JPH10287662A - Fo-5637a and b substance, and their production - Google Patents

Fo-5637a and b substance, and their production

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Publication number
JPH10287662A
JPH10287662A JP8932697A JP8932697A JPH10287662A JP H10287662 A JPH10287662 A JP H10287662A JP 8932697 A JP8932697 A JP 8932697A JP 8932697 A JP8932697 A JP 8932697A JP H10287662 A JPH10287662 A JP H10287662A
Authority
JP
Japan
Prior art keywords
substance
culture
substances
penicillium
present
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
Application number
JP8932697A
Other languages
Japanese (ja)
Inventor
Satoshi Omura
智 大村
Hiroshi Koda
洋 供田
Rokurou Masuma
碌郎 増間
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kitasato Institute
Original Assignee
Kitasato Institute
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kitasato Institute filed Critical Kitasato Institute
Priority to JP8932697A priority Critical patent/JPH10287662A/en
Publication of JPH10287662A publication Critical patent/JPH10287662A/en
Pending legal-status Critical Current

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  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Furan Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PROBLEM TO BE SOLVED: To obtain a new substance having an action for inhibiting a cholesteryl ester-transporting protein and useful for preventing and treating geriatric diseases such as cardiac infarction based on arteriosclerosis. SOLUTION: The substances are expressed by the formula. The physicochemical properties of the substances are follows. Molecular formula: C30 H30 O10 , mol.wt.: 550, specific rotary factor: [α]<23> D-223. (c=1, methanol), solubility in solvents: soluble in methanol, ethanol; the classification of basic, acidic or neutral substance: neutral, the color and shape of the substance: orange color powder, etc. The substance is obtained by culturing a microorganism [Penicillium s.p. FO-5637 (FERM P-16101)] belonging to the genus Penicillium and having an ability to produce the substance in a culture medium, accumulating the substance in the culture product and collecting the substance from the culture product.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【0001】[0001]

【発明の属する技術分野】本発明はFO−5637A物
質及びB物質並びにそれらの製造法に関する。更に詳し
くいえば、コレステリルエステル転送タンパク質阻害作
用を有する新規物質、FO−5637A物質及びB物質
並びにそれらの製造法に関する。
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to FO-5637 substances A and B and a method for producing them. More specifically, the present invention relates to novel substances having a cholesteryl ester transfer protein inhibitory activity, FO-5637A substances and B substances, and methods for producing them.

【0002】[0002]

【従来の技術】成人の高脂血症に起因する動脈硬化など
血管壁にコレステロールが蓄積することに基づく心筋硬
塞や脳卒中などに対するいくつかの予防治療剤は知られ
ていたが、未だに有効な物質は得られていない。
2. Description of the Related Art Some prophylactic and / or therapeutic agents for myocardial infarction and stroke based on the accumulation of cholesterol in blood vessel walls such as arteriosclerosis caused by hyperlipidemia in adults have been known, but are still effective. No substance was obtained.

【0003】[0003]

【発明が解決しようとする課題】近年、食生活の向上に
伴い成人の高脂血症に起因する動脈硬化など血管壁にコ
レステロールが蓄積し、心筋硬塞や脳卒中などの疾病に
よる死亡原因が上昇し、現代病として問題視されてい
る。血中ではコレステロールは主として長鎖脂肪酸によ
りエステル化され、コレステリルエステルとして低密度
リポタンパク質や高密度リポタンパク質中に取り込まれ
て循環している。
In recent years, cholesterol has accumulated in blood vessel walls such as arteriosclerosis caused by hyperlipidemia in adults with the improvement of dietary habits, and the cause of death due to diseases such as myocardial infarction and stroke has increased. And is regarded as a problem as a modern disease. In blood, cholesterol is mainly esterified by long-chain fatty acids, and is circulated as cholesteryl ester incorporated in low-density lipoproteins and high-density lipoproteins.

【0004】肝臓から供給されるコレステロールを末梢
組織へ輸送していく低密度リポタンパク質は動脈硬化を
促進する危険因子であるのに対し、高密度リポタンパク
質は逆に末梢組織からコレステロールを汲み出し、動脈
硬化の進展を抑制する因子と考えられている。この両リ
ポタンパク質間でコレステリルエステルの交換反応を司
るのがコレステリルエステル転送タンパク質であり、低
密度リポタンパク質の成熟化に関与している。
[0004] Low-density lipoprotein, which transports cholesterol supplied from the liver to peripheral tissues, is a risk factor for promoting arteriosclerosis, whereas high-density lipoprotein, on the other hand, pumps cholesterol out of peripheral tissues and causes arteriosclerosis. It is considered a factor that suppresses the progress of hardening. Cholesteryl ester transfer protein is responsible for the cholesteryl ester exchange reaction between both lipoproteins, and is involved in maturation of low density lipoprotein.

【0005】従って、このコレステリルエステル転送タ
ンパク質の機能を阻害する物質は、血中において、動脈
硬化の危険因子である低密度リポタンパク質量の低下、
逆に動脈硬化を抑制する高密度リポタンパク質量の上昇
による抗動脈硬化作用を惹起せしめ、かかる疾病に有効
と推察される。かかる実情において、コレステリルエス
テル転送タンパク質阻害活性を有する物質を提供するこ
とは、動脈硬化に基づく心筋硬塞や脳卒中などの成人病
の予防治療上きわめて有用なことである。
[0005] Therefore, substances that inhibit the function of this cholesteryl ester transfer protein can reduce the amount of low-density lipoprotein, which is a risk factor for arteriosclerosis, in blood.
Conversely, it induces an anti-atherosclerotic effect due to an increase in the amount of high-density lipoprotein that suppresses arteriosclerosis, and is presumed to be effective for such diseases. Under such circumstances, providing a substance having a cholesteryl ester transfer protein inhibitory activity is extremely useful for the preventive treatment of adult diseases such as myocardial infarction and stroke due to arteriosclerosis.

【0006】[0006]

【課題を解決するための手段】そこで、本発明者らは、
新規な生理活性物質の探索を目的として種々の土壌から
菌株を分離し、その生産する代謝産物について研究を続
けた結果、新たに土壌から分離したFO−5637菌株
の培養物中に、コレステリルエステル転送タンパク質阻
害活性を有する物質が産生されることを見出した。次い
で、該培養物から該コレステリルエステル転送タンパク
質阻害活性物質を分離、精製した結果、このような化学
構造を有する物質は従来全く知られていないことから、
本物質をFO−5637A物質及びB物質と称すること
にした。本発明は、かかる知見に基づいて完成されたも
のであって、下記式、
Means for Solving the Problems Accordingly, the present inventors have:
Isolation of strains from various soils for the purpose of searching for new physiologically active substances and continued research on the metabolites produced by the isolation resulted in the transfer of cholesteryl ester into cultures of FO-5637 strains newly isolated from soil. It has been found that a substance having a protein inhibitory activity is produced. Next, the cholesteryl ester transfer protein inhibitory active substance was separated and purified from the culture, and as a result, no substance having such a chemical structure has been known at all.
This substance was designated as FO-5637A substance and B substance. The present invention has been completed based on such knowledge, and the following formula,

【0007】[0007]

【化3】 で表される新規物質、FO−5637A物質を提供する
ものである。また本発明は下記の式、
Embedded image And FO-5637A. The present invention also has the following formula:

【0008】[0008]

【化4】 で表される新規物質、FO−5637B物質を提供する
ものである。
Embedded image And FO-5637B.

【0009】更に本発明は、ペニシリウム属に属し、F
O−5637A及びB物質を生産する能力を有する微生
物を培地に培養し、培養物にFO−5637A物質及び
B物質を蓄積せしめ、該培養物からFO−5637A物
質及びB物質を採取することを特徴とする新規物質FO
−5637A物質及びB物質あるいはそれらの塩の製造
法を提供するものである。
Further, the present invention belongs to the genus Penicillium,
A microorganism having the ability to produce O-5637A and B substances is cultured in a medium, FO-5637A substances and B substances are accumulated in the culture, and FO-5637A substances and B substances are collected from the culture. New substance FO
It is intended to provide a method for producing a substance 5637A and a substance B or a salt thereof.

【0010】本発明のFO−5637A物質及びB物質
を生産する能力を有する微生物(以下、FO−5637
物質生産菌と称する)は、ペニシリウム属に属するが、
例えば本発明らが沖縄県沖永良部島の土壌から新たに分
離したペニシリウム エスピー(Penicilliu
m sp.)FO−5637株は、本発明に最も有効に
使用される菌株の一例であって、本菌株の菌学的性質を
示すと下記の通りである。
A microorganism capable of producing the FO-5637A and B substances of the present invention (hereinafter referred to as FO-5637)
Substance-producing bacteria) belongs to the genus Penicillium,
For example, the present inventors have newly isolated Penicillium sp. From the soil of Okinoerabu Island in Okinawa Prefecture.
m sp. ) The FO-5637 strain is an example of a strain most effectively used in the present invention, and shows the bacteriological properties of the present strain as follows.

【0011】I.形態的性質 本菌株はツャペック・イーストエキストラクト寒天培地
(CYA)、麦芽汁寒天培地、バレイショ・ブドウ糖寒
天培地(PDA)などで良好に生育し、分生子の着生も
良好である。しかし、25%グリセリン・硝酸塩寒天培
地では、生育は抑制的であった。CYA培地に生育した
コロニーを顕微鏡観察すると、菌糸は透明で隔壁を有し
ており、分生子柄は基底菌糸より直生している。
I. Morphological properties This strain grows well on Tjapek yeast extract agar medium (CYA), wort agar medium, potato / glucose agar medium (PDA), etc., and has good conidia formation. However, the growth was inhibited on a 25% glycerin / nitrate agar medium. When the colonies grown on the CYA medium are observed under a microscope, the hyphae are transparent and have partition walls, and the conidiophores grow directly from the basal hyphae.

【0012】ペニシルスは複輪生である。フィアライド
はペン先型で5〜8本が輪生体を形成し、大きさは7.
5〜10×2〜2.5μmである。分生子は球形〜亜球
形で大きさは2.5μmである。表面は平滑である。
[0012] Penicillus is a bicyclic. The phialide is a nib type, and 5 to 8 phialides form a ring-shaped body, and the size is 7.
5 to 10 × 2 to 2.5 μm. Conidia are spherical to subspherical in shape and 2.5 μm in size. The surface is smooth.

【0013】II.各種培地上での培養性状 各種寒天培地上で25℃、7日間培養した場合の肉眼的
観察結果を表1に示した。なお、各種寒天培地におい
て、菌核の形成は観察されなかった。また、ツャペック
・イーストエキストラクト寒天培地(CYA)培地にお
ける37℃および5℃、7日間培養した場合、菌の生育
は観察されなかった。
II. Cultural properties on various media Table 1 shows the results of macroscopic observation when cultured on various agar media at 25 ° C for 7 days. No sclerotium formation was observed in various agar media. In addition, when the cells were cultured at 37 ° C. and 5 ° C. for 7 days in a Tjapek yeast extract agar medium (CYA) medium, no growth of the bacteria was observed.

【0014】[0014]

【表1】 [Table 1]

【0015】III.生理学的性質 1)最適生育条件 本菌の最適生育条件は、バレイショ・ブドウ糖寒天培地
(PDA)培地においてpH4〜7、温度は14〜26
℃である。 2)生育の範囲 本菌の生育範囲はPDA培地においてpH2〜8、温度
は9〜32℃である。 3)好気性、嫌気性の区別 好気性
III. Physiological properties 1) Optimum growth conditions The optimum growth conditions of the present bacterium are as follows: potato-glucose agar medium (PDA) medium, pH 4-7, temperature 14-26.
° C. 2) Range of growth The growth range of this bacterium is pH 2 to 8 and temperature is 9 to 32 ° C. in PDA medium. 3) distinction between aerobic and anaerobic aerobic

【0016】以上、本菌FO−5637株の形態的特
徴、培養性状および生理的性状に基づき、既知菌種との
比較を試みた結果、本菌株はペニシリウム(Penic
illium)属に属する一菌株と判断され、本菌株を
ペニシリウム エスピー(Penicillium s
p.)FO−5637と命名した。本菌株は、ペニシリ
ウム エスピー(Penicillium sp.)F
O−5637として、平成9年2月27日に茨城県つく
ば市東1丁目1番3号に所在する工業技術院生命工学工
業技術研究所にFERM P−16101として寄託さ
れている。
As described above, based on the morphological characteristics, culture characteristics, and physiological characteristics of the FO-5637 strain, a comparison with known strains revealed that the strain was Penicillium (Penicium).
It is determined that the strain belongs to the genus illium, and this strain is referred to as Penicillium sp.
p. ) FO-5637. This strain is Penicillium sp. F.
It was deposited as O-5637 on February 27, 1997 at the Institute of Biotechnology and Industrial Technology, Institute of Industrial Science, located at 1-3 1-3 Higashi, Tsukuba, Ibaraki Prefecture, Japan as FERM P-16101.

【0017】本発明の好ましい菌株として、FO−56
37物質生産菌について説明したが、菌の一般的性状と
して菌学上の性状はきわめて変異し易く、一定したもの
ではなく、自然的にあるいは通常行われる紫外線照射、
X線照射または変異誘導体剤、例えばN−メチル−N−
ニトロ−N−ニトロソグアニジン、エチルメタンスルホ
ネートなどを用いる人工的変異手段により変異すること
は周知の事実であり、このような人工的変異株は勿論、
自然変異株も含め、ペニシリウム属に属し、FO−56
37物質を生産する能力を有する菌株はすべて本発明に
使用することができる。また、細胞融合、遺伝子操作な
どの細胞工学的に変異させた菌株もFO−5637物質
生産菌として包含される。
A preferred strain of the present invention is FO-56
Although 37 substances producing bacteria have been described, as a general property of the bacteria, the mycological properties are extremely susceptible to variation, are not constant, and are naturally or normally performed by ultraviolet irradiation.
X-ray irradiation or mutant derivative agents such as N-methyl-N-
It is a well-known fact that mutation is performed by artificial mutation using nitro-N-nitrosoguanidine, ethyl methanesulfonate, or the like.
FO-56 belongs to the genus Penicillium, including spontaneous mutants.
All strains capable of producing 37 substances can be used in the present invention. Strains mutated by cell engineering such as cell fusion and genetic manipulation are also included as FO-5637 substance producing bacteria.

【0018】本発明においては、先ずペニシリウム属に
属するFO−5637物質生産菌が、適当な培地に培養
される。本菌の培養においては、通常の真菌の培養方法
が一般に適用される。培地としては微生物が同化し得る
炭素源、消化し得る窒素源、さらに必要に応じて無機塩
などを含有させた栄養培地が用いられる。
In the present invention, first, a FO-5637 substance-producing bacterium belonging to the genus Penicillium is cultured in an appropriate medium. In the cultivation of the fungus, ordinary fungal culturing methods are generally applied. As the medium, a nutrient medium containing a carbon source that can be assimilated by microorganisms, a nitrogen source that can be digested, and, if necessary, inorganic salts and the like is used.

【0019】上記の同化し得る炭素源としては、ブドウ
糖、ショ糖、糖密、澱粉、デキストリン、セルロース、
グリセリン、有機酸などが単独または組み合わせて用い
られる。消化し得る窒素源としては、ペプトン、肉エキ
ス、酵母エキス、乾燥酵母、大豆粉、コーン・スティー
プ・リカー、綿実粕、カゼイン、大豆蛋白加水分解物、
アミノ酸、尿素などの有機窒素源、硝酸塩、アンモニウ
ム塩などの無機窒素化合物が単独または組み合わせて用
いられる。
The assimilable carbon sources include glucose, sucrose, molasses, starch, dextrin, cellulose,
Glycerin, organic acids and the like are used alone or in combination. Digestible nitrogen sources include peptone, meat extract, yeast extract, dried yeast, soy flour, corn steep liquor, cottonseed meal, casein, soy protein hydrolyzate,
Organic nitrogen sources such as amino acids and urea, and inorganic nitrogen compounds such as nitrates and ammonium salts are used alone or in combination.

【0020】また、必要に応じてナトリウム塩、カリウ
ム塩、カルシウム塩、マグネシウム塩、リン酸塩などの
無機塩、重金属塩類が添加される。さらに、培地には、
必要に応じて、本菌の生育やFO−5637物質の生産
を促進する微量栄養素、発育促進物質、前駆物質を適当
に添加してもよい。
If necessary, an inorganic salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a phosphate, or a heavy metal salt is added. In addition, the medium contains
If necessary, micronutrients, growth promoting substances, and precursors that promote the growth of the bacterium and the production of the FO-5637 substance may be appropriately added.

【0021】培養は通常振とうまたは通気攪拌培養など
の好気的条件下で行うのがよい。工業的には深部通気攪
拌培養が好ましい。培地のpHは中性付近で培養を行う
のが好ましい。培養温度は20〜37℃の範囲でも行い
得るが、通常は24〜30℃、好ましくは27℃付近に
保つのがよい。培養時間は、液体培養の場合、通常3〜
6日培養を行うと、本物質FO−5637が生成蓄積さ
れるので、好ましくは培養中の蓄積量が最大に達したと
きに培養を終了すればよい。
The cultivation is usually carried out under aerobic conditions such as shaking or aeration-agitation culture. Industrially, deep aeration stirring culture is preferred. The culture is preferably carried out at a pH around neutrality. The cultivation temperature may be in the range of 20 to 37 ° C., but is usually maintained at 24 to 30 ° C., preferably around 27 ° C. The culturing time is usually 3 to
When the culture is performed for 6 days, the substance FO-5637 is produced and accumulated. Therefore, preferably, the culture should be terminated when the accumulated amount during the culture reaches the maximum.

【0022】これらの培養組成、培地の液性、培養温
度、攪拌速度、通気量などの培養条件は使用する菌株の
種類や外部の条件などに応じて好ましい結果が得られる
ように適宜調節、選択されることはいうまでもない。液
体培養において発泡があるときは、シリコン油、植物
油、界面活性剤などの消泡剤を適宜使用してもよい。
The culture conditions, such as the culture composition, the liquid properties of the medium, the culture temperature, the agitation speed, and the aeration rate, are appropriately adjusted and selected so as to obtain preferable results according to the type of the strain used and external conditions. Needless to say. When foaming occurs in the liquid culture, an antifoaming agent such as silicone oil, vegetable oil, or a surfactant may be appropriately used.

【0023】このようにして得られた培養物中に蓄積さ
れたFO−5637物質は、培養濾液または培養菌体中
に含まれているので、培養濾液を必要に応じて濾過補助
剤、例えばセライト、ハイフロースーパーセル等を加え
て濾過するか、または遠心分離して培養濾液と菌体とに
分離し、培養濾液と菌体との有機溶媒抽出物を濃縮した
ものの中からFO−5637物質を採取するのが有利で
ある。
Since the FO-5637 substance accumulated in the culture thus obtained is contained in the culture filtrate or the cultured cells, the culture filtrate may be used, if necessary, with a filter aid such as Celite. Add a high flow supercell, etc. and filter or centrifuge to separate the culture filtrate and the cells, and collect the FO-5637 substance from the concentrated organic solvent extract of the culture filtrate and the cells Advantageously.

【0024】また、培養濾液からFO−5637物質を
採取するには、先ず培養濾液を酢酸エチル、酢酸ブチ
ル、ベンゼンなどの非親水性有機溶媒で抽出し、抽出液
を減圧濃縮して粗製の物質、FO−5637物質が得ら
れる。該粗製物質はさらに脂溶性物質の精製に通常用い
られる公知の方法、例えばシリカゲル、アルミナなどの
担体を用いるカラムクロマトグラフイーによるFO−5
637物質を分離精製することできる。
In order to collect the FO-5637 substance from the culture filtrate, the culture filtrate is first extracted with a non-hydrophilic organic solvent such as ethyl acetate, butyl acetate or benzene, and the extract is concentrated under reduced pressure to obtain a crude substance. FO-5637 material is obtained. The crude substance is further purified by a known method usually used for purifying a fat-soluble substance, for example, FO-5 by column chromatography using a carrier such as silica gel or alumina.
637 substances can be separated and purified.

【0025】菌体からFO−5637物質を採取するに
は、菌体を含水アセトン、含水メタノールなどの含水親
水性有機溶媒で抽出し、得られた抽出液を減圧濃縮し、
その濃縮物を酢酸エチル、酢酸ブチル、ベンゼンなどの
非親水性有機溶媒で抽出し、得られた抽出液は、前記の
培養液から得た抽出液と合わせて分離精製するか、ある
いは前記と同じ方法によりFO−5637物質を分離精
製することができる。
To collect the FO-5637 substance from the cells, the cells are extracted with a water-containing hydrophilic organic solvent such as water-containing acetone and water-containing methanol, and the obtained extract is concentrated under reduced pressure.
The concentrate is extracted with a non-hydrophilic organic solvent such as ethyl acetate, butyl acetate, and benzene, and the obtained extract is separated and purified together with the extract obtained from the culture solution, or the same as above. The FO-5637 substance can be separated and purified by the method.

【0026】次に、本発明のFO−5637物質の理化
学的性状について述べる。 〔1〕FO−5637A物質 (1)分子式:C303010(高分解能FABマススペ
クトル(positive)でm/z551.1956
(M+H)が観察された)(計算値551.1970) (2)分子量:550(FABマススペクトル(pos
itive)よりm/z551(M+H)+ ,573
(M+Na)+ ,(negative)549(M−
H)- が観察された)
Next, the physicochemical properties of the FO-5637 substance of the present invention will be described. [1] FO-5637A substance (1) Molecular formula: C 30 H 30 O 10 (m / z 551.1956 by high-resolution FAB mass spectrum (positive))
(M + H) observed (calculated value 551.1970) (2) Molecular weight: 550 (FAB mass spectrum (pos
m / z 551 (M + H) + , 573
(M + Na) + , (negative) 549 (M−
H) - was observed)

【0027】(3)比旋光度:〔α〕D 23 −223°
(C=1、メタノール) (4)紫外線吸収スペクトル:メタノール中で測定した
紫外部吸収スペクトルは図1に示す通りであり、21
6、240、246(肩)、286、322(肩)、4
07nm付近に特徴的な吸収極大を示す (5)赤外部吸収スペクトル:臭化カリウム錠剤法で測
定した赤外部吸収スペクトルは図2に示す通りであり、
λmax KBr cm-1:3400、1624、1504、1
446、1388、1369、1180、1025に特
徴的な吸収帯を有する
(3) Specific rotation: [α] D 23 -223 °
(C = 1, methanol) (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in methanol is as shown in FIG.
6, 240, 246 (shoulder), 286, 322 (shoulder), 4
(5) Infrared absorption spectrum: the infrared absorption spectrum measured by the potassium bromide tablet method is as shown in FIG.
λ max KBr cm -1 : 3400, 1624, 1504, 1
Has characteristic absorption bands at 446, 1388, 1369, 1180, 1025

【0028】(6)溶媒に対する溶解性:メタノール、
エタノール、アセトニトリル、酢酸エチル、クロロホル
ム、ジメチルスルホキシドに可溶、水に不溶 (7)塩基性、酸性、中性の区別:中性 (8)物質の色、形状:橙色粉末
(6) Solubility in solvent: methanol,
Soluble in ethanol, acetonitrile, ethyl acetate, chloroform, dimethyl sulfoxide, insoluble in water (7) Basic, acidic, neutral: neutral (8) Color and shape of substance: orange powder

【0029】(9)プロトン核磁気共鳴スペクトル:V
arian社製、核磁気共鳴スペクトロメータを用いて
測定したプロトン核磁気共鳴スペクトル(重クロロホル
ム中で測定、400MHz)は図3に示すとおり (10)カーボン核磁気共鳴スペクトル:Varian
社製、核磁気共鳴スペクトロメータを用いて測定したカ
ーボン核磁気共鳴スペクトル(重クロロホルム中で測
定、100MHz)は図4に示すとおり (11)化学構造:下記式の通り
(9) Proton nuclear magnetic resonance spectrum: V
The proton nuclear magnetic resonance spectrum (measured in deuterated chloroform, 400 MHz) measured using a nuclear magnetic resonance spectrometer manufactured by Arian Co. as shown in FIG. 3 (10) Carbon nuclear magnetic resonance spectrum: Varian
The carbon nuclear magnetic resonance spectrum (measured in deuterated chloroform, 100 MHz) measured using a nuclear magnetic resonance spectrometer manufactured by the company is as shown in FIG. 4 (11) Chemical structure:

【0030】[0030]

【化5】 Embedded image

【0031】〔2〕FO−5637B物質 (1)分子式:C20206 (高分解能FABマススペ
クトル(positive)でm/z357.1338
(M+H)が観察された)(計算値 357.133
8) (2)分子量:356(FABマススペクトル(pos
itive)よりm/z357(M+H)+ ,379
(M+Na)+ が観察された)
[2] FO-5637B substance (1) Molecular formula: C 20 H 20 O 6 (m / z 357.1338 by high-resolution FAB mass spectrum (positive))
(M + H) observed) (calcd 357.133)
8) (2) Molecular weight: 356 (FAB mass spectrum (pos
m / z 357 (M + H) + , 379
(M + Na) + was observed)

【0032】(3)比旋光度:〔α〕D 23 −220°
(C=1、メタノール) (4)紫外線吸収スペクトル:メタノール中で測定した
紫外部吸収スペクトルは図5に示す通りであり、20
8、226(肩)、263、297(肩)、356、3
72、435nm付近に特徴的な吸収極大を示す (5)赤外部吸収スペクトル:臭化カリウム錠剤法で測
定した赤外部吸収スペクトルは図6に示す通りであり、
λmax KBr cm-1:3400、1595、1458、1
419、1383、1294、1215、1165、1
128、1036に特徴的な吸収帯を有する
(3) Specific rotation: [α] D 23 -220 °
(C = 1, methanol) (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in methanol is as shown in FIG.
8, 226 (shoulder), 263, 297 (shoulder), 356, 3
(5) Infrared absorption spectrum: The infrared absorption spectrum measured by the potassium bromide tablet method is as shown in FIG.
λ max KBr cm -1 : 3400, 1595, 1458, 1
419, 1383, 1294, 1215, 1165, 1
Has characteristic absorption bands at 128 and 1036

【0033】(6)溶媒に対する溶解性:メタノール、
エタノール、アセトニトリル、酢酸エチル、クロロホル
ム、ジメチルスルホキシドに可溶、水に不溶 (7)塩基性、酸性、中性の区別:中性 (8)物質の色、形状:橙色粉末
(6) Solubility in solvent: methanol,
Soluble in ethanol, acetonitrile, ethyl acetate, chloroform, dimethyl sulfoxide, insoluble in water (7) Basic, acidic, neutral: neutral (8) Color and shape of substance: orange powder

【0034】(9)プロトン核磁気共鳴スペクトル:V
arian社製、核磁気共鳴スペクトロメータを用いて
測定したプロトン核磁気共鳴スペクトル(重クロロホル
ム中で測定、400MHz)は図7に示すとおり (10)カーボン核磁気共鳴スペクトル:Varian
社製、核磁気共鳴スペクトロメータを用いて測定したカ
ーボン核磁気共鳴スペクトル(重クロロホルム中で測
定、100MHz)は図8に示すとおり (11)化学構造:下記式の通り
(9) Proton nuclear magnetic resonance spectrum: V
Proton nuclear magnetic resonance spectrum (measured in deuterated chloroform, 400 MHz) measured using a nuclear magnetic resonance spectrometer manufactured by Arian Co. as shown in FIG. 7 (10) Carbon nuclear magnetic resonance spectrum: Varian
The carbon nuclear magnetic resonance spectrum (measured in deuterated chloroform, 100 MHz) measured by using a nuclear magnetic resonance spectrometer manufactured by the company is shown in FIG. 8 (11) Chemical structure:

【0035】[0035]

【化6】 Embedded image

【0036】次に本発明のFO−5637物質の生物学
的性質および阻害活性について述べる。 (1)ヒト由来コレステリルエステル転送タンパク質に
対する阻害作用 コレステリルエステル転送タンパク質に対する影響はヒ
ト血漿より調整した粗タンパク質を用いKato等
(J.Biol.Chem.264,4082−408
7,1989)の方法に従った。
Next, the biological properties and inhibitory activity of the FO-5637 substance of the present invention will be described. (1) Inhibitory effect on cholesteryl ester transfer protein derived from human The effect on cholesteryl ester transfer protein was determined by using a crude protein prepared from human plasma using Kato et al. (J. Biol. Chem. 264, 4082-408).
7, 1989).

【0037】即ち、〔1−14C〕コレステリルエステル
を含む再構成の高密度リポタンパク質(High de
nsity lipoprotein;以下HDLと称
す)25μl、ヒト由来の低密度リポタンパク質(Lo
w density lipoprotein;以下L
DLと称する)10μl、7mMの5,5−ジチオビス
ニトロ安息香酸30μl、3mM脂肪酸10μl、部分
精製したヒトコレステリルエステル転送タンパク質5μ
lを合わせ、全部で150μlの反応系で37℃、30
分間反応させた。
[0037] That is, [1-14 C] high density lipoprotein reconstruction including cholesteryl esters (High de
25 μl of nsity lipoprotein (hereinafter referred to as HDL), low-density lipoprotein (Lo)
w density lipoprotein; hereinafter L
DL) 10 μl, 7 mM 5,5-dithiobisnitrobenzoic acid 30 μl, 3 mM fatty acid 10 μl, partially purified human cholesteryl ester transfer protein 5 μl
and a total of 150 μl of the reaction system at 37 ° C. and 30 ° C.
Allowed to react for minutes.

【0038】反応後、0.1%デキストラン硫酸5μ
l、6mM MgCl2 5μl、イオン強度0.16に
調整したリン酸緩衝液20μlを加え、氷上で20分間
放置させた。続いて4℃、13,000rpm、15分
間遠心し、LDLを沈澱画分として集め、0.1N N
aOH180μlにLDLを溶解させ、液体シンチレー
ションカウンターでLDLに転送されたコレステリルエ
ステルの転送量を測定した。本タンパク質によるコレス
テリルエステル転送活性を50%阻害する薬剤濃度を算
定した結果は、FO−5637A物質では40μg/m
lであり、FO−5637B物質では17μg/mlで
あった。
After the reaction, 0.1% dextran sulfate 5 μm
1, 5 mM of 6 mM MgCl 2 and 20 μl of a phosphate buffer adjusted to an ionic strength of 0.16 were added, and the mixture was allowed to stand on ice for 20 minutes. Subsequently, the mixture was centrifuged at 13,000 rpm for 15 minutes at 4 ° C., and LDL was collected as a precipitate fraction.
LDL was dissolved in 180 μl of aOH, and the amount of cholesteryl ester transferred to LDL was measured by a liquid scintillation counter. The result of calculating the concentration of the drug that inhibits the cholesteryl ester transfer activity by 50% by the present protein is 40 μg / m for the FO-5637A substance.
1 and 17 μg / ml for the FO-5637B material.

【0039】以上のように、本発明のFO−5637物
質はコレステリルエステル転送タンパク質に対して著し
い阻害活性を示すことから、ヒトのコレステロール蓄積
に起因する疾病の予防および治療に有用であると考えら
れる。
As described above, since the FO-5637 substance of the present invention has a remarkable inhibitory activity against cholesteryl ester transfer protein, it is considered to be useful for prevention and treatment of diseases caused by cholesterol accumulation in humans. .

【0040】[0040]

【実施例】次に、実施例を挙げて本発明を具体的に説明
するが、本発明はこれのみに限定されるものではない。
500ml容三角フラスコにグルコース2.0%、イー
ストエキストラクト0.2%、MgSO4 ・7H2
0.05%、ポリペプトン0.5%、KH2 PO4 0.
1%および寒天0.1%を含む培地(pH6.0に調
製)100mlを仕込み、綿栓後、蒸気滅菌し、寒天培
地上に生育させたペニシリウム エスピー(Penic
illium sp.)FO−5637(FERM P
−16101)を白金耳にて無菌的に接種し、27℃で
96時間振とう培養して種培養液を得た。
EXAMPLES Next, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.
500ml erlenmeyer flasks glucose 2.0%, yeast extract 0.2%, MgSO 4 · 7H 2 O
0.05%, polypeptone 0.5%, KH 2 PO 4 0.
100 ml of a medium (prepared at pH 6.0) containing 1% and 0.1% agar was charged, cotton-plugged, steam-sterilized, and grown on an agar medium, Penicillium sp.
illium sp. ) FO-5637 (FERM P
-16101) was aseptically inoculated with a platinum loop and shake-cultured at 27 ° C. for 96 hours to obtain a seed culture.

【0041】一方、30l 容ジャーファーメンター1基
に、スクロース2.0%、グルコース1.0%、コーン
スティープ・リカー1.0%、肉エキス0.5%、KH
2 PO4 0.1%、MgSO4 ・7H2 O 0.05
%、微量金属としてFeSO4・7H2 O 1g/l、
MnCl2 ・4H2 O 1g/l、ZnSO4 ・7H2
O 1g/l、CuSO4 ・5H2 O 1g/l、Co
Cl2 ・2H2 O 1g/lを合わせて200ml、C
aCO3 0.3%、寒天0.1%(pH6.0に調製)
に仕込み、蒸気滅菌冷却後、種培養した種培養液200
mlを無菌的に移植し、攪拌速度250rpm、通気量
10リットル/分の培養条件下で27℃で96時間通気
攪拌培養した。
On the other hand, sucrose 2.0%, glucose 1.0%, corn steep liquor 1.0%, meat extract 0.5%, KH
2 PO 4 0.1%, MgSO 4 · 7H 2 O 0.05
%, FeSO 4 · 7H 2 O 1g / l as trace metals,
MnCl 2 · 4H 2 O 1g / l, ZnSO 4 · 7H 2
O 1g / l, CuSO 4 · 5H 2 O 1g / l, Co
200 ml combined with 1 g / l of Cl 2 .2H 2 O, C
aCO 3 0.3%, agar 0.1% (adjusted to pH 6.0)
, And then steam-sterilized, cooled, and then seed-cultured.
The mixture was aseptically transplanted, and cultured under aeration and agitation at 27 ° C. for 96 hours at a stirring speed of 250 rpm and an aeration rate of 10 L / min.

【0042】培養後、培養液を酢酸エチル18リットル
で抽出し、抽出液を減圧濃縮して粗製物5.12gを得
た。この粗製物をヘキサン、メタノール、水(40:1
9:1)で分配させ、下層に分配されたFO−5637
物質を集め、減圧濃縮して粗製物1.4gを得た。この
粗製物をアセトニトリル10mlに懸濁し、ODS(2
40ml、センシュー社製、SSC−ODS−7515
−12)のカラムにチャージし、0.05%リン酸を含
むアセトニトリルで溶出するカラムクロマトグラフイー
を行った。
After the culture, the culture was extracted with 18 liters of ethyl acetate, and the extract was concentrated under reduced pressure to obtain 5.12 g of a crude product. This crude product was treated with hexane, methanol and water (40: 1).
9: 1) and FO-5637 distributed to the lower layer
The material was collected and concentrated under reduced pressure to give 1.4 g of crude. This crude product was suspended in 10 ml of acetonitrile, and ODS (2
40 ml, manufactured by Senshu, SSC-ODS-7515
-12), the column was charged, and column chromatography was performed by elution with acetonitrile containing 0.05% phosphoric acid.

【0043】各フラクションは10mlづつ分画し、活
性成分を含むフラクションを集め、アセトニトリルを除
いた後、水層画分を酢酸エチルで抽出し、それを減圧乾
固して粗活性物質94mgと、102mgとをそれぞれ
得た。94mgの粗活性物質を5回に分けて高速液体ク
ロマトグラフイーにより分離精製した。装置はトリロー
タV(日本分光社製)を用い、カラムはYMC−Pac
k A−343(ODS系樹脂、山村化学研究所製)を
用い、溶媒系は48%のアセトニトリル水(0.05%
リン酸を含む)を用い、検出はUV225nm、流速は
6ml/分で行った。その結果、FO−5637A物質
の23mgを得た。
Each fraction was fractionated in 10 ml portions, the fraction containing the active ingredient was collected, and after removing acetonitrile, the aqueous layer fraction was extracted with ethyl acetate, which was dried under reduced pressure to obtain 94 mg of a crude active substance. 102 mg each. 94 mg of the crude active substance was separated and purified by high performance liquid chromatography in 5 divided portions. The device used was Trirotor V (manufactured by JASCO Corporation) and the column was YMC-Pac.
kA-343 (ODS resin, manufactured by Yamamura Chemical Laboratory) was used, and the solvent system was 48% acetonitrile water (0.05%
(Including phosphoric acid), and detection was performed at UV 225 nm at a flow rate of 6 ml / min. As a result, 23 mg of FO-5637A substance was obtained.

【0044】また、前記102mgの粗活性物質を5回
に分けて高速液体クロマトグラフイーにより分離精製し
た。装置はトリロータV(日本分光社製)を用い、カラ
ムはYMC−Pack A−343(ODS系樹脂、山
村化学研究所製)を用い、溶媒系は45%のアセトニト
リル水(0.05%リン酸を含む)を用い、検出はUV
225nm、流速は6ml/分で行った。その結果、F
O−5637B物質の9.5mgを単離した。
The 102 mg of the crude active substance was separated and purified by high-performance liquid chromatography in 5 divided portions. The apparatus used was Trirotor V (manufactured by JASCO Corporation), the column used was YMC-Pack A-343 (ODS resin, manufactured by Yamamura Chemical Laboratory), and the solvent system was 45% acetonitrile water (0.05% phosphoric acid). And UV detection
The measurement was performed at 225 nm at a flow rate of 6 ml / min. As a result, F
9.5 mg of O-5637B material was isolated.

【0045】[0045]

【発明の効果】以上のとおり、ペニシリウム属に属する
FO−5637A物質及びB物質を生産する能力を有す
る微生物を培地に培養して、その培養物中にFO−56
37A物質及びB物質を蓄積せしめ、該培養物からFO
−5637A物質及びB物質を採取することにより、コ
レステリルエステル転送タンパク質阻害活性を有する物
質が得られ、該物質は動脈硬化に基づく心筋硬塞や脳卒
中などの成人病の予防、治療効果が期待される。
As described above, a microorganism having the ability to produce FO-5637A and B substances belonging to the genus Penicillium is cultured in a medium, and FO-56 is contained in the culture.
The substances 37A and B were accumulated and FO was recovered from the culture.
A substance having cholesteryl ester transfer protein inhibitory activity can be obtained by collecting -5637A substance and B substance, and this substance is expected to have the effect of preventing and treating adult diseases such as myocardial infarction and stroke based on arteriosclerosis. .

【図面の簡単な説明】[Brief description of the drawings]

【図1】本発明によるFO−5637A物質の紫外線吸
収スペクトルである。
FIG. 1 is an ultraviolet absorption spectrum of FO-5637A substance according to the present invention.

【図2】本発明によるFO−5637A物質の赤外線吸
収スペクトルである。
FIG. 2 is an infrared absorption spectrum of FO-5637A substance according to the present invention.

【図3】本発明によるFO−5637A物質のプロトン
核磁気共鳴スペクトルである。
FIG. 3 is a proton nuclear magnetic resonance spectrum of the FO-5637A substance according to the present invention.

【図4】本発明によるFO−5637A物質のカーボン
核磁気共鳴スペクトルである。
FIG. 4 is a carbon nuclear magnetic resonance spectrum of the FO-5637A material according to the present invention.

【図5】本発明によるFO−5637B物質の紫外線吸
収スペクトルである。
FIG. 5 is an ultraviolet absorption spectrum of the FO-5637B substance according to the present invention.

【図6】本発明によるFO−5637B物質の赤外線吸
収スペクトルである。
FIG. 6 is an infrared absorption spectrum of FO-5637B substance according to the present invention.

【図7】本発明によるFO−5637B物質のプロトン
核磁気共鳴スペクトルである。
FIG. 7 is a proton nuclear magnetic resonance spectrum of the FO-5637B substance according to the present invention.

【図8】本発明によるFO−5637B物質のカーボン
核磁気共鳴スペクトルである。
FIG. 8 is a carbon nuclear magnetic resonance spectrum of the FO-5637B material according to the present invention.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 FI C12N 1/14 C12N 1/14 A C12P 17/04 C12P 17/04 17/16 17/16 //(C12N 1/14 C12R 1:80) (C12P 17/04 C12R 1:80) (C12P 17/16 C12R 1:80) ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code FI C12N 1/14 C12N 1/14 A C12P 17/04 C12P 17/04 17/16 17/16 // (C12N 1/14 C12R 1 : 80) (C12P 17/04 C12R 1:80) (C12P 17/16 C12R 1:80)

Claims (6)

【特許請求の範囲】[Claims] 【請求項1】 下記式 【化1】 で表されるFO−5637A物質またはその塩。[Claim 1] The following formula: Or a salt thereof. 【請求項2】 下記式 【化2】 で表されるFO−5637B物質またはその塩。2. The following formula: Or a salt thereof. 【請求項3】 ペニシリウム属に属し、FO−5637
A物質及びB物質を生産する能力を有する微生物を培地
に培養して、その培養物中にFO−5637A物質及び
B物質を蓄積せしめ、該培養物からFO−5637A物
質及びB物質を採取することを特徴とするFO−563
7A物質及びB物質あるいはそれらの塩の製造法。
3. FO-5637 belonging to the genus Penicillium
Culturing a microorganism capable of producing substances A and B in a culture medium to accumulate FO-5637A and B in the culture, and collecting FO-5637A and B from the culture; FO-563 characterized by the following
Method for producing 7A and B substances or salts thereof.
【請求項4】 ペニシリウム属に属し、FO−5637
A物質及びB物質を生産する能力を有する微生物が、ペ
ニシリウム エスピー(Penicillium s
p.)FO−5637である請求項3に記載の製造法。
4. FO-5637 belonging to the genus Penicillium
Microorganisms having the ability to produce substance A and substance B are Penicillium sp.
p. 4. The method according to claim 3, wherein the method is FO-5637.
【請求項5】 ペニシリウム属に属し、FO−5637
A物質及びB物質を生産する能力を有する微生物。
5. FO-5637 belonging to the genus Penicillium
A microorganism capable of producing the substance A and the substance B.
【請求項6】 微生物が、ペニシリウム エスピー(P
enicillium sp.)FO−5637(FE
RM P−16101)である請求項5に記載の微生
物。
6. The method according to claim 6, wherein the microorganism is penicillium sp.
enicilium sp. ) FO-5637 (FE
The microorganism according to claim 5, which is RMP-16101).
JP8932697A 1997-04-08 1997-04-08 Fo-5637a and b substance, and their production Pending JPH10287662A (en)

Priority Applications (1)

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US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
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US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6521607B1 (en) 1999-09-23 2003-02-18 Pharmacia Corporation (R)-chiral halogenated substituted N-phenoxy N-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6562860B1 (en) 1998-12-23 2003-05-13 G. D. Searle & Co. Combinations of ileal bile acid transport inhibitors and bile acid sequestering agents for cardiovascular indications
US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US6638969B1 (en) 1998-12-23 2003-10-28 G.D. Searle, Llc Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
US6677382B1 (en) 1999-09-23 2004-01-13 Pharmacia Corporation Substituted N,N-bis-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
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US6787570B2 (en) 1999-09-23 2004-09-07 Pfizer, Inc. Substituted N-cycloalkyl-N-benzyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
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US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7235259B2 (en) 2000-08-03 2007-06-26 Pfizer Inc Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
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
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US6784201B2 (en) 1994-09-13 2004-08-31 G.D. Searle & Company Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
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US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6458850B1 (en) 1998-12-23 2002-10-01 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications
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US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
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US6890958B2 (en) 1998-12-23 2005-05-10 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
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US6723753B2 (en) 1999-09-23 2004-04-20 Pharmacia Corporation Substituted n-benzyl-n-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6476057B1 (en) 1999-09-23 2002-11-05 G.D. Searle & Co. Use of substituted N, N-disubstituted cycloalkyl aminoalcohol compounds for inhibiting cholesteryl ester transfer protein activity
US6544974B2 (en) 1999-09-23 2003-04-08 G.D. Searle & Co. (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesteryl ester transfer protein activity
US6476075B1 (en) 1999-09-23 2002-11-05 G.D. Searle & Co. Use of substituted N, N-bis-benzyl aminoalcohol compounds inhibiting cholesteryl ester transfer protein activity
US6462092B1 (en) 1999-09-23 2002-10-08 G.D. Searle & Co. Use of substituted N, N-disubstituted reverse aminoalcohol compounds for inhibiting cholesteryl ester transfer protein activity
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US7253211B2 (en) 1999-09-23 2007-08-07 Pfizer Inc. (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesterol ester transfer protein activity
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US6699898B2 (en) 1999-09-23 2004-03-02 Pharmacia Corporation Global Patent Department Substituted N,N-disubstituted non-fused heterocyclo amino compounds useful for inhibiting cholesteryl ester transfer protein activity
US6710089B2 (en) 1999-09-23 2004-03-23 Pharmacia Corporation Substituted N-fused-phenyl-N-benzyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6479552B2 (en) 1999-09-23 2002-11-12 G.D. Searle & Co. Use of substituted N, N-disubstituted diamino compounds for inhibiting cholesteryl ester transfer protein activity
US6723752B2 (en) 1999-09-23 2004-04-20 Pharmacia Corporation (R)-chiral halogenated substituted n-benzyl-n-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US7122536B2 (en) 1999-09-23 2006-10-17 Pfizer Inc. (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesterol ester transfer protein activity
US6765023B2 (en) 1999-09-23 2004-07-20 Pfizer, Inc. Use of substituted N, N-disubstituted reverse aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6458852B1 (en) 1999-09-23 2002-10-01 G.D. Searle & Co. Use of substituted N, N-bis-phenyl aminoalcohol compounds for inhibiting cholesteryl ester transfer protein activity
US6787570B2 (en) 1999-09-23 2004-09-07 Pfizer, Inc. Substituted N-cycloalkyl-N-benzyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6803388B2 (en) 1999-09-23 2004-10-12 Pfizer, Inc. (R)-Chiral halogenated substituted n,n-bis-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity
US6448295B1 (en) * 1999-09-23 2002-09-10 G.D. Searle & Co. Use of substituted N-fused-phenyl-N-benzyl aminoalcohol compounds for inhibiting cholesteryl ester transfer protein activity
US6451823B1 (en) * 1999-09-23 2002-09-17 G.D. Searle & Co. Use of substituted N-phenoxy-N-phenyl aminoalcohol compounds for inhibiting cholesteryl ester transfer protein activity
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US8389011B2 (en) 2000-08-03 2013-03-05 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7115279B2 (en) 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US7235259B2 (en) 2000-08-03 2007-06-26 Pfizer Inc Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8197848B2 (en) 2000-08-03 2012-06-12 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
US8048452B2 (en) 2000-08-03 2011-11-01 Bend Research, Inc. Pharmaceutical compositions of cholesteryl ester transfer protein inhibitor
US7887840B2 (en) 2001-06-22 2011-02-15 Bend Research, Inc. Pharmaceutical compositions comprising drug and concentration-enhancing polymers
US6740663B2 (en) 2001-11-02 2004-05-25 G.D. Searle, Llc Mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
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
EP2098512A1 (en) 2003-10-08 2009-09-09 Eli Lilly &amp; Company Compounds and methods for treating dyslipidemia
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WO2008060476A2 (en) 2006-11-15 2008-05-22 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
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