WO1998012170A1 - Nouveaux derives tricycliques a anneaux condenses - Google Patents

Nouveaux derives tricycliques a anneaux condenses Download PDF

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Publication number
WO1998012170A1
WO1998012170A1 PCT/JP1997/003291 JP9703291W WO9812170A1 WO 1998012170 A1 WO1998012170 A1 WO 1998012170A1 JP 9703291 W JP9703291 W JP 9703291W WO 9812170 A1 WO9812170 A1 WO 9812170A1
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WO
WIPO (PCT)
Prior art keywords
group
aryl
compound
fused ring
lower alkyl
Prior art date
Application number
PCT/JP1997/003291
Other languages
English (en)
Japanese (ja)
Inventor
Koyo Matsuda
Masahiko Isaka
Tsukasa Ishihara
Hirotoshi Kakuta
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU42216/97A priority Critical patent/AU4221697A/en
Publication of WO1998012170A1 publication Critical patent/WO1998012170A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • 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
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones

Definitions

  • the present invention relates to a medicament, particularly a novel condensed tricyclic derivative having a squalene synthase inhibitory activity or a salt thereof, and a squalene synthase inhibitor containing these as an active ingredient.
  • Arteriosclerosis is known to cause various diseases. For example, mortality from ischemic heart disease caused by coronary atherosclerosis is the second highest in Japan after cancer, and cerebral infarction caused by cerebral atherosclerosis is associated with severe sequelae such as movement disorders and dementia. Have been. In addition, the various diseases caused by arteriosclerosis are on a growing trend due to the aging of the population and the westernization of the diet, and effective therapeutic agents are strongly desired.
  • triparanol known as an enzyme inhibitor located downstream of the cholesterol biosynthesis system, accumulates desmosterol, which causes cataracts.
  • the compound of the present invention has a structural feature in that it is a tricyclic fused ring derivative having a secondary aminoalkyl (alkenyl) oxy group, and has a strong squalene synthase inhibitory activity and It has pharmacological characteristics in that it has a cholesterol biosynthesis inhibitory effect.
  • the present invention relates to a medicament comprising a tricyclic fused ring derivative having an aminoalkyl (alkenyl) oxy group represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a squalene synthase.
  • a pharmaceutical comprising the compound (I) of the present invention having an inhibitory activity as an active ingredient, and a pharmaceutical comprising the compound (I) of the present invention having a squalene synthase inhibitory activity as a cholesterol-lowering agent, particularly hyperlipidemia.
  • lower alkyl group specifically refers to, for example, methyl, ethyl, propyl, butyl, pentyl (amyl), hexyl group, or their structural isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl. , Isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, isohexyl, 1-methylpentyl, 2-methylpentyl,
  • lower alkenyl group is specifically, for example, vinyl, 1-probenyl, arylene, 1-butenyl, 2-butenyl, 2-buten-2-yl, 1-pentenyl, 2-pentenyl, Examples include 1-hexenyl, 2-hexenyl and their structural isomers, preferably an aryl group.
  • Alkenylene group means a linear or branched alkenylene group having 2 to 10 carbon atoms, and specifically includes, for example, ethenylene, probenylene, butenylene, pentenylene, hexenylene, Heptenylene, octenylene, nonenylene, dekenylene, or their structural isomers, and preferably a butenylene group.
  • cycloalkyl group is a hydrocarbon ring group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. A cyclopropyl group and a cyclohexyl group.
  • the compound may have a substituent on one of the R 1 and R 2 groups, and may be a lower alkyl group or a lower alkenyl group, and may be substituted at the 1- or 3-position of the tricyclic fused ring group. It is a compound in which one ( ⁇ A—NH—R 3 group is substituted at the 2-position.
  • the ring group is
  • R, group, one of R 9 groups are substituted in the 1-position of the thick tricyclic fused ring group propyl or Ariru group, - 0 ⁇ A- NH- R 3 groups at the 2-position A compound in which A is ethylene, trimethylene or butenylene.
  • A is ethylene, trimethylene or butenylene.
  • the following compounds are exemplified as the most suitable compounds.
  • the compound (I) of the present invention may have an asymmetric carbon atom or a double bond depending on the type of the group. Accordingly, the compound (I) of the present invention includes a mixture of various isomers such as optical isomers, geometric isomers (cis-isomer, trans-isomer) and ill-isolated ones.
  • the compound (I) of the present invention can form an acid addition salt.
  • the compounds of the present invention also include these salts.
  • Specific examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • Organic acids such as acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.
  • the compound (I) of the present invention or a salt thereof, a hydrate, an ethanolate and the like may be isolated as various solvates or as a crystalline polymorphic substance thereof.
  • Various hydrates, solvates and polymorphic substances are also included.
  • the compound of the present invention represented by the general formula (I) can be synthesized, for example, by the following method, but the production method of the compound of the present invention is not limited thereto.
  • the present invention since the present invention includes novel intermediates, its production method is also described in detail.
  • Tricyclic phenol derivative which is an intermediate used in the synthesis of the compound (I) of the present invention (IV) can be synthesized as follows,
  • the rearrangement product (I Va) is obtained by subjecting the aryl ether (III) obtained by allylation of the hydroxyl group of a commercially available or known tricyclic phenol derivative (II) to a Claisen rearrangement reaction under heating at 200 ° C. Can be synthesized.
  • a compound having two arylyl groups can be obtained.
  • the aryl group of the compound (I Va) can be converted to a propyl group or a 3-hydroxypropyl group by catalytic reduction or hydroboration oxidation by a conventional method.
  • the compound (I) of the present invention is prepared by subjecting the tricyclic phenol derivative (IV) to a monoalkylation with a dialkylating agent (V) in the presence of a base (first step). It can be synthesized by reacting primary amine (second step). In addition, or when R 2 is an aryl group, the same conditions as in the first process In some cases, functional group conversion can be performed.
  • dialkylating agent (V) in the first step examples include dibromides such as 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, and 1,3-dichloropropane, 1,4-dichloro-2.
  • dibromides such as 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, and 1,3-dichloropropane, 1,4-dichloro-2.
  • dichlorides such as butene
  • mixed dihalides such as 1-bromo-13-chloropropane and the corresponding iodides
  • a leaving group other than a halogen atom an alkyne or alkene having a mesiloxy group, a tosyloxy group, or the like may be used.
  • Examples of the base used in the reaction include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydride, lithium hydride and the like.
  • As the reaction solvent dimethylformamide (DMF), dimethyl sulfoxide, acetate nitrile, acetone, 2-butanone, tetrahydrofuran (THF), ether, 1,2-dimethoxetane (DME), etc.
  • Rukoto can be used.
  • an excess (2 to 3 equivalents) of the alkylating agent (V) is added to the dimethylformamide, compound (IV), in the presence of an excess (1.5 to 2 equivalents) of potassium carbonate at room temperature. By stirring under reflux with heating, the desired compound (VI) can be obtained in good yield.
  • an excess amount of primary amine for example, isopropylamine
  • a solvent inert such as methanol, ethanol, isopropanol, THF, ether, and 1,2-dimethoxetane.
  • the compound (I) of the present invention thus produced is isolated and purified as a salt, a hydrate, a solvate, or a polymorphic substance as it is.
  • the salt of the compound (I) of the present invention can be produced by subjecting the salt to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers can be separated by selecting appropriate starting compounds or by utilizing the difference in physical properties between the isomers.
  • optical isomers can be prepared by selecting appropriate raw materials or by a racemic resolution method (for example, Derivation into diastereomeric salts with common optically active acids or bases, optical resolution, etc.) can lead to stereochemically pure isomers.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent squalinase inhibitory activity and an excellent in vivo cholesterol biosynthesis inhibitory activity based on this activity. Furthermore, it is also effective in experiments using cultured cells derived from humans, and is effective in the treatment of humans and warm-blooded animals caused by the action of cholesterol, especially hyperlipidemia in humans and familial hypercholesterolemia. Useful for prevention or treatment.
  • the compound of the present invention selectively inhibits squalencin enzyme, which is an enzyme located at the middle stage of the cholesterol biosynthesis system.
  • dolichol ubiquinone
  • isopentenyl tRNA p21Ras
  • low molecular weight G Enzyme inhibitors located early or late in the cholesterol biosynthesis system, such as the inhibition of the synthesis of important metabolites such as proteins and the development of hepatotoxicity (myopathy) due to the accumulation of harmful substances such as desmosterol, may be present. It has significantly reduced or no side effects.
  • the squalenthine inhibitory effect and cholesterol lowering effect of the compound of the present invention were confirmed by the following methods.
  • the culture medium is 10% Humanlipoproteinde ⁇ icientser um (LPD S)
  • the medium was replaced with DMEM and cultured for another 24 hours. This was washed twice with PBS, the cells were collected with a rubber policeman, and centrifuged. The precipitate was homogenized with 50 mM Hepes buffer (pH 7.5) containing 5 volumes of 5 mM EDTA. After centrifugation at 20,000 xg for 15 minutes, the supernatant was centrifuged again. The supernatant was further centrifuged at 100,000 X g for 1 hour, and the obtained microsomes were suspended in the same buffer and used as a HepG2 squalene synthase fraction for testing. Provided.
  • Sukuarenshin evening Ichize fraction prepared above protein amount 10 ng, 5 OmM He 6 3 buffer ( ⁇ 7. 5), 1 1 mM ⁇ a F, 5. 5 mM M g C 1 2, 3
  • Add the test drug in dimethyl sulfoxide to a solution consisting of mM DTT, 1 mM NAD PH, 1 mM pyrophosphate, 2.5 ⁇ M 3 H-FPP, bring the total volume to 0.2 ml, and shake at 30 for 20 minutes.
  • the reaction was stopped by adding 100% of a 20% potassium hydroxide-50% ethanol solution and heated for 30 minutes at 65.
  • 13 volumes were added to a liquid scintillation counter. were measured in one. by the 3 H radioactivity of non-saponified and the product after squalene cholesterol biosynthesis system, comparing the 3 H radioactivity of the for inhibitory effect of squalene sintering Ichize the test group the control group Asked by.
  • concentration (IC5 () value) at which the compound of the present invention inhibits squalene synthase by 50% was calculated.
  • a male SD rat 120 g to 150 g, 6 rats per group
  • 5 OmgZkg of the present compound was orally administered 5 OmgZkg of the present compound as a 0.5% methylcellulose solution.
  • the volume of the solution was 10 ml / Zkg, and only 0.5% methylcellulose was administered to the control group.
  • Oral administration was performed at 9:00 am and 7:00 pm for 2 days a day under satiety for 3 yen. The third mouth was fasted from 7:00 pm, and the last dose was administered at 9:00 am on the fourth day. Blood was collected 2 hours after the last administration, and the cholesterol level was measured with an automatic analyzer (Hitachi 736).
  • the compound of the present invention exhibited strong and inhibitory activity against human squalene synthase.
  • the compound of the present invention was also found to be effective in rat squalencin inhibitor assay.
  • the compound of the present invention exhibited a strong cholesterol lowering effect.
  • Compound (I) of the present invention or a pharmaceutically acceptable salt thereof (one or more of such)
  • Pharmaceutical compositions containing as an active ingredient tablets, powders, fine granules, granules, capsules, pills, liquids, etc., using carriers commonly used for formulation, excipients and other additives. It is prepared into injections, suppositories, ointments, patches, etc., and is administered orally (including sublingual administration) or parenterally.
  • the clinical dose of the compound (I) of the present invention to humans is appropriately determined according to the individual case in consideration of the symptoms of the patient to be applied, age of the subject to be administered, gender, and the like.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. , Mixed with magnesium aluminate metasilicate.
  • the composition may be formulated in accordance with the usual practice with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, gnoretamic acid. Alternatively, a solubilizing agent such as aspartic acid may be contained. Tablets or pills may be coated with gastric or enteric film such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcell orifice as needed.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Contains water and ethanol.
  • This composition may contain, in addition to the inert diluent, solubilizers, solubilizers, auxiliary agents such as wetting agents and suspending agents, sweeteners, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solutions and suspensions examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (trade name).
  • Such compositions may further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. .
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • These are, for example, filtered through a pacteria retention filter and sterilized by mixing with a fungicide by irradiation. They can also be used in the manufacture of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.
  • a mixed solution of ethyl acetate and hexane (15:85, 15 ml) was added to the obtained crystals, and the mixture was stirred under reflux with heating for 20 minutes, allowed to cool, and allowed to cool. Was collected by filtration as colorless crystals.
  • Example 18 The following compound of Example 18 was obtained in the same manner as in Example 1 ⁇ . -Example 18
  • Table 3 shows the chemical structural formulas of the compounds obtained in Examples 1 to 18 above.

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

Abstract

Cette invention se rapporte à des dérivés tricycliques à anneaux condensés représentés par la formule générale (I), qui s'avèrent utiles en tant qu'hypocholestérolémiants dotés d'une puissante activité inhibitrice sur les squalène synthases non associée à un quelconque effet secondaire. L'invention se rapporte également à des sels pharmaceutiquement acceptables de ces dérivés. Dans ladite formule (I), R1 et R2 sont identiques ou différents et sont chacun hydrogène, alkyle inférieur éventuellement substitué ou alknényle inférieur; X et Y sont identiques ou différents et sont chacun -CH2-, -CO-, -O- ou -NR4-; A est alkylène ou alkénylène; R3 est alkyle inférieur, cycloalkyle ou alkylaryle inférieur et R4 est hydrogène ou -CO-alkyle inférieur.
PCT/JP1997/003291 1996-09-20 1997-09-18 Nouveaux derives tricycliques a anneaux condenses WO1998012170A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42216/97A AU4221697A (en) 1996-09-20 1997-09-18 Novel tricyclic fused ring derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP24940396 1996-09-20
JP8/249403 1996-09-20

Publications (1)

Publication Number Publication Date
WO1998012170A1 true WO1998012170A1 (fr) 1998-03-26

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AU (1) AU4221697A (fr)
WO (1) WO1998012170A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0997458A1 (fr) * 1997-07-03 2000-05-03 Asahi Kasei Kogyo Kabushiki Kaisha Nouveaux composes tricycliques presentant des noyaux satures et compositions medicinales les contenant
JP2007315852A (ja) * 2006-05-24 2007-12-06 Mitsubishi Pharma Corp 脂質代謝異常症の予測方法
JP2010100573A (ja) * 2008-10-24 2010-05-06 Sumitomo Chemical Co Ltd キサンテン誘導体及び該誘導体を含有する熱可塑性ポリマー組成物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF PHARMACEUTICAL SCIENCES, 1994, Vol. 82, No. 3, SHORONG-SHI LIOU et al., "Gamma-Pyrone Compounds. 5. Synthesis and Antiplatelet Effects of Xanthonoxypropanolamines and Related Compounds", pages 391-395. *
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1996, Vol. 48, No. 9, CHUN-NAN LIN et al., "Synthesis and Antithrombic Effect of Xanthone Derivatives", pages 887-890. *
MEDICINAL CHEMISTRY RESEARCH, 1995, Vol. 5, No. 4, VALCINI PIERO et al., "Cholinergic Agents. Synthesis and Acetylcholinesterase Inhibitory Activity of Some Omega-[N-Methyl-N-(3-Alkylcarbamoyloxypheny l)-Methyl]Aminoalkoxyxanthen-9-Ones", pages 255-264. *
THROMBOSIS RESEARCH, 1994, Vol. 75, No. 1, WEN-YING CHEN et al., "The Effect of 3-[2-(Cyclopropylamino)Ethoxy]Xanthone on Platelet Thromboxane Formation", pages 81-90. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0997458A1 (fr) * 1997-07-03 2000-05-03 Asahi Kasei Kogyo Kabushiki Kaisha Nouveaux composes tricycliques presentant des noyaux satures et compositions medicinales les contenant
EP0997458A4 (fr) * 1997-07-03 2003-03-05 Asahi Chemical Ind Nouveaux composes tricycliques presentant des noyaux satures et compositions medicinales les contenant
JP2007315852A (ja) * 2006-05-24 2007-12-06 Mitsubishi Pharma Corp 脂質代謝異常症の予測方法
JP2010100573A (ja) * 2008-10-24 2010-05-06 Sumitomo Chemical Co Ltd キサンテン誘導体及び該誘導体を含有する熱可塑性ポリマー組成物

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