JPH10182596A - Lipid metabolism improver - Google Patents
Lipid metabolism improverInfo
- Publication number
- JPH10182596A JPH10182596A JP8342822A JP34282296A JPH10182596A JP H10182596 A JPH10182596 A JP H10182596A JP 8342822 A JP8342822 A JP 8342822A JP 34282296 A JP34282296 A JP 34282296A JP H10182596 A JPH10182596 A JP H10182596A
- Authority
- JP
- Japan
- Prior art keywords
- imidazolyl
- group
- lipid metabolism
- compound
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、高脂血症などに代表さ
れる脂質代謝異常を伴う疾患の予防及び／又は治療に有
用な脂質代謝改善剤に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for improving lipid metabolism which is useful for preventing and / or treating diseases accompanied by abnormal lipid metabolism such as hyperlipidemia.
【０００２】[0002]
【従来の技術】高脂血症は、血清脂質のうち主としてコ
レステロール、トリグリセリド、リン脂質、遊離脂肪酸
などが異常に増加した病態を特徴としており、脂質代謝
異常を伴う疾患の代表的な疾患である。高脂血症は動脈
硬化症の発症の危険因子としてもっとも重要であり、血
清コレステロール高値により惹起された動脈硬化症がさ
らに進展すると、虚血性心疾患や脳血管疾患が発症する
可能性がある。従って、脂質代謝改善剤（総コレステロ
ール、 LDLコレステロール、及びトリグリセリドの低下
作用、並びに HDLコレステロール増加作用などを有する
薬剤）を用いて高脂血症を治療・予防し、動脈硬化症や
冠及び脳血管疾患を予防することが重要である。2. Description of the Related Art Hyperlipidemia is characterized by a condition in which cholesterol, triglycerides, phospholipids, free fatty acids and the like among serum lipids are abnormally increased, and is a typical disease accompanied by abnormal lipid metabolism. . Hyperlipidemia is the most important risk factor for the development of arteriosclerosis, and further progression of arteriosclerosis caused by high serum cholesterol may lead to ischemic heart disease and cerebrovascular disease. Therefore, hyperlipidemia is treated and prevented using lipid metabolism improvers (drugs having a total cholesterol, LDL cholesterol and triglyceride lowering action, and an HDL cholesterol increasing action), and arteriosclerosis and coronary and cerebral vascular diseases are prevented. It is important to prevent the disease.
【０００３】最近、カリウムチャンネル開口作用を有す
るシアノグアニジン誘導体である「ピナジジル」の投与
により高血圧患者の総コレステロール、LDL コレステロ
ール、及びトリグリセリドが有意に低下し、HDL コレス
テロールが有意に増加したことが報告された（Drugs, 3
9(6), pp.929-967, 1990) 。また、カリウムチャンネル
開口作用を有するクロマン-3- オール誘導体である「レ
ブクロマカリウム」の投与により、同様の結果が得られ
たことも報告されている（薬理と治療, 22(6),pp.2481-
2870, 1994)。しかしながら、ピナジジルやレブクロマ
カリムの投与により、副作用として頻脈が発生すること
が指摘されている（Drugs, 39(6), pp.929-967, 1990;
薬理と治療, 22(Suppl.7), pp.245-257, 1994)。頻脈
は、患者のクオリティ・オブ・ライフを低下させるばか
りでなく、心機能の悪化を招く恐れがある。[0003] Recently, it has been reported that administration of "pinazidil", a cyanoguanidine derivative having a potassium channel opening effect, significantly reduced total cholesterol, LDL cholesterol, and triglyceride and significantly increased HDL cholesterol in hypertensive patients. (Drugs, 3
9 (6), pp.929-967, 1990). In addition, it has been reported that similar results were obtained by administration of “Rebchroma potassium” which is a chroman-3-ol derivative having a potassium channel opening action (Pharmacology and Therapy, 22 (6), pp. 147-146). 2481-
2870, 1994). However, it has been pointed out that administration of pinazidil or lebucromakalim causes tachycardia as a side effect (Drugs, 39 (6), pp.929-967, 1990;
Pharmacology and Therapy, 22 (Suppl.7), pp.245-257, 1994). Tachycardia not only reduces the patient's quality of life, but can also lead to poor cardiac function.
【０００４】一方、下記の式：On the other hand, the following equation:
【化２】 （式中、R1及びR2はそれぞれ独立して水素原子、C1〜C6
のアルキル基又はC3〜C6のシクロアルキル基を表すか、
あるいはR1及びR2が一緒になってC3〜C6のアルキレン基
を表す。R3は水素原子、C1〜C6のアルキル基又はC3〜C6
のシクロアルキル基を表し、R4はC1〜C6のアルキル基又
はC3〜C6のシクロアルキル基を表すか、あるいはR3及び
R4が一緒になってC2〜C5のアルキレン基を表す。X1、X2
及びX3はそれぞれ独立して水素原子、ハロゲン原子、C1
〜C6のアルキル基、C3〜C6のシクロアルキル基、C1〜C6
のアルコキシ基、トリフルオロメチル基、シアノ基、ニ
トロ基、C2〜C12 のジアルキルアミノ基、スルファモイ
ル基、又は置換基を有していてもよい異項原子として窒
素原子を含有する５員環もしくは６員環複素環基を表
す。ただし、R1が水素原子、R2がn-プロピル基、R3が水
素原子、R4がメチル基を表し、X1、X2及びX3が水素原子
を表す場合並びにR1が水素原子、R2、R3、及びR4がとも
にメチル基を表し、X1、X2及びX3が水素原子を表す場合
を除く）で表されるβ- オキソ- β- ベンゼンプロパン
チオアミド誘導体が知られている（特開平5-246980号公
報）。Embedded image (Wherein R 1 and R 2 are each independently a hydrogen atom, C 1 -C 6
Or represents an alkyl group or a cycloalkyl group of C 3 -C 6,
Alternatively, R 1 and R 2 together represent a C 3 -C 6 alkylene group. R 3 is a hydrogen atom, a C 1 -C 6 alkyl group or C 3 -C 6
It represents a cycloalkyl group, or R 4 represents an alkyl group or a cycloalkyl group of C 3 -C 6 of C 1 -C 6, or R 3 and
R 4 together represent a C 2 -C 5 alkylene group. X 1 , X 2
And X 3 are each independently a hydrogen atom, a halogen atom, C 1
Alkyl group -C 6, cycloalkyl group C 3 ~C 6, C 1 ~C 6
Alkoxy group, a trifluoromethyl group, a cyano group, a nitro group, C 2 -C 12 dialkylamino group, a sulfamoyl group, or a 5-membered ring containing a nitrogen atom as a good diplomatic atoms which may have a substituent Alternatively, it represents a 6-membered heterocyclic group. However, when R 1 is a hydrogen atom, R 2 is an n-propyl group, R 3 is a hydrogen atom, R 4 is a methyl group, and X 1 , X 2 and X 3 represent a hydrogen atom, and R 1 is a hydrogen atom , R 2 , R 3 , and R 4 each represent a methyl group, and X 1 , X 2, and X 3 each represent a hydrogen atom), except that a β-oxo-β-benzenepropanethioamide derivative represented by (JP-A-5-246980).
【０００５】この刊行物には、上記の一般式で示される
β- オキソ- β- ベンゼンプロパンチオアミド誘導体が
カリウムチャンネル開口作用を有し、血管拡張作用、気
管支拡張作用、胃腸管平滑筋弛緩作用などの薬理作用に
より、高血圧、喘息、過敏性腸症候群や腸炎などの治療
に有用であることが開示されている。具体的には、R1=
H; R2=Me; R3=Me; R4=Me; X1=4-シアノ; X2=H; X3=Hの
化合物(No.224)、R1=H;R2=Me; R3=Me; R4=Me; X1=4-(1-
イミダゾリル); X2=H; X3=H の化合物(No.226)、R1=H;
R2=Me; R3=Me; R4=Me; X1=3-(1- イミダゾリル); X2=
H; X3=H の化合物(No.265)、R1=H; R2=Me; R3 及びR4=-
CH2CH2CH2-; X1=4-(1-イミダゾリル); X2=H; X3=H の化
合物(No.356)；及びR1=H; R2=Me; R3 及びR4=-CH2CH2CH
2-; X1=4-(2-メチル-1- イミダゾリル); X2=H; X3=H の
化合物(No.357)について、ラットの胸部大動脈を用いて
20 mMカリウム収縮を30% 抑制する薬物用量(IC30)が開
示されている。In this publication, the β-oxo-β-benzenepropanethioamide derivative represented by the above general formula has a potassium channel opening action, a vasodilator action, a bronchodilator action, a gastrointestinal smooth muscle relaxation action and the like. It is disclosed that its pharmacological action is useful for treating hypertension, asthma, irritable bowel syndrome, enteritis and the like. Specifically, R 1 =
R 2 = Me; R 3 = Me; R 4 = Me; X 1 = 4-cyano; X 2 = H; X 3 = H compound (No.224), R 1 = H; R 2 = Me ; R 3 = Me; R 4 = Me; X 1 = 4- (1-
Imidazolyl); X 2 = H; X 3 = H compound (No.226), R 1 = H;
R 2 = Me; R 3 = Me; R 4 = Me; X 1 = 3- (1-imidazolyl); X 2 =
H; compound of X 3 = H (No.265), R 1 = H; R 2 = Me; R 3 and R 4 =-
CH 2 CH 2 CH 2- ; X 1 = 4- (1-imidazolyl); X 2 = H; X 3 = H (No.356); and R 1 = H; R 2 = Me; R 3 and R 4 = -CH 2 CH 2 CH
2 -; X 1 = 4- ( 2- methyl-1-imidazolyl); X 2 = H; X 3 = compound of H for (No.357), using thoracic aorta of rats
A drug dose that inhibits 20% potassium contraction by 30% (IC 30 ) is disclosed.
【０００６】また、同公報には、上記のNo.224の化合
物、No.226の化合物、No.265の化合物、R1=H; R2=Me; R
3 =Me; R4=Me; X1=2-(1-イミダゾリル); X2=H; X3=H の
化合物(No.302)、R1=H; R2=Me; R3 及びR4=-CH2CH2-; X
1=4-(1- イミダゾリル); X2=H;X3=H の化合物(No.34
2)、No.356の化合物、及びNo.357の化合物について、高
血圧自然発症ラットに対する血圧降下作用が開示されて
いる。[0006] The same publication also discloses the compounds of No. 224, No. 226, No. 265, R 1 = H; R 2 = Me;
3 = Me; R 4 = Me; X 1 = 2- (1-imidazolyl); X 2 = H; X 3 = H (No. 302), R 1 = H; R 2 = Me; R 3 and R 4 = -CH 2 CH 2- ; X
1 = 4- (1-imidazolyl); X 2 = H; X 3 = H compound (No. 34
2), No. 356 compound and No. 357 compound disclose blood pressure lowering effects on spontaneously hypertensive rats.
【０００７】さらに、PCT 国際公開 WO96/22086 号公報
には、下記の式：Further, PCT International Publication WO96 / 22086 discloses the following formula:
【化３】 （式中、R1およびR2はそれぞれ独立にC1〜C6のアルキル
基を示すか、互いに連結してC2〜C5のアルキレン基を示
し、R3およびR4はそれぞれ独立に水素原子；ハロゲン原
子；C1〜C6のアルキル基；C1〜C6のアルコキシ基; トリ
フルオロメチル基；シアノ基；ニトロ基；C2〜C6のジア
ルキルアミノ基；またはC1〜C6のアルキル基、C1〜C6の
アルコキシ基ならびにハロゲン原子から選ばれる１以上
の置換基を有していてもよいイミダゾリル基を示す）で
示されるβ−オキソ−β−ベンゼンプロパンチオアミド
誘導体が開示されている。Embedded image (Wherein, R 1 and R 2 each independently represent a C 1 -C 6 alkyl group, or are linked to each other to represent a C 2 -C 5 alkylene group, and R 3 and R 4 each independently represent hydrogen. atoms; dialkylamino group C 2 -C 6;; halogen atom; C 1 alkyl group -C 6; C 1 alkoxy group -C 6; trifluoromethyl group; a cyano group; a nitro group or a C 1 -C 6 -Oxo-β-benzenepropanethioamide derivative represented by an alkyl group, a C 1 -C 6 alkoxy group and an imidazolyl group optionally having one or more substituents selected from halogen atoms). Have been.
【０００８】この刊行物には、上記の一般式で示される
β−オキソ−β−ベンゼンプロパンチオアミド誘導体
が、腎疾患；平滑筋細胞の増殖に起因する疾患；並び
に、狭心症、心筋梗塞症、及び心不全等の心疾患の予防
及び／又は治療に有用であることが開示されている。具
体的には、R1=-CH2CH2CH2-; R2=-CH2CH2CH2-; R3=4-(1-
イミダゾリル); R4=H の化合物(No. 116) について、腎
血流量の増加作用、平滑筋細胞増殖抑制作用、冠血流量
増加作用、冠スパズム緩解作用、虚血心筋保護作用、心
筋スタンニング（局所収縮不全）改善作用が開示されて
いる。しかしながら、これらの刊行物には、上記の化合
物が脂質代謝改善剤として有用であることは何ら示唆な
いし教示されていない。[0008] In this publication, β-oxo-β-benzenepropanethioamide derivatives represented by the above-mentioned general formula include renal diseases; diseases caused by proliferation of smooth muscle cells; and angina pectoris and myocardial infarction. And heart disease such as heart failure. Specifically, R 1 = -CH 2 CH 2 CH 2- ; R 2 = -CH 2 CH 2 CH 2- ; R 3 = 4- (1-
Imidazolyl); compound with R 4 = H (No. 116), which increases renal blood flow, suppresses smooth muscle cell proliferation, increases coronary blood flow, relieves coronary spasm, protects ischemic myocardium, and performs myocardial stunning (Local contraction failure) is disclosed. However, these publications do not suggest or teach that the above compounds are useful as lipid metabolism improving agents.
【０００９】[0009]
【発明が解決しようとする課題】本発明は、脂質代謝改
善作用を有する医薬を提供することを課題としている。
また、本発明の別の課題は、上記の作用を有し、かつ、
頻脈などの副作用が実質的に軽減された医薬を提供する
ことにある。An object of the present invention is to provide a medicament having an action of improving lipid metabolism.
Another object of the present invention is to have the above-mentioned action, and
An object of the present invention is to provide a medicament in which side effects such as tachycardia are substantially reduced.
【００１０】[0010]
【課題を解決するための手段】本発明者は上記の課題を
解決すべく鋭意努力した結果、カリウムチャンネル開口
作用を有することが知られている特定のβ−オキソ−β
−ベンゼンプロパンチオアミド誘導体が優れた脂質代謝
改善作用を有しており、高脂血症の予防や治療に有用で
あること、並びに、レブクロマカリムなどに比べて頻脈
等の副作用が軽減されていることを見いだした。本発明
は上記の知見を基にして完成されたものである。The present inventor has made intensive efforts to solve the above-mentioned problems, and as a result, a specific β-oxo-β which is known to have a potassium channel opening action.
-That the benzenepropanethioamide derivative has an excellent lipid metabolism-improving activity and is useful for the prevention and treatment of hyperlipidemia, and that side effects such as tachycardia are reduced as compared with lebuchromalim and the like. Was found. The present invention has been completed based on the above findings.
【００１１】すなわち本発明は、下記の式(I) ：That is, the present invention provides the following formula (I):
【化４】 （式中、R1およびR2はそれぞれ独立にC1〜C6のアルキル
基を示すか、互いに連結してC2〜C5のアルキレン基を示
し、R3およびR4はそれぞれ独立に水素原子；ハロゲン原
子；C1〜C6のアルキル基；C1〜C6のアルコキシ基; トリ
フルオロメチル基；シアノ基；ニトロ基；C2〜C6のジア
ルキルアミノ基；またはC1〜C6のアルキル基、C1〜C6の
アルコキシ基ならびにハロゲン原子から選ばれる１以上
の置換基を有していてもよいイミダゾリル基を示す）で
示されるβ- オキソ- β- ベンゼンプロパンチオアミド
誘導体、その薬学的に許容される塩、それらの水和物ま
たは溶媒和物を有効成分とする脂質代謝改善剤を提供す
るものである。Embedded image (Wherein, R 1 and R 2 each independently represent a C 1 -C 6 alkyl group, or are linked to each other to represent a C 2 -C 5 alkylene group, and R 3 and R 4 each independently represent hydrogen. atoms; dialkylamino group C 2 -C 6;; halogen atom; C 1 alkyl group -C 6; C 1 alkoxy group -C 6; trifluoromethyl group; a cyano group; a nitro group or a C 1 -C 6 Oxo-β-benzenepropanethioamide derivative represented by an alkyl group, a C 1 -C 6 alkoxy group and an imidazolyl group optionally having one or more substituents selected from halogen atoms). An object of the present invention is to provide a lipid metabolism improving agent comprising a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient.
【００１２】上記発明の好ましい態様として、高脂血症
の予防及び／又は治療に用いる上記の脂質代謝改善剤が
提供される。また、本発明のさらに好ましい態様とし
て、R3がC1〜C6のアルキル基、C1〜C6のアルコキシ基お
よびハロゲン原子から選ばれる1 以上の置換基を有して
いてもよいイミダゾリル基である上記脂質代謝改善剤；
R4が水素原子である上記脂質代謝改善剤；R1およびR2が
連結してトリメチレン基を形成する上記脂質代謝改善
剤；R3がフェニル基上でカルボニル基に対してパラ位に
結合する上記脂質代謝改善剤；R3が1-イミダゾリル基で
ある上記脂質代謝改善剤が提供される。As a preferred embodiment of the present invention, there is provided the above agent for improving lipid metabolism, which is used for prevention and / or treatment of hyperlipidemia. Also, further preferred embodiments, the alkyl group, C 1 -C 6 alkoxy groups and one or more may have a substituent group imidazolyl group selected from halogen atoms R 3 is C 1 -C 6 of the present invention The lipid metabolism improving agent, which is
The lipid metabolism improving agent R 4 is a hydrogen atom; the lipid metabolism improving agent R 1 and R 2 form a trimethylene group linked; R 3 is bonded in the para-position to the carbonyl group on the phenyl group The above-mentioned lipid metabolism-improving agent; the above-mentioned lipid metabolism-improving agent, wherein R 3 is a 1-imidazolyl group.
【００１３】また、本発明の別の態様により、有効成分
である上記式(I) で表されるβ- オキソ- β- ベンゼン
プロパンチオアミド誘導体と製剤用添加物とを含む医薬
組成物の形態の上記脂質代謝改善剤；上記脂質代謝改善
剤の製造のための上記式(I)で表されるβ- オキソ- β-
ベンゼンプロパンチオアミド誘導体、その薬学的に許
容される塩、又はそれらの水和物若しくは溶媒和物の使
用；並びに、上記の医薬を哺乳類動物に投与することに
より脂質代謝の異常を伴う疾患、例えば高脂血症を予防
および／または治療する方法が提供される。According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a β-oxo-β-benzenepropanethioamide derivative represented by the above formula (I) as an active ingredient and a pharmaceutical additive. The lipid metabolism improving agent; β-oxo-β- represented by the above formula (I) for producing the lipid metabolism improving agent
Use of a benzenepropanethioamide derivative, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; and a disease associated with abnormal lipid metabolism due to administration of the above medicine to a mammal, such as Methods for preventing and / or treating lipemia are provided.
【００１４】[0014]
【発明の実施の形態】本発明の上記予防・治療剤は、前
記式(I) で示されるβ- オキソ- β- ベンゼンプロパン
チオアミド誘導体、その薬学的に許容される塩、それら
の水和物または溶媒和物を有効成分とすることを特徴と
している。前記の定義中、C1〜C6のアルキル基として
は、例えば、メチル基、エチル基、n-プロピル基、イソ
プロピル基、n-ブチル基、n-ペンチル基、n-ヘキシル基
等を挙げることができ、C2〜C5のアルキレン基として
は、例えば、エチレン基、トリメチレン基、テトラメチ
レン基、ペンタメチレン基等を挙げることができる。ハ
ロゲン原子としてはフッ素原子、塩素原子、臭素原子、
又はヨウ素原子のいずれを用いてもよく、C1〜C6のアル
コキシ基としては、例えば、メトキシ基、エトキシ基、
n-プロポキシ基、イソプロポキシ基、n-ブトキシ基、n-
ペンチルオキシ基、n-ヘキシルオキシ基等を挙げること
ができる。C2〜C6のジアルキルアミノ基としては、例え
ば、ジメチルアミノ基、メチルエチルアミノ基、ジエチ
ルアミノ基、ジプロピルアミノ基等を挙げることがで
き、イミダゾリル基は任意の位置でフェニル基に結合す
ることができる。BEST MODE FOR CARRYING OUT THE INVENTION The above-mentioned prophylactic / therapeutic agent of the present invention comprises a β-oxo-β-benzenepropanethioamide derivative represented by the above formula (I), a pharmaceutically acceptable salt thereof, and a hydrate thereof. Alternatively, a solvate is used as an active ingredient. During the definitions, the alkyl group of C 1 -C 6, for example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, n- pentyl group, be mentioned n- hexyl The C 2 -C 5 alkylene group includes, for example, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group and the like. As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom,
Or any of iodine atoms, and as the C 1 to C 6 alkoxy group, for example, a methoxy group, an ethoxy group,
n-propoxy group, isopropoxy group, n-butoxy group, n-
Examples include a pentyloxy group and an n-hexyloxy group. The dialkylamino group of C 2 -C 6, for example, dimethylamino group, methylethylamino group, diethylamino group, and a dipropylamino group, an imidazolyl group be bonded to the phenyl group at any position Can be.
【００１５】式（I)で表される化合物の薬学的に許容さ
れる塩として酸付加塩等を用いることができ、例えば、
塩酸塩、硫酸塩、リン酸塩等の鉱酸塩や、酢酸塩、マロ
ン酸塩、フマル酸塩、マレイン酸塩、メタンスルホン酸
塩、パラトルエンスルホン酸塩等の有機酸塩等を酸付加
塩として用いることができる。塩や遊離形態の化合物の
他、これらの任意の水和物あるいは溶媒和物を本発明の
医薬の有効成分として用いてもよい。上記の化合物と溶
媒和物を形成し得る溶媒として、例えば、メタノール、
エタノール、イソプロパノール、アセトン、酢酸エチ
ル、塩化メチレン等が挙げることができるが、本発明の
医薬には生理学上許容される溶媒和物であるエタノール
溶媒和物などを用いることが好ましい。さらに、式(I)
で示される化合物は、R1およびR2の種類により１個また
は２個以上の不斉炭素原子を有する場合があるが、これ
らの不斉中心に基づく任意の光学異性体やその任意の混
合物、光学異性体の等量混合物であるラセミ体、２個以
上の不斉中心に基づく任意のジアステレオ異性体あるい
はその任意の混合物などは、すべて本発明の医薬の有効
成分として用いることが可能である。As a pharmaceutically acceptable salt of the compound represented by the formula (I), an acid addition salt and the like can be used.
Acid addition of mineral salts such as hydrochloride, sulfate, phosphate, and organic acid salts such as acetate, malonate, fumarate, maleate, methanesulfonate, paratoluenesulfonate It can be used as a salt. Any hydrate or solvate thereof may be used as an active ingredient of the medicament of the present invention, in addition to a salt or a compound in a free form. As a solvent capable of forming a solvate with the above compound, for example, methanol,
Ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like can be mentioned, and it is preferable to use ethanol solvate which is a physiologically acceptable solvate for the medicament of the present invention. Further, the formula (I)
The compound represented by may have one or more asymmetric carbon atoms depending on the type of R 1 and R 2 , any optical isomer based on these asymmetric centers and any mixture thereof, The racemic form, which is an equal mixture of optical isomers, any diastereoisomer based on two or more asymmetric centers, or any mixture thereof, can all be used as the active ingredient of the medicament of the present invention. .
【００１６】上記一般式(I) に包含される化合物は、そ
れ自体が特開平5-246980号公報 (EP548680号公報) に開
示された公知の化合物であるか、あるいは、同公報に記
載された方法により容易に合成することができ、当業者
が容易に入手することができる化合物である。上記の一
般式に包含される化合物のうち、R1およびR2が連結して
トリメチレン基を形成する化合物；R3がC1〜C6のアルキ
ル基、C1〜C6のアルコキシ基およびハロゲン原子から選
ばれる1 以上の置換基を有していてもよいイミダゾリル
基、または1-イミダゾリル基である化合物；R3がフェニ
ル基上でカルボニル基に対してパラ位に結合する化合
物；またはR4が水素原子である化合物は好ましい化合物
である。本発明の医薬の有効成分として好適な化合物を
以下に例示するが、本発明の医薬の有効成分は下記の化
合物に限定されることはない。The compound included in the general formula (I) is a known compound disclosed in Japanese Patent Application Laid-Open No. 5-246980 (EP548680), or described in the same. These compounds can be easily synthesized by a method, and can be easily obtained by those skilled in the art. R 1 and R 2 are linked to form a trimethylene group among the compounds included in the above general formula; R 3 is a C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group and a halogen A compound in which an imidazolyl group optionally having one or more substituents selected from atoms or a 1-imidazolyl group; a compound in which R 3 is bonded to a carbonyl group in a para position on a phenyl group; or R 4 Are preferred compounds. Preferred compounds as the active ingredient of the medicament of the present invention are shown below, but the active ingredients of the medicament of the present invention are not limited to the following compounds.
【００１７】[0017]
【表１】 化合物 No. R1 R2 R3 R4 ──────────────────────────────────── 1 H Me H H 2 H Me 4-F H 3 H Me 4-OMe H 4 H Me 2-(1- イミダゾリル) H 5 H Me 3-(1- イミダゾリル) H 6 H Me 4-(1- イミダゾリル) H 7 H Me 4-(1- イミダゾリル) 3-Cl 8 H Et 4-(1- イミダゾリル) H 9 H i-Pr 4-(1- イミダゾリル) H 10 H n-Pr 4-(1- イミダゾリル) H 11 H Hex H H 12 Me Me 4-Me H 13 Me Me 4-OMe H 14 Me Me 4-F H 15 Me Me 4-Br H 16 Me Me 4-Cl H 17 Me Me 4-CN H 18 Me Me 4-CF3 H 19 Me Me 4-(1- イミダゾリル) H 20 Me Me 4-(2-Me-1-イミダゾリル) H 21 Me Me 4-(2-Et-1-イミダゾリル) H 22 Me Me 4-(2-i-Pr-1-イミダゾリル) H 23 Me Me 4-(2-n-Pr-1-イミダゾリル) H 24 Me Me 4-(2-I-1- イミダゾリル) H 25 Me Me 4-(2-OMe-1- イミダゾリル) H 26 Me Me 4-(2-Cl-1-イミダゾリル) H 27 Me Me 4-(4-Me-1-イミダゾリル) H 28 Me Me 4-(5-Me-1-イミダゾリル) H 29 Me Me 4-(4,5-di-Cl-1- イミダゾリル) H 30 Me Me 4-(1- イミダゾリル) 3-F 31 Me Me 4-(1- イミダゾリル) 3-Cl 32 Me Me 4-(1- イミダゾリル) 3-Br 33 Me Me 4-(1- イミダゾリル) 3-I 34 Me Me 4-(1- イミダゾリル) 3-CN 35 Me Me 4-(1- イミダゾリル) 3-Me 36 Me Me 4-(1- イミダゾリル) 3-Et 37 Me Me 4-(1- イミダゾリル) 3-i-Pr 38 Me Me 4-(1- イミダゾリル) 3-n-Pr 39 Me Me 4-(1- イミダゾリル) 3-OMe 40 Me Me 4-(1- イミダゾリル) 3-OEt 41 Me Me 4-(1- イミダゾリル) 3-O-iPr 42 Me Me 4-(1- イミダゾリル) 3-OPr 43 Me Me 4-(1- イミダゾリル) 3-CF3 44 Me Me 3-F H 45 Me Me 3-Cl H 46 Me Me 3-Me H 47 Me Me 3-OMe H 48 Me Me 3-(1- イミダゾリル) H 49 Me Me 3-(2-Et-1-イミダゾリル) H 50 Me Me 3-(2-i-Pr-1-イミダゾリル) H 51 Me Me 3-(2-n-Pr-1-イミダゾリル) H 52 Me Me 3-(2-I-1- イミダゾリル) H 53 Me Me 3-(2-OMe-1- イミダゾリル) H 54 Me Me 3-(2-Cl-1-イミダゾリル) H 55 Me Me 3-(2-Me-1-イミダゾリル) H 56 Me Me 3-(4-Me-1-イミダゾリル) H 57 Me Me 3-(5-Me-1-イミダゾリル) H 58 Me Me 3-(4,5-di-Cl-1- イミダゾリル) H 59 Me Me 3-(1- イミダゾリル) 4-F 60 Me Me 3-(1- イミダゾリル) 4-Cl 61 Me Me 3-(1- イミダゾリル) 4-Br 62 Me Me 3-(1- イミダゾリル) 4-I 63 Me Me 3-(1- イミダゾリル) 4-CN 64 Me Me 3-(1- イミダゾリル) 4-Me 65 Me Me 3-(1- イミダゾリル) 4-Et 66 Me Me 3-(1- イミダゾリル) 4-i-Pr 67 Me Me 3-(1- イミダゾリル) 4-n-Pr 68 Me Me 3-(1- イミダゾリル) 4-OMe 69 Me Me 3-(1- イミダゾリル) 4-OEt 70 Me Me 3-(1- イミダゾリル) 4-O-iPr 71 Me Me 3-(1- イミダゾリル) 4-OPr 72 Me Me 3-(1- イミダゾリル) 4-CF3 73 Me Me 2-(1- イミダゾリル) H 74 Me Me 2-(2-Me-1-イミダゾリル) H 75 Me Me 2-(2-Et-1-イミダゾリル) H 76 Me Me 2-(2-i-Pr-1-イミダゾリル) H 77 Me Me 2-(2-n-Pr-1-イミダゾリル) H 78 Me Me 2-(2-I-1- イミダゾリル) H 79 Me Me 2-(2-OMe-1- イミダゾリル) H 80 Me Me 2-(2-Cl-1-イミダゾリル) H 81 Me Me 2-(4-Me-1-イミダゾリル) H 82 Me Me 2-(5-Me-1-イミダゾリル) H 83 Me Me 2-(4,5-di-Cl-1- イミダゾリル) H 84 Me Me 2-(1- イミダゾリル) 3-F 85 Me Me 2-(1- イミダゾリル) 3-Cl 86 Me Me 2-(1- イミダゾリル) 3-Br 87 Me Me 2-(1- イミダゾリル) 3-I 89 Me Me 2-(1- イミダゾリル) 3-Me 90 Me Me 2-(1- イミダゾリル) 3-Et 91 Me Me 2-(1- イミダゾリル) 3-i-Pr 92 Me Me 2-(1- イミダゾリル) 3-n-Pr 93 Me Me 2-(1- イミダゾリル) 3-OMe 94 Me Me 2-(1- イミダゾリル) 3-OEt 95 Me Me 2-(1- イミダゾリル) 3-O-iPr 96 Me Me 2-(1- イミダゾリル) 3-OPr 97 Me Me 2-(1- イミダゾリル) 3-CF3 98 Me Me OMe OMe 99 Et Et 4-(1- イミダゾリル) H 100 Et Et 4-(1- イミダゾリル) 3-F 101 Hex Hex 4-(1- イミダゾリル) H 102 Me Hex 4-(1- イミダゾリル) H 103 -CH2CH2- 4-(1- イミダゾリル) H 104 -CH2CH2- 3-(1- イミダゾリル) H 105 -CH2CH2- 2-(1- イミダゾリル) H 106 -CH2CH2CH2- H H 107 -CH2CH2CH2- 4-F H 108 -CH2CH2CH2- 4-Cl H 109 -CH2CH2CH2- 4-Br H 110 -CH2CH2CH2- 4-I H 111 -CH2CH2CH2- 4-Me H 112 -CH2CH2CH2- 4-OMe H 113 -CH2CH2CH2- 4-CF3 H 114 -CH2CH2CH2- 4-CN H 115 -CH2CH2CH2- 4-NO2 H 116 -CH2CH2CH2- 4-(1- イミダゾリル) H 117 -CH2CH2CH2- 4-(2-Me-1-イミダゾリル) H 118 -CH2CH2CH2- 4-(2-Et-1-イミダゾリル) H 119 -CH2CH2CH2- 4-(2-i-Pr-1-イミダゾリル) H 120 -CH2CH2CH2- 4-(2-n-Pr-1-イミダゾリル) H 121 -CH2CH2CH2- 4-(2-I-1- イミダゾリル) H 122 -CH2CH2CH2- 4-(2-OMe-1- イミダゾリル) H 123 -CH2CH2CH2- 4-(2-Cl-1-イミダゾリル) H 124 -CH2CH2CH2- 4-(2-Me-1-イミダゾリル) H 125 -CH2CH2CH2- 4-(4-Me-1-イミダゾリル) H 126 -CH2CH2CH2- 4-(5-Me-1-イミダゾリル) H 127 -CH2CH2CH2- 4-(4,5-di-Cl-1- イミダゾリル) H 128 -CH2CH2CH2- 4-(1- イミダゾリル) 3-F 129 -CH2CH2CH2- 4-(1- イミダゾリル) 3-Cl 130 -CH2CH2CH2- 4-(1- イミダゾリル) 3-Br 131 -CH2CH2CH2- 4-(1- イミダゾリル) 3-I 132 -CH2CH2CH2- 4-(1- イミダゾリル) 3-CN 133 -CH2CH2CH2- 4-(1- イミダゾリル) 3-Me 134 -CH2CH2CH2- 4-(1- イミダゾリル) 3-Et 135 -CH2CH2CH2- 4-(1- イミダゾリル) 3-i-Pr 136 -CH2CH2CH2- 4-(1- イミダゾリル) 3-n-Pr 137 -CH2CH2CH2- 4-(1- イミダゾリル) 3-OMe 138 -CH2CH2CH2- 4-(1- イミダゾリル) 3-OEt 139 -CH2CH2CH2- 4-(1- イミダゾリル) 3-O-i-Pr 140 -CH2CH2CH2- 4-(1- イミダゾリル) 3-OPr 141 -CH2CH2CH2- 4-(1- イミダゾリル) 3-CF3 142 -CH2CH2CH2- 3-F H 143 -CH2CH2CH2- 3-Cl H 144 -CH2CH2CH2- 3-CN H 145 -CH2CH2CH2- 3-Me H 146 -CH2CH2CH2- 3-OMe H 147 -CH2CH2CH2- 3-(1- イミダゾリル) H 148 -CH2CH2CH2- 3-(2-Me-1-イミダゾリル) H 149 -CH2CH2CH2- 3-(2-Et-1-イミダゾリル) H 150 -CH2CH2CH2- 3-(2-i-Pr-1-イミダゾリル) H 151 -CH2CH2CH2- 3-(2-n-Pr-1-イミダゾリル) H 152 -CH2CH2CH2- 3-(2-I-1- イミダゾリル) H 153 -CH2CH2CH2- 3-(2-OMe-1- イミダゾリル) H 154 -CH2CH2CH2- 3-(2-Cl-1-イミダゾリル) H 155 -CH2CH2CH2- 3-(2-Me-1-イミダゾリル) H 156 -CH2CH2CH2- 3-(4-Me-1-イミダゾリル) H 157 -CH2CH2CH2- 3-(5-Me-1-イミダゾリル) H 158 -CH2CH2CH2- 3-(4,5-di-Cl-1- イミダゾリル) H 159 -CH2CH2CH2- 3-(1- イミダゾリル) 4-F 160 -CH2CH2CH2- 3-(1- イミダゾリル) 4-Cl 161 -CH2CH2CH2- 3-(1- イミダゾリル) 4-Br 162 -CH2CH2CH2- 3-(1- イミダゾリル) 4-I 163 -CH2CH2CH2- 3-(1- イミダゾリル) 4-CN 164 -CH2CH2CH2- 3-(1- イミダゾリル) 4-Me 165 -CH2CH2CH2- 3-(1- イミダゾリル) 4-Et 166 -CH2CH2CH2- 3-(1- イミダゾリル) 4-i-Pr 167 -CH2CH2CH2- 3-(1- イミダゾリル) 4-n-Pr 168 -CH2CH2CH2- 3-(1- イミダゾリル) 4-OMe 169 -CH2CH2CH2- 3-(1- イミダゾリル) 4-OEt 170 -CH2CH2CH2- 3-(1- イミダゾリル) 4-O-i-Pr 171 -CH2CH2CH2- 3-(1- イミダゾリル) 4-OPr 172 -CH2CH2CH2- 3-(1- イミダゾリル) 4-CF3 173 -CH2CH2CH2- 3-CF3 4-Cl 174 -CH2CH2CH2- 4-(2- イミダゾリル) H 175 -CH2CH2CH2- 2-(1- イミダゾリル) H 176 -CH2CH2CH2- 2-(2-Me-1-イミダゾリル) H 177 -CH2CH2CH2- 2-(2-Et-1-イミダゾリル) H 178 -CH2CH2CH2- 2-(2-i-Pr-1-イミダゾリル) H 179 -CH2CH2CH2- 2-(2-n-Pr-1-イミダゾリル) H 180 -CH2CH2CH2- 2-(2-I-1- イミダゾリル) H 181 -CH2CH2CH2- 2-(2-OMe-1- イミダゾリル) H 182 -CH2CH2CH2- 2-(2-Cl-1-イミダゾリル) H 183 -CH2CH2CH2- 2-(4-Me-1-イミダゾリル) H 184 -CH2CH2CH2- 2-(5-Me-1-イミダゾリル) H 185 -CH2CH2CH2- 2-(4,5-di-Cl-1- イミダゾリル) H 186 -CH2CH2CH2- 2-(1- イミダゾリル) 3-F 187 -CH2CH2CH2- 2-(1- イミダゾリル) 3-Cl 188 -CH2CH2CH2- 2-(1- イミダゾリル) 3-Br 189 -CH2CH2CH2- 2-(1- イミダゾリル) 3-I 190 -CH2CH2CH2- 2-(1- イミダゾリル) 3-CN 191 -CH2CH2CH2- 2-(1- イミダゾリル) 3-Me 192 -CH2CH2CH2- 2-(1- イミダゾリル) 3-Et 193 -CH2CH2CH2- 2-(1- イミダゾリル) 3-i-Pr 194 -CH2CH2CH2- 2-(1- イミダゾリル) 3-n-Pr 195 -CH2CH2CH2- 2-(1- イミダゾリル) 3-OMe 196 -CH2CH2CH2- 2-(1- イミダゾリル) 3-OEt 197 -CH2CH2CH2- 2-(1- イミダゾリル) 3-O-i-Pr 198 -CH2CH2CH2- 2-(1- イミダゾリル) 3-OPr 199 -CH2CH2CH2- 2-(1- イミダゾリル) 3-CF3 200 -CH2CH2CH2- 2-CN 3-CF3 201 -CH2CH2CH2- 3-NO2 4-OMe 202 -CH2CH2CH2- 3-Cl 4-Cl 203 -CH2CH2CH2- 3-OPr H 204 -CH2CH2CH2- 3-CN 4-CN 205 -CH2CH2CH2- 2-OMe 4-OMe 206 -CH2CH2CH2- H H 207 -CH2CH2CH2- 4-F H 208 -(CH2)4- 4-(1- イミダゾリル) H 209 -(CH2)5- H H 210 Me Me 3-(2-I-1- イミダゾリル) 4-OMe 211 Me Me 3-(2-Me-1-イミダゾリル) 4-OMe 212 -CH2CH2CH2- 4-(2-Br-1-イミダゾリル) H 213 Me Me 3-(2-OMe-1- イミダゾリル) 4-OMe 214 Me Me 3-(2-I-1- イミダゾリル) 4-Et 215 Me Me 3-(2-Me-1-イミダゾリル) 4-Et 216 -CH2CH2CH2- 4-(1- イミダゾリル) 2-OMe ────────────────────────────────────[Table 1] Compound No. R 1 R 2 R 3 R 4 ─────────────────────────────────── ─ 1 H Me HH 2 H Me 4-FH 3 H Me 4-OMe H 4 H Me 2- (1-imidazolyl) H 5 H Me 3- (1-imidazolyl) H 6 H Me 4- (1-imidazolyl) H 7 H Me 4- (1-imidazolyl) 3-Cl 8 H Et 4- (1-imidazolyl) H 9 Hi-Pr 4- (1-imidazolyl) H 10 H n-Pr 4- (1-imidazolyl) H 11 H Hex HH 12 Me Me 4-Me H 13 Me Me 4-OMe H 14 Me Me 4-FH 15 Me Me 4-Br H 16 Me Me 4-Cl H17 Me Me 4-CN H 18 Me Me 4 -CF 3 H 19 Me Me 4- (1-imidazolyl) H 20 Me Me 4- (2-Me-1-imidazolyl) H 21 Me Me 4- (2-Et-1-imidazolyl) H 22 Me Me 4- (2-i-Pr-1-imidazolyl) H 23 Me Me 4- (2-n-Pr-1-imidazolyl) H 24 Me Me 4- (2-I-1-imidazolyl) H 25 Me Me 4- ( 2-OMe-1-imidazolyl) H 26 Me Me 4- (2-Cl-1-imidazolyl) H 27 Me Me 4- (4-Me-1-imidazolyl) H 28 Me Me 4- (5-Me-1 -Imidazolyl) H 29 Me Me 4- (4,5-di-Cl -1-Imidazolyl) H 30 Me Me 4- (1-Imidazolyl) 3-F 31 Me Me 4- (1-Imidazolyl) 3-Cl 32 Me Me 4- (1-Imidazolyl) 3-Br 33 Me Me 4- (1-imidazolyl) 3-I 34 Me Me 4- (1-imidazolyl) 3-CN 35 Me Me 4- (1-imidazolyl) 3-Me 36 Me Me 4- (1-imidazolyl) 3-Et 37 Me Me 4- (1-imidazolyl) 3-i-Pr 38 Me Me 4- (1-imidazolyl) 3-n-Pr 39 Me Me 4- (1-imidazolyl) 3-OMe 40 Me Me 4- (1-imidazolyl) 3-OEt 41 Me Me 4- (1-imidazolyl) 3-O-iPr 42 Me Me 4- (1-imidazolyl) 3-OPr 43 Me Me 4- (1-imidazolyl) 3-CF 3 44 Me Me 3- FH 45 Me Me 3-Cl H 46 Me Me 3-Me H 47 Me Me 3-OMe H 48 Me Me 3- (1-imidazolyl) H 49 Me Me 3- (2-Et-1-imidazolyl) H 50 Me Me 3- (2-i-Pr-1-imidazolyl) H 51 Me Me 3- (2-n-Pr-1-imidazolyl) H 52 Me Me 3- (2-I-1-imidazolyl) H 53 Me Me 3- (2-OMe-1-imidazolyl) H 54 Me Me 3- (2-Cl-1-imidazolyl) H 55 Me Me 3- (2-Me-1-imidazolyl) H 56 Me Me 3- (4-Me-1-imidazolyl) H 57 Me Me 3- (5-Me-1-imidazolyl) H 58 Me Me 3- (4,5-di-Cl-1-imidazolyl) H 59 Me Me 3- ( 1-imidazolyl) 4-F 60 Me Me 3- (1-imidazolyl) 4-Cl 61 Me Me 3- (1-imidazolyl) 4-Br 62 Me Me 3- (1-imidazolyl) 4-I 63 Me Me 3 -(1-Imidazolyl) 4-CN 64 Me Me 3- (1-Imidazolyl) 4-Me 65 Me Me 3- (1-Imidazolyl) 4-Et 66 Me Me 3- (1-Imidazolyl) 4-i-Pr 67 Me Me 3- (1-imidazolyl) 4-n-Pr 68 Me Me 3- (1-imidazolyl) 4-OMe 69 Me Me 3- (1-imidazolyl) 4-OEt 70 Me Me 3- (1-imidazolyl) ) 4-O-iPr 71 Me Me 3- (1-imidazolyl) 4-OPr 72 Me Me 3- (1-imidazolyl) 4-CF 3 73 Me Me 2- (1-imidazolyl) H 74 Me Me 2- ( 2-Me-1-imidazolyl) H 75 Me Me 2- (2-Et-1-imidazolyl) H 76 Me Me 2- (2-i-Pr-1-imidazolyl) H 77 Me Me 2- (2-n -Pr-1-imidazolyl) H 78 Me Me 2- (2-I-1-imidazolyl) H 79 Me Me 2- (2-OMe-1-imidazolyl) H 80 Me Me 2- (2-Cl-1- I Dazolyl) H 81 Me Me 2- (4-Me-1-imidazolyl) H 82 Me Me 2- (5-Me-1-imidazolyl) H 83 Me Me 2- (4,5-di-Cl-1-imidazolyl) ) H 84 Me Me 2- (1-imidazolyl) 3-F 85 Me Me 2- (1-imidazolyl) 3-Cl 86 Me Me 2- (1-imidazolyl) 3-Br 87 Me Me 2- (1-imidazolyl) ) 3-I 89 Me Me 2- (1-imidazolyl) 3-Me 90 Me Me 2- (1-imidazolyl) 3-Et 91 Me Me 2- (1-imidazolyl) 3-i-Pr 92 Me Me 2- (1-imidazolyl) 3-n-Pr 93 Me Me 2- (1-imidazolyl) 3-OMe 94 Me Me 2- (1-imidazolyl) 3-OEt 95 Me Me 2- (1-imidazolyl) 3-O- iPr 96 Me Me 2- (1-imidazolyl) 3-OPr 97 Me Me 2- (1-imidazolyl) 3-CF 3 98 Me Me OMe OMe 99 Et Et 4- (1-imidazolyl) H 100 Et Et 4- ( 1-imidazolyl) 3-F 101 Hex Hex 4- (1- imidazolyl) H 102 Me Hex 4- (1- imidazolyl) H 103 -CH 2 CH 2 - 4- (1- imidazolyl) H 104 -CH 2 CH 2 - 3- (1-imidazolyl) H 105 -CH 2 CH 2 - 2- (1- imidazolyl) H 106 -CH 2 CH 2 CH 2 -HH 107 -CH 2 CH 2 CH 2-4 -FH 108 -CH 2 CH 2 CH 2-4 -Cl H 109 -CH 2 CH 2 CH 2-4 -Br H 110 -CH 2 CH 2 CH 2 -4-IH 111 -CH 2 CH 2 CH 2-4 -Me H 112 -CH 2 CH 2 CH 2-4 -OMe H 113 -CH 2 CH 2 CH 2-4 -CF 3 H 114 -CH 2 CH 2 CH 2 - 4-CN H 115 -CH 2 CH 2 CH 2 - 4-NO 2 H 116 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) H 117 -CH 2 CH 2 CH 2 - 4- ( 2-Me-1-imidazolyl) H 118 -CH 2 CH 2 CH 2 - 4- (2-Et-1- imidazolyl) H 119 -CH 2 CH 2 CH 2 - 4- (2-i-Pr-1- imidazolyl) H 120 -CH 2 CH 2 CH 2 - 4- (2-n-Pr-1- imidazolyl) H 121 -CH 2 CH 2 CH 2 - 4- (2-I-1- imidazolyl) H 122 -CH 2 CH 2 CH 2 - 4- ( 2-OMe-1- imidazolyl) H 123 -CH 2 CH 2 CH 2 - 4- (2-Cl-1- imidazolyl) H 124 -CH 2 CH 2 CH 2 - 4- (2-Me-1- imidazolyl) H 125 -CH 2 CH 2 CH 2 - 4- (4-Me-1- imidazolyl) H 126 -CH 2 CH 2 CH 2 - 4- (5-Me-1- imidazolyl ) H 127 -CH 2 CH 2 CH 2 - 4- (4,5-di-Cl-1- imidazolyl) H 128 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-F 129 -CH 2 CH 2 CH 2 - 4- (1-imidazolyl) 3-Cl 130 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-Br 131 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-I 132 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-CN 133 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-Me 134 -CH 2 CH 2 CH 2 - 4- (1 - imidazolyl) 3-Et 135 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-i-Pr 136 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-n-Pr 137 - CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-OMe 138 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-OEt 139 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-Oi-Pr 140 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-OPr 141 -CH 2 CH 2 CH 2 - 4- (1- imidazolyl) 3-CF 3 142 -CH 2 CH 2 CH 2 -3-FH 143 -CH 2 CH 2 CH 2 -3-Cl H 144 -CH 2 CH 2 CH 2 -3-CN H 145 -CH 2 CH 2 CH 2 -3-Me H 146 -CH 2 CH 2 CH 2 - 3- OMe H 147 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) H 148 -CH 2 CH 2 CH 2 - 3- (2-Me-1- imidazolyl) H 149 - CH 2 CH 2 CH 2 - 3- (2-Et-1- imidazolyl) H 150 -CH 2 CH 2 CH 2 - 3- (2-i- Pr-1- imidazolyl) H 151 -CH 2 CH 2 CH 2 - 3- (2-n-Pr-1- imidazolyl) H 152 -CH 2 CH 2 CH 2 - 3- (2-I-1-imidazolyl) H 153 -CH 2 CH 2 CH 2 -3- (2-OMe-1-imidazolyl) H 154 -CH 2 CH 2 CH 2 -3- (2-Cl-1-imidazolyl) ) H 155 -CH 2 CH 2 CH 2 -3- (2-Me-1-imidazolyl) H 156 -CH 2 CH 2 CH 2 -3- (4-Me-1-imidazolyl) H 157 -CH 2 CH 2 CH 2 - 3- (5-Me -1- imidazolyl) H 158 -CH 2 CH 2 CH 2 - 3- (4,5-di-Cl-1- imidazolyl) H 159 -CH 2 CH 2 CH 2 - 3 - (1-imidazolyl) 4-F 160 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) 4-Cl 161 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) 4-Br 162 -CH 2 CH 2 CH 2 -3- (1-imidazolyl) 4-I 163 -CH 2 CH 2 CH 2 -3- (1-imidazolyl) 4-CN 164 -CH 2 CH 2 CH 2 -3- (1-imidazolyl ) 4-Me 165 -CH 2 CH 2 CH 2 -3- (1-imidazolyl) 4-Et 166 -CH 2 CH 2 CH 2 -3- (1-imidazolyl) 4-i-Pr 167 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) 4-n-Pr 168 -CH 2 CH 2 CH 2 - 3- (1- imidazo Le) 4-OMe 169 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) 4-OEt 170 -CH 2 CH 2 CH 2 - 3- (1- imidazolyl) 4-Oi-Pr 171 -CH 2 CH 2 CH 2 -3- (1-Imidazolyl) 4-OPr 172 -CH 2 CH 2 CH 2 -3- (1-Imidazolyl) 4-CF 3 173 -CH 2 CH 2 CH 2 -3-CF 3 4-Cl 174 -CH 2 CH 2 CH 2 -4- (2-imidazolyl) H 175 -CH 2 CH 2 CH 2 -2- (1-imidazolyl) H 176 -CH 2 CH 2 CH 2 -2- (2-Me- 1-imidazolyl) H 177 -CH 2 CH 2 CH 2 -2- (2-Et-1-imidazolyl) H 178 -CH 2 CH 2 CH 2 -2- (2-i-Pr-1-imidazolyl) H 179 -CH 2 CH 2 CH 2 - 2- (2-n-Pr-1- imidazolyl) H 180 -CH 2 CH 2 CH 2 - 2- (2-I-1- imidazolyl) H 181 -CH 2 CH 2 CH 2 - 2- (2-OMe- 1- imidazolyl) H 182 -CH 2 CH 2 CH 2 - 2- (2-Cl-1- imidazolyl) H 183 -CH 2 CH 2 CH 2 - 2- (4-Me -1-imidazolyl) H 184 -CH 2 CH 2 CH 2 -2- (5-Me-1-imidazolyl) H 185 -CH 2 CH 2 CH 2 -2- (4,5-di-Cl-1-imidazolyl) ) H 186 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-F 187 -CH 2 CH 2 CH 2 - 2- (1- Imidazolyl) 3-Cl 188 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-Br 189 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-I 190 -CH 2 CH 2 CH 2 - 2- (1-imidazolyl) 3-CN 191 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-Me 192 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-Et 193 -CH 2 CH 2 CH 2 -2- (1-imidazolyl) 3-i-Pr 194 -CH 2 CH 2 CH 2 -2- (1-imidazolyl) 3-n-Pr 195 -CH 2 CH 2 CH 2 - 2- (1-imidazolyl) 3-OMe 196 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-OEt 197 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-Oi- Pr 198 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-OPr 199 -CH 2 CH 2 CH 2 - 2- (1- imidazolyl) 3-CF 3 200 -CH 2 CH 2 CH 2 - 2 -CN 3-CF 3 201 -CH 2 CH 2 CH 2 - 3-NO 2 4-OMe 202 -CH 2 CH 2 CH 2 - 3-Cl 4-Cl 203 -CH 2 CH 2 CH 2 - 3-OPr H 204 -CH 2 CH 2 CH 2 - 3-CN 4-CN 205 -CH 2 CH 2 CH 2 - 2-OMe 4-OMe 206 -CH 2 CH 2 CH 2 - HH 207 -CH 2 CH 2 CH 2 - 4 -FH 208-(CH 2 ) 4 -4- (1-Imidazolyl) H 209-(CH 2 ) 5 -HH 210 Me Me 3- (2-I 1-imidazolyl) 4-OMe 211 Me Me 3- (2-Me-1- imidazolyl) 4-OMe 212 -CH 2 CH 2 CH 2 - 4- (2-Br-1- imidazolyl) H 213 Me Me 3 -(2-OMe-1-imidazolyl) 4-OMe 214 Me Me 3- (2-I-1-imidazolyl) 4-Et 215 Me Me 3- (2-Me-1-imidazolyl) 4-Et 216 -CH 2 CH 2 CH 2 - 4- ( 1- imidazolyl) 2-OMe ────────────────────────────────── ──
【００１８】例えば、上記表１に例示された化合物のう
ち、No.52 の化合物 (R1及びR2=-CH3; R3=3-(2-I-1- イ
ミダゾリル); R4=H)、No.73 の化合物 (R1及びR2=-CH3;
R3=2-(1- イミダゾリル); R4=H)、No.116の化合物 (R1
及びR2=-CH2CH2CH2-; R3=4-(1-イミダゾリル); R4=H)、
No.119の化合物 (R1及びR2=-CH2CH2CH2-; R3=4-(2-i-Pr
-1- イミダゾリル); R4=H)、No.121の化合物 (R1及びR2
=-CH2CH2CH2-; R3=4-(2-I-1-イミダゾリル); R4=H)、N
o.138の化合物 (R1及びR2=-CH2CH2CH2-; R3=4-(1-イミ
ダゾリル); R4=3-OEt)などの化合物は、本発明の医薬の
有効成分として好ましい化合物である。For example, among the compounds exemplified in Table 1 above, the compound of No. 52 (R 1 and R 2 = -CH 3 ; R 3 = 3- (2-I-1-imidazolyl); R 4 = H), the compound of No. 73 (R 1 and R 2 = -CH 3 ;
R 3 = 2- (1-imidazolyl); R 4 = H), No. 116 compound (R 1
And R 2 = -CH 2 CH 2 CH 2- ; R 3 = 4- (1-imidazolyl); R 4 = H),
No. 119 compound (R 1 and R 2 = -CH 2 CH 2 CH 2- ; R 3 = 4- (2-i-Pr
-1-imidazolyl); R 4 = H), compound of No. 121 (R 1 and R 2
= -CH 2 CH 2 CH 2- ; R 3 = 4- (2-I-1-imidazolyl); R 4 = H), N
Compounds such as o.138 (R 1 and R 2 = -CH 2 CH 2 CH 2- ; R 3 = 4- (1-imidazolyl); R 4 = 3-OEt) Preferred compounds as components.
【００１９】特に好ましい化合物として、上記表１に例
示されたNo.116の化合物を例示することができるが、こ
の化合物は特開平5-246980号公報表１中にNo.356の化合
物として具体的に示されており、実施例１にはその製造
方法が詳細に説明されている。なお、特開平5-246980号
公報には、本発明の有効成分である前記化合物がカリウ
ムチャンネル開口作用を有していること、並びに、これ
らの化合物について血管拡張作用、気管支拡張作用、胃
腸管平滑筋弛緩作用等の薬理作用が期待できることが示
されているが、これらの化合物が脂質代謝を改善する作
用を有することは具体的に何ら説明されていない。As a particularly preferred compound, the compound of No. 116 shown in Table 1 above can be exemplified, and this compound is specifically described as a compound of No. 356 in Table 1 of JP-A-5-246980. In Example 1, the manufacturing method is described in detail. JP-A-5-246980 discloses that the compound, which is an active ingredient of the present invention, has a potassium channel opening action, and that these compounds have a vasodilator action, a bronchodilator action, and a gastrointestinal smoothing action. Although it has been shown that pharmacological actions such as muscle relaxation actions can be expected, there is no specific explanation that these compounds have an action to improve lipid metabolism.
【００２０】本発明の医薬は脂質代謝改善作用を有して
おり、主としてコレステロール、トリグリセリド、リン
脂質、及び遊離脂肪酸からなる血清脂質のいずれか又は
全部が異常に増加した状態を改善することができる。従
って、本発明の医薬は、脂質代謝異常を伴う疾患、例え
ば高脂血症などの治療及び／又は予防を目的とする脂質
代謝改善剤として用いることができる。高脂血症はＩ型
〜Ｖ型までの種々の表現型（WHO 分類, 高脂血症ポケッ
トマニュアル, p.17, メディカルビュー社, 1993）に分
類できることが知られており、一方、原発性高脂血症や
二次性高脂血症などの病因により分類できることも知ら
れているが、本発明の医薬の適用は特定の分類に属する
高脂血症に限定されることはない。また、本発明の医薬
は高コレステロール血症及び高トリグリセリド血症のい
ずれに対して適用可能であるが、高トリグリセリド血症
は本発明の医薬の好適な適用対象である。The medicament of the present invention has an effect of improving lipid metabolism, and can improve a state in which any or all of serum lipids mainly composed of cholesterol, triglycerides, phospholipids and free fatty acids are abnormally increased. . Therefore, the medicament of the present invention can be used as a lipid metabolism improving agent for the treatment and / or prevention of diseases associated with abnormal lipid metabolism, such as hyperlipidemia. It is known that hyperlipidemia can be classified into various phenotypes from type I to type V (WHO classification, Hyperlipidemia Pocket Manual, p. 17, Medical View, 1993), while It is also known that classification can be based on the etiology such as hyperlipidemia and secondary hyperlipidemia, but the application of the medicament of the present invention is not limited to hyperlipidemia belonging to a specific classification. Further, the medicament of the present invention is applicable to both hypercholesterolemia and hypertriglyceridemia, and hypertriglyceridemia is a suitable application target of the medicament of the present invention.
【００２１】高脂血症、特に高コレステロール血症と動
脈硬化症との関連については多くの疫学的調査が行われ
ており、血清コレステロール高値が冠動脈や脳血管の硬
化を惹起し、虚血性心疾患や脳血管疾患の発症の重大な
危険因子となることが知られている。従って、本発明の
脂質代謝改善薬を用いて高脂血症を治療及び／又は予防
することにより、動脈硬化症の発症や進展を防止するこ
とができ、ひいては冠・脳血管疾患を予防することがで
きることはいうまでもない。Many epidemiological investigations have been conducted on the relationship between hyperlipidemia, especially hypercholesterolemia and arteriosclerosis, and high serum cholesterol causes hardening of coronary arteries and cerebral blood vessels, resulting in ischemic heart disease. It is known to be a significant risk factor for the development of disease and cerebrovascular disease. Therefore, the onset and progression of arteriosclerosis can be prevented by treating and / or preventing hyperlipidemia using the lipid metabolism-improving agent of the present invention, and thus preventing coronary / cerebrovascular disease. It goes without saying that you can do it.
【００２２】本発明の医薬の有効成分である上記化合
物、その薬学的に許容される塩、またはそれらの溶媒和
物若しくは水和物は、それ自体を医薬として患者に投与
してもよいが、一般的には、これらの有効成分の１種又
は２種以上を含む医薬組成物を製造して患者に投与する
ことが好適である。このような医薬組成物として、錠
剤、カプセル剤、細粒剤、散剤、丸剤、トローチ、舌下
剤、または液剤などの経口投与用の製剤、あるいは、注
射剤、座剤、軟膏、貼付剤などの非経口投与用の製剤を
例示することができる。The above compound, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof which is an active ingredient of the medicament of the present invention may be administered to a patient as a medicament itself. In general, it is preferable to prepare and administer a pharmaceutical composition containing one or more of these active ingredients to a patient. Such pharmaceutical compositions include tablets, capsules, fine granules, powders, pills, troches, sublinguals, or liquid preparations for oral administration, or injections, suppositories, ointments, patches and the like. Preparations for parenteral administration can be exemplified.
【００２３】経口投与用の錠剤またはカプセル剤は、通
常は単位投与物として提供され、結合剤、充填剤、希釈
剤、打錠剤、滑沢剤、崩壊剤、着色剤、香味剤及び湿潤
剤のような通常の製剤用担体を添加して製造することが
できる。錠剤は、この当業界で周知の方法に従って、例
えば、腸溶性コーティング剤を用いてコーティングする
ことができ、例えば、セルロース、マンニトール、又は
ラクトースなどの充填剤；澱粉、ポリビニルポリピロリ
ドン、澱粉誘導体、又はナトリウム澱粉グリコラートな
どの崩壊剤；ステアリン酸マグネシウムなどの滑沢剤；
ラウリル硫酸ナトリウムなどの湿潤剤を用いて製造して
もよい。Tablets or capsules for oral administration are usually presented as unit doses, containing binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding such ordinary carriers for pharmaceuticals. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrrolidone, a starch derivative, or Disintegrants such as sodium starch glycolate; lubricants such as magnesium stearate;
It may be manufactured using a wetting agent such as sodium lauryl sulfate.
【００２４】経口投与用の液剤は、例えば水性又は油性
懸濁液、溶液、エマルジョン、シロップ剤又はエリキシ
ル剤などの他、使用前に水又は適当な媒体により再溶解
されうる乾燥製剤として提供される。このような液剤に
は、通常の添加剤、例えばソルビトール、シロップ、メ
チルセルロース、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
ニウムゲル又は水素化食用脂肪のような沈澱防止剤、レ
シチン、ソルビタンモノオレート、アラビアゴムのよう
な乳化剤、アーモンド油、精留ココナッツ油、油状エス
テル（例えばグリセリンのエステル）、プロピレングリ
コール、エチルアルコールのような（食用油も包含しう
る）非水性媒体、p-ヒドロキシ安息香酸のメチルエステ
ル、エチルエステル、若しくはプロピルエステル、又は
ソルビン酸のような保存剤、及び必要に応じて通常の香
味剤又は着色剤を配合することができる。Solutions for oral administration are provided, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry preparations which can be redissolved with water or a suitable vehicle before use. . Such solutions include conventional additives such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, precipitation inhibitors such as aluminum stearate gel or hydrogenated edible fat, lecithin, sorbitan monooleate, and arabic. Emulsifiers such as gums, almond oil, rectified coconut oil, non-aqueous media (including edible oils) such as oily esters (eg glycerin), propylene glycol, ethyl alcohol, methyl p-hydroxybenzoate Preservatives such as esters, ethyl esters, or propyl esters, or sorbic acid, and if desired, conventional flavoring or coloring agents can be included.
【００２５】経口投与用の製剤は、混合、充填、又は打
錠などの当業界で周知の方法により製造することができ
る。また反復配合操作を用いて、多量の充填剤などを使
用した製剤中に有効成分を分布させてもよい。非経口投
与用の製剤は、一般には、有効成分である化合物と滅菌
媒体とを含有する液体単位投与量製剤として提供され
る。非経口投与用の溶液は、通常、化合物を媒体に溶解
させて滅菌濾過し、次に適当なバイアル又はアンプルに
充填して密封することにより製造される。安定性を高め
るために、組成物を凍結させた後にバイアル中に充填
し、水を真空下で除去してもよい。非経口懸濁液は、実
質的に非経口溶液の場合と同じ方法で製造されるが、有
効成分を媒体に懸濁させてエチレンオキシドなどにより
滅菌することにより好適に製造できる。また、有効成分
が均一分布となるように、必要に応じて界面活性剤、湿
潤剤等を添加してもよい。Preparations for oral administration can be manufactured by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation. Formulations for parenteral administration are generally provided as liquid unit dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solutions for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtering and then filling suitable vials or ampoules and sealing. To enhance stability, the composition may be filled into vials after freezing and the water removed under vacuum. Parenteral suspensions are prepared substantially in the same manner as for parenteral solutions, but can be suitably prepared by suspending the active ingredient in a vehicle and sterilizing the suspension with ethylene oxide or the like. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.
【００２６】有効成分である上記化合物の投与量は、治
療や予防の目的、治療または予防すべき疾患の種類、患
者の症状、体重、年齢や性別等を考慮して適宜決定すれ
ばよいが、通常の場合、成人１日あたり経口投与により
0.01 mg〜1,000 mg程度を投与することができ、好まし
くは 1〜100 mgである。このような投与量を１日あたり
１〜数回に分けて投与するのが望ましい。The dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the condition, weight, age, sex, etc. of the patient. Normally, by oral administration per day for adults
About 0.01 mg to 1,000 mg can be administered, preferably 1 to 100 mg. It is desirable to administer such a dosage in one to several portions per day.
【００２７】[0027]
【実施例】本発明の医薬の有効成分として、上記表１に
例示されたNo.116の化合物 (R1及びR2=-CH2CH2CH2-; R3
=4-(1-イミダゾリル); R4=H: 4-(1-イミダゾリル)-N-メ
チル- β- オキソ- α, α- トリメチレンベンゼンプロ
パンチオアミド：以下、実施例において「本発明化合
物」と略記する) を用い、以下の試験を行った。EXAMPLE As the active ingredient of the medicament of the present invention, the compound of No. 116 exemplified in Table 1 above (R 1 and R 2 = -CH 2 CH 2 CH 2- ; R 3
= 4- (1-imidazolyl); R 4 = H: 4- (1-imidazolyl) -N-methyl-β-oxo-α, α-trimethylenebenzenepropanethioamide: Hereinafter, the “compound of the present invention” in Examples The following tests were performed using the following.
【００２８】例１：Zucker fatty ratを用いたトリグリ
セリド低下作用 ５周齢の雄性 Zucker fatty rat を購入し（チャールズ
・リバー）、予備飼育の後、13〜14周齢で実験に供し
た。コントロール群には 5% アラビアゴム溶液を5 ml/k
gの用量で投与し、他の２群には5%アラビアゴム溶液で
懸濁した本発明化合物をそれぞれ５及び10 mg/kgの用量
で２週間経口投与した。薬物投与前と投与２週間後に採
血を行い、血漿を採取してトリグリセリド値を測定し
た。トリグリセリド値の測定はニュークリンテックTG
（ヤトロン）のアッセイキットを用いて行ない、有意差
検定は各時点におけるダネットの多量検定を用いて行っ
た。表２に結果を示す。本発明化合物を２週間の連続経
口投与した試験群では、コントロール群に比べて血中ト
リグリセリド値が有意に低下していた。この結果は、本
発明の医薬が脂質代謝改善剤として有用であることを示
している。Example 1: Triglyceride lowering effect using Zucker fatty rats Five-week-old male Zucker fatty rats were purchased (Charles River), and were subjected to experiments at 13-14 weeks of age after preliminary rearing. 5% gum arabic solution 5 ml / k for control group
g of the compound of the present invention, and the other two groups were orally administered a compound of the present invention suspended in a 5% gum arabic solution at a dose of 5 and 10 mg / kg, respectively, for 2 weeks. Blood was collected before and 2 weeks after drug administration, and plasma was collected to measure triglyceride levels. Measurement of triglyceride value is Newclintec TG
(Yatron) assay kit, and a significant difference test was performed using Dunnett's mass test at each time point. Table 2 shows the results. In the test group to which the compound of the present invention was orally administered continuously for 2 weeks, the blood triglyceride level was significantly lower than that in the control group. This result indicates that the medicament of the present invention is useful as a lipid metabolism improving agent.
【００２９】[0029]
【表２】 ─────────────────────────────────── 試験群 動物数 血中トリグリセリド (mg/dl) (平均値） 投与前 投与２週間後 ─────────────────────────────────── コントロール 9 718 975 本発明化合物 (5 mg/kg) 8 668 574 * 本発明化合物 (10 mg/kg) 8 715 616 * ───────────────────────────────────* p ＜0.05[Table 2] ─────────────────────────────────── Test group Number of animals Blood triglyceride (mg / dl ) (Average value) Before administration 2 weeks after administration ─────────────────────────────────── Control 9 718 975 Compound of the present invention (5 mg / kg) 8 668 574 * Compound of the present invention (10 mg / kg) 8 715 616 * ──────────────────────── ─────────── * p <0.05
【００３０】例２：Zucker fatty ratを用いたトリグリ
セリド低下作用及び頻脈発生作用の比較 例１と同様の方法で試験を行った。コントロール群には
5% アラビアゴム溶液を 5 ml/kgの用量で投与し、他の
２群には 5% アラビアゴム溶液に懸濁した本発明化合物
(5 mg/kg)又はレブクロマカリム (0.3 mg/kg)をそれぞ
れ２週間経口投与した。薬物投与前と投与２週間後に血
漿中トリグリセリド値及び心拍数の測定を行ない、有意
差検定は各時点におけるダネットの多量検定を用いて行
った。表３に結果を示す。本発明化合物及びレブクロマ
カリムを２週間の連続経口投与した群では、コントロー
ル群に比べて血中トリグリセリド値が有意に低下してお
り、両者の改善度はほぼ同程度であった。一方、心拍数
については、本発明化合物を投与した群では変化は認め
られなかったが、レブクロマカリム投与群では有意な増
加が認められた。この結果は、本発明の医薬はレブクロ
マカリムと比較して頻脈を発生させるおそれが少なく、
医薬として優れた有用性を有していることを示してい
る。Example 2: Comparison of triglyceride lowering action and tachycardia generating action using Zucker fatty rats A test was conducted in the same manner as in Example 1. The control group
A 5% gum arabic solution was administered at a dose of 5 ml / kg, and the other two groups were administered with the compound of the present invention suspended in a 5% gum arabic solution.
(5 mg / kg) or lebucromakalim (0.3 mg / kg), respectively, was orally administered for 2 weeks. Plasma triglyceride levels and heart rate were measured before and 2 weeks after drug administration, and significant difference tests were performed using Dunnett's high-volume test at each time point. Table 3 shows the results. In the group to which the compound of the present invention and lebucromakalim were orally administered continuously for 2 weeks, the blood triglyceride level was significantly lower than that in the control group, and the degree of improvement of both was almost the same. On the other hand, as for the heart rate, no change was observed in the group to which the compound of the present invention was administered, but a significant increase was observed in the group to which levocromakalim was administered. This result indicates that the medicament of the present invention is less likely to cause tachycardia as compared to lebucromakalim,
It shows that it has excellent utility as a medicine.
【００３１】[0031]
【表３】 ─────────────────────────────────── 試験群 動物数 心拍数 血中トリグリセリド値 心拍数／分（平均値） (mg/dl) (平均値） 投与前 投与２週間後 投与前 投与２週間後 ─────────────────────────────────── コントロール 8 395 397 1238 1005 本発明化合物 8 379 399 1244 435 * (5 mg/kg) レブクロマカリム 8 374 458 * 1259 529 * (0.3 mg/kg) ───────────────────────────────────* p ＜0.05[Table 3] ─────────────────────────────────── Test group Number of animals Heart rate Blood triglyceride level Heart rate Number / min (mean) (mg / dl) (mean) Before administration 2 weeks after administration Before administration 2 weeks after administration ────────────────────── ───────────── Control 8 395 397 1238 1005 Compound of the present invention 8 379 399 1244 435 * (5 mg / kg) Levcromakalim 8 374 458 * 1259 529 * (0.3 mg / kg) ── ───────────────────────────────── * p <0.05
【００３２】[0032]
【発明の効果】本発明の医薬は脂質代謝改善作用を有し
ており、高脂血症などの脂質代謝異常を伴う疾患の予防
及び／又は治療に有用である。また、本発明の医薬は頻
脈などの副作用が軽減されており、安全性が高いという
特徴を有している。The medicament of the present invention has an effect of improving lipid metabolism, and is useful for preventing and / or treating diseases associated with abnormal lipid metabolism such as hyperlipidemia. In addition, the medicament of the present invention is characterized in that side effects such as tachycardia are reduced and safety is high.
フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ｃ０７Ｄ 233/68 Ｃ０７Ｄ 233/68 233/70 233/70 Continued on the front page (51) Int.Cl. 6 Identification code FI C07D 233/68 C07D 233/68 233/70 233/70
Claims (2)
基を示すか、互いに連結してC2〜C5のアルキレン基を示
し、R3およびR4はそれぞれ独立に水素原子；ハロゲン原
子；C1〜C6のアルキル基；C1〜C6のアルコキシ基; トリ
フルオロメチル基；シアノ基；ニトロ基；C2〜C6のジア
ルキルアミノ基; またはC1〜C6のアルキル基、C1〜C6の
アルコキシ基ならびにハロゲン原子から選ばれる１以上
の置換基を有していてもよいイミダゾリル基を示す）で
示されるβ- オキソ- β- ベンゼンプロパンチオアミド
誘導体、その薬学的に許容される塩、それらの水和物ま
たは溶媒和物を有効成分とする脂質代謝改善剤。1. The following formula: (Wherein, R 1 and R 2 each independently represent a C 1 -C 6 alkyl group, or are linked to each other to represent a C 2 -C 5 alkylene group, and R 3 and R 4 each independently represent hydrogen. atoms; dialkylamino group C 2 -C 6;; halogen atom; C 1 alkyl group -C 6; C 1 alkoxy group -C 6; trifluoromethyl group; a cyano group; a nitro group or a C 1 -C 6 Oxo-β-benzenepropanethioamide derivative represented by an alkyl group, a C 1 -C 6 alkoxy group and an imidazolyl group optionally having one or more substituents selected from halogen atoms). An agent for improving lipid metabolism comprising a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient.
請求項１に記載の脂質代謝改善剤。2. The lipid metabolism improving agent according to claim 1, which is used for prevention and / or treatment of hyperlipidemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8342822A JPH10182596A (en) | 1996-12-24 | 1996-12-24 | Lipid metabolism improver |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8342822A JPH10182596A (en) | 1996-12-24 | 1996-12-24 | Lipid metabolism improver |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10182596A true JPH10182596A (en) | 1998-07-07 |
Family
ID=18356765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8342822A Pending JPH10182596A (en) | 1996-12-24 | 1996-12-24 | Lipid metabolism improver |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH10182596A (en) |
-
1996
- 1996-12-24 JP JP8342822A patent/JPH10182596A/en active Pending
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