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WO1997015546A1 - Derives d'acide carboxylique et compositions pharmaceutiques - Google Patents

Derives d'acide carboxylique et compositions pharmaceutiques Download PDF

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Publication number
WO1997015546A1
WO1997015546A1 PCT/JP1996/003056 JP9603056W WO9715546A1 WO 1997015546 A1 WO1997015546 A1 WO 1997015546A1 JP 9603056 W JP9603056 W JP 9603056W WO 9715546 A1 WO9715546 A1 WO 9715546A1
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WIPO (PCT)
Prior art keywords
compound
dimethyl
hydrogen
tert
alkyl
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PCT/JP1996/003056
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English (en)
Japanese (ja)
Inventor
Tomiyoshi Aoki
Kenji Kuwabara
Original Assignee
Nippon Shinyaku Co., Ltd.
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Publication of WO1997015546A1 publication Critical patent/WO1997015546A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings

Definitions

  • the present invention relates to a novel carboxylic acid derivative and a pharmaceutically acceptable salt thereof, and a solvate thereof.
  • TC blood cholesterol
  • Lp lipoprotein
  • Lp (a) is similar in structure to plasminogen, it is thought to be involved in the suppression of fibrin degradation in blood and to inhibit the fibrinolytic system (Fibrinolysis, 5, 135 (1991)). .
  • Lp (a) promotes the proliferation of vascular smooth muscle cells because it suppresses the activation of TGF-(Transforming Growth Factor ⁇ ) by suppressing the production of plasman (Science, 260 , 1655 (1993)). From these facts, it is considered that substances that lower the Lp (a) value suppress thrombotic and proliferative vascular stenosis and suppress the onset of ischemic heart disease.
  • Lp (a) levels are independent of other risk factors for ischemic heart disease, including TC values, and are independent risk factors (Clin. Chem., 36, 20). (1990); "Lipoprotein (a)", 151, Scanu A (ed), New York, Academic Press (1990)).
  • high Lp (a) increases the risk of coronary artery disease in patients with high TC or a major component of low-density lipoprotein cholesterol (Atherosclerosis, 62, 249). (1986)).
  • a compound having both a TC lowering effect and an Lp (a) lowering effect is considered to be more useful as an anti-arteriosclerosis agent.
  • 2,2-Dimethyl- ⁇ -aryloxycarboxylic acid derivative is a lipid in blood
  • An object of the present invention is to provide a novel compound which has both a TC lowering action and an Lp (a) lowering action and is more useful as an anti-atherosclerotic agent.
  • the present invention provides a carboxylic acid derivative represented by the following formula [1] and a pharmaceutically acceptable salt thereof, and a solvate thereof. (a) It has a lowering effect and is useful for treatment and prevention of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, etc. [1]
  • RR 2 , R 3 and R 4 are the same or different and represent hydrogen, alkyl, halogen, hydroxy or alkoxy.
  • R 5 and R 6 are the same or different and represent alkyl.
  • R 7 represents hydrogen or alkyl.
  • —X— represents one or one S—.
  • R 8 represents alkyl
  • R 9 represents alkyl or aryl.
  • n an integer from 1 to 15, and f, g, h, and j each represent an integer from 0 to 13.
  • f + g is 0: 13 is set to an integer
  • h + j is c where, R 2 is hydroxy an integer of 0 to 13, Y is hydrogen, in one X- is one 0- And Z 1 and Z 2 are hydrogen, one A— is CH 2 , one T— is — Q—, — Q— is — (CH 2 ) n —, and n is 1 to Integer of 8 And
  • R 2 is hydrogen, alkyl or halogen
  • — X— is — 0—
  • Z 1 and Z 2 are hydrogen
  • —A— is CH 2
  • — T— is one Q— Yes, unless Q is — (CH 2 ) n — and n is an integer from 1 to 4.
  • the compound of the present invention is a novel compound not described in the literature.
  • Examples of the alkyl represented by R 1 to R 9 and ⁇ include linear or branched alkyl groups having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, i Examples include sobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, and isoheptyl.
  • R 1 to R 4 and alkoxy represented by ⁇ are straight-chain or branched-chain alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.
  • Examples of the halogen represented by R 1 to R 4 and ⁇ include fluorine, chlorine, bromine and iodine.
  • particularly preferred compounds include the following compounds.
  • the compound [1] of the present invention can be produced, for example, by the following method.
  • the compound of the present invention [101] can be produced by reacting a phenol or thiophenol represented by the formula [2] with an epoxide [3].
  • This reaction is usually carried out using a suitable solvent (for example, a polar solvent such as acetonitrile, N, N-dimethylformamide (DMF), an ether-based solvent such as tetrahydrofuran (THF), getyl ether, chloroform, Halogenated hydrocarbon solvents such as methylene chloride, ester solvents such as methyl acetate and ethyl acetate, hydrocarbon solvents such as benzene, toluene, n-hexane, methanol, ethanol, isopropanol, tert-butyl alcohol Bases (eg, potassium carbonate, sodium carbonate, etc.) in alcoholic solvents such as In the presence of inorganic bases such as sodium hydride, sodium hydroxide, and hydroxylated water, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine), the reaction can be performed at -20 to 150. Although it depends on the type of [2]
  • L represents a leaving group such as halogen (eg, chlorine, bromine or iodine) -p-toluenesulfonyloxy, methanesulfonyloxy and the like.
  • the compound [102] of the present invention can be produced by reacting the compound [5] with 0-formylphenol or 0-formylthiophenol represented by the formula [4].
  • This reaction is usually carried out in a non-protonic solvent (for example, a polar solvent such as acetonitrile-N, N-dimethylformamide (DMF), an ether such as tetrahydrofuran (THF), or getyl ether).
  • a non-protonic solvent for example, a polar solvent such as acetonitrile-N, N-dimethylformamide (DMF), an ether such as tetrahydrofuran (THF), or getyl ether.
  • solvents for example, a polar solvent such as acetonitrile-N, N-dimethylformamide (DMF), an ether such as tetrahydrofuran (THF), or getyl ether.
  • Solvents halogenated hydrocarbon solvents such as chloroform and methylene chloride
  • ester solvents such as methyl acetate and ethyl acetate, benzene, and toluene.
  • inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, and organic bases such as pyridine, 4-dimethylaminopyridine, and triethylamine Base
  • the reaction time varies depending on the types of the compounds [4] and [5] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of the compound [4] to be used is preferably 1 to 1.2 times the molar amount of the compound [5].
  • Production method 3 (— A— is CH 2 , Z 1 and Z 2 are hydrogen,
  • T— is — Q— and one Q— is (CH 2 ) n —
  • RR 2 , R 3 , RR 5 , R 6 , R 7 , X, Y and L are as defined above.
  • m represents an integer of n + 2 (n represents an integer of 1 to 15). That is, m represents an integer of 3 to 17. ]
  • the compound [103] of the present invention can be produced by reacting the phenol or thiophenol represented by the formula [2] with the compound [6].
  • This reaction can be carried out in the same manner as in the reaction between compound [4] and compound [5].
  • Another compound of the present invention can be produced by converting the A moiety of the compound of the present invention in the formula [1], for example, by the method shown below.
  • R 1 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , XY, Z ⁇ , Z 2 and T have the same meanings as described above. ]
  • the compound [201] (hydroxy compound) is the case where -A- is> CH-OH in the compound [1] of the present invention.
  • Compound [2 0 3] (Ashiruokishi body) is one among the present compounds [1] A- is> CH- is 0 C 0 For R 9.
  • Compound [205] (deoxy form) is the case where —A— is CH 2 in compound [1] of the present invention.
  • the compound obtained in Preparation 3 [1 03] is Z 1 and Z 2 are hydrogen in the compound [2 0 5], - a T- gar Q-,
  • Q— is — (CH 2 ) n —.
  • the hydroxy compound represented by the formula [201] is reacted with an alkylating agent (eg, alkyl halide, alkyl p-toluenesulfonate) to form an alkoxy compound represented by the formula [202].
  • an alkylating agent eg, alkyl halide, alkyl p-toluenesulfonate
  • Body can be manufactured.
  • This reaction is usually carried out in a nonprotonic solvent (eg, acetonitrile, polar solvent such as N, N-dimethylformamide (DMF), tetrahydrofuran (THF), Such as ether solvents, halogenated hydrocarbon solvents such as chloroform and methylene chloride, and acetic acid Ester solvents such as methyl and ethyl acetate, hydrocarbon solvents such as benzene, toluene and n- hexane, or mixed solvents thereof), base
  • a nonprotonic solvent eg, acetonitrile, polar solvent such as N, N-dimethylformamide (DMF), tetrahydrofuran (THF),
  • ether solvents e.g, ether solvents, halogenated hydrocarbon solvents such as chloroform and methylene chloride, and acetic acid Ester solvents such as methyl and ethyl acetate, hydrocarbon solvents such as
  • inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, pyridine,
  • reaction time varies depending on the type of the compound [201], the type of the alkylating agent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of the alkylating agent used depends on the compound
  • the molar amount is preferably 1 to 1.2 times the amount of [201].
  • the hydroxy compound represented by the formula [201] is reacted with an acylating agent (eg, acyl halide, carboxylic anhydride, etc.) to give the compound of formula
  • An acyloxy compound represented by [203] can be produced. This reaction can be carried out in the same manner as in the reaction of the above-mentioned compound [201] with an alkylating agent.
  • the oxo form represented by [204] can be produced.
  • the oxidizing agent include chromium oxide (VI) —sulfuric acid (Jones reagent), pyridinium chromate (PCC), chromium oxide (VI) —pyridin complex, and dichromate monosulfate. it can.
  • chromium (VI) oxide when a dilute sulfuric acid solution of chromium (VI) oxide is used, this reaction can be performed in an acetate solvent at -20 to 30.
  • the reaction time varies depending on the compound [201] and the reaction temperature, but usually 5 minutes to 12 hours is appropriate.
  • the amount of chromium (VI) oxide to be used is preferably 1- to 1.2-fold the molar amount of compound [201].
  • the reducing agent for example, metal hydride complex compounds (sodium borohydride, sodium cyanoborohydride, etc.) can be used.
  • R 7 is alkyl
  • diborane can be used.
  • the reaction is carried out in a polar solvent (eg, water, methanol, ethanol, isopropanol, N, N-dimethylformamide, dimethyl sulfoxide), -20 to 100 t : Can do it.
  • a polar solvent eg, water, methanol, ethanol, isopropanol, N, N-dimethylformamide, dimethyl sulfoxide
  • the reaction time varies depending on the compound [204] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of sodium borohydride to be used is preferably 0.25 to 0.5 times the molar amount of the compound [201].
  • the oxo form represented by the formula [204] can be reduced to produce the dex form represented by the formula [205].
  • the reducing agent for example, p-tosylhydrazine-metal hydride complex compound (for example, sodium borohydride, sodium cyanoborohydride), zinc-hydrogen chloride gas, hydrazine monoalkali (for example, sodium hydroxide) And potassium hydroxide).
  • reaction when tosylhydrazine or sodium cyanoborohydride is used, this reaction can be carried out in N, N-dimethylformamide-sulfolane at 80 to 150 in the presence of a tosylate catalyst.
  • the reaction time varies depending on the compound [204] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of sodium borohydride to be used is preferably 0.5 to 1.0 times the molar amount of the compound [204].
  • the compound produced by the above method is an ester (R 7 is an alkyl), it can be hydrolyzed and converted to a carboxylic acid (R 7 is hydrogen) if desired.
  • the reaction can be carried out usually in water, methanol, ethanol or a mixed solvent thereof at 0 to 150 * C, preferably 20 to 100.X.
  • the amount of the alkali to be used is 1-5 mol, preferably 2-3 mol, per 1 mol of the ester.
  • This hydrolysis reaction is carried out in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, in a suitable solvent (for example, aqueous alcohol such as aqueous methanol or aqueous ethanol, or acetic acid) from room temperature to sot: You can also.
  • a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid
  • a suitable solvent for example, aqueous alcohol such as aqueous methanol or aqueous ethanol, or acetic acid
  • the produced compound is a carboxylic acid (R 7 is hydrogen)
  • it can be converted to an ester (R 7 is alkyl) by esterification, if desired.
  • esterification reaction a large excess of alcohol is used in the presence of an acid such as ⁇ -toluenesulfonic acid, hydrochloric acid, sulfuric acid or the like, or using a Dean-Stark water separator or the like using benzene or toluene as a solvent.
  • an acid such as ⁇ -toluenesulfonic acid, hydrochloric acid, sulfuric acid or the like, or using a Dean-Stark water separator or the like using benzene or toluene as a solvent.
  • it is 0 to 150, preferably 20 to 100 ", for example, at the boiling point of the solvent.
  • the raw material when the raw material has a substituent (for example, hydroxy, carboxy, etc.) which is not desired to react, the raw material is converted to benzyl, acetyl, tert-butyl by a known method in advance. It is generally used in the reaction after protection with toxic carbonyl and the like. After the reaction, known methods such as catalytic reduction, alkali treatment, and acid treatment Can remove the protecting group.
  • a substituent for example, hydroxy, carboxy, etc.
  • compounds in which A is> CH—OH or compounds in which R 5 and R 6 are different have optically active isomers due to having an asymmetric carbon.
  • optically active isomer and a mixture thereof are also included in the present invention.
  • the optically active substance can be obtained from the mixture using liquid chromatography using a column for separating an optically active substance (for example, CH I RALCEL OD, CH I RALCEL OF manufactured by Daicel).
  • the optically active substance in which A— is CH—OH can be produced by the following method according to the method described in W094 / 24117.
  • R 1 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, Z 1 , Z 2 and T are as defined above.
  • R 2 0 represents an alkyl of from 1 to 1 0 carbon atoms
  • R 2 1 is haloalkyl (e.g., 2,2,2 Torifuruoroechi Le, 2, 2, 2-trichloromethyl E chill) or alkenyl (e.g., vinyl, isopropenyl Benyl).
  • P and M indicate that these marked carbons are asymmetric carbons which are mirror images of each other.
  • compound [201-P] and compound [201-M] are enantiomers. ]
  • Examples of the compound [50] include alkenyl esters such as vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, isopropenyl propionate, and isopropenyl butyrate; and 2,2,2-trifluoroethyl acetate Active esters such as haloalkyl esters such as 2,2,2-trichloroethyl propionate, 2,2,2-trichloroethyl acetate, and 2,2,2-trichloroethyl propionate may be used. it can.
  • the solvent to be used depends on the type of the compound [201], and examples thereof include polar solvents such as acetonitrile, N, N-dimethylformamide, and ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether and the like. Examples include a system solvent, a halogenated hydrocarbon solvent such as chloroform, methylene chloride and the like, and a hydrocarbon solvent such as benzene, toluene and n-hexane.
  • the reaction temperature can be carried out at 20-40 You.
  • the reaction time varies depending on the type of compound [201] and compound [50] and the reaction temperature, but is usually 30 minutes to 24 hours.
  • the resulting mixture is subjected to column chromatography to obtain an optically active compound.
  • the present invention compounds having carboxyl (1) can be formed with pharmaceutically acceptable salts by known methods.
  • the salt include an alkali metal salt such as a sodium salt and a potassium salt and an alkaline earth metal salt such as a potassium salt (e.g., the alkali metal salt of the compound of the present invention has carboxy).
  • the compound of the present invention can be obtained by adding one equivalent of sodium hydroxide or a hydroxylating power, preferably in an alcohol solvent.
  • the alkaline earth metal salt of the compound of the present invention can be obtained by dissolving the alkali metal salt produced by the above method in water, methanol, ethanol or a mixed solvent thereof and adding one equivalent of calcium chloride or the like. it can.
  • Solvates are usually obtained by recrystallizing the compound of the present invention or a salt thereof from a solvent corresponding to the desired solvate or an appropriate mixed solvent containing the corresponding solvent. There are cases. These solvates (including hydrates) are also included in the present invention.
  • the hydrate of the compound of the present invention is obtained by recrystallizing the compound of the present invention from aqueous alcohol. In some cases.
  • the compound of the present invention may be in a polymorphic form. The polymorph is also included in the present invention.
  • the compound of the present invention or a salt thereof can be separated from the above reaction mixture by the usual separation and purification.
  • Manufacturing method for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography
  • Compound [3] used as a starting material for the production of the compound of the present invention can be produced, for example, by the following method.
  • the compound [9] can be produced by reacting the compound [7] with the compound [8]. This reaction is usually performed at -80 to 0 in the presence of a strong base (eg, lithium diisopropylamide (LDA), n-butyllithium) in the nonprotonic solvent described in Production Method 2. Can be.
  • a strong base eg, lithium diisopropylamide (LDA), n-butyllithium
  • LDA lithium diisopropylamide
  • n-butyllithium e.g, lithium diisopropylamide (LDA), n-butyllithium
  • the reaction time depends on the type of compound [7] and compound [8] and the reaction temperature. However, usually 30 minutes to 24 hours are appropriate.
  • the amount of compound [8] to be used is preferably 1- to 1.2-fold the molar amount of compound [7].
  • the compound [3-1] can be produced by reacting the compound [9] with an organic peracid (for example, m-chloroperbenzoic acid, perbenzoic acid, peracetic acid).
  • an organic peracid for example, m-chloroperbenzoic acid, perbenzoic acid, peracetic acid.
  • This reaction is usually carried out in an appropriate solvent (eg, a halogenated hydrocarbon solvent such as chloroform, methylene chloride, etc., or an ether solvent such as tetrahydrofuran (THF) or dimethyl ether). It can be carried out.
  • the reaction time varies depending on the type of the compound [9] and the organic peracid, and the reaction temperature, but is usually 30 minutes to 24 hours.
  • the amount of the organic peracid to be used is preferably 1 to 1.2 equivalents to the compound [9].
  • Compound [9] can also be produced as follows. iXCE k—L 2 + C00R 7
  • R 5 , R 6 , R 7 and n are as defined above.
  • L 1 and L 2 each represent a leaving group such as halogen (eg, chlorine, bromine, iodine), p-toluenesulfonyloxy, methanesulfonyloxy, and k is an integer of n + 2 (n is 1 to 15 Represents an integer.) Represents. That is, k represents an integer of 3 to 17.
  • Compound [11] can be produced by reacting compound [7] with compound [10]. This reaction can be carried out in the same manner as in the reaction between compound [7] and compound [8].
  • the compound [9] can be obtained by heating the compound [11] to -120-250 in hexamethylphosphate triamide (HMPA).
  • HMPA hexamethylphosphate triamide
  • T— is — CH 2 — ⁇ — Q- and one Q— is one (CH 2 ) n-
  • R 5 , R 6 , R 7 , n, L 1 and L 2 are as defined above.
  • Compound [14] can be produced by reacting compound [12] with compound [13].
  • This reaction is usually carried out in a nonprotonic solvent described in Production Method 2 with a base.
  • a base Eg, sodium hydride, lithium diisopropylamide (LDA), pyridine, triethylamine
  • the reaction time varies depending on the kind of the compound [12] and the compound [13] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of compound [13] to be used is preferably 1- to 1.2-fold the molar amount of compound [12].
  • Compound [15] can be produced by reacting compound [7] with compound [14]. This reaction can be carried out in the same manner as in the reaction of compound [7] with compound [8].
  • the compound [3-2] can be produced by reacting the compound [15] with an organic peracid. This reaction can be carried out in the same manner as in the reaction of the above compound [9] with an organic peroxide.
  • Compound [18] can be produced by reacting compound [16] with compound [8]. This reaction can be carried out in the same manner as in the reaction between compound [12] and compound [13].
  • Compound [3-3] can be produced by reacting compound [18] with an organic peracid. This reaction can be carried out in the same manner as in the reaction of the above compound [9] with an organic peroxide. 4) One T and one is Q,
  • R 5 , R 6 , R 7 , L 1 and L 2 are as defined above.
  • ⁇ , g, h, j are as defined above.
  • Compound [20] can be produced by reacting compound [7] with compound [19]. This reaction can be carried out in the same manner as in the reaction between compound [7] and compound [8]. By reacting the compound [20] with bis (triptyltin) oxide and silver nitrate in a polar solvent such as DMF at 0-40 :, the hydroxy compound [21] can be produced.
  • the formyl compound [22] can be produced by oxidizing the hydroxy compound [21].
  • the oxidizing agent include pyridinium chromate (PCC), chromium oxide (VI) —pyridine complex, dimethyl sulfoxide (DMSO) —dicyclohexylcarbodiimide (DCC), and the like.
  • PCC pyridinium chromate
  • VI chromium oxide
  • DMSO dimethyl sulfoxide
  • DCC dicyclohexylcarbodiimide
  • the reaction can be carried out in a suitable solvent (such as methylene chloride) at 0-25.
  • the compound [3-4] can be produced by cycloaddition of a methylene unit to the formyl [22].
  • a methylene unit monolithium bromochloromethane, trimethyloxosulfonium monohydrogen sodium, and the like can be used.
  • the reaction can be carried out in a suitable solvent (DMSO, THF, etc.) at 20-70.
  • R 5 , R 6 , R 7 and Q 1 are as defined above.
  • R 10 represents alkyl, and L 3 represents halogen (eg, chlorine, bromine, iodine). ]
  • the compound [25] can be produced by reacting the compound [23] with a dialkyl haloacetal [24].
  • a dialkyl haloacetal dimethylchloroacetal, methylbutane moisetal, and the like can be used. This reaction can be carried out in the same manner as in the reaction between compound [12] and compound [13] (compound [25] in an alcoholic solvent (such as methanol and ethanol).
  • acid dilute hydrochloric acid, dilute sulfuric acid, etc.
  • the compound [3-5] can be produced by cycloaddition of a methylene unit to the formyl derivative [26]. This reaction is performed by The reaction can be performed in the same manner as in the reaction for cycloaddition of a methylene unit to the product [22].
  • Compound [27] can be produced by reacting compound [16] with compound [19]. This reaction can be carried out in the same manner as in the reaction between compound [16] and compound [8].
  • the compound [27] can be converted to the hydroxy form [28].
  • This reaction can be carried out in the same manner as the above-mentioned reaction for converting the compound [20] to the compound [21].
  • the formyl form [29] can be produced by oxidizing the hydroxy form [28].
  • This reaction can be carried out in the same manner as in the above-mentioned reaction for converting the compound [21] into the compound [22].
  • the compound [3-6] can be produced by cycloaddition of a methylene unit to the formyl [29]. This reaction can be carried out in the same manner as in the above reaction for cycloaddition of a methylene unit to compound [22].
  • the compound [5] used as a starting material in the production of the compound of the present invention can be produced, for example, by the following method.
  • the compound [30] can be produced by reacting the epoxide [3] with lithium chloride in the presence of an acid.
  • This reaction can be usually performed in the nonprotonic solvent described in Production Method 2 in the presence of an acid (eg, diacid) at -20 to 50.
  • the reaction time varies depending on the type of compound [3] and the reaction temperature, but usually 30 minutes to 48 hours is appropriate.
  • the amount of lithium chloride used is based on Compound [3]. Thus, a molar amount of 1 to 1.2 times is preferable.
  • Compound [5-1] can be produced by oxidizing compound [30]. This reaction can be carried out in the same manner as in the above-mentioned reaction for converting compound [201] to compound [204].
  • the compound [5] can be produced by reacting the compound [5-1] with a nucleophile such as lithium bromide, lithium iodide, silver p-toluenesulfonate, silver methanesulfonate or the like. .
  • a nucleophile such as lithium bromide, lithium iodide, silver p-toluenesulfonate, silver methanesulfonate or the like.
  • This reaction can be usually performed in a nonprotonic solvent described in Production Method 2 at 0 to L00.
  • the reaction time varies depending on the compound [5-1], the type of the nucleophilic reagent, and the reaction temperature, but usually 30 minutes to 48 hours is appropriate.
  • the amount of the nucleophile to be used is preferably 1 to 1.2 times the molar amount of the compound [5-1].
  • the compound (6) used as a starting material for the production of the compound of the present invention can be produced in the same manner as in the above-mentioned reaction for producing the compound (11) from the compound (10) and the compound (7). it can.
  • Compound [2], Compound [4], Compound [7], Compound [8], Compound [10], Compound [13], Compound [1] used as a starting material in the production of the compound of the present invention 6], compound [17] and compound [19] are known compounds or can be produced by a method according to a known method, for example, as shown in Reference Examples described later.
  • the compound of the present invention is effective for treating and preventing hyper-Lp (a) emia or hypercholesterolemia and diseases caused by these. Since the compound of the present invention has both Lp (a) lowering action and TC lowering action, it is expected to be a particularly excellent therapeutic agent for arteriosclerosis as compared with known compounds. Also the book The compound of the present invention also has a blood high specific gravity lipoprotein cholesterol-elevating action (see, for example, the compounds of the present invention (for example, Example 8, Example 10, Example 12-Example 20 and Example 2). 2, Example 24, Example 33, Example 34-Example 48, Example 59, Example 61 The acute toxicity (eg, in male mice) of the compound of Example 1 is greater than the effective dose.
  • the compound of the present invention and the pharmaceutical composition of the present invention are effective for treating and preventing arteriosclerosis caused by hyperlipidemia.
  • Coronary artery disease including re-occlusion after coronary angioplasty (PTCA; Percutaneous Transluminal Coronary Angioplasty); angina pectoris and ischemic heart disease caused by coronary artery disease; Applicable to the treatment of infarction, thrombus and arteriosclerosis caused by it Rukoto can.
  • the compound of the present invention When the compound of the present invention is administered as a medicament, the compound of the present invention contains 0.1 to 99.5%, preferably 0.5 to 90% as it is or in a pharmaceutically acceptable nontoxic and inert carrier. As a composition. Administered to animals, including humans.
  • the carrier one or more solid, semi-solid or liquid diluents, fillers and other auxiliaries for formulation are used.
  • the pharmaceutical compositions are administered in dosage unit form.
  • the pharmaceutical composition of the present invention can be administered intravenously. Oral administration, intradermal administration, topical administration (such as transdermal administration), or rectal administration. It is needless to say that the composition is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.
  • the dose of the pharmaceutical composition for treating high Lp (a) emia is determined in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, and the like.
  • the amount of the active ingredient of the present invention for an adult is in the range of 50 to 600 mg / h, preferably 100 to 300 mg / h, for an adult. In some cases, less is sufficient. Conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.
  • composition for treating arteriosclerosis and other prophylactic or therapeutic compositions can be applied using the same dose as described above.
  • reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate (the organic layer was washed with brine, The residue was dried over anhydrous magnesium sulfate and concentrated, and the residue was distilled under reduced pressure to obtain 33.2 g of a slightly yellow oily substance.
  • Hexamethylphosphoric acid triamide (HMPA) (20.9 g) was added to 25 g of the compound obtained in Reference Example 1, and the mixture was stirred at 190 to I95 for 1 hour.
  • the reaction solution was cooled, poured into ice water, and extracted with n-hexane.
  • the organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain 8.0 g of a pale yellow oil.
  • reaction solution was poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to obtain 24 g of a slightly yellow oily substance.
  • Boiling point 13 0 to 13 5 ° C / 17 mmH g The following compounds were produced in the same manner as in Reference Example 3.
  • the solution was dissolved in 200 ml, and 8.6 g of 60% sodium hydride was gradually added to the solution under water cooling, followed by stirring at room temperature for 10 minutes. Subsequently, 17.4 g of aryl bromide was added, and the mixture was stirred at room temperature for 5 hours.
  • the reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain a pale yellow oil (16.5 g).
  • a pale yellow oil was obtained in the same manner as in Reference Example 4 using the compound obtained in Reference Example 9.
  • the extract was washed once with a 10% aqueous sodium hydrogen carbonate solution, washed with water, dried over anhydrous magnesium sulfate, and concentrated.
  • Example 2 The compound (24.0 g) obtained in Example 1 was dissolved in methanol (240 ml), and sodium borohydride (2.11 g) was added thereto under ice-cooling and stirring, followed by stirring at room temperature for 3 hours.
  • the reaction solution was poured into ice water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 24.9 g of a pale yellow oil.
  • the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue is purified by silica gel column chromatography ( ⁇ -gel C-200 (registered trademark), chromate form) to give a colorless oil. 8 g were obtained.
  • Example 3 The compound 19.Og obtained in Example 3 was dissolved in 190 ml of methanol, and 50 ml of a methanol solution of 1.80 g of sodium hydroxide was added thereto, followed by concentration. Benzene was added to the residue, and the mixture was further concentrated, n-hexane was added, and the crystals were collected by filtration to obtain 18.18 g of white crystals.
  • Elemental analysis value (as C 2 H 2 9 N a ⁇ 4 ⁇ 1 / 2H 20 )
  • Example 9 Using 19 g of the compound obtained in Example 9, the reaction was carried out in the same manner as in Example 3. After the reaction solution was concentrated under reduced pressure, ice water was added to the residue, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from n-hexane to give white crystals.
  • Example 11 Using 25 g of the compound obtained in Example 11, 21.2 g of white crystals were obtained in the same manner as in Example 10.
  • Example 13 7- (4-tert-Butylphenoxy) -12,2-dimethyl-16-hydroxyheptanoic acid
  • Example 13 7- (4-tert-Butylphenoxy) -12,2-dimethyl-16-hydroxyheptanoic acid
  • Example 17 Using the compound obtained in Example 17, white crystals were obtained in the same manner as in Example 10.
  • Example 21 white crystals were obtained in the same manner as in Example 10.
  • Example 23 Using 9.23 g of the compound obtained in Example 23, 7.22 g of white crystals were obtained in the same manner as in Example 10.
  • Example 3 1 2-(4-tert-butylphenylthio) -1,2,2-dimethyl-1-
  • Example 35 A mixture of the optically active isomers of (+) and ( ⁇ ) of 111- (4-tert-butylphenoxy) -2,2-dimethyl-10-hydroxy-decanoate obtained in Example 35 was used. Used and white in the same manner as in Example 34.
  • Example 41 Using the compound obtained in Example 41, white crystals were obtained in the same manner as in Example 40.
  • Example 45 Using the compound obtained in Example 45, white crystals were obtained in the same manner as in Example 44.
  • Example 47 Using the compound obtained in Example 47, white crystals were obtained in the same manner as in Example 10.
  • Example 51 white crystals were obtained in the same manner as in Examples 3 and 4.
  • the obtained compound (18.0 g) was dissolved in ethanol (180 ml), a solution prepared from sodium hydroxide (5.2 g) and water (18 ml) was added thereto, and the mixture was heated under reflux for 5 hours. . After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and 4.1 g of calcium chloride was added under ice cooling to precipitate crystals. The crystals were separated by filtration, washed with water, and dried to obtain 16.8 g of white crystals.
  • Example 58 Using the compound obtained in Example 58, white crystals were obtained in the same manner as in Example 10.
  • Example 60 Using the compound obtained in Example 60, white crystals were obtained in the same manner as in Example 10.
  • Example 13 Using 13- (4-tert-butylbutyloxy) -2- (1,2-dimethyl-12-hydroxytriethyl decanoate) obtained in Example 1. White crystals were obtained in the same manner as in Example 33. .
  • Example 10 Compound 100 mg Lactose 45 mg Corn starch 20 mg Low-substituted hydroxypropylcellulose 9 mg Polyvinyl alcohol (partially saponified) 5 mg Magnesium stearate 1 mg And take it internally.
  • Example 5 Compound of 7 100 mg Lactose 45 mg Tomato starch 20 mg Low substituted hydroxypropyl cellulose 9 mg Polyvinyl alcohol (partially saponified) 5 mg Magnesium stearate 1 mg And take it internally. The results of pharmacological tests showing the utility of representative examples of the present compound are shown below.
  • APF containing 0.1% of the control compound and the compound of the present invention was used in each of the administration groups using 3 to 7 male cynomolgus monkeys (body weight 2 to 9 kg) in each group.
  • gemfiprodil which has been reported to have an Lp (a) lowering effect in cynomolgus monkeys, was used.
  • Plasma was prepared by adding 1/10 volume of 3.8% aqueous solution of sodium citrate to blood, and TC and Lp (a) were measured by enzymatic method and ELISA method, respectively.
  • the average of the TC and Lp (a) measured values two weeks before the start of dosing and on the day of starting the dosing was used as the pre-value, and the percentage of each measured value at the fourth week of dosing to the pre-value was calculated.
  • the control group was subjected to the Student's t test for the administration group, and in Experiments 2 to 5, the administration group was subjected to the significant difference test by the Dunnet's multiple test for the control group.
  • Table 1 shows the results. Table 1 Effects on TC and Lp (a) i! K. Rei ⁇ T3 ⁇ 4y ⁇ ⁇ ⁇ p L p (a) number
  • Example 12 Compound 4 2 4 62 ⁇ 25 23 Sat 2 ** or Example 9 9 k Compound t 7 / fi r +? ⁇ ⁇ ) 37 g ** Example 5 7 Compound Q r ⁇ 26 Sat
  • Example 3 Compound 6 6 80 ⁇ 13 36 Sat 4 ** Example 3 Compound 6 90 ⁇ 15 40 3 **
  • the compound of the present invention has an excellent TC lowering action and an Lp (a) lowering action, and is effective for treatment and prevention of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des dérivés d'acide carboxylique de formule générale (1), des sels de ces composés acceptables en pharmacologie et des solvates de ces derniers. Dans la formule (1), R?1, R2, R3 et R4¿ sont chacun, de manière indépendante, hydrogène, alkyle, halogéno, hydroxy ou alcoxy; R5 et R6 sont alkyle, chacun de manière indépendante; R7 est hydrogène ou alkyle; -X- est -O- ou -S-; Y est hydrogène, alkyle, halogéno, hydroxy ou alcoxy, et Z1 et Z2 sont chacun hydrogène, ou bien, en variante, Y, Z1 et Z2 sont réunis pour représenter -CH=; -A- est ⊃CH-OH, ⊃C=O, ⊃CH-OR8 ou ⊃CH-OCOR9, R8 étant alkyle et R9 étant alkyle ou aryle, et T est alkylène comportant éventuellement une liaison multiple, ou autre. Les composés indiqués sont efficaces dans la prévention et le traitement de l'artériosclérose, des cardiopathies ischémiques, de l'infarctus cérébral, de la resténose post-ACTP, etc.
PCT/JP1996/003056 1995-10-26 1996-10-21 Derives d'acide carboxylique et compositions pharmaceutiques WO1997015546A1 (fr)

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US6121319A (en) * 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US6852878B2 (en) 1998-05-14 2005-02-08 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of VCAM-1
US6887712B1 (en) 1998-11-09 2005-05-03 Atherogenics, Inc. Methods and compositions to lower plasma cholesterol levels
US7071158B2 (en) 1997-07-01 2006-07-04 Atherogenics, Inc. Antioxidant enhancement of therapy for hyperproliferative conditions
US7271274B2 (en) 2004-04-20 2007-09-18 Ahterogenics, Inc. Phenolic antioxidants for the treatment of disorders including arthritis, asthma and coronary artery disease
US7294737B2 (en) 2004-04-20 2007-11-13 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
JP2009537462A (ja) * 2006-05-15 2009-10-29 西北大学 置換β−フェニル−α−ヒドロキシプロピオン酸、その合成方法及び使用
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7375252B2 (en) 1997-05-14 2008-05-20 Atherogenics, Inc. Compounds and method for the inhibition of the expression of VCAM-1
US6147250A (en) * 1997-05-14 2000-11-14 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6548699B1 (en) 1997-05-14 2003-04-15 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6602914B2 (en) 1997-05-14 2003-08-05 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6617352B2 (en) 1997-05-14 2003-09-09 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6670398B2 (en) 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US6828447B2 (en) 1997-05-14 2004-12-07 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6121319A (en) * 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
US7087645B2 (en) 1997-05-14 2006-08-08 Atherogenics, Inc. Compounds and methods for treating transplant rejection
US7189870B2 (en) 1997-05-14 2007-03-13 Atherogenic, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US7071158B2 (en) 1997-07-01 2006-07-04 Atherogenics, Inc. Antioxidant enhancement of therapy for hyperproliferative conditions
US6852878B2 (en) 1998-05-14 2005-02-08 Atherogenics, Inc. Thioketals and thioethers for inhibiting the expression of VCAM-1
US6887712B1 (en) 1998-11-09 2005-05-03 Atherogenics, Inc. Methods and compositions to lower plasma cholesterol levels
US7294737B2 (en) 2004-04-20 2007-11-13 Atherogenics, Inc. Process of preparing esters and ethers of probucol and derivatives thereof
US7271274B2 (en) 2004-04-20 2007-09-18 Ahterogenics, Inc. Phenolic antioxidants for the treatment of disorders including arthritis, asthma and coronary artery disease
JP2009537462A (ja) * 2006-05-15 2009-10-29 西北大学 置換β−フェニル−α−ヒドロキシプロピオン酸、その合成方法及び使用
US8252840B2 (en) 2007-03-26 2012-08-28 Salutria Pharmaceuticals Llc Methods of derivatives of probucol for the treatment of type II diabetes

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