JPH0959155A - Cholesteryl ester transfer reaction inhibitor - Google Patents
Cholesteryl ester transfer reaction inhibitorInfo
- Publication number
- JPH0959155A JPH0959155A JP23596495A JP23596495A JPH0959155A JP H0959155 A JPH0959155 A JP H0959155A JP 23596495 A JP23596495 A JP 23596495A JP 23596495 A JP23596495 A JP 23596495A JP H0959155 A JPH0959155 A JP H0959155A
- Authority
- JP
- Japan
- Prior art keywords
- cholesteryl ester
- ester transfer
- transfer reaction
- compound
- salt
- 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
Landscapes
- Pyrane Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Compounds Of Unknown Constitution (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明はペニシリウム・エス
ピー（Penicillium sp. ）ＢＭ−９９株（ＦＥＲＭ Ｐ
−１４２３１）の生産する化合物ＢＭ９９−１、ＢＭ９
９−２およびＢＭ９９−３を有効成分として含有するコ
レステリルエステル転送反応阻害剤並びに動脈硬化予防
および治療剤に関するものであり、医療の分野で利用さ
れる。TECHNICAL FIELD The present invention relates to a Penicillium sp. BM-99 strain (FERM P.
-14231) produced compounds BM99-1 and BM9
The present invention relates to a cholesteryl ester transfer reaction inhibitor containing 9-2 and BM99-3 as active ingredients and an agent for preventing and treating arteriosclerosis, which is used in the medical field.
【０００２】[0002]
【従来の技術】コレステリルエステル転送蛋白質（ＣＥ
ＴＰ）は、生体内において低比重リポ蛋白質（ＬＤＬ）
や高比重リポ蛋白質（ＨＤＬ）などの間でコレステリル
エステルやトリグリセリド、リン脂質などを輸送する蛋
白質である。ＬＤＬコレステロール値と虚血性心疾患と
は正の相関があり、ＨＤＬコレステロール値とは負の相
関があるという統計的データがある。また、ＣＥＴＰ活
性とＬＤＬ値とは正の相関があり、ＨＤＬ値とは負の相
関がある（新井洋由ら，Ｔｈｅ Ｌｉｐｉｄ，Ｖｏｌ．
２，Ｎｏ．２，１８３頁，１９９１年）。さらに、遺伝
的にＣＥＴＰ活性を欠損している家系には多くの長寿例
が見られ、そのＣＥＴＰ欠損による影響として、リポ蛋
白の組成が高ＨＤＬ、低ＬＤＬなど抗動脈硬化性の症状
を有していることが知られている（馬渕宏，細胞工学，
Ｖｏｌ．１０，Ｓｕｐｐｌ．２，１１頁，１９９１
年）。BACKGROUND OF THE INVENTION Cholesteryl ester transfer protein (CE
TP) is a low-density lipoprotein (LDL) in vivo
It is a protein that transports cholesteryl esters, triglycerides, phospholipids and the like between and high specific gravity lipoprotein (HDL). There is statistical data that the LDL cholesterol level is positively correlated with ischemic heart disease and the HDL cholesterol level is negatively correlated. Further, there is a positive correlation between the CETP activity and the LDL value and a negative correlation with the HDL value (Hiroyoshi Arai et al., The Lipid, Vol.
2, No. 2, 183, 1991). Furthermore, many long-lived cases were found in families with a genetically deficient CETP activity, and as a result of the CETP deficiency, lipoprotein composition has high arteriosclerotic symptoms such as high HDL and low LDL. It is known that (Hiroshi Mabuchi, Cell Engineering,
Vol. 10, Suppl. 2, 11 and 1991
Year).
【０００３】動脈硬化症は高齢化社会を迎えた今日にお
いて、医療上の最も重要な問題の一つである。アテロー
ム性動脈硬化症に伴う症状として動脈の内壁にコレステ
リルエステルやトリグリセリドなどが蓄積されているこ
とが知られている。そのため様々な研究機関において、
動脈硬化を予防および治療する目的で、生体内のコレス
テロールの調節をする薬剤の開発が行なわれてきてい
る。例えば、その様な薬剤として、ＨＭＧ−ＣｏＡ還元
酵素阻害剤であるプラバスタチン、アンジオテンシン変
換酵素阻害剤であるアラセプリル、高脂血症治療剤であ
るプロブコール等が有る。Atherosclerosis is one of the most important medical problems in today's aging society. It is known that cholesteryl ester, triglyceride and the like are accumulated on the inner wall of the artery as a symptom associated with atherosclerosis. Therefore, in various research institutions,
For the purpose of preventing and treating arteriosclerosis, drugs for regulating cholesterol in the body have been developed. Examples of such agents include pravastatin which is an HMG-CoA reductase inhibitor, alacepril which is an angiotensin converting enzyme inhibitor, and probucol which is a therapeutic agent for hyperlipidemia.
【０００４】[0004]
【発明が解決しようとする課題】しかしながら、依然と
して動脈硬化症が完全に克服されたわけではなく、新し
い作用機序を有するより効果的な薬剤の開発が求められ
ている。However, arteriosclerosis has not been completely overcome, and there is a need for the development of more effective drugs having a new mechanism of action.
【０００５】[0005]
【課題を解決するための手段】これらのことから、本発
明者らは、ＣＥＴＰの活性を抑制することで動脈硬化の
予防および治療の効果が得られると考え、種々の発酵産
物を用いてコレステリルエステル転送反応阻害作用を有
する化合物を探索するべく鋭意研究を重ねた結果、ＢＭ
９９−１、ＢＭ９９−２およびＢＭ９９−３にコレステ
リルエステル転送反応阻害作用を有することを発見し
た。その結果、ＣＥＴＰが関与する動脈硬化の予防およ
び治療に該化合物が有用なことを見いだし、本発明を完
成するに至った。Based on the above, the inventors of the present invention believe that suppressing the activity of CETP has the effect of preventing and treating arteriosclerosis, and therefore, using various fermentation products, cholesteryl compounds are used. As a result of intensive research to find compounds having an inhibitory effect on ester transfer reaction, BM
It was discovered that 99-1, BM99-2 and BM99-3 have a cholesteryl ester transfer reaction inhibitory action. As a result, they have found that the compound is useful for prevention and treatment of CETP-related arteriosclerosis, and completed the present invention.
【０００６】[0006]
【発明の実施の形態】本発明で使用される化合物ＢＭ９
９−１およびＢＭ９９−２は公知であり、本発明者らが
第３６回天然有機化合物討論会講演要旨集７６０頁にそ
れらのホスホリパーゼＡ２阻害作用を報告している。ま
た、本発明で使用される化合物ＢＭ９９−３は、本発明
者らによる特許出願（特願平６−１９１３４６）にその
物理化学的性状を開示している。しかしながら、コレス
テリルエステル転送反応阻害作用については一切報告さ
れていない。BEST MODE FOR CARRYING OUT THE INVENTION Compound BM9 used in the present invention
9-1 and BM99-2 are known, and the present inventors have reported their phospholipase A2 inhibitory action on page 760 of the 36th Annual Meeting of the Natural Organic Compound Conference. Further, the compound BM99-3 used in the present invention is disclosed in its patent application (Japanese Patent Application No. 6-191346) filed by the present inventors for its physicochemical properties. However, no cholesteryl ester transfer reaction inhibitory action has been reported.
【０００７】本発明で使用される化合物ＢＭ９９−１、
ＢＭ９９−２およびＢＭ９９−３の物理化学的性状およ
び調製法は特願平６−１９１３４６に記載した通りであ
り、ＢＭ９９−１およびＢＭ９９−２の構造式は以下に
示される。The compound BM99-1, used in the present invention,
The physicochemical properties and preparation method of BM99-2 and BM99-3 are as described in Japanese Patent Application No. 6-191346, and the structural formulas of BM99-1 and BM99-2 are shown below.
【化３】 Embedded image
【化４】 また、ＢＭ９９−３の物理化学的性状は以下に示され
る。 （１）質量分析値（m/z）：805(M-H)-（ネガティブファ
ブマスによる。） （２）紫外吸収スペクトル（nm）:388,300(sh),268,212
（メタノール溶液中） （３）13Ｃ−核磁気共鳴スペクトル（δ：ppm）：208.1
7, 190.66, 170.80, 166.65, 162.63, 156.79, 151.54,
145.31, 145.08, 139.27, 136.72, 133.71, 128.77, 1
22.78, 121.01, 115.74, 112.88, 106.23, 104.70, 10
1.74, 86.36, 71.26, 64.65, 62.38, 56.35, 56.01, 4
8.32, 44.66, 44.38, 43.52, 42.58, 41.94,40.66, 40.
22, 37.50, 37.39, 37.32, 34.39, 33.83, 32.38, 25.5
1, 24.27, 21.46, 20.84, 20.47, 20.13, 19.90, 18.4
3, 18.24, （重メタノール中のケミカルシフト）Embedded image The physicochemical properties of BM99-3 are shown below. (1) Mass spectrum (m / z): 805 (MH) - (by negative fab mass) (2) Ultraviolet absorption spectrum (nm): 388,300 (sh), 268,212
(In methanol solution) (3) 13 C-nuclear magnetic resonance spectrum (δ: ppm): 208.1
7, 190.66, 170.80, 166.65, 162.63, 156.79, 151.54,
145.31, 145.08, 139.27, 136.72, 133.71, 128.77, 1
22.78, 121.01, 115.74, 112.88, 106.23, 104.70, 10
1.74, 86.36, 71.26, 64.65, 62.38, 56.35, 56.01, 4
8.32, 44.66, 44.38, 43.52, 42.58, 41.94, 40.66, 40.
22, 37.50, 37.39, 37.32, 34.39, 33.83, 32.38, 25.5
1, 24.27, 21.46, 20.84, 20.47, 20.13, 19.90, 18.4
3, 18.24, (Chemical shift in heavy methanol)
【０００８】本発明におけるＢＭ９９−１、ＢＭ９９−
２およびはＢＭ９９−３の塩としては例えばナトリウ
ム、カリウム、カルシウム等のアルカリ金属との塩、ア
ンモニア、トリエチルアミン、エタノールアミン等の有
機アミンとの塩またはリジン、アルギニン等の塩基性ア
ミノ酸との塩など、生理学的に許容される塩があげられ
る。BM99-1 and BM99- in the present invention
Examples of the salts of 2 and BM99-3 include salts with alkali metals such as sodium, potassium and calcium, salts with organic amines such as ammonia, triethylamine and ethanolamine, or salts with basic amino acids such as lysine and arginine. , Physiologically acceptable salts.
【０００９】本発明の動脈硬化予防および治療剤として
用いる場合の投与量は、通常、投与方法、剤形によって
異なるが、成人で１日当たり１ｍｇから１ｇの範囲であ
る。この１日投与量を１日１回あるいは数回に分けて投
与する。また１日量は必要に応じて上記の量を超えて投
与してもさしつかえない。When used as a prophylactic or therapeutic agent for arteriosclerosis of the present invention, the dose is usually 1 mg to 1 g per day for an adult, although it varies depending on the administration method and dosage form. This daily dose is administered once or several times a day. Further, the daily dose may be administered in excess of the above dose as needed.
【００１０】本発明の動脈硬化予防および治療剤は投与
方法に応じて適当な剤型を選択し、通常行われている各
種剤型の調製法により製剤され、錠剤、散剤、顆粒剤、
カプセル剤、水剤およびシロップ剤などの経口用製剤、
経鼻製剤、経皮製剤などの外用製剤、注射剤、坐剤など
とすることができる。これらの製剤は、通常用いられる
公知の方法により製造することができる。The agent for preventing and / or treating arteriosclerosis of the present invention is prepared by selecting an appropriate dosage form according to the administration method and using various preparation methods commonly used to prepare tablets, powders, granules,
Oral formulations such as capsules, solutions and syrups,
It may be an external preparation such as a nasal preparation or a transdermal preparation, an injection, a suppository and the like. These preparations can be produced by a commonly used known method.
【００１１】次に製剤処方例を示す。 〔製剤例１〕 ＢＭ９９−２ １００ｇ コーンスターチ ４０ｇ アビセル ３０ｇ ステアリン酸マグネシウム ３ｇ ＢＭ９９−２、コーンスターチ、アビセルおよびステア
リン酸マグネシウムを混和し、打錠することにより、１
錠中ＢＭ９９−２を１００ｍｇ含有する錠剤を製造す
る。Next, an example of drug formulation will be shown. [Formulation Example 1] BM99-2 100 g Corn starch 40 g Avicel 30 g Magnesium stearate 3 g BM99-2, corn starch, Avicel and magnesium stearate are mixed and tableted to give 1
A tablet containing 100 mg of BM99-2 in the tablet is produced.
【００１２】〔製剤例２〕 ＢＭ９９−２ ２００ｍｇ ブドウ糖 ２５０ｍｇ 注射用蒸留水 適 量 注射用蒸留水にＢＭ９９−２およびブドウ糖を溶解させ
た後、アンプルに注入し窒素置換後１２１℃で１５分間
加圧殺菌し、上記組成の注射剤を得る。[Formulation Example 2] BM99-2 200 mg Glucose 250 mg Distilled water for injection Appropriate amount After dissolving BM99-2 and glucose in distilled water for injection, injected into an ampoule and replaced with nitrogen, and pressurized at 121 ° C. for 15 minutes Sterilize to obtain an injection having the above composition.
【００１３】[0013]
【実施例】次に、本発明化合物の生理活性について例を
挙げて説明する。EXAMPLES Next, the physiological activity of the compound of the present invention will be described with reference to examples.
【００１４】＜実施例１＞コレステリルエステル転送反
応阻害作用 コレステリルエステル転送反応阻害作用は、加藤らの方
法（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，Ｖｏｌ．２６４，Ｎ
ｏ．７，ｐ．４０８２−４０８７）に準じて行なった。
すなわち、［14Ｃ］コレステリルエステルで標識した再
構成ＨＤＬをドナーとし、ヒト血漿より調製したＬＤＬ
をアクセプターとして、阻害物存在下でのアクセプター
に転送された放射活性の変動をその物質の阻害活性とし
て測定した。その結果、ＢＭ９９−１のＩＣ50値は１３
０μＭ、ＢＭ９９−２のＩＣ50値は１２．４μＭであっ
た。Example 1 Inhibitory Action of Cholesteryl Ester Transfer Reaction The inhibitory action of cholesteryl ester transfer reaction was determined by the method of Kato et al. (J. Biol. Chem., Vol. 264, N.
o. 7, p. 4082-4087).
That is, LDL prepared from human plasma using reconstituted HDL labeled with [ 14 C] cholesteryl ester as a donor
Was used as the acceptor, and the change in radioactivity transferred to the acceptor in the presence of the inhibitor was measured as the inhibitory activity of the substance. As a result, the IC 50 value of BM99-1 was 13
The IC 50 value of 0 μM and BM99-2 was 12.4 μM.
【００１５】[0015]
【発明の効果】これらの結果から明らかなように、本発
明の有効成分であるＢＭ９９−１、ＢＭ９９−２および
ＢＭ９９−３はコレステリルエステル転送反応阻害作用
を有し、コレステリルエステル転送蛋白質が関与する動
脈硬化症などの様々な病態の治療および予防に有用であ
る。As is clear from these results, BM99-1, BM99-2 and BM99-3, which are the active ingredients of the present invention, have a cholesteryl ester transfer reaction inhibitory action and involve cholesteryl ester transfer protein. It is useful for treating and preventing various pathological conditions such as arteriosclerosis.
Claims (4)
１またはその塩を有効成分として含有するコレステリル
エステル転送反応阻害剤。 【化１】 1. A compound BM99- having the following structural formula:
A cholesteryl ester transfer reaction inhibitor containing 1 or a salt thereof as an active ingredient. Embedded image
２またはその塩を有効成分として含有するコレステリル
エステル転送反応阻害剤。 【化２】 2. A compound BM99- represented by the following structural formula:
A cholesteryl ester transfer reaction inhibitor containing 2 or a salt thereof as an active ingredient. Embedded image
たはその塩を有効成分として含有するコレステリルエス
テル転送反応阻害剤。 （１）質量分析値（m/z）：805(M-H)-（ネガティブファ
ブマスによる。） （２）紫外吸収スペクトル（nm）:388,300(sh),268,212
（メタノール溶液中） （３）13Ｃ−核磁気共鳴スペクトル（δ：ppm）：208.1
7, 190.66, 170.80, 166.65, 162.63, 156.79, 151.54,
145.31, 145.08, 139.27, 136.72, 133.71, 128.77, 1
22.78, 121.01, 115.74, 112.88, 106.23, 104.70, 10
1.74, 86.36, 71.26, 64.65, 62.38, 56.35, 56.01, 4
8.32, 44.66, 44.38, 43.52, 42.58, 41.94,40.66, 40.
22, 37.50, 37.39, 37.32, 34.39, 33.83, 32.38, 25.5
1, 24.27, 21.46, 20.84, 20.47, 20.13, 19.90, 18.4
3, 18.24, （重メタノール中のケミカルシフト）3. A cholesteryl ester transfer reaction inhibitor containing the compound BM99-3 having the following properties or a salt thereof as an active ingredient. (1) Mass spectrum (m / z): 805 (MH) - (by negative fab mass) (2) Ultraviolet absorption spectrum (nm): 388,300 (sh), 268,212
(In methanol solution) (3) 13 C-nuclear magnetic resonance spectrum (δ: ppm): 208.1
7, 190.66, 170.80, 166.65, 162.63, 156.79, 151.54,
145.31, 145.08, 139.27, 136.72, 133.71, 128.77, 1
22.78, 121.01, 115.74, 112.88, 106.23, 104.70, 10
1.74, 86.36, 71.26, 64.65, 62.38, 56.35, 56.01, 4
8.32, 44.66, 44.38, 43.52, 42.58, 41.94, 40.66, 40.
22, 37.50, 37.39, 37.32, 34.39, 33.83, 32.38, 25.5
1, 24.27, 21.46, 20.84, 20.47, 20.13, 19.90, 18.4
3, 18.24, (Chemical shift in heavy methanol)
９−１、ＢＭ９９−２およびＢＭ９９−３またはそれら
の塩を有効成分として含有する動脈硬化予防および治療
剤。4. The compound BM9 according to claims 1, 2 and 3.
An agent for preventing and treating arteriosclerosis containing 9-1, BM99-2 and BM99-3 or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23596495A JPH0959155A (en) | 1995-08-23 | 1995-08-23 | Cholesteryl ester transfer reaction inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23596495A JPH0959155A (en) | 1995-08-23 | 1995-08-23 | Cholesteryl ester transfer reaction inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0959155A true JPH0959155A (en) | 1997-03-04 |
Family
ID=16993827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23596495A Pending JPH0959155A (en) | 1995-08-23 | 1995-08-23 | Cholesteryl ester transfer reaction inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0959155A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002525351A (en) * | 1998-09-25 | 2002-08-13 | モンサント カンパニー | (R) -Chiral halogenated 1-substituted amino- (n + 1) -alkanols useful for inhibiting cholesteryl ester transfer protein activity |
| US7276536B2 (en) | 2003-03-17 | 2007-10-02 | Japan Tobacco Inc. | Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate |
| EP2316447A1 (en) | 2003-09-26 | 2011-05-04 | Japan Tobacco, Inc. | Method of inhibiting remnant lipoprotein production |
| WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
-
1995
- 1995-08-23 JP JP23596495A patent/JPH0959155A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002525351A (en) * | 1998-09-25 | 2002-08-13 | モンサント カンパニー | (R) -Chiral halogenated 1-substituted amino- (n + 1) -alkanols useful for inhibiting cholesteryl ester transfer protein activity |
| JP2002525348A (en) * | 1998-09-25 | 2002-08-13 | モンサント カンパニー | Substituted polycyclic aryl and heteroaryl tertiary heteroalkylamines effective for inhibiting cholesterol ester transfer protein activity |
| JP2007112804A (en) * | 1998-09-25 | 2007-05-10 | Pharmacia Corp | (r)-chiral halogenated 1-substituted amino-(n+1)-alkanol useful for inhibiting cholesteryl ester transfer protein activity |
| JP2007126460A (en) * | 1998-09-25 | 2007-05-24 | Pharmacia Corp | Substituted polycyclic aryl and heteroaryl tertiary heteroalkylamine useful for inhibiting cholesterol ester transfer protein activity |
| US7276536B2 (en) | 2003-03-17 | 2007-10-02 | Japan Tobacco Inc. | Method for increasing the bioavailability of the active form of S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino) phenyl] 2-methylpropanethioate |
| EP2316447A1 (en) | 2003-09-26 | 2011-05-04 | Japan Tobacco, Inc. | Method of inhibiting remnant lipoprotein production |
| EP2319509A1 (en) | 2003-09-26 | 2011-05-11 | Japan Tobacco, Inc. | Method of Inhibiting remnant lipoprotein production |
| WO2012027331A1 (en) | 2010-08-27 | 2012-03-01 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
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