.000 claims description 3
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 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 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229960001214 clofibrate Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 5
- 230000000871 hypocholesterolemic effect Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 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
- 229940127226 anticholesterol agent Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 235000019441 ethanol Nutrition 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
- 239000005457 ice water Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid 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
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 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
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-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
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 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
- 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 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
- 235000014443 Pyrus communis Nutrition 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
- 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
- 239000002253 acid Substances 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
- 230000002484 anti-cholesterolemic effect Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000011230 binding agent Substances 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
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 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
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000009472 formulation Methods 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
- 235000001727 glucose Nutrition 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 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
- 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
- 230000007721 medicinal effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 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
- 235000010981 methylcellulose Nutrition 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
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 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
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
本発明は優れた医薬作用を有するクロマン化合
物に関する。更に詳しく述べれば、
次の一般式（）
（式中Ｒは、ピリジルカルボニル基または、フエ
ニルアミノカルボニル基を意味する）
で表わされるクロマン化合物およびそれを含有す
る降コレステロール剤に関する。
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
法で合成され得るが、例えば、後記の実施例の方
法で製造することができる。
次に本発明の効果を詳しく説明するため、以下
に薬理実験例を掲げる。
薬理実験例
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−（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 Ｎ−フエニ
ルカルバメート（以下化合物Ａと称す）
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 ニコチネー
ト（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
ストの血清中の総コレステロール値、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、および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。
The present invention relates to chroman compounds having excellent medicinal effects. In more detail, the following general formula () (In the formula, R means a pyridylcarbonyl group or a phenylaminocarbonyl group.) The present invention relates to a chroman compound represented by the following formula and a cholesterol-lowering agent containing the same. 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 by several methods due to its chemical structure, and for example, it can be produced by the method described in the Examples below. Next, in order to explain the effects of the present invention in detail, pharmacological experimental examples are listed below. Pharmacological Experimental Examples Test Compounds 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-(2,2,5,7,8-pentamethyl-6
-chromanyloxy)-isobutyl N-phenylcarbamate (hereinafter referred to as compound A) 2-(2.2.5.7.8-pentamethyl-6
-chromanyloxy)-isobutyl nicotinate (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
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 hypocholesterolemic effect (total cholesterol reduction amount in serum) of clofibrate and compounds A and B was calculated from the serum total cholesterol 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 hypocholesterolemic 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てに認
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Ｂは３倍
の作用であつた。
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、メチルセルロース、
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
はソルビタ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−（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 Ｎ−フエ
ニルカルバメート
(i) ２−（２・２・５・７・８−ペンタメチル−
６−クロマニルオキシ）−イソブタノール
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13.4ｇを全
量60mlのベンゼン溶液となし、これを10〜13℃
にてヴイドライト15mlを撹拌下に滴下、さらに
25〜30℃にて６時間撹拌を継続した。反応混合
物を氷水に注ぎ入れ、酢酸エチルエステルで抽
出し、抽出分を芒硝で乾燥、減圧濃縮し、濃縮
物にｎ−ヘキサンを加え、析出する結晶を目的
物として取つた。収量10.6ｇ
融点：75〜76℃
元素分析値：分子式C18H28O3として
Ｃ Ｈ
理論値（％） 73.93 9.65
実測値（％） 74.02 9.68
(ii) 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 Ｎ−フ
エニルカルバメート
(i)で得た２−（２・２・５・７・８−ペンタ
メチル−６−クロマニルオキシ）−イソブタノ
ール2.3ｇを全量20mlのベンゼン溶液となし、
これにフエニルイソシアナート2.2mlを加え、
８時間加熱還流した。反応終了後、溶媒を減圧
留去し、残渣をエチルエーチル・ｎ−ヘキサン
混合溶媒より再結晶した。収量2.1ｇ
融点：93〜94℃
元素分析値：分子式C25H33NO4
Ｃ Ｈ Ｎ
理論値（％） 72.96 8.08 3.40
実測値（％） 73.10 8.14 3.41
実施例 ２
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 ニコチネ
ート
実施例−(i)で得た２−（２・２・５・７・８−
ペンタメチル−６−クロマニルオキシ）−イソブ
タノール2.9ｇ、ピリジン1.9ｇを全量20mlのエチ
ルエーテル溶液とし、これにニコチン酸クロライ
ド塩酸塩1.78ｇをエチルエーテル懸濁液20mlとし
たものを８〜10℃にて撹拌下に滴下、さらに２時
間撹拌下に加熱還流した。反応混合物を氷水に注
ぎ入れ、苛性ソーダ水溶液にて液性をアルカリ性
となし、エチルエーテルにて抽出、抽出分を減圧
蒸留し、残渣にエタノール性塩酸を加え、析出物
を取し、エチルエーテル・エタノール混合溶媒
より再結晶し目的物をその塩酸塩として得た。収
量2.2ｇ
融点：〜153℃
元素分析値：分子式C24H31NO4・HClとして
Ｃ Ｈ Ｎ
理論値（％） 66.42 7.43 3.23
実測値（％） 66.30 7.35 3.25[Table] As is clear from this table, it was observed in all the test compounds, and in comparison with the standard compound clofibrate, compounds A and B showed a stronger hypocholesterolemic effect than clofibrate. It was an effect. 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 500-1000mg/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, methyl cellulose,
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 sorbitanic acid. Next, the present invention will be explained with reference to examples. Example 1 2-(2.2.5.7.8-pentamethyl-6
-chromanyloxy)-isobutyl N-phenylcarbamate (i) 2-(2,2,5,7,8-pentamethyl-
6-chromanyloxy)-isobutanol 2-(2,2,5,7,8-pentamethyl-
13.4g of 6-chromanyloxy)-isobutyric acid was made into a benzene solution with a total volume of 60ml, and this was heated at 10 to 13℃.
Add 15ml of Vidolite while stirring, and then add
Stirring was continued for 6 hours at 25-30°C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. N-hexane was added to the concentrate, and the precipitated crystals were collected as the target product. Yield 10.6g Melting point: 75-76℃ Elemental analysis value: Molecular formula C 18 H 28 O 3 C H Theoretical value (%) 73.93 9.65 Actual value (%) 74.02 9.68 (ii) 2-(2.2.5.7・8-Pentamethyl-
6-Chromanyloxy)-isobutyl N-phenylcarbamate 2.3 g of 2-(2.2.5.7.8-pentamethyl-6-chromanyloxy)-isobutanol obtained in (i) was added to a total of 20 ml of benzene. solution and pear,
Add 2.2ml of phenyl isocyanate to this,
The mixture was heated under reflux for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl ethyl and n-hexane. Yield 2.1g Melting point: 93-94℃ Elemental analysis: Molecular formula C 25 H 33 NO 4 C H N Theoretical value (%) 72.96 8.08 3.40 Actual value (%) 73.10 8.14 3.41 Example 2 2-(2.2.5・7,8-pentamethyl-6
-chromanyloxy)-isobutyl nicotinate 2-(2.2.5.7.8-) obtained in Example-(i)
A solution of 2.9 g of pentamethyl-6-chromanyloxy)-isobutanol and 1.9 g of pyridine in a total volume of 20 ml of ethyl ether was mixed with a suspension of 1.78 g of nicotinic acid chloride hydrochloride in 20 ml of ethyl ether at 8 to 10°C. The mixture was added dropwise to the mixture under stirring, and the mixture was further heated to reflux while stirring for 2 hours. Pour the reaction mixture into ice water, make the liquid alkaline with aqueous caustic soda solution, extract with ethyl ether, distill the extract under reduced pressure, add ethanolic hydrochloric acid to the residue, remove the precipitate, and dilute with ethyl ether/ethanol. Recrystallization from a mixed solvent gave the desired product as its hydrochloride. Yield 2.2g Melting point: ~153℃ Elemental analysis: Molecular formula C 24 H 31 NO 4・HCl C H N Theoretical value (%) 66.42 7.43 3.23 Actual value (%) 66.30 7.35 3.25
Claims (1)
ニルアミノカルボニル基を意味する） で表わされるクロマン化合物。 ２ 化合物が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
Ｎ−フエニルカルバメートである特許請求の範囲
第１項記載のクロマン化合物。 ３ 化合物が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
ニコチネートである特許請求の範囲第１項記載の
クロマン化合物。 ４ 次の一般式 （式中Ｒは、ピリジルカルボニル基または、フエ
ニルアミノカルボニル基を意味する） で表わされるクロマン化合物を有効成分とする降
コレステロール剤。[Claims] First-order general formula (In the formula, R means a pyridylcarbonyl group or a phenylaminocarbonyl group.) A chroman compound represented by: 2 The compound is 2-(2.2.5.7.8-pentamethyl-6-chromanyloxy)-isobutyl
The chroman compound according to claim 1, which is an N-phenyl carbamate. 3 The compound is 2-(2.2.5.7.8-pentamethyl-6-chromanyloxy)-isobutyl
The chroman compound according to claim 1, which is nicotinate. 4 The following general formula (In the formula, R means a pyridylcarbonyl group or a phenylaminocarbonyl group.) A hypocholesterolemic agent containing a chroman compound represented by the following as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27907085A JPS61143372A (en) | 1985-12-13 | 1985-12-13 | Chroman compound and cholesterol-lowering agent containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27907085A JPS61143372A (en) | 1985-12-13 | 1985-12-13 | Chroman compound and cholesterol-lowering agent containing same |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP98879A Division JPS5594382A (en) | 1979-01-11 | 1979-01-11 | Chroman-based compound and cholestrol lowering drug comprising it |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61143372A JPS61143372A (en) | 1986-07-01 |
| JPS6144874B2 true JPS6144874B2 (en) | 1986-10-04 |
Family
ID=17605993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27907085A Granted JPS61143372A (en) | 1985-12-13 | 1985-12-13 | Chroman compound and cholesterol-lowering agent containing same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61143372A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR950007045B1 (en) * | 1992-04-14 | 1995-06-30 | 주식회사태평양 | Skin cosmetic material containing polyethoxylate vitamin e. |
-
1985
- 1985-12-13 JP JP27907085A patent/JPS61143372A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61143372A (en) | 1986-07-01 |
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