WO1992008712A1 - Derive de flavane ou son sel et nouveau procede de production - Google Patents

Derive de flavane ou son sel et nouveau procede de production Download PDF

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Publication number
WO1992008712A1
WO1992008712A1 PCT/JP1991/001529 JP9101529W WO9208712A1 WO 1992008712 A1 WO1992008712 A1 WO 1992008712A1 JP 9101529 W JP9101529 W JP 9101529W WO 9208712 A1 WO9208712 A1 WO 9208712A1
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WO
WIPO (PCT)
Prior art keywords
group
same
different
hydrogen atom
general formula
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Application number
PCT/JP1991/001529
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English (en)
Japanese (ja)
Inventor
Katuhiko Hamaguchi
Akio Koda
Hirokazu Yamamoto
Akira Miyake
Akira Isogai
Akinori Suzuki
Sheng-Ji Pei
Yan-Hui Li
Chun Wang
Chuan-de SONG
Pei-qiong SHEN
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Kunming Institute Of Botany Academia Sinica
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
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Application filed by Yamanouchi Pharmaceutical Co., Ltd., Kunming Institute Of Botany Academia Sinica filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1992008712A1 publication Critical patent/WO1992008712A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2

Definitions

  • the present invention relates to a novel flavan derivative having a phospholipase A 2 (PLA 2 ) inhibitory activity, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and a method for producing them.
  • PPA 2 phospholipase A 2
  • the novel compound of the present invention has a PLA 2 inhibitory effect and is useful as an anti-inflammatory agent and the like. That is, prostaglandins, leukotrienes, and the like have been conventionally known as in vivo substances involved in inflammation, allergy, and the like.
  • the mechanism of producing these in vivo substances is as follows. First, PLA 2 is activated by a variety of stimuli, Araki Don acid is liberated from the cell Macri phospholipid by for action of this enzyme, Burosutagura engine this Araki de phosphate as starting material, Roy co Application Benefits E down like Is synthesized in vivo.
  • PLA 2 is considered to be the rate-limiting enzyme in this series of in vivo reaction systems.
  • steroid drugs and non-steroid drugs are known as examples of anti-inflammatory drugs.
  • the former inhibits the biosynthetic pathways of both brostaglandin and leukotriene, and has strong anti-inflammatory effects, but often produces undesirable side effects.
  • the latter has a weaker anti-inflammatory effect than the former.
  • the compounds of the present invention Ki out to suppress prostaglandin and B A co Application Benefits E down both biosynthesis by inhibiting the activity of PLA 2, fewer side effects, may be potent anti-inflammatory agent. Also, an antiallergic agent can be provided. Furthermore, it can be expected that PLA 2 is ischemic vascular disorders are said to be involved, the compounds of the present invention is also applicable to ulcers, sepsis, treatment of such ⁇ is effective.
  • the present inventors have conducted a search study on compounds having PLA 2 inhibitory activity, and as a result, have found that a natural dirtaceous plant, Horsfieldia miguta * lin (Wonore) diving [Horsiieldia] amygdaline
  • the present inventors have further various attempts subscription the Synthesis of the compound or compounds that have a more PLA 2 inhibitory activity - results have advanced training, full Laban derivatives and represented by the following general formula (I) salt, the known compounds as anti-inflammatory effects superior based on PLA 2 inhibitory activity compared, Koa Rerugi - by findings that have an effect, was Itaritsu completed the present invention.
  • R 1 and R 1 are different or different from each other, and represent a hydrogen atom, a hydroxyl group, an aralkyl group or a lower alkoxy group
  • R 3 and R 4 are the same or different.
  • R 5 , R e and R 7 are the same or different and represent a hydroxyl group or a lower alkoxy group
  • Except for R 1 ⁇ beauty is hydroxyl, while the hydrogen atoms of R 3 and R 4, the other is a compound having a Dodekanoiru group of the formula one C (CH 2) 10 CH 3 . .)
  • an object of the present invention is to provide a flavan derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
  • It is another object of the present invention to provide a pharmaceutical composition comprising the above derivative or a salt thereof and a pharmaceutically acceptable carrier.
  • Still another object of the present invention is to provide a method for producing the above derivative or a salt thereof.
  • examples of the “lower acyloxy group” include, for example, a holmyloxy group, an acetoxy group, a propionyl group, a butyryl group, an isobutylyl group, a vivaloyl group, Hexanoyl groups and the like.
  • R 4 indicates "alkylcarbonyl group", preferably it has a carbon number of 1-20, specifically formyl group, Asechiru group, a propionyl group, a butyryl group, I Sobuchiriru group, valeryl group, Isobareriru Group, pivaloyl group, hexanoyl group, heptanyl group, heptanol group, nonanoyl group, decanoyl group, decaneyl group, dodecanoyl group, lauroyl group, tridecanol group, myristyl group Pentadecanoyl group, palmitoyl group, stearoyl group, icosanoyl group and the like.
  • the “aralkyl group” includes benzyloxy group, phenetine reoxy group, 1-phenylinoleoxy group, 3—phenylinolepropoxy group, 2-phenylinolepropoxy group, 1-phenylpropoxy group, 712
  • the compound of the present invention has a double bond, and may contain an asymmetric carbon atom depending on the type of the substituent. Therefore, the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers, and optical isomers, and isolated isomers.
  • the compound (I) of the present invention may form an acid addition salt.
  • a salt with a base may be formed.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, sulfuric acid, propionic acid, oxalic acid, malonic acid, Organic acids such as succinic acid, fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, etc., and acidic amino acids such as polyspartic acid and glutamic acid.
  • Inorganic bases such as acid addition salts with acids, sodium, calcium, magnesium, sodium cadmium, and anolemme
  • organic bases such as methylamine, ethylamine, ethanolamine, lysine, ordinium Examples thereof include salts with basic amino acids such as tin and ammonium salts.
  • the compound of the present invention and a salt thereof have a different basic skeleton or a different type of substituent. It can be manufactured by applying various synthesizing methods using the characteristics based on the above. The typical production method is illustrated below.
  • R 1 ′ and ′ are the same or different and represent a hydrogen atom, a hydroxyl group, an aralkyloxy group or a lower oxy group
  • R 3 ′ and R 4 ′ are the same or different and represent a hydrogen atom or an alkylcarbonyl group.
  • R 5 ′, R 6 / and R 7 ′ are the same or different and each represents a hydroxyl group or a lower alkoxy group.
  • an organic solvent such as ether, dioxane, tetrahydrofuran or the like is used in the presence of an acid catalyst such as hydrochloric acid, acetic acid, sulfuric acid or zinc tetrachloride.
  • an acid catalyst such as hydrochloric acid, acetic acid, sulfuric acid or zinc tetrachloride.
  • the target compound in which R 1 ′ and / or R 2 ′ is a hydroxyl group is obtained from the target compound having an aralkyloxy group in R 1 ′ and / or R 2 ′ as a raw material. It can be obtained by applying conventional methods such as catalytic reduction using palladium-carbon as a catalyst, reduction with sodium metal in liquid ammonia, or acid hydrolysis or alkaline hydrolysis.
  • the compound (I) of the present invention thus produced can be isolated by applying ordinary chemical operations such as recrystallization, extraction, and various types of chromatography. Purified.
  • the compound represented by the formula ( ⁇ ′) has stereoisomers such as optical isomers and geometric isomers, and the compound of the present invention is obtained as a mixture of these isomers. Can be separated by utilizing the difference in their physicochemical properties, and diastereomers can be separated by applying a conventional diastereomer separation method. Further, among the compounds (1 ′) of the present invention, those having a phenolic hydroxyl group can produce salts thereof.
  • the salt of the compound of the present invention is produced, for example, by subjecting it to a usual salt-forming reaction. Representative examples thereof include salts with inorganic salts such as sodium, potassium, magnesium, and calcium.
  • PLA 2 releases arachidonic acid from cell membrane phospholipids, and starting from this arachidonic acid, substances such as brostaglandin and loycotrien, which are involved in inflammation, allergy, etc. Synthesized in vivo.
  • the compounds of the present invention since having PLA 2 inhibitory activity, various diseases (inflammation (rheumatoid Riumachi due to physiological effects of PLA 2, organ inflammation), asthma, allergic diseases, ischemic vascular disease (myocardial infarction, cerebral It is useful for the treatment or control of infarction, ulcer, sepsis, ARDS, inflammation, etc.).
  • diseases inflammation (rheumatoid Riumachi due to physiological effects of PLA 2, organ inflammation), asthma, allergic diseases, ischemic vascular disease (myocardial infarction, cerebral It is useful for the treatment or control of infarction, ulcer, sepsis, ARDS, inflammation, etc.).
  • the compound of the present invention it is possible to suppress the biosynthesis of both flop Kuchisu Tagra down Gin and Roy co Toryen by inhibiting the activity of PLA 2, as compared to the steroid-based drugs and non-steroid drugs side effects Low anti-inflammatory and strong anti-allergic action.
  • L-Ct-1 Ichipa see Toiru 2 - Arakidoniru [Arakidoniru 1 - "C] -.
  • phosphatidylcholine PLA 2 as intracellular PL A 2
  • Homoji Ne one mouse peritoneal macro port off Aji
  • the enzyme reaction was performed using the substrate, 0.2 mM Triton X-100, 10 salted calcium carbonate, 250 AgZm bovine serum albumin, and 40% (v / v) glycerol.
  • the reaction was started by adding the enzyme and the compound of the present invention in a Tris-HCl buffer (50 mM, pH 8.0, total amount: 0.1).
  • the Dolls reagent (isopro Panol: heptane: 1 N sulfuric acid diacid 78: 20: 2) 0.5 was added to stop the reaction, distilled water 0.2 m heptane 0.3 was added, the mixture was centrifuged with stirring, and the supernatant was collected. Furthermore, 0.3 mZ of heptane and 40 mg of silica gel were added, and the mixture was centrifuged. Was separated Qing, liquid scintillator sheet Yo down counter -.
  • Examples 2 and IC 50 of PL A 2 inhibitory activity of the compound of Example 7 values respectively 3.7 X 10 "6 M and 8.0 X 10 -. Atsuta in 6 M formulation example
  • compositions containing one or more of the compound of the present invention or a salt thereof as an active ingredient include tablets, powders, and fine granules using commonly used carriers for pharmaceuticals, excipients, and other additives. Preparations, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., and are administered orally (including sublingually) or parenterally.
  • Examples of carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceutical substances. These include, for example, lactose, magnesium stearate, starch, tanolek, gelatin, agar, pectin, arabian gum, olive oil, sesame, oil, cocoa butter, ethylene glycol, and others commonly used. Is exemplified.
  • the clinical dose of the compound of the present invention is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which the compound is applied, and is usually 0.1 to 30 tu intravenously per adult day. The dose is 10 to 500 mg orally, and is to be administered once or in several divided doses.
  • the starting material compound of the present invention also contains a novel substance, and its production method is shown in Reference Examples.
  • Example 1 The cis-l7-benzyloxy-2 (4-i-n-dioxyphenyl)-4- (3-dodecanyl-24,6-trihydroxyloxyphenyl) chroman obtained in Example 1 was used as a starting compound, and Example 2 was repeated. In the same manner, cis-41 (3-dodecanol-1, 2, 4, 6-trihydroxifene) and 7-hydroxy-12- (4-hydroxyfrenole) chroman were obtained.
  • Example 5 7-benzyloxy-2- (4-benzyloxyphenyl) obtained in Example 5 141- (3,5-didocanyl-1,2,4,6-trihydroxybenzoyl) chromone 1.0 Then, 10% palladium-carbon 100 fflg was added to 50 ra of the methylene chloride solution, and the mixture was subjected to catalytic reduction for 4 hours. The reaction mixture was filtered to remove the palladium-carbon, the solvent was distilled off, and the residue was dried and dried (4,3,5-didodecanoyl 2,4,6—trihydroxy-2-yl) 1-7-hydroxy2— (4-Hydroxyphenyl) chroman 800 was obtained.
  • reaction mixture was filtered to remove palladium-carbon, and the solvent was distilled off.
  • residue was purified by silica column chromatography. From the fraction eluted with ethyl hexane monoacetate (2: 1), 4-(3,5-diisanolyl-l24, 6-trihydroxyl-ethanol) 7-hydroxyl There were obtained 780 mg of 1— (p-hydroxy ethoxylate) chromane.
  • Example 7 7-Benzene reoxy-1- (4- ⁇ -quinolone) xylene 4- (4-, 2-, 4,6-)-trihydroxy-2-isobutyrolopenone as a starting compound
  • 7-hydroxy-1- (p-hydroxyl-yl) -14- (3-isobutyryl 2,4,6-tri-hydroxyphenyl) chroman was obtained.
  • Example 7 Venzinole 2- (4-benzinole xifeninole) chroman 4-ol and 2,4-dioctanol-1,3,5-benzentriol were used as the starting compounds in Example 7 and In the same manner, forty-one (3,5-dioctanol-1,2,4,6-trihydroxyphenyl) -7-hydroxy-1- (p-hydroxyphenyl) chromans were obtained.
  • Cis-141 (3—dodecanol 2, 4, 6—trihydroquinine) 1 7-hydroxy-12- (4-hydroxy-2) chromane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivé de flavane représenté par la formule générale (I), son sel pharmaceutiquement acceptable, composition médicinale le contenant et son procédé de production. Le composé (I) présente une activité inhibant la phospholipase A2 (PLA2).
PCT/JP1991/001529 1990-11-08 1991-11-07 Derive de flavane ou son sel et nouveau procede de production WO1992008712A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2/303560 1990-11-08
JP30356090 1990-11-08
JP30356190 1990-11-08
JP2/303561 1990-11-08
JP3/108894 1991-04-12
JP10889491 1991-04-12

Publications (1)

Publication Number Publication Date
WO1992008712A1 true WO1992008712A1 (fr) 1992-05-29

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WO (1) WO1992008712A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074420A1 (fr) * 2006-12-19 2008-06-26 Intermed Discovery Gmbh Extraits de plantes pour une utilisation dans la modulation cérébrale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59210078A (ja) * 1983-02-16 1984-11-28 アルカロイダ・ベギエスゼテイ・ギヤル クロメン類の製造方法
JPS60224685A (ja) * 1984-03-31 1985-11-09 バイエル・アクチエンゲゼルシヤフト 置換ベンゾピラン類、その製造法及びその用途
JPH03157380A (ja) * 1989-11-13 1991-07-05 Yamanouchi Pharmaceut Co Ltd 新規フラバン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59210078A (ja) * 1983-02-16 1984-11-28 アルカロイダ・ベギエスゼテイ・ギヤル クロメン類の製造方法
JPS60224685A (ja) * 1984-03-31 1985-11-09 バイエル・アクチエンゲゼルシヤフト 置換ベンゾピラン類、その製造法及びその用途
JPH03157380A (ja) * 1989-11-13 1991-07-05 Yamanouchi Pharmaceut Co Ltd 新規フラバン誘導体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008074420A1 (fr) * 2006-12-19 2008-06-26 Intermed Discovery Gmbh Extraits de plantes pour une utilisation dans la modulation cérébrale
EP1939166A1 (fr) * 2006-12-19 2008-07-02 InterMed Discovery GmbH Extraits de plantes à utiliser dans une modulation cérébrale
JP2010513344A (ja) * 2006-12-19 2010-04-30 インターメッド ディスカヴァリー ゲゼルシャフト ミット ベシュレンクテル ハフツング 脳内活動変化において使用するための植物抽出物

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