WO1994018167A1 - Substituted dibenzylamine derivative - Google Patents
Substituted dibenzylamine derivative Download PDFInfo
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- WO1994018167A1 WO1994018167A1 PCT/JP1994/000132 JP9400132W WO9418167A1 WO 1994018167 A1 WO1994018167 A1 WO 1994018167A1 JP 9400132 W JP9400132 W JP 9400132W WO 9418167 A1 WO9418167 A1 WO 9418167A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
Definitions
- the present invention relates to a novel substituted dibenzylamine derivative, and more particularly to a substituted dibenzilamin derivative which is useful in the fields of prevention and treatment of hyperlipidemia, hypercholesterolemia, arteriosclerosis, and the like. It relates to a benzylamine derivative and a salt thereof.
- Increased blood lipids promote lipid deposition in the intima of the blood vessels, and in particular, increased cholesterol in the blood promotes atherosclerosis, atherosclerosis, coronary and brain! ) It is considered to be a major factor causing an increase in vascular diseases. At present, reduction of blood cholesterol to normal levels is considered to be the most effective means for preventing and treating arterial stiffness.
- a reductase inhibitor represented by bravastatin inhibits the early stages of the cholesterol biosynthesis system Therefore, it has the disadvantage of suppressing the production of important physiological metabolites other than cholesterol, such as dolichol and ubiquinone.
- an inhibitor of an enzyme that plays a role in the late stage of the cholesterol biosynthesis system has side effects such as cataract, which is considered to be caused by accumulation of desmosterol.
- squalene epoxidase inhibitors which suppress the middle stage of cholesterol biosynthesis, are expected to solve the above problems.
- the main object of the present invention is to find a compound that specifically inhibits squalene epoxidase in mammals, and to predict hyperlipidemia, hypercholesterolemia, and arteriosclerosis.
- the purpose is to provide a compound having excellent activity as a preventive or therapeutic agent.
- the present inventors have already developed butenafine, a compound that specifically and potently inhibits fungal sclarene epoxidase (Maeda et al., Pharmaceutical Journal, Vol. 11, pp. 126 ( 1991)), which is used as an antifungal agent, (2) It had little effect on mammalian squalene epoxidase.
- the present inventors have performed the conversion of the naphthalen portion of butenafin, and as a result, have extremely excellent cholesterol biosynthesis inhibition, which selectively inhibits mammalian epoxidase.
- the present inventors have found compounds having activity and have led to the present invention.
- the invention is general
- R ′ represents a lower alkyl group or a lower alkenyl group
- R 2 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group
- R 3 represents 1-4 heteroatoms.
- a salt thereof or a hyperlipidemia containing the derivative as an active ingredient;
- the present invention relates to an agent for preventing or treating hypercholesterolemia or arteriosclerosis, and a method for treating hyperlipidemia, hypercholesterolemia or arteriosclerosis using the derivative.
- examples of the lower alkyl group represented by R ′ and R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Shi click b blanking port building group, .pi.-butyl group, tert- heptyl group and the like, is a lower alkenyl group represented by R ', for example, ⁇ Li group, click b chill - etc., represented by R 2
- Examples of the lower alkoxy group include methoxy, ethoxy, and the like.
- Hetero atoms in R 3 include a nitrogen atom, an acid purple atom, and a sulfur atom.
- Examples of a ⁇ line include, for example, phenyl, biaryl group, furyl S, and oxalate.
- the substituted dibenzyldiamine derivative of the present invention can be converted into an acid addition salt, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts, or organic acid salts with acetic acid, maleic acid, citric acid, oxalic acid, linoleic acid, methansulphonic acid, p-transylsulfonate, etc. Is raised.
- a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the compound of the present invention can be obtained, for example, by any of the following production methods A, B, C and D.
- R′R 2 and R 3 in each formula have the same meaning as described above, and Z represents a halogen atom or an organic sulfonoxy group.
- a solvent that does not affect the reaction in any case is used.
- ether solvents such as ethyl ether, tetrahydrofuran, dioxane, etc.
- aromatic hydrocarbons such as benzene, toluene, etc.
- Alcohol solvents such as propanol
- Various solvents such as halogenated hydrocarbon solvents such as dichloromethane and chloroform are used, and a single solvent or a mixture of these solvents can be used. .
- the reaction conditions used may be a force that causes the respective compounds to react in approximately equimolar amounts, either from a small excess to 5 times the molar amount, and the reaction temperature may be adjusted.
- reaction temperatures may be adjusted.
- reaction times are usually from 5 minutes to 5 days, preferably from 1 hour to 24 hours. is there.
- alkylation reactions are preferably carried out in the presence of a base.
- the base used include alkali metal hydrides such as sodium hydride and lithium hydride, and water.
- Alkali metal hydroxides such as sodium oxide and hydroxylating power, alkaline metal carbonates such as sodium carbonate and potassium carbonate, triethylamine and the like.
- Organic amines such as pyridine are exemplified.
- the compound of the present invention obtained in the above step may be isolated and purified by appropriately combining, for example, electrochromatography, solvent extraction, precipitation, and recrystallization. I can do it.
- Examples of the halogen atom represented by Z include a chlorine atom, a bromine atom, and an iodine atom, and the organic sulfonyloxy group includes a methansulfonyloxy group. And p-toluenesulfonyl-ox group.
- the compound represented by the general formula [I] of the present invention has a function of inhibiting squalene dipoxidase in mammals and thereby suppressing cholesterol biosynthesis. It is a useful compound for the prevention and treatment of hyperlipidemia, hypercholesterol D-leukemia, and arteriosclerosis.
- NMR scan Bae click DOO Le is heavy click B port E Lum (CDC 1 3) or d 6 - dimethyl Chi pulse Ruhoki Shi de (DMS 0 - d 6) solution in Te preparative ra Ji Le Shi Using a run (TMS) as an internal standard, a JM-EX270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.) Measured and ⁇ values are given in ppm.
- the compound of the present invention has excellent cholesterol biosynthesis inhibitory activity.
- Various diseases caused by excess cholesterol for example, hyperlipidemia, high cholesterol A compound that is effective for the prevention and treatment of blood bleeding or arteriosclerosis.
- the dosage and frequency of administration depend on the patient's sex, age, weight, and symptoms. In general, oral administration is performed on a platform, from 0.01 to 200 1 3 1 ⁇ per adult per day, divided into 1 to several times, and in the case of parenteral administration, 0.00 It is preferable to administer 1 to 2 mkg in 1 to several divided doses.
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Abstract
A substituted dibenzylamine derivative represented by general formula (I) or a salt thereof; and a drug and a method for preventing and treating hyperlipemia, hypercholesterolemia or arteriosclerosis by using the same; wherein R1 represents lower alkyl or lower alkenyl; R2 represents hydrogen, lower alkyl or lower alkoxy; and R3 represents phenyl or thienyl each substituted by a heterocyclic group having one to four heteroatoms.
Description
明 細 書 置換ジベ ン ジルァ ン誘導体 Description Substituted dibenziridine derivative
技術分野 Technical field
本発明は新規な置換ジべン ジルァ ミ ン誘導体に関し、 更に詳し く は高脂血症、 高コ レ ス テ ロ ール血症、 動脈硬化症等の予防および治療の分野で有用な置換ジべ ン ジルァ ミ ン誘導体およびその塩に関する ものである。 The present invention relates to a novel substituted dibenzylamine derivative, and more particularly to a substituted dibenzilamin derivative which is useful in the fields of prevention and treatment of hyperlipidemia, hypercholesterolemia, arteriosclerosis, and the like. It relates to a benzylamine derivative and a salt thereof.
背景技術 Background art
血中脂質の増加は血管内膜での脂質沈着を促進し、 特に血中コ レス テ ロ ールの 増加は動脈硬化を促進し、 動脈硬化症、 冠および脳！)脈系疾患の増加をきたす大 きな要因と されている。 現在、 血中コ レ ス テ ロ ール量の正常値への低下は動脈硬 化の予防および治療の上で最も有効な手段と考えられている。 Increased blood lipids promote lipid deposition in the intima of the blood vessels, and in particular, increased cholesterol in the blood promotes atherosclerosis, atherosclerosis, coronary and brain! ) It is considered to be a major factor causing an increase in vascular diseases. At present, reduction of blood cholesterol to normal levels is considered to be the most effective means for preventing and treating arterial stiffness.
ブラ バス タ チ ンに代表される 3 — ヒ ド ロ キ シメ チ ルグルタ リ ル一 コ ェ -ンザィ ム A還元酵素阻害剤は、 コ レ ス テ ロ ール生合成系の初期の段階を阻害する ことから コ レ ス テ ロ ー ル以外の重要な生理的代謝物である ド リ コール、 ュ ビキ ノ ンなどの 生成までも抑制する欠点がある。 またコ レ ス テ ロ ール生合成系の後期の段階を担 う酵素の阻害剤では、 デス モ ス テ ロ ールの蓄積によると考えられる白内障等の副 作用が報告されている。 一方コ レ ステロール生合成系の中期の段階を抑制する ス ク ワ レ ンエ ポキ シダ一ゼ阻害剤は、 上記の問題点を解決できる ものと期待されて いる。 3—Hydroxymethylglutaryl-coenzyme A reductase inhibitor represented by bravastatin inhibits the early stages of the cholesterol biosynthesis system Therefore, it has the disadvantage of suppressing the production of important physiological metabolites other than cholesterol, such as dolichol and ubiquinone. In addition, it has been reported that an inhibitor of an enzyme that plays a role in the late stage of the cholesterol biosynthesis system has side effects such as cataract, which is considered to be caused by accumulation of desmosterol. On the other hand, squalene epoxidase inhibitors, which suppress the middle stage of cholesterol biosynthesis, are expected to solve the above problems.
本発明の主な目的は、 哺乳動物のス ク ワ レ ンエ ポキ シダーゼを特異的に阻害す る化合物を見いだし、 高脂血症、 高コ レ ス テ ロール血症、 更には動脈硬化症の予 防または治療剤と して優れた活性を有する化合物を供給するこ とである。 The main object of the present invention is to find a compound that specifically inhibits squalene epoxidase in mammals, and to predict hyperlipidemia, hypercholesterolemia, and arteriosclerosis. The purpose is to provide a compound having excellent activity as a preventive or therapeutic agent.
本発明者らは既に真菌のスク ヮ レンエポキシダ一ゼを特異的に、 かつ強力に阻 害する化合物であるブテナフ ィ ンを開発し （前田ら、 薬学雑誌、 第 1 1 1 巻、 1 2 6頁 （ 1 9 9 1 年） 参照） 、 抗真菌剤と して使用されている が、 こ の化合物は
( 2 ) 哺乳動物のス ク ワ レ ンエポキ シダーゼに対 してほとんど影響を及ぼさなかつ た。 そこで、 本発明者らはブテナフ ィ ンのナ フ タ レ ン部分の変換を行つた結果、 哺 乳動物のス ク ヮ レンエポキ シダーゼを選択的に阻害する という、 極めて優れた コ レステ ロール生合成阻害活性を有する化合物を見いだし本発明にいた った。 The present inventors have already developed butenafine, a compound that specifically and potently inhibits fungal sclarene epoxidase (Maeda et al., Pharmaceutical Journal, Vol. 11, pp. 126 ( 1991)), which is used as an antifungal agent, (2) It had little effect on mammalian squalene epoxidase. Thus, the present inventors have performed the conversion of the naphthalen portion of butenafin, and as a result, have extremely excellent cholesterol biosynthesis inhibition, which selectively inhibits mammalian epoxidase. The present inventors have found compounds having activity and have led to the present invention.
発明の開示 Disclosure of the invention
本発明は一般 The invention is general
(式中、 R 'は低級アルキ ル基ま たは低級アルケニル基を示 し、 R 2は水素原子、 低級ア ルキル基または低級アルコ キ シ基を示し、 R 3は 1 ~ 4 個のへテロ原子を有 する複素環基で置換された フ ュ ニル基またはチェ二ル基を示す） で表される置換 ジベ ン ジルァ ミ ン誘導体またはその塩、 該誘導体を有効成分とする高脂血症、 高 コ レス テ ロ ール血症または動脈硬化症の予防または治療剤、 更に、 該誘導体を用 いた高脂血症、 高コ レ ステ ロ一ル血症または動脈硬化症の治療方法に関する。 一般式 [ I ] において、 R 'および R 2で示される低級ア ルキ ル基と しては、 例 えばメ チ ル基、 ェ チ ル基、 n—プ ロ ビル基、 イ ソ プロ ビル基、 シ ク ロ ブ 口 ビル基、 π—ブチル基、 t e r t—プチル基等が、 R 'で示される低級アルケニル基と しては、 例えばァ リ ル基、 ク ロ チル -等が、 R 2で示される低級ア ルコ キ シ基-と しては、 例 えばメ ト キ シ 、 エ ト ヰ シ ¾等があげられる。 R 3におけるヘテロ原子と しては窒 紫原子、 酸紫原子および硫¾原子があげられ、 ^索 ¾ と しては、 例えばチェ二 ル 、 ビ口 リ ル基、 フ リ ル S、 ォ キサ ゾ リ ル基、 ィ ソ 才 キサ ゾ リ ル基、 チ ァ ゾ リ ル基、 イ ソ チ ア ゾ リ ル S、 ィ ミ ダゾ リ ル · 、 ビラ ゾ リ ル ト リ ァ ゾ リ ル¾£、 テ ト ラ ゾ リ ル基、 チ ア ジア ゾ リ ル基、 ビ リ ジル^、 ビ リ ダ ジ ニル基、 ビ リ ミ ジニ ル 基、 ビ ラ ジ ニ ル基、 ビ ロ リ ジニル ¾ζ、 ビペ リ ジル s、 モ ルホ リ ニ ル^、 ビペ ラ ジ
ニル基などがあげられ、 これらの 1 ~ 2 個力 フ ヱ ニル基またはチェニル基の置 換可能な位置に置換 していて もよい。 (In the formula, R ′ represents a lower alkyl group or a lower alkenyl group, R 2 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R 3 represents 1-4 heteroatoms. Represents a phenyl or phenyl group substituted with a heterocyclic group having an atom) or a salt thereof, or a hyperlipidemia containing the derivative as an active ingredient; The present invention relates to an agent for preventing or treating hypercholesterolemia or arteriosclerosis, and a method for treating hyperlipidemia, hypercholesterolemia or arteriosclerosis using the derivative. In the general formula [I], examples of the lower alkyl group represented by R ′ and R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Shi click b blanking port building group, .pi.-butyl group, tert- heptyl group and the like, is a lower alkenyl group represented by R ', for example, § Li group, click b chill - etc., represented by R 2 Examples of the lower alkoxy group include methoxy, ethoxy, and the like. Hetero atoms in R 3 include a nitrogen atom, an acid purple atom, and a sulfur atom. Examples of a ^ line include, for example, phenyl, biaryl group, furyl S, and oxalate. Zolyl group, isoxazole group, thiazolyl group, thiazolyl group, isothiazolyl S, imidazolyl, virazolyl triazole Tetrazolyl group, thiaziazolyl group, biridyl ^, biridazinyl group, bilimidinyl group, virazinyl group, vilolizinyl ¾ζ, bipe Rizil s, Morpholinil ^, Biperadi And one or two of these groups may be substituted at a replaceable position of the phenyl group or the phenyl group.
本発明の置換ジベ ン ジルア ミ ン誘導体は酸付加塩とする こ とができ る力 、 例え ば塩酸、 臭化水素酸、 ヨ ウ化水素酸、 硝酸、 硫酸、 リ ン酸等との鉱酸塩、 あるい は、 酢酸、 マ レイ ン酸、 ク ェ ン酸、 シユ ウ酸、 リ ンゴ酸、 メ タ ン ス ルホ ン酸、 p - ト ルヱ ン ス ルホ ン 等との有機酸塩等があげられる。 The substituted dibenzyldiamine derivative of the present invention can be converted into an acid addition salt, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts, or organic acid salts with acetic acid, maleic acid, citric acid, oxalic acid, linoleic acid, methansulphonic acid, p-transylsulfonate, etc. Is raised.
本発明の化合物は、 例えば下記の製法 A、 B、 Cおよび Dのいずれかの方法に よ り得る こ とができ る。 The compound of the present invention can be obtained, for example, by any of the following production methods A, B, C and D.
製法 A
Formula A
[I I] [I I I] [I I] [I I I]
製法 BFormula B
[IV] [V] [IV] [V]
ノ
製法 C No Manufacturing method C
これらのアルキル化反応は、 いずれの ¾合においても反応に ¾ を及ぼさない 溶媒が用いられる。 例えばェ チ ルエーテ ル、 テ ト ラ ヒ ド ロ フ ラ ン、 ジォ キサ ン等 のエ ー テ ル系溶 ¾ ベ ンゼ ン、 ト ルエ ン等の芳香族炭化水 -系溶媒、 ア セ ト ン、 ァセ ト ニ ト リ ジ メ チ ノレホ ノレム ア ミ ド、 ジ メ チ ノレ ス ホ キ ン ド等の ) £プロ ト ン 性極性溶媒、 メ タ ノ ー ル、 エ タ ノ ール、 イ ソ プロ パノ ール等のア ル コ ー ル系溶媒、
ジ ク ロ ロ メ タ ン、 ク ロ ロ ホ ルム等のハ 口 ゲ ン化炭化水素系溶媒などの各溶媒が用 い られ、 単一溶媒も し く はこ れら の混台溶媒が使用できる。 In these alkylation reactions, a solvent that does not affect the reaction in any case is used. For example, ether solvents such as ethyl ether, tetrahydrofuran, dioxane, etc., aromatic hydrocarbons such as benzene, toluene, etc. , Acetonitrile methyl meth oleno lem amide, di meth oleno s le f nd) £ proton polar solvent, methanol, ethanol, iso Alcohol solvents such as propanol, Various solvents such as halogenated hydrocarbon solvents such as dichloromethane and chloroform are used, and a single solvent or a mixture of these solvents can be used. .
こ の際に採用される反応条件と しては、 それぞれの化合物をほぼ等モルで反応 させる力 いずれかを小過剰から 5倍モ ル量用いて実施する こ とがで き、 反応温 度は一般に— 2 0 °Cから 1 0 0 °Cまで、 好ま し く は 0 °Cから 4 0てまでであり、 反応時間は通常 5分間から 5 日間、 好ま し く は 1 時間から 2 4時間である。 In this case, the reaction conditions used may be a force that causes the respective compounds to react in approximately equimolar amounts, either from a small excess to 5 times the molar amount, and the reaction temperature may be adjusted. Generally — from 20 ° C to 100 ° C, preferably from 0 ° C to 40 ° C, and reaction times are usually from 5 minutes to 5 days, preferably from 1 hour to 24 hours. is there.
これらアルキル化反応は、 塩基の存在下実施する ことが好ま し く、 用いる塩基 と しては、 例えば水素化ナ ト リ ゥムゃ水素化リチ ウ ム等の水素化アル力 リ金属類、 水酸化ナ ト リ ゥ ムゃ水酸化力 リ ゥ ム等の水酸化ァ ルカ リ金属類、 炭酸ナ ト リ ウ ム や炭酸カ リ ウ ム等の炭酸ア ルカ リ金属類、 ト リ ェチルァ ミ ンやピリ ジ ン等の有機 ァ ミ ン類等があげられる。 These alkylation reactions are preferably carried out in the presence of a base. Examples of the base used include alkali metal hydrides such as sodium hydride and lithium hydride, and water. Alkali metal hydroxides such as sodium oxide and hydroxylating power, alkaline metal carbonates such as sodium carbonate and potassium carbonate, triethylamine and the like. Organic amines such as pyridine are exemplified.
上記の工程で得られる本発明の化合物は、 例えば力 ラ ム ク ロ マ ト グラ フ ィ ー、 溶媒抽出法、 沈殿法および再結晶法を適宜組み合わせる こ と によつて単離精製す る こ と がで き る。 The compound of the present invention obtained in the above step may be isolated and purified by appropriately combining, for example, electrochromatography, solvent extraction, precipitation, and recrystallization. I can do it.
尚、 Zで示されるハ ロ ゲン原子と しては、 例えば塩素原子、 臭素原子、 ヨ ウ素 原子があげられ、 有機ス ルホ ニルォ キ シ基と しては、 メ タ ン ス ルホ ニルォキ シ基 や p — ト ルエ ン ス ルホ ニルォ牛シ基等があげられる。 Examples of the halogen atom represented by Z include a chlorine atom, a bromine atom, and an iodine atom, and the organic sulfonyloxy group includes a methansulfonyloxy group. And p-toluenesulfonyl-ox group.
本発明の一般式 [ I ] で示される化合物は、 哺乳動物のス ク ワ レ ンヱポキシダ 一ゼを阻害する こ と に よ っ て コ レ ス テ ロ一ルの生合成を抑制する働き を有し、 高 脂血症、 高コ レ ス テ D—ル血症、 動脈硬化症の予防および治療に有用な化合物で あ る。 The compound represented by the general formula [I] of the present invention has a function of inhibiting squalene dipoxidase in mammals and thereby suppressing cholesterol biosynthesis. It is a useful compound for the prevention and treatment of hyperlipidemia, hypercholesterol D-leukemia, and arteriosclerosis.
薬理試験例 Pharmacological test example
[培養細胞におけるコ レス テ ロ一ル生台成阻害作用] [Cholesterol growth inhibition in cultured cells]
ヒ ュ ー マ ン · へノ、。 ト ブラ ス ト ーマ （Human Hepa tobl as tonia (Hep G2) ) 細胞を 1 0 c m 2シ ャ ー レ にて 5 %炭酸ガス存在下で単層になるまで培養する。 試験化台物 の ジ メ チ ル ス ルホキ シ ド溶液を添加し （終濃度 1 M ) 、 1 時間後 C —酢酸ナ ト リ ウ ム （ 1 ^ C i ,- m I ) を加え更に 2時間培養する。 培養終了後、 培養液を 吸引除去後氷冷し、 細胞を冷ダルベ ッ コ · リ ン酸緩衝液 （Dulbecco' s Phosphate
Buffer Saline) (一） で洗浄する。 1 m 1 の 1 5 %水酸化カ リ ウ ム にて細胞を 溶解し、 一部を蛋白定量用に供試し、 他は抽出用検体とする。 Human Heno. Incubate tomato toma (Human Hepa tobl as tonia (Hep G2)) cells in a 10 cm 2 dish in the presence of 5% CO 2 until a monolayer is formed. Add the dimethyl sulfonide solution of the test platform (final concentration 1 M), and 1 hour later add sodium C-acetate (1 ^ Ci, -mI) for another 2 hours Incubate. After completion of the culture, the culture solution is removed by aspiration, cooled on ice, and the cells are cooled in a cold Dulbecco's Phosphate buffer. Buffer Saline) (1). Lyse the cells with 1 ml of 15% potassium hydroxide, use a portion for protein quantification, and use the other sample for extraction.
抽出用検体に 1 5 %水酸化力 リ ウム ー エ タ ノ ールを加え、 7 5 °Cで 1 時間ケ ン 化処理後、 水 1 m 1 を加えて非ゲ ン化物を石油ヱ一テル 2 m 1 で 2回抽出する。 得られた石油ヱ一テル抽出液を水 1 m 1 で洗浄し、 硫酸マ グネ シ ゥ ムで脱水後、 窒素気流下濃縮乾固する。 少量のク ロ口ホ ルム にて濃縮物を溶解し、 プ レコー ト • シ リ カ ゲル （ Precoated S i 1 i c age 1 ) T L Cに ス ポ ッ 卜 し、 へキサ ン 一 エーテ ル 一酢酸 （ 8 5 ： 1 5 ： 4 ) で展開する。 T L C上のコ レ ス テ ロ ールをヨ ウ素蒸気 にて検出し該当部分を切り取る。 該 T L C片を ト ルエ ン系シ ンチ レ一ターに浸し- 液体シ ンチ レー シ ョ ン カ ウ ン タ ー にて放射活性を測定する。 To the sample for extraction, add 15% hydroxylated lithium-ethanol and after saponification at 75 ° C for 1 hour, add 1 ml of water to remove non-genated petroleum ether. Extract twice with 2 ml. The obtained petroleum ether extract is washed with 1 ml of water, dehydrated with magnesium sulfate, and concentrated to dryness under a stream of nitrogen. Dissolve the concentrate with a small amount of black mouth, and then spot it on precoated silica gel (Precoated Silicon Gel 1) TLC. 5: 15: 4) Detect cholesterol on TLC with iodine vapor and cut off the relevant part. The TLC piece is immersed in a toluene scintillator, and the radioactivity is measured using a liquid scintillation counter.
尚、 結果は ジ ャ ーナ ル ' ォ ブ ' ノ、'ィ ォ ロ ジカ ルケ ミ ス ト リ ー第 1 9 3巻、 2 6 5頁 （ 1 9 5 1 年） に記載の方法により測定した蛋白量で補正する。 これにより . 本発明の化合物の H e p G 2培養細胞におけるコ レ ス テ ロ一ル生合成阻害活性を 求め、 その結果を表 1 に示す。 The results were measured according to the method described in Journal of Natural Chemistry, Vol. 193, pp. 265 (1951). Correct for protein content. From this, the cholesterol biosynthesis inhibitory activity of the compound of the present invention in HepG2 cultured cells was determined. The results are shown in Table 1.
表 1 培養細胞における コ レ ステロ ール生合成阻害作用 Table 1 Inhibition of cholesterol biosynthesis in cultured cells
[試験化合物] [コ レステロール生合成阻害] 実施例 1 の化合物 （塩酸塩） 9 4. 3 % [Test compound] [Cholesterol biosynthesis inhibition] Compound of Example 1 (hydrochloride) 94.3%
実施例 2 の化台物 （塩酸塩） 9 3. 4 % Compound of Example 2 (hydrochloride) 93.4%
実施例 3 の化合物 （塩酸塩） 8 8. 7 % Compound of Example 3 (hydrochloride) 88.7%
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
実施例 Example
以下に実施例を挙げて本発明を更に具体的に説明する。 尚、 'Η— N M R ス ぺ ク ト ルは、 重ク ロ 口 ホ ルム （ C D C 1 3 ) または d 6— ジメ チ ルス ルホキ シ ド （ D M S 0 - d 6) 溶液でテ ト ラ メ チ ル シ ラ ン （ T M S ) を内部標準と して使用し、 J M— E X 2 7 0型ス ペ ク ト ル メ ー タ ー （ 2 7 0 M H z、 日本電子株式会社製） で
測定し、 < 値は p p mで示した。 Hereinafter, the present invention will be described more specifically with reference to examples. Incidentally, '.eta. NMR scan Bae click DOO Le is heavy click B port E Lum (CDC 1 3) or d 6 - dimethyl Chi pulse Ruhoki Shi de (DMS 0 - d 6) solution in Te preparative ra Ji Le Shi Using a run (TMS) as an internal standard, a JM-EX270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.) Measured and <values are given in ppm.
マ ス ス ぺ ク ト ルは Q P 1 0 0 0 E X型ス ぺ ク ト ルメ ー タ ー （島津製作所製） で 測定した。 融点は未補正であり、 微量融点測定器 （柳本製作所製） で測定した。 実施例 1 The mass spectrum was measured with a QP1000EX X-type spectrum meter (manufactured by Shimadzu Corporation). Melting points are uncorrected and were measured with a micro melting point analyzer (Yanagimoto Seisakusho). Example 1
N_[4— (tert—ブチ ノレ） ベ ン ジル]一 N—ェチ ル—3— —( 3—チ ェ 二 ノレ）— 2—チ ェニ ル メ チ ノレ ォ キ シ]ベ ン ジルァ ミ ン N_ [4— (tert-butyl) benzyl] -1-N—ethyl—3 —— (3-chloro-2) —2—phenyl methyl benzoylamine N
( 1 ) N— [4-(tert-ブチノレ） ベ ン ジノレ ] ェチル— 3-ヒ ド ロ キ シベ ン ジルァ ミ ン 1. 7g、 および炭酸カ リ ウ ム 4. lgの ジ メ チルホ ルム ア ミ ド懸濁溶液（20ml)に、 氷冷下 で 2-ブ ロ モ メ チ ル -4-(3-チ ェ ニ ル）チ ォ フ ェ ン 1.7gの ジ メ チ ノレ ホ ノレムア ミ ド溶液 (10ml)を滴下し、 更に室温で終夜攪拌後、 水 ΙΟΟπιΙと酢酸ヱ チ ル 150mlを加えて抽 出する。 有機層を分取後、 飽和食塩水で洗浄し、 無水硫酸マ グネ シ ウ ムで乾燥後、 溶媒を留去する。 残渣をシ リ カ ゲルカ ラ ム ク ロ マ ト グラ フ ィ ー （ n—へキサ ン ： 酢酸ヱ チル = 30 : 1) によ り分離精製を行って、 無色油状の N- [4- (terいプチル） ベ ン ジル] ェ チ ノレ一 3-[4-(3—チ ェ 二ル）一 2—チ ェニノレ メ チ ノレオ キ シ ]ペ ン ジノレア ミ ン 1.6g (収率 ： 65% ) が得られる。 (1) N— [4- (tert-butynole) benzinole] ethyl—1.7 g of 3-hydroxybenzilamine and potassium carbonate 4.lg of dimethylformamide To a 20 mL suspension solution, add 1.7 g of 2-bromo-4- (3-phenyl) thiophene amide under ice-cooling. 10 ml), and after stirring at room temperature overnight, water (ππΙ) and 150 ml of methyl acetate are added and extracted. The organic layer is separated, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel chromatography (n-hexane: ethyl acetate = 30: 1) to give a colorless oily N- [4- (ter 1.6g (Yield: 65%) of 3- [4- (3-Chenyl) 1-2-Chenynolemethinoleoxy] pentinoleamine can get.
MS( /Z) ： 475 ( +). 60, 325, 295, 179 MS (/ Z): 475 ( + ). 60, 325, 295, 179
'H -画（CDC") δ ： 1.06(311. t. J = 6.9Hz), 1.30(9H. s), 2.50(2H, q. J = 6.9ΙΙζ), 3.54 (4H, s).5.22 (2H. s) .6.84-7.35 ( 1311, m) 'H-picture (CDC ") δ: 1.06 (311. t. J = 6.9Hz), 1.30 (9H.s), 2.50 (2H, q. J = 6.9ΙΙζ), 3.54 (4H, s) .5.22 ( 2H.s) .6.84-7.35 (1311, m)
( 2 ) 上記化合物 1.4gをヱタ ノ ー ル 5nilに懸 ¾1させ、 氷冷下で 塩酸を 300 1加え て 袢した ί &、 溶 ½を留去して酢酸ェチルー η—ペ ン タ ンから再結晶すると無色 粉末状の λに [4- (ter ブチ ル） ベ ン ジル]- N -ェ チ ル -3- - (3-チ ェ 二 ル 〉 - 2-チ ェ 二 ノレ メ チ ルォ キ ン ]ベ ン ジルァ ミ ン塩酸塩 1.4 gが得られる。 (2) 1.4 g of the above compound was suspended in 5 nil of ethanol, and 300 l of hydrochloric acid was added thereto under ice cooling. The solution was distilled off, and the solvent was distilled off to remove ethyl acetate-η-pentane. When recrystallized, [4- (terbutyl) benzyl] -N-ethyl-3-(3-chloro)-2-chloro-2-methylene is obtained as a colorless powdery λ. 1.4 g of benzylamine hydrochloride are obtained.
m. p. ： 165 ~ 167 °C
'H-NMR(DMSO-d6) δ ： 1.24- 1.30 ( 3 H, br m).1.29(9H, s), 2.92-2.99 ( 2H, br m).4. 21-4.29(4H, br s), 5. Λ4(2Η, s), 7.08-7.16 and 7.35-7.75 ( 13 H, m) mp: 165 to 167 ° C 'H-NMR (DMSO-d 6 ) δ: 1.24- 1.30 (3 H, br m) 1.29 (9H, s), 2.92-2.99 (2H, br m). 4.21-4.29 (4H, br s ), 5. Λ 4 (2Η, s), 7.08-7.16 and 7.35-7.75 (13 H, m)
上記実施例 1 の N- [4-(terいプチル）ベ ン ジル]- N-ェチ ル- 3-ヒ ド ロ キ シベ ン ジル ァ ミ ンに代えて対応する各種の 3-ヒ ド ロ キ シベ ン ジルア ミ ン誘導体を、 2-ブロ モ メ チ ル -4- (3-チ ェ ニ ル）チ オ フ ュ ンに代えて対応する各種 3-ヘテ ロ環置換べン ジル ハラ イ ドまたはス ルホネー ト体を用いて同様の反応を行い、 実施例 2 ~ 1 2 の化 合物およびその塩を得る こ とができ る。 N- [4- (tert-butyl) benzyl] -N-ethyl-3-hydroxybenzilamine of Example 1 above was replaced with various corresponding 3-hydroxy. Various 3-heterocyclic-substituted benzyl halides that substitute xylenebenzilamin derivatives for 2-bromomethyl-4- (3-phenyl) thiophene Alternatively, the same reaction is carried out using a sulfonate form to obtain the compounds of Examples 2 to 12 and salts thereof.
実施例 2 Example 2
MS( /Z) ： 461 ( +).283.176, 147 MS (/ Z): 461 ( + ). 283.176, 147
'H-NMR(CDC13) δ ： 1.31 ( 9Η, s) .2.18 ( 3 Η , s) , 3.50 ( 4Η, s) .5.23 ( 2 H, s ) , 6.87 -7.35 (13H, m) 'H-NMR (CDC1 3) δ: 1.31 (9Η, s) .2.18 (3 Η, s), 3.50 (4Η, s) .5.23 (2 H, s), 6.87 -7.35 (13H, m)
( 2 ) その塩酸塩 (2) its hydrochloride
m. p. ： 11卜 113。C m. p .: 11 113 113. C
'H-NMR(DMSO-de) <5 ： 1.29 ( 9 H, s) , .08-4.46 ( 7H, s ) , 5.34 ( 211, s) .6.85- 7.78 ( 13 II . m) 'H-NMR (DMSO-d e ) <5: 1.29 (9H, s), .08-4.46 (7H, s), 5.34 (211, s) .6.85- 7.78 (13II.m)
実施例 3 Example 3
MS(M/Z) ： 489 (M + ), 461.309, 179, 147 MS (M / Z): 489 (M + ), 461.309, 179, 147
'H-NMR(CDC13) δ ： 0.86 (3Η. t ) , 1.30 ( 9Η, s) , 1.55 ( 2Η, sex, J = 7.3ΙΙζ) , 2.38 ( 2Η, t , J = 7.6Hz).3.52(2Η, s), 3.53(2Η, s), 5.22(2Η, s), 6.83 -7.36 ( 13H.ra) 'H-NMR (CDC1 3) δ: 0.86 (. 3Η t), 1.30 (9Η, s), 1.55 (2Η, sex, J = 7.3ΙΙζ), 2.38 (2Η, t, J = 7.6Hz) .3.52 ( 2Η, s), 3.53 (2Η, s), 5.22 (2Η, s), 6.83 -7.36 (13H.ra)
( 2 ) その塩酸塩 (2) its hydrochloride
m. p. ： 68 ~ 73 °C m. p .: 68 to 73 ° C
'H-N R(DMSO-d6) <5 : 0.77 (3H, t, J = 6.2Hz) , 1.28 (9H, s) , 1.68-1.79 ( 2H, br s), 2. 77-2.89(2H, br ra). .27 (4H, br s), 5.34(2H, s), 7.12-7.77(13H,m) 'HN R (DMSO-d 6 ) <5: 0.77 (3H, t, J = 6.2Hz), 1.28 (9H, s), 1.68-1.79 (2H, br s), 2. 77-2.89 (2H, br ra). .27 (4H, br s), 5.34 (2H, s), 7.12-7.77 (13H, m)
実施例 4 Example 4
( 1 ) N— [4— (tert—ブチ ノレ） ベ ン ジル] -N—シ ク ロ プロ ピル— 3— [4— (3 チ ェ二 ノレ）— 2 チ ェ ニ ノレ メ チ ノレオ キ シ ]ペ ン ジノレア ミ ン (1) N— [4— (tert—butyl) benzyl] -N—cyclopropyl—3— [4— (3 ェ 2 二) —2 2 ] Penzinorea Min
MS(M/Z) ： 487 ( +), 340, 308.202, 179, 147 MS (M / Z): 487 ( + ), 340, 308.202, 179, 147
'H -匪（CDC") δ ： 0.29-0.45 (4H, m).1.31(911, s), 1.84-1.78 (1H, m), 3.65( H, s), 5.22(2H. s), 6.87-7.36 ( 13 H, m) 'H-Marauder (CDC ") δ: 0.29-0.45 (4H, m) .1.31 (911, s), 1.84-1.78 (1H, m), 3.65 (H, s), 5.22 (2H.s), 6.87 -7.36 (13 H, m)
( 2 ) その塩酸塩 (2) its hydrochloride
m. p. ： 168〜 m。C m. p .: 168-m. C
'H- MR(DMSO-de) <5 ： 0.49-0.65 (411, br m), 1.30 (911, s).4.23-4.47 (511. m).5.33 (211. s), 7.11-7.77(13!!. m)
実施例 5 'H-MR (DMSO-de) <5: 0.49-0.65 (411, br m), 1.30 (911, s) .4.23-4.47 (511.m) .5.33 (211.s), 7.11-7.77 (13 !!. m) Example 5
( 1 ) N-[4- (tert-ブチ ル）ベ ン ジル] -N-ァ リ ール- 3- [4- (3-チ ェ 二ル）- 2-チ ェ ニル メ チ ルォキ シ ]ベ ン ジルァ ミ ン (1) N- [4- (tert-butyl) benzyl] -N-aryl-3- [4- (3-chloro) -2-phenylmethyloxy] Benjilamin
MS(M/Z) ： 487 (M+), 307, 179, 147 MS (M / Z): 487 (M + ), 307, 179, 147
'Η-匪（CDC13) δ ： 1.31 (9Η, s) , 3.06(2H, d, J = 6.3Hz), 3.55(4H, s), 5.11-5.24(2Η, ra), 5.22(2Η, s), 5.90(lH,ddt, J = 17.1.10.2, 6.3Ηζ), 6.87 -7.36 ( 13H,m) '.Eta. negation (CDC1 3) δ: 1.31 ( 9Η, s), 3.06 (2H, d, J = 6.3Hz), 3.55 (4H, s), 5.11-5.24 (2Η, ra), 5.22 (2Η, s ), 5.90 (lH, ddt, J = 17.1.10.2, 6.3Ηζ), 6.87 -7.36 (13H, m)
( 2 ) その塩酸塩 (2) its hydrochloride
ra. p. ： 80~ 84°C ra. p .: 80 ~ 84 ° C
lH-NMR(D SO-de) <5 ： 1.28(9H, s), 3.59(2Ii, br s).4.22(411, br s).5.33 (2H. s) , 5. 51 (2H. m).5.99-6.17(1H. br m).6.87-7.77(13H, s) lH-NMR (D SO-de) <5: 1.28 (9H, s), 3.59 (2Ii, br s) .4.22 (411, br s) .5.33 (2H.s), 5.51 (2H.m) .5.99-6.17 (1H.br m) .6.87-7.77 (13H, s)
実施例 6 Example 6
( 1 ) N— [4 - (sec プロ ピル）ベ ン ジル] -N—ェチ 3- [4— (3 チ ェ 二 2—チ ェ 二 メ チ ルォキ シ ]ベ ン ジルァ ミ ン (1) N— [4- (sec propyl) benzyl] -N—ethyl 3- [4— (3 2- 二 2-methyloxy) benzylamine
MS(M/Z) ： 461 (M + ).281.179, 133 MS (M / Z): 461 (M + ). 281.179, 133
'II-NMR(C C1,) δ ： 1.06(311. t, J = 7. ΙΙΙζ), 1.23(611. d, J = 6.9ilz).2.49(211, q, J = 7.1 Hz).2.87(111. hep, J = 6.9IIz).3.54(411, s).5.22(211. s).6.84- 7.36 ( 1311. m) 'II-NMR (C C1,) δ: 1.06 (311.t, J = 7.ΙΙΙζ), 1.23 (611.d, J = 6.9ilz) 2.49 (211, q, J = 7.1 Hz) 2.87 ( 111.hep, J = 6.9IIz) .3.54 (411, s) .5.22 (211.s) .6.84- 7.36 (1311.m)
( 2 ) その塩酸塩 (2) its hydrochloride
m. p. ： 67 ~ 73 °C
!H-NMR (DMS0-d6) δ ： 1. 19 -1. 30 ( 9 H, s ) , 2.86 -3. 06 ( 3 H , m ) , 4. 2 ( H . br s), 5. 33 (2H, s) , 6. 87-7. 75 (13H, m) mp: 67 to 73 ° C ! H-NMR (DMS0-d 6) δ:.. 1. 19 -1 30 (9 H, s), 2.86 -3 06 (3 H, m), 4. 2 (. H br s), 5. 33 (2H, s), 6.87-7.75 (13H, m)
実施例 7 Example 7
N— [4— (tert ブチ ル）ベ ン ジル] -N-ェ チ ル—3— [3— (3-チ ェ 二 ノレ）ペ ン ジノレオキ シ ]ベ ン ジルア ミ ン N— [4— (tert-butyl) benzyl] -N-ethyl—3— [3- (3-Chenanol) penzinoreoxy] benzylamine
iMS(M/Z) ： 469 ( +), 454, 190, 173, 147 iMS (M / Z): 469 ( + ), 454, 190, 173, 147
'H-NMRiCDCl 3) <5 ： 1.06 (3H, t , J = 7. 2Ηζ) , 1. 30 (9H, S) , 2.49 ( 2H, q, J = 7. 2Hz) ,.3. 54 (4H, s). 5. 25 (2H. s). 6. 82-7.77 (15H, m) 'H-NMRiCDCl 3 ) <5: 1.06 (3H, t, J = 7.2Ηζ), 1.30 (9H, S), 2.49 (2H, q, J = 7.2Hz), 3.5.54 (4H , s) .5.25 (2H.s) .6.82-7.77 (15H, m)
実施例 8 Example 8
N - [4-(ter卜ブチ ル）ベ ン ジル] -N-ァ リ ール -3- [3- (3-チ ェ ニ ル〉ベ ン ジルォ キ シ ] ペ ン ジ ノレア ミ ン N- [4- (tert-butyl) benzyl] -N-aryl-3- [3- (3-phenyl> benzyloxy) pentinoreamin
MS(M/Z) ： 481 (M + ). 308, 202. 173. 147 MS (M / Z): 481 (M +). 308, 202. 173. 147
'il-N R(CDC ) δ ： 1. 30 (911. S) , 3. 05 (211, q. J = 6. 3ΙΙζ), 3.54 (411. s). 5. 11 (2I!, s) , 5. 15-5. 30 (211. m). 5. 79-5.98 ( 111, in) , 6. 85 - 7. 57 ( 1511, m)
実施例 9 'il-N R (CDC) δ: 1.30 (911.S), 3.05 (211, q.J = 6.3ΙΙζ), 3.54 (411.s). 5.11 (2I !, s) , 5.15-5. 30 (211.m) .5.79-5.98 (111, in), 6.85-7.57 (1511, m) Example 9
N - _(sec-プ口 ピル）ベ ン ジル]- N-ェ チ ル- 3- [3- (3-チ ェ ニル）ベ ン ジルォ キ シ] ベ ン ジルァ ミ ン N-_ (sec-pip pill) benzyl]-N-ethyl-3- [3- (3-phenyl) benzyloxy] benzylamine
MS( /Z) ： 455 ( +), 40, 176, 173, 133 MS (/ Z): 455 ( + ), 40, 176, 173, 133
'H-NMR(CDC13) δ 1.05 ( 3 H, t . J = 7.1Hz) , 1.23 ( 6 H. d, J = 7. ΟΗζ ) , 2. 9 ( 2Η , q, J = 7.1 Hz).2.88(1H, hep. J = 7.0Hz) , 3.54 (4H. s) , 5.10 (2H, s) , 6.84-7.68 (15H, in) 'H-NMR (CDC1 3) δ 1.05 (3 H, t. J = 7.1Hz), 1.23 (6 H. d, J = 7. ΟΗζ), 2. 9 (2Η, q, J = 7.1 Hz). 2.88 (1H, hep.J = 7.0Hz), 3.54 (4H.s), 5.10 (2H, s), 6.84-7.68 (15H, in)
実施例 1 0 Example 10
MS(M/Z) ： 452 (M+). 37.305, 190.156, 147 MS (M / Z): 452 (M + ). 37.305, 190.156, 147
'H-麵（CDC1J δ 1.06 (3Η, t, J = 7.2Hz), 1.30(9H, S).2.49 (2H, q, J = 7.2Hz), 3.54 (4H. s), 5.11 (2H, s) , 6.35(211, dd. J = 2.3, 2. OHz), 6.86-7.46 ( 1411, m) 'H- 麵 (CDC1J δ 1.06 (3Η, t, J = 7.2Hz), 1.30 (9H, S) 2.49 (2H, q, J = 7.2Hz), 3.54 (4H.s), 5.11 (2H, s ), 6.35 (211, dd.J = 2.3, 2.OHz), 6.86-7.46 (1411, m)
実施例 1 1 Example 1 1
S(M/Z) ： 440(M+), 383, 265, 176, 158, 147 S (M / Z): 440 (M + ), 383, 265, 176, 158, 147
'H-NMR(CDC1 ,) δ 1.31 (9Η, S) , 2.19 ( 3Η, s) , 3.50 (4Η, s) , 5.12 (2Η, s) , 6.89-7.76 (13H. m), 7.92(1H, s) 'H-NMR (CDC1,) δ 1.31 (9Η, S), 2.19 (3Η, s), 3.50 (4Η, s), 5.12 (2Η, s), 6.89-7.76 (13H.m), 7.92 (1H, s)
実施例 1 2 Example 1 2
N-[4— (tert-ブチ ル）ベ ン ジル] -N-シク 口 プロ ビル— 3- [3- (5-ォキサ ゾ リ ノレ）ベ ン ジノレオ キ シ ]ペ ン ジノレア ミ ンN- [4 -— (tert-butyl) benzyl] -N-cyclopropyl- 3- [3- (5-oxazolinole) benzinoreoxy] penzinoleamine
S(M/Z) ： 466 (,M + ), 319.202.158, 147 S (M / Z): 466 (, M + ), 319.202.158, 147
'H-NMR(CDC ) δ ： 0.34-0.43 (4Η, m) , 1.31 ( 9Η. S) , 1.76-1.88 ( 1Η. m) , 3.64 ( 4Η. s) . 5.11 (ZH, s).6.86-7.75 ( 13H, m), 7.93 (1H. s) 'H-NMR (CDC) δ: 0.34-0.43 (4Η, m), 1.31 (9Η.S), 1.76-1.88 (1Η.m), 3.64 (4Η.s) .5.11 (ZH, s) .6.86- 7.75 (13H, m), 7.93 (1H.s)
産業上の利用可能性 Industrial applicability
本発明化合物は、 優れたコ レス テ ロー ル生合成阻害活性を有している ことから. コ レス テ ロ ール過剰に起因する種々の疾患例えば、 高脂血症、 高コ レ ス テ ロ ール 血症または動脈硬化症などの予防および治療に対して有効な化合物であり、 予防 または治療剤と して使用する場合、 その投与量および投与回数は患者の性別、 年 齢、 体重、 症状の程度などにより異なるが、 一般に経口投与の場台、 成人一日あ たり 0. 0 1 から 2 0 01 3 1^ を 1 から数回に分けて、 また非経口投与の場合 は 0. 0 0 1 から 2 m k gを 1 から数回に分けて投与する のが好ま しい。
The compound of the present invention has excellent cholesterol biosynthesis inhibitory activity. Various diseases caused by excess cholesterol, for example, hyperlipidemia, high cholesterol A compound that is effective for the prevention and treatment of blood bleeding or arteriosclerosis.When used as a prophylactic or therapeutic agent, the dosage and frequency of administration depend on the patient's sex, age, weight, and symptoms. In general, oral administration is performed on a platform, from 0.01 to 200 1 3 1 ^ per adult per day, divided into 1 to several times, and in the case of parenteral administration, 0.00 It is preferable to administer 1 to 2 mkg in 1 to several divided doses.
Claims
1 . 一般式 [ I ] 1. General formula [I]
(式中、 R 'は低級アルキル基または低級アルケ ニ ル基を示し、 R 2は水素原子、 低級ア ルキ ル基または低級ア ルコ キ シ基を示し、 R 3は 1 ~ 4個のへテ ロ原子を有 する複素環基で置換されたフ ヱニル基またはチヱ二ル基を示す） で表される置換 ジベ ン ジルァ ミ ン誘導体またはその塩。 (In the formula, R ′ represents a lower alkyl group or a lower alkyl group, R 2 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R 3 represents 1 to 4 hetero atoms. A phenyl group or a diphenyl group substituted with a heterocyclic group having a hydrogen atom, or a salt thereof.
2 . R 3が 1〜 4個のへテロ原子を有する複素環基で置換されたフ ユ ニ ル基である 請求項 1 記載の置換ジベ ン ジルァ ミ ン誘導体またはその塩。 2. Substituted Jibe down Jirua Mi emissions derivative or its salt according to claim 1, wherein a full Yu two Le group substituted with a heterocyclic group having R 3 is 1-4 pieces heteroatom.
3 . R 3が 1 ~ 4個のへテロ原子を有する複素環基で置換されたチェニ ル基である 請求項 1 記載の置換ジベ ンジルァ ミ ン誘導体またはその塩。 3. The substituted dibenzylamine derivative or a salt thereof according to claim 1, wherein R 3 is a phenyl group substituted with a heterocyclic group having 1 to 4 hetero atoms.
4 . 請求項 1 ないし 3記載の置換ジベ ン ジルァ ミ ン S!導体またはその塩を有効成 分とする高脂血症の予防または治療剤。 4. A preventive or therapeutic agent for hyperlipidemia, comprising the substituted dibenzilamin S! Conductor or the salt thereof according to claims 1 to 3 as an active ingredient.
5 . 請求項 1 ないし 3記鉞の置換ジベ ン ジルァ ミ ン誘導体またはその塩を有効成 分とする高コ レ ス テ ロ ール血症の予防または治療剤。 5. A preventive or therapeutic agent for hypercholesterolemia, which comprises a substituted dibenzilamin derivative of acetane or a salt thereof as an effective component according to claims 1 to 3.
6 . 請求項 1 ないし 3記載の置換ジベ ン ジルア ミ ン誘導体またはその塩を有効成 分とする動脈硬化症の予防または治療剤。 6. A prophylactic or therapeutic agent for arteriosclerosis, comprising the substituted dibenzyldiamine derivative or a salt thereof according to claims 1 to 3 as an active ingredient.
7 . 請求項 1 ないし 3記載の置換ジベ ンジルア ミ ン誘導体またはその塩を用いた 高脂血症、 高コ レ ステロ一ル血症または動脈硬化症の治療方法。
7. A method for treating hyperlipidemia, hypercholesterolemia or arteriosclerosis using the substituted dibenzylamine derivative or a salt thereof according to any one of claims 1 to 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5/36160 | 1993-02-01 | ||
| JP3616093 | 1993-02-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994018167A1 true WO1994018167A1 (en) | 1994-08-18 |
Family
ID=12462021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1994/000132 WO1994018167A1 (en) | 1993-02-01 | 1994-01-31 | Substituted dibenzylamine derivative |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1994018167A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996001253A2 (en) * | 1994-07-01 | 1996-01-18 | Warner-Lambert Company | Pla2 inhibitors and their use for inhibition of intestinal cholesterol absorption |
| US5783593A (en) * | 1993-11-04 | 1998-07-21 | Abbott Laboratories | Inhibitors of squalene synthetase and protein farnesyltransferase |
| JP2016536333A (en) * | 2013-09-04 | 2016-11-24 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Compounds useful as immunomodulators |
| WO2023286713A1 (en) * | 2021-07-14 | 2023-01-19 | 日本曹達株式会社 | Novel polymer, resin composition including same, and molded body thereof |
-
1994
- 1994-01-31 WO PCT/JP1994/000132 patent/WO1994018167A1/en active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| YAKUGAKU ZASSHI, Vol. 111(2), p. 126-137 (1991). * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5783593A (en) * | 1993-11-04 | 1998-07-21 | Abbott Laboratories | Inhibitors of squalene synthetase and protein farnesyltransferase |
| WO1996001253A2 (en) * | 1994-07-01 | 1996-01-18 | Warner-Lambert Company | Pla2 inhibitors and their use for inhibition of intestinal cholesterol absorption |
| WO1996001253A3 (en) * | 1994-07-01 | 1996-07-18 | Warner Lambert Co | PLA2 inhibitors and their use for inhibition of intestinal cholesterol absorption |
| US5968963A (en) * | 1994-07-01 | 1999-10-19 | Warner-Lambert Company | PLA2 inhibitors and their use for inhibition of intestinal cholesterol absorption |
| JP2016536333A (en) * | 2013-09-04 | 2016-11-24 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Compounds useful as immunomodulators |
| WO2023286713A1 (en) * | 2021-07-14 | 2023-01-19 | 日本曹達株式会社 | Novel polymer, resin composition including same, and molded body thereof |
| TWI822177B (en) * | 2021-07-14 | 2023-11-11 | 日商日本曹達股份有限公司 | Novel polymer, resin composition containing the same, and molded article thereof |
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