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WO2001085670A1 - Derives d'acide malonanilique, compositions medicinales les contenant et leur utilisation - Google Patents

Derives d'acide malonanilique, compositions medicinales les contenant et leur utilisation Download PDF

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Publication number
WO2001085670A1
WO2001085670A1 PCT/JP2001/003499 JP0103499W WO0185670A1 WO 2001085670 A1 WO2001085670 A1 WO 2001085670A1 JP 0103499 W JP0103499 W JP 0103499W WO 0185670 A1 WO0185670 A1 WO 0185670A1
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Prior art keywords
group
alkyl
compound
nmr
acid
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PCT/JP2001/003499
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English (en)
Japanese (ja)
Inventor
Hiroaki Shiohara
Tetsuya Nakamura
Norihiko Kikuchi
Hideki Ohnota
Takashi Koizumi
Makio Kitazawa
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Kissei Pharmaceutical Co., Ltd.
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Priority to AU48847/01A priority Critical patent/AU4884701A/en
Publication of WO2001085670A1 publication Critical patent/WO2001085670A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D237/14—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to a malonanilide acid derivative useful as an agent for preventing or treating a circulatory disease, a pharmaceutical composition containing the same and a use thereof.
  • diet therapy and drug therapy are used for hyperlipidemia and arteriosclerosis.
  • clofibrate which has a blood neutral fat / cholesterol lowering effect, causes the accumulation of neutral fat in the liver as a side effect and causes liver hypertrophy.
  • diet therapy is generally used to improve it.
  • Interferon is used for hepatitis, but its application still has many challenges.
  • Japanese Patent Application Laid-Open No. Hei 6-172725 discloses that a heteroacetic acid derivative is useful as a hypercholesterolemia-lowering agent. It is stated that there is.
  • the malonanilide acid derivative of the present invention has a blood neutral fat and cholesterol lowering action and a liver function protecting or improving action in addition to a liver neutral fat accumulation suppressing or lowering action. What is effective for lipemia, arteriosclerosis, fatty liver, hepatitis, etc. Not reported.
  • the present inventors have conducted intensive studies to find a compound having both a blood lipid lowering effect and a liver neutral fat accumulation suppressing effect.
  • a malonanilide acid derivative represented by the following general formula (I) was obtained. Show an excellent blood triglyceride and cholesterol lowering action as well as an inhibitory or lowering action of hepatic triglyceride accumulation as described below. And obtained the present invention.
  • the present invention provides a compound represented by the general formula (I):
  • [W in the formula represents an oxygen atom, sulfur atom, methylene group, hydroxymethylene group, carbonyl group, sulfinyl group or sulfonyl group
  • R represents a hydrogen atom, an alkyl group or aryl (C i- 6 alkyl)
  • R 1 and R 2 may be the same or different and each represents a Ci- 3 alkyl group, trifluoromethyl group or halogen atom
  • R 3 is a hydrogen atom, — 3 alkyl group , A trifluoromethyl group or a halogen atom
  • Y is an alkyl group, a trifluoromethyl group, a 6-oxo_1,6-dihydropyridazine-13-ylmethyl group or a general formula -Q-T (wherein Q is an oxygen atom , A methylene group, a hydroxymethylene group or a hydroxyl group, and T represents a hydroxyl group, an alkyl group,
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a malonanilide acid derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention provides a method for treating hyperlipidemia, arteriosclerosis, fatty liver and hepatitis, which comprises, as an active ingredient, a malonanilide acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. It relates to a prophylactic or therapeutic agent.
  • the present invention provides a malonanilide acid derivative represented by the above general formula (I) for producing a preventive or therapeutic agent for hyperlipidemia, arteriosclerosis, fatty liver and hepatitis, or a pharmaceutically acceptable salt thereof.
  • a malonanilide acid derivative represented by the above general formula (I) for producing a preventive or therapeutic agent for hyperlipidemia, arteriosclerosis, fatty liver and hepatitis, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for administering an effective amount of a malonanilide acid derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, comprising hyperlipidemia, arteriosclerosis, and fatty liver. And a method for preventing or treating hepatitis.
  • Rupokishimechiru group means the above C E _ 6 alkyl group substituted by a carboxy group such as Karubokishechiru group, the alkyl group, methyl group, Echiru group, propylidene Or isopropyl group.
  • An alkoxy group is a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert —A linear or branched alkoxy group having 1 to 6 carbon atoms, such as a pentyloxy group and a hexyloxy group.
  • a C x - 6 alkyloxycarbonylalkyl) group is a methoxycarbonyl or ethoxycarbonyl group above ( ⁇ etc - 6 C ⁇ containing alkoxy group - refers to 6 substituted with alkoxide aryloxycarbonyl group (E group, the 3 alkoxy group, a methoxy group, an ethoxy group, a propoxy group or isopropoxy group
  • An aryl group is an aromatic carbon composed of one to three rings, such as a phenyl group and a naphthyl group.
  • a hydrogen radical Ariru - The (C ⁇ 6 alkyl) group, a benzyl group, refers to a phenethyl group, upper Symbol alkyl group substituted by the above ⁇ Li Ichiru group such as naphthylmethyl group, and Arirumechiru group, A methyl group substituted by the above aryl group such as a benzyl group, a naphthylmethyl group, etc.
  • a cycloalkyl group refers to a 5- to 6-membered saturated cyclic hydrocarbon group having an oxygen atom in the ring.
  • the cycloalkyl group refers to the above cycloalkyl group including a 5- to 6-membered saturated cyclic hydrocarbon group having an oxygen atom in the ring such as a tetrahydrofurer group, a tetrahydropyranyl group, etc., and cycloalkylmethyl
  • the group means a methyl group substituted by the above cycloalkyl group, and the cycloalkylmethyl group which may have an oxygen atom in the ring means an oxygen atom in the ring.
  • Halogen atom means a fluorine atom, chlorine atom, bromine atom or iodine atom.
  • the compound of the present invention represented by the general formula (I) is, for example,
  • L represents a hydrogen atom or a protecting group for a hydroxyl group
  • W 1 represents an oxygen atom, a sulfur atom, a methylene group, a hydroxymethylene group or a hydroxyl group
  • RR 2 R 3 , Y and Z Anilin derivatives represented by the same meaning as above
  • R 4 represents an alkyl group
  • a protective group of 7 acid groups is prepared. It can be produced by removing, oxidizing a sulfur atom or hydrolyzing an ester group. This reaction is represented by Scheme 1 below.
  • Compound (II) and 120 equivalents of compound (III) are reacted with an acid halide, a mixed acid anhydride, a reactive functional derivative such as an active ester or the like in a solvent-free or inert solvent such as tetrahydrofuran or methylene chloride.
  • Compound (IV) can be obtained by reacting at 0 ° C. to reflux temperature for 20 minutes to 24 hours, usually in the presence or absence of a base such as potassium carbonate, triethylamine, pyridine and the like.
  • the protecting group can be removed by appropriately treating the compound according to the kind of the protecting group by an ordinary method.
  • one or more equivalents of peroxy acid such as m-chloroperbenzoic acid and peracetic acid are used as an oxidizing agent in a solvent such as methylene chloride or tetrahydrofuran.
  • a solvent such as methylene chloride or tetrahydrofuran.
  • the ester group is hydrolyzed in the obtained compound (IV) or its sulfoxide derivative or sulfone derivative
  • the corresponding carboxylic acid derivative can be obtained by carrying out hydrolysis in a conventional manner.
  • the compound represented by the following general formula (la) can also be produced according to the reaction represented by the following scheme 2.
  • Compound (V) is prepared by using an oxidizing agent such as manganese dioxide or potassium permanganate in an inert solvent such as methylene chloride. After oxidizing for 17 hours at 0 ° C to reflux temperature, it is treated appropriately according to the type of hydroxyl-protecting group, if necessary. Removal of the protecting group gives compound (Ia).
  • an oxidizing agent such as manganese dioxide or potassium permanganate in an inert solvent such as methylene chloride. After oxidizing for 17 hours at 0 ° C to reflux temperature, it is treated appropriately according to the type of hydroxyl-protecting group, if necessary. Removal of the protecting group gives compound (Ia).
  • the compound represented by the following general formula (Ib) can also be produced according to the reaction represented by the following scheme 3.
  • compound (VI) is catalytically hydrogenated in a solvent such as tetrahydrofuran, methanol, ethanol, or ethyl acetate in the presence of a catalyst such as palladium carbon or platinum oxide, usually at room temperature to reflux for 148 hours at 15 atm.
  • a catalyst such as palladium carbon or platinum oxide
  • the compound represented by the following general formula (Ic) can also be produced according to the reaction represented by the following scheme 4.
  • Compound (VII) is usually reduced to 0 ° (: 1 to 48 hours at reflux temperature) using triethylsilane and trifluoroacetic acid or boron trifluoride getyl ether complex in a solvent such as methylene chloride. Accordingly, the compound (Ic) is obtained by appropriately treating the protective group according to the type of the protective group for the hydroxyl group and removing the protective group by a conventional method.
  • compound (VII) is catalytically hydrogenated in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, or acetic acid in the presence of a catalyst such as palladium carbon, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • a catalyst such as palladium carbon
  • X 1 in the formula represents a halogen atom or a hydroxyl group
  • Z 1 is a hydrogen atom or an alkoxy group
  • R, RR 2 , R 3 , T and W have the same meaning as described above.
  • Compound (VIII) is replaced with 1 to 2 equivalents of compound (IX), such as titanium tetrachloride.
  • the compound (X) is obtained by performing an acylation reaction by a Friedel-Craft reaction in a solvent such as methylene chloride in the presence of isocyanic acid or trifluoromethanesulfonic anhydride, usually at 0 to room temperature for 3 to 72 hours. Is obtained.
  • the resulting compound (X) is treated in a solvent such as methylene chloride in the presence of a Lewis acid such as titanium tetrachloride, usually at room temperature to reflux temperature for 3 to 72 hours, or in a solvent such as methylene chloride.
  • a Lewis acid such as titanium tetrachloride
  • boron trichloride, boron tribromide and other boron trihalides at a temperature of usually from 178 ° C to a reflux temperature for 1 to 24 hours, the compound ( I d) is obtained.
  • the ester group can be simultaneously converted to a carboxy group.
  • Compound (XI) was reduced in a polar solvent such as methanol or acetic acid using a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, usually at 0 ° C to room temperature for 1 to 48 hours. Thereafter, if necessary, the compound (Ie) is obtained by removing the protecting group by appropriately treating the protecting group according to the type of the 7-acid group according to a conventional method.
  • a polar solvent such as methanol or acetic acid
  • a reducing agent such as sodium borohydride or sodium triacetoxyborohydride
  • compound (XI) is usually prepared in a solvent such as tetrahydrofuran, methanol, ethanol or ethyl acetate in the presence of a catalyst such as palladium carbon, platinum oxide or the like, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • a catalyst such as palladium carbon, platinum oxide or the like
  • the compound (Ie) can be obtained by appropriately treating the protective group according to an ordinary method according to the type of the hydroxyl-protecting group to remove the protective group.
  • the compound represented by the following general formula (If) can also be produced according to the reaction represented by the following scheme 7.
  • T 3 in the formula is a hydroxyl group, an alkyl group, a Ci- 6 alkoxy group, a carboxy (Ci-e alkyl) group, an alkyloxycarbonylalkyl) group or an aryl group which may have a halogen atom as a substituent.
  • X 2 represents a halogen atom, and R, RR 2 , R 3 , W and Z 1 have the same meaning as described above
  • Compound (XII) is mixed with 1 to 1.5 equivalents of compound (XIII) in a solvent such as acetone, N, N-dimethylformamide, or dimethylsulfoxide in the presence of a base such as potassium carbonate or cesium carbonate.
  • Compound (XIV) is obtained by reacting at room temperature to reflux temperature for 1 to 48 hours.
  • the compound represented by the following general formula (Ig) can also be produced according to the reaction represented by the following scheme 8.
  • Compound (XV) is reduced with triethylsilane and trifluoroacetic acid in a solvent such as methylene chloride at a temperature of usually from 0 ° C to reflux for 1 to 48 hours.
  • Compound (Ig) is obtained by removing the protecting group by appropriate treatment according to a conventional method depending on the type of the compound.
  • the compound (XV) is contacted with a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, acetic acid, etc., in the presence of a catalyst such as palladium carbon, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • a catalyst such as palladium carbon
  • W 3 represents an oxygen atom or a sulfur atom
  • Y 3 represents an alkyl group, a 6-chloro-3-pyridazinylmethyl group or a general formula —Q—T (wherein Q and T are the same as above.
  • Y 4 represents an alkyl group, a 6-hydroxy-3-pyridazinylmethyl group having a protecting group or a Q—T
  • Z 2 and Z 3 represent a hydrogen atom or a —3 alkoxy group, or bind to Y 3 or Y 4 L, RR 2 , R 3 , X 2 , Y and Z have the same meaning as above)
  • the obtained compound (XX) is heated in a solvent such as tetrahydrofuran, methanol, ethanol, or ethyl acetate in the presence of a catalyst such as palladium carbon, platinum oxide or the like, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • a catalyst such as palladium carbon, platinum oxide or the like
  • the compound of the following general formula (lib) can be produced, for example, according to the reaction represented by the following scheme 10. .
  • L 1 represents a protecting group for a hydroxyl group
  • R 5 represents a protecting group for an amino group
  • L, RR 2 , R 3 , X 2 , ⁇ , ⁇ 4 , ⁇ and ⁇ 3 have the same meanings as described above.
  • the compound (XXII) is dissolved in an inert solvent such as tetrahydrofuran, and reacted with 1 to 1.5 equivalents of an organic lithium such as tert-butyllithium for 1 minute to 100 times for 20 minutes to 1 hour. Reaction with 7 to 1.5 equivalents of compound (XXI) at 100 ° C. to room temperature for 30 minutes to 2 hours, if necessary, depending on the type of hydroxyl-protecting group, appropriate treatment by a conventional method to protect the protecting group Is removed to obtain the compound (XXIII).
  • an inert solvent such as tetrahydrofuran
  • Compound (XXIV) is converted to a solvent such as methanol, acetic acid, or tetrahydrofuran in a polar solvent such as sodium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, or the like at 0 ° C to reflux temperature.
  • a polar solvent such as sodium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, or the like at 0 ° C to reflux temperature.
  • the compound (XXI II) is obtained by reduction for 1 to 48 hours.
  • Compound (XXIV) is dissolved in a solvent such as tetrahydrofuran, methanol, ethanol or ethyl acetate in the presence of a catalyst such as palladium carbon, platinum oxide or the like, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • Compound (XXIII) is obtained by reduction by catalytic hydrogenation.
  • the reaction is carried out at 00 ° C. to room temperature for 30 minutes to 2 hours. If necessary, the compound (XXIV) can be obtained by appropriately treating the protective group according to the type of the protective group for the hydroxyl group to remove the protective group. .
  • Compound (XXIII) is oxidized in an inert solvent such as methylene chloride using an oxidizing agent such as manganese dioxide or potassium permanganate at a temperature of usually from 0 ° C to a reflux temperature for 1 to 72 hours.
  • an oxidizing agent such as manganese dioxide or potassium permanganate
  • the compound (I) after appropriately treating the protecting group for the amino group and removing the protecting group according to the type of the protecting group for the amino group, if necessary, depending on the type of the protecting group for the ZR acid group, the compound (I) can be appropriately treated by a conventional method to remove the protecting group.
  • the compound of the following general formula (IId) can be produced, for example, according to the reaction represented by the following scheme 12. it can.
  • Compound (XXV II) was mixed with triethylsilane in a solvent such as methylene chloride. Using trifluoroacetic acid, reduction is usually carried out at 0 ° C to reflux temperature for 1 to 48 hours, and depending on the type of the protecting group for the amino group, appropriate treatment is carried out according to a conventional method to remove the protecting group.
  • Compound (IId) is obtained by appropriately treating the protective group according to the type of the protective group to remove the protective group.
  • Compound (XXV II) can be prepared by reacting compound (XXV II) in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, or acetic acid in the presence of a catalyst such as palladium carbon, at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atmospheres Catalytic hydrogenation and reduction, depending on the type of amino-protecting group, appropriate treatment according to a conventional method to remove the protecting group, and then, if necessary, according to the type of hydroxyl-protecting group, from the conventional method By treating to remove the protecting group, compound (IId) is obtained.
  • a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, or acetic acid
  • a catalyst such as palladium carbon
  • the compound of the following general formula (lie) can be produced, for example, according to the reaction represented by the following scheme 13. it can.
  • Compound (XXV III) is treated with 5 equivalents of compound (IX) in the presence of a Lewis acid such as titanium tetrachloride or a trianhydride,
  • the compound (XXIX) can be obtained by carrying out an acylation reaction by a Friedel-Crafts reaction in a solvent such as styrene, usually at 0 to room temperature for 3 to 72 hours.
  • the obtained compound (XX IX) is treated in a solvent such as methylene chloride in the presence of a Lewis acid such as titanium tetrachloride or concentrated acetic acid monoacetic acid at room temperature to reflux temperature for 3 to 72 hours, Alternatively, treatment with a solvent such as methylene chloride or the like in the presence of boron trihalide such as tetrachloroanilide tin, trichloroanilide boron, boron tribromide, etc., usually at 1 78 to reflux temperature for 1 to 24 hours After removing the group, the trifluoroacetyl group is removed in the presence of an alkali according to a conventional method, and if necessary, an appropriate protecting group is introduced into the 7-acid group by a conventional method to obtain the compound (lie). .
  • a Lewis acid such as titanium tetrachloride or concentrated acetic acid monoacetic acid
  • boron trihalide such as tetrachloroanilide
  • the compound of the following general formula (IIf) can be produced, for example, according to the reaction represented by the following scheme 14. It can.
  • Scheme 14 (Wherein M represents a hydrogen atom or an amino protecting group, and L, RR 2 , R 3 ,
  • the compound (IIf) can be obtained by removing the protecting group by appropriately treating the amino group according to the type of the protecting group.
  • compound (XXX) is contacted with a solvent such as tetrahydrofuran, methanol, ethanol, or ethyl acetate in the presence of a catalyst such as palladium carbon, platinum oxide, etc., at a normal room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm.
  • a catalyst such as palladium carbon, platinum oxide, etc.
  • the compound (IIf) can be obtained by appropriately treating the amino group according to the type of protecting group to remove the protecting group.
  • Step 2 Removal of protecting group for amino group
  • the resulting compound (XXXII) is treated with no solvent or in an inert solvent such as methylene chloride in the presence of a strong acid such as trifluoroacetic acid, usually at room temperature to reflux temperature for 1 to 48 hours to perform rearrangement.
  • a strong acid such as trifluoroacetic acid
  • the protecting group is removed by appropriate treatment according to a conventional method, and if necessary, a suitable protecting group is introduced to the hydroxyl group by a conventional method.
  • the compound of the following general formula (IIh) can be produced, for example, according to the reaction represented by the following scheme 16. it can.
  • Compound (XXXIII) is reduced with triethylsilane and trifluoroacetic acid in a solvent such as methylene chloride at 0 ° C to reflux temperature for 1 to 48 hours, and then, if necessary, according to the type of amino-protecting group.
  • the compound (Ilh) can be obtained by removing the protecting group by appropriate treatment according to a conventional method.
  • Compound (XXXIII) is dissolved in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, or acetic acid in the presence of a catalyst such as palladium carbon, usually at room temperature to reflux temperature for 1 to 48 hours at 1 to 5 atm. After reduction by catalytic hydrogenation, if necessary, the compound (IIh) is obtained by removing the protecting group by appropriately treating the amino group according to the type of protecting group by an ordinary method.
  • a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, or acetic acid
  • a catalyst such as palladium carbon
  • the compound of the following general formula (IIi) can be produced, for example, according to the reaction represented by the following scheme 17. it can.
  • Compound (XXX IV) was treated with a halogenating agent such as N-fluoro-6- (trifluoromethyl) pyridinium 2-sulfonate in a solvent such as methylene chloride, 1,2-dichloroethane or tetrahydrofuran at room temperature. After halogenation at about to reflux temperature for 12 to 24 hours, compound (IIi) can be obtained by removing the protecting group by appropriately treating the amino group according to the kind of protecting group for the amino group by a conventional method.
  • a halogenating agent such as N-fluoro-6- (trifluoromethyl) pyridinium 2-sulfonate
  • a solvent such as methylene chloride, 1,2-dichloroethane or tetrahydrofuran
  • Haldroxyl group as T 4 are substituents wherein the alkyl group, an alkoxy group, a carboxy alkyl) groups, C ⁇ alkyl O alkoxycarbonyl ( ⁇ DOO 6 ⁇ alkyl) group or a halogen atom may Ariru group or have a Represents a cycloalkyl group which may have an oxygen atom in the ring, and T 5 is a hydroxyl group as a substituent.
  • the compound of the following general formula (Ilk) can be produced, for example, according to the reaction represented by the following scheme 19. it can.
  • compound (XL) is converted to 1 to 5 atmospheres in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, acetic acid, etc., usually in the presence of a catalyst such as palladium carbon at room temperature to reflux temperature for 1 to 48 hours at 1 to 48 hours.
  • a catalyst such as palladium carbon at room temperature to reflux temperature for 1 to 48 hours at 1 to 48 hours.
  • Compound (III) is obtained by catalytic hydrogenation and reduction.
  • the compound of the following general formula (XXa) can be produced, for example, according to the reaction represented by the following scheme 21.
  • the compound (XL I) is 1 to 1.5 equivalents of the compound (IX), such as titanium tetrachloride.
  • the compound (XXa) is obtained by performing an acylation reaction by a Friedel-Crafts reaction in a solvent such as methylene chloride in the presence of a Lewis acid or trifluoromethanesulfonic anhydride, usually at 0 ° C to room temperature for 3 to 72 hours. Is obtained.
  • the compound of the general formula (XX) used in the production method can be produced, for example, according to the reaction represented by the following Scheme 22.
  • Compound (XXX IX) is dissolved in a polar solvent such as methanol, acetic acid or the like in sodium borohydride.
  • the compound (XXb) can be obtained by reduction using a reducing agent such as sodium triacetoxypol hydride and the like, usually at 0 ° C. to room temperature for 1 to 48 hours.
  • the compound (XL III) is rearranged by treating the compound (XL III) without solvent or in an inert solvent such as methylene chloride in the presence of a strong acid such as trifluoroacetic acid at room temperature to reflux temperature for 1 to 48 hours. Accordingly, compound (XXc) is obtained by introducing an appropriate protecting group into the hydroxyl group by a conventional method.
  • Compound (XXd) can be obtained by reducing compound (XL) with triethylsilane and trifluoroacetic acid in a solvent such as methylene chloride, usually at 0 ° C. to reflux temperature for 1 to 48 hours.
  • the compound represented by the general formula (XVI) can be produced according to a known method.
  • the general formula (XVI) can be produced according to a known method.
  • the general formula (XVI) can be produced according to a known method.
  • the compound represented by the general formula (XVIII) can be produced according to a known method.
  • a compound represented by the general formula (XXI) is oxidized under a Baeyer-Vi11iger condition using a peroxide acid such as m-chloroperbenzoic acid to obtain After hydrolyzing the resulting formate, if necessary, the method of MS Newman et al. (J. Org. Chem., Vol. 31, p p. 39 80-3984 (1966)) To a thiophenol derivative.
  • the compound represented by the general formula (XXI) is, for example, a compound represented by the general formula (XXI)
  • the compound represented by the general formula (XIX) can be produced according to a known method. For example, after a compound represented by the above general formula (XV II) wherein W 3 is an oxygen atom is reacted with trifluoromethanesulfonic anhydride and esterified,
  • the compound represented by the general formula (XV II) is, for example, a compound represented by the general formula:
  • RR 2 , R 3 and W 3 have the same meanings as above
  • the compound represented by the general formula (XXII) can be produced according to a known method. For example, after reducing the compound represented by the general formula (XIX) by catalytic hydrogenation in a solvent such as acetic acid, ethanol, ethyl acetate, or tetrahydrofuran using platinum oxide or palladium carbon as a catalyst, It can be produced by introducing an appropriate protecting group into an amino group by a conventional method.
  • a solvent such as acetic acid, ethanol, ethyl acetate, or tetrahydrofuran using platinum oxide or palladium carbon as a catalyst
  • the compound represented by the general formula (XXXV) is obtained by reducing the compound represented by the general formula (XXXVI) in a polar solvent such as methanol or acetic acid using a reducing agent such as sodium borohydride;
  • a polar solvent such as methanol or acetic acid
  • a reducing agent such as sodium borohydride
  • the obtained alcohol form is halogenated by using carbon tetrabromide and triphenylphosphine in a solvent such as tetrahydrofuran or methylene chloride to obtain a halogen form, and then triphenylphosphine is dissolved in a solvent such as toluene. It can be produced by reacting.
  • the protective group for the hydroxyl amino group used in the above-mentioned production method is described in, for example, "Protecti ve Grown Up Organic Synt hesis", TW Gr eeneetal., Wiley (1999). It can be appropriately selected and used according to the reaction conditions.
  • the compound of the present invention obtained in the above production method can be isolated and purified by a conventional separation means such as fractional recrystallization, purification using chromatography, solvent extraction, or the like. Can be manufactured.
  • the malonanilide acid derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method.
  • Such salts include addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Acid, propionic acid, cunic acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, addition salts with organic acids such as glutamic acid, aspartic acid, sodium salt, Examples thereof include salts with inorganic bases such as potassium salts and calcium salts, and addition salts with organic bases such as arginine, lysine, and tyrosine amide.
  • the compound represented by the general formula (I) of the present invention also includes hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.
  • the present invention includes any of the compounds in the R configuration, the compounds in the S configuration and mixtures thereof.
  • the compound of the present invention has an excellent blood neutral fat and non-HDL L cholesterol lowering action as well as an excellent liver neutral fat accumulation inhibitory and lowering action as shown in the following tests. Furthermore, for example, it significantly suppresses the elevation of ALT and AST values and has an excellent liver function protecting or improving effect. Therefore, the compounds of the present invention are useful for the prevention or treatment of cardiovascular diseases, particularly as agents for preventing or treating hyperlipidemia, arteriosclerosis, fatty liver, or for preventing hepatitis. Or it is extremely useful as a therapeutic agent.
  • the substituent W is preferably an oxygen atom.
  • substituent Y an alkyl group, a 6-oxo-1,6-dihydropyridazine-13-ylmethyl group and a general formula —Q 1 —T 1 (wherein Q 1 represents a methylene group or a hydroxymethylene group, 1 represents a hydroxyl group as a substituent, alkyl group, - 6 alkoxy groups, Karupokishi alkyl Le) group, - 6 alkyl O alkoxycarbonyl alkyl) group or a halogen atom which may Ariru groups have an oxygen atom in the ring May have Preferably a group represented by black alkyl represents a group or ring optionally cycloalkyl methylation group optionally having an oxygen atom in the), ⁇ - 6 alkyl group Contact Yopi formula one Q 2 - T 2 (wherein Q 2 in represents a
  • dosage forms are used depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and the like. Or it is administered parenterally.
  • compositions are suitable for use in pharmacy according to the dosage form.
  • Pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizing agents, etc. It can be manufactured by appropriately mixing or diluting / dissolving with and dispensing according to a conventional method.
  • the dose of the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient depends on the age of the patient, It is determined as appropriate depending on gender, body weight, disease, degree of treatment, etc., but in the case of oral administration, it is generally in the range of 1 g to 100 mg per day for adults, and in the case of parenteral administration, it is approximately 0.1 per day for adults. It can be administered once or several times as appropriate in the range of g to 3 Omg.
  • reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2-C4-benzyloxy-3- (4-fluorophenoxy) phenyl] 356 mg of 1,3-dioxolan was obtained.
  • the obtained residue was dissolved in ethanol (3 mL), 2 mol / L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 60 in an argon atmosphere for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized by adding 2mo 1ZL hydrochloric acid.
  • the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel thin-layer chromatography (developing solvent: hexane / monoethyl acetate). 14 lmg of monobenzyloxy 3- (4-fluorophenoxy) phenol was obtained.
  • the organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was suspended in 5 mL of hexane and 5 mL of getyl ether. After filtering off the insoluble material, the residue was washed with hexane to obtain 5.56 g of 5- (2,6-dimethyl-14-212-trophenoxy) -12-methoxybenzaldehyde.
  • the reaction mixture was concentrated under reduced pressure, and 25 OmL of methanol, 20 OmL of a 10% aqueous solution of sodium hydrogen sulfite, and 125 OmL of a 2 M aqueous solution of sodium tetrafluoroborate were sequentially added to the residue, followed by stirring for 2 hours. After the precipitate aggregated, the supernatant was removed. The residue is suspended in hexane, the insolubles are collected by filtration, washed with hexane, dried at 40 ° C under reduced pressure, and bis (4-benzyloxy-3-isopropylphenyl) tetrafluoroborate 55. 96 g of donium was obtained.
  • Trifluorophenylphosphonium chloride 50 Omg is suspended in dimethylsulfoxide (5 OmL), and sodium hydride (3 Omg) is added at room temperature. The mixture was stirred for 5 minutes. 0.1 mL of tetrahydropyran-4-one was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. Dilute hydrochloric acid was added dropwise to the reaction mixture to make it sufficiently acidic, and the mixture was extracted with ethyl acetate.
  • the obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain 205 mg of the olefin compound.
  • the obtained olefin form was dissolved in a mixed solvent of 10 mL of ethanol and 2 mL of ethyl acetate, 10 Omg of a 10% palladium-carbon catalyst was added under ice cooling, and the mixture was stirred at room temperature under a hydrogen atmosphere at normal pressure for 24 hours.
  • 2,6_Dimethyl-4_Nito-mouth benzenethiol 6.O g, bis (4-benzyloxy-3-isopropylphenyl) tetrafluoroborate 28.3 g, 2.71 g of copper powder at room temperature The suspension was suspended in 10 OmL, 6 mL of triethylamine was added with stirring, and the mixture was stirred at room temperature for 5 days. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the organic layer is washed successively with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried with 4- (4-benzyloxy-13-isopropylbenzyl) -3,5-dimethyl. 38 mg of ethyl maronanilide were obtained.
  • reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate.
  • the organic layer is washed with a 1: 1 mixed solution of saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue is subjected to silica gel thin-layer chromatography (eluent: hexane-hexane). (Ethyl acetate) to give 18 mg of 4- [3-[(4-fluorophenyl) hydroxymethyl] -14-hydroxyphenoxy] -3,5-dimethylmalonanilide acid ester. Obtained.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • organic layer was washed successively with a 10% aqueous sodium hydrogen sulfite solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (elution solvent: hexane-monoacetic acid ethyl) to give (1-) 1- [3-((4-fluorophenyl) hydroxymethyl] —4-hydroxyphenoxy] -1 0.315 g of 3,5-dimethylmalonanilide ethyl ester was obtained.
  • (+) 14- [3-((4-fluorophenyl) hydroxymethyl] sodium 4-hydroxyphenoxy 3,5-dimethylmalonanilide 1.0 g of L-tyrosinamide hydrochloride 0. 51 g was suspended in water 2 OmL and dissolved at 50 ° C. The mixture was cooled and stirred at room temperature, and the precipitate was collected by filtration. (+)-4-1 [3-[(4-Fluorophenyl) hydroxymethyl] -4-hydroxyphenoxy] —3,5-dimethylmalone 1, llg of anilide acid L-tyrosinamide salt was obtained.
  • TC total cholesterol
  • HDL cholesterol and triglyceride were determined using cholesterol C—test cholesterol,
  • Tridalicelide reduction rate (%) TG before administration of X100
  • the ethanol solution of the test drug was diluted 20-fold with a 0.5% carboxymethylcellulose aqueous solution and orally administered once daily at a dose of 5 mLZkg (final dose of the test drug was 30 nmo1 / kg).
  • final dose of the test drug was 30 nmo1 / kg.
  • a group to which a 5% carboxymethylcellulose aqueous solution was administered was provided for comparison.
  • the administration was continued for 2 weeks, and the whole day after the completion of the administration, blood was collected under ether anesthesia, and the liver was removed.
  • mice Male KK-Ay mice (35 to 45 g, manufactured by Nippon Clea Co., Ltd.) were bred under a normal diet for one day (CE-2 (Clea Japan Co., Ltd.)) under a feed restriction of about 7 g.
  • the ethanol solution of the test drug was diluted 20-fold with a 0.5% aqueous solution of carboxymethylcellulose, and orally administered once a day for 2 weeks at a dose of l OmLZkg (final dose of the test drug was 3 OnmolZkg).
  • a 0.5% aqueous solution of carboxymethylcellulose containing 5% ethanol was similarly administered.
  • the solution in the glass tube was dried under a nitrogen stream. After re-dissolving with 1 mL of Fo 1 ch solution, dispensing the required amount into a tube for measuring lipid and drying to dryness, use triglyceride E-Test Co. (Wako Pure Chemical Industries, Ltd.) to reduce the amount of triglyceride.
  • the triglyceride lowering activity was evaluated by measuring and calculating the amount of triglyceride per lg of the wet weight of the liver. The results are as shown in Table 3 below, and the compound of the present invention showed an excellent action of significantly reducing triglyceride in the liver.
  • an ethanol solution of the test drug was diluted 20-fold with a 0.5% strength aqueous solution of ropoxymethylcellulose and orally administered once daily for 5 days at a dose of 5 mL Zkg.
  • a 0.5% carboxymethylcellulose aqueous solution containing 5% ethanol was similarly administered.
  • lipopolysaccharide final dose of 5 ⁇ gZkg
  • D-galactosamine final dose of 70 OmgZkg
  • Test Example 5 Male Wistar rats were orally administered once a day for 20 weeks after a 20-fold dilution of a test drug ethanol solution in 0.5% carboxylmethylcellulose aqueous solution for 2 weeks. Observed.
  • the results are as shown in Table 5 below.
  • the compound of the present invention was a highly safe compound with no deaths observed at the following doses.
  • the malonanilide acid derivative represented by the general formula (I) of the present invention has an excellent blood triglyceride and non-HD L cholesterol lowering effect, and has an excellent hepatic triglyceride accumulation inhibitory or lowering effect. have. Further, the malonanilide derivative has a function of protecting or improving liver function. Therefore, the present invention can provide a drug suitable for preventing or treating circulatory diseases such as hyperlipidemia, arteriosclerosis, fatty liver, and hepatitis.

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Abstract

L'invention concerne des composés représentés par la formule générale ou leurs sels pharmacologiquement acceptables lesquels présentent d'excellents effets abaissant le niveau de matières grasses neutres et le niveau de cholestérol non-HDL dans le sang, inhibant ou supprimant l'accumulation de matières grasses neutres dans le foie et protégeant ou améliorant la fonction hépatique et, par conséquent, lesquels sont utiles en tant que préventifs ou remèdes contre des maladies circulatoires telles que l'hyperlipidémie, l'artériosclérose, la stéatose hépatique et l'hépatite, formule dans laquelle W représente oxygène, soufre, méthylène, etc.; R représente hydrogène, alkyle ou arylalkyle C1-6; R1 et R2 représentent chacun alkyle, halogéno, etc.; R3 représente hydrogène, alkyle, halogéno, etc.; Y représente alkyle, -Q-T (où Q représente oxygène, méthylène, hydroxyméthylène, etc.); et T représente aryle facultativement substitué, etc.); et Z représente hydrogène, alcoxy, etc..
PCT/JP2001/003499 2000-05-12 2001-04-24 Derives d'acide malonanilique, compositions medicinales les contenant et leur utilisation WO2001085670A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004500382A (ja) * 2000-02-17 2004-01-08 ブリストル−マイヤーズ　スクイブ　カンパニー 甲状腺受容体に対するアニリン系リガンド
WO2004085406A1 (fr) 2003-03-24 2004-10-07 F. Hoffmann-La Roche Ag Benzyl-pyridazinones en tant qu'inhibiteurs de transcriptase inverse
WO2007110225A1 (fr) * 2006-03-28 2007-10-04 Karo Bio Ab Matériau cristallin amélioré
US7279593B2 (en) 2001-08-24 2007-10-09 Karo Bio Ab Prime ring substituted thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US7342127B2 (en) 2003-01-24 2008-03-11 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor
US8877816B2 (en) 2007-11-21 2014-11-04 Decode Genetics Ehf 4-(or 5-) substituted catechol derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0580550A1 (fr) * 1992-07-21 1994-01-26 Ciba-Geigy Ag Dérivés de l'acide oxamique utilisés comme agents hypocholestérémiques
WO2000058279A1 (fr) * 1999-03-29 2000-10-05 Novartis Ag Derives diaryle et utilisations de ceux-ci comme medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0580550A1 (fr) * 1992-07-21 1994-01-26 Ciba-Geigy Ag Dérivés de l'acide oxamique utilisés comme agents hypocholestérémiques
WO2000058279A1 (fr) * 1999-03-29 2000-10-05 Novartis Ag Derives diaryle et utilisations de ceux-ci comme medicaments

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004500382A (ja) * 2000-02-17 2004-01-08 ブリストル−マイヤーズ　スクイブ　カンパニー 甲状腺受容体に対するアニリン系リガンド
US7109164B2 (en) 2000-02-17 2006-09-19 Bristol-Myers Squibb Company Aniline-derived ligands for the thyroid receptor
US7279593B2 (en) 2001-08-24 2007-10-09 Karo Bio Ab Prime ring substituted thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US7342127B2 (en) 2003-01-24 2008-03-11 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor
WO2004085406A1 (fr) 2003-03-24 2004-10-07 F. Hoffmann-La Roche Ag Benzyl-pyridazinones en tant qu'inhibiteurs de transcriptase inverse
US7189718B2 (en) 2003-03-24 2007-03-13 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
WO2007110225A1 (fr) * 2006-03-28 2007-10-04 Karo Bio Ab Matériau cristallin amélioré
EP2368873A1 (fr) * 2006-03-28 2011-09-28 Karo Bio Ab Matériau cristallin amélioré
US8877816B2 (en) 2007-11-21 2014-11-04 Decode Genetics Ehf 4-(or 5-) substituted catechol derivatives

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