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WO1994024117A1 - Derive de l'acide benzofurancarboxylique et composition pharmaceutique - Google Patents

Derive de l'acide benzofurancarboxylique et composition pharmaceutique Download PDF

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Publication number
WO1994024117A1
WO1994024117A1 PCT/JP1994/000664 JP9400664W WO9424117A1 WO 1994024117 A1 WO1994024117 A1 WO 1994024117A1 JP 9400664 W JP9400664 W JP 9400664W WO 9424117 A1 WO9424117 A1 WO 9424117A1
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Prior art keywords
compound
hydrogen
alkyl
tert
pharmaceutical composition
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PCT/JP1994/000664
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English (en)
Japanese (ja)
Inventor
Shoichi Chokai
Masayuki Nakane
Original Assignee
Nippon Shinyaku Co., Ltd.
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Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to AU65810/94A priority Critical patent/AU6581094A/en
Publication of WO1994024117A1 publication Critical patent/WO1994024117A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to a novel benzofurancarboxylic acid derivative, and a pharmacologically acceptable salt thereof.
  • the compound according to the present invention has a therapeutic effect on high Lp (a) blood pressure, a blood lipid lowering effect, and a fibrinogen lowering effect, and is useful for treating coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, etc. Useful for treatment and prevention.
  • TC Blood total cholesterol
  • Fg fibrinogen
  • Lp a blood lipid lowering agent having both an Fg and Lp (a) lowering effect in addition to a TC lowering effect is considered to be more useful as an anti-arterial stiffening agent.
  • Fg levels can be measured by measuring the clotting time of plasma, since a decrease in Fg prolongs the blood clotting time.
  • Activated partial thromboblastin time can be measured as the blood clotting time including the intrinsic coagulation system. These substances that prolong blood clotting time can suppress blood clot formation and suppress the onset of ischemic heart disease.
  • Lp (a) has a similar 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- ⁇ by suppressing plasmin production (Science, 2, 1655 (1993)). . From these facts, it is considered that substances that lower Lp (a) suppress thrombotic and proliferative vascular stenosis and suppress the onset of ischemic heart disease.
  • Nicotinic acid (J. Int. Med.,, 111 (1989)) is known as a lipid-lowering agent that has already been used in clinical practice and has an Lp (a) lowering effect.
  • nicotinic acid preparations have no lowering effect.
  • a fibrate-based preparation (Thromb. Haemostas., 70, 241 993)) is known to have a lowering effect, but a fibrate-based preparation does not have an Lp (a) lowering effect.
  • the TC lowering effect of these preparations is weaker than HMG CoA reductase inhibitors.
  • the present inventors have found a benzoic acid derivative and a related compound having both excellent TC lowering action and Lp (a) lowering action, and have previously filed an international application (W093 / 01180).
  • the present inventors have sought to find such a compound and have been conducting research.
  • the benzofurancarboxylic acid derivative represented by the following formula [I] and a pharmacologically acceptable salt thereof have excellent TC lowering action, and The present inventors have found that they have an Fg lowering effect in addition to the Lp (a) lowering effect, and have completed the present invention.
  • R represents hydrogen, alkyl or arylalkyl
  • CO OR is substituted at the 4-, 5-, 6-, or 7-position of the benzofuran ring
  • B is one CO— or one CH (0H)
  • one A represents Q—0—CH2— or the following formula [II].
  • Q represents a substituted or unsubstituted cycloalkyl, and the substituent is selected from alkyl, aryl, hydroxy, alkoxy, and halogen.
  • R 1 R 2 , R 3 and R 4 are the same or different and represent hydrogen, hydroxy, alkyl or halogen.
  • X represents one 0— or one CH 2 —.
  • Y represents hydrogen, hydroxy, alkyl, or halogen
  • Z 1 and Z 2 each represent hydrogen.
  • a feature of the present invention resides in the structure itself of the compound represented by the formula [I].
  • the compound according to the present invention is a novel compound not described in the literature.
  • the compounds described in W093 / 01180 are benzoic acid derivatives and related compounds, and have excellent TC lowering action and Lp (a) lowering action.
  • the compound having is 4- [2- (5-tert-butylbenzofuran-2-yl) -2-hydroxyethoxy] benzoic acid.
  • the compound of the present invention is a benzofuran carboxylic acid derivative and has a different chemical structure from the compound described in WO93 / Q118.
  • examples of the alkyl represented by R include straight-chain or branched ones having 1 to 7 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, etc. be able to.
  • aryl portion of the aryl alkyl examples include those having 6 to 10 carbon atoms.
  • phenyl, naphthyl and the like can be mentioned.
  • alkyl moiety examples include the alkyls exemplified for R above.
  • arylalkyl examples include benzyl, 2-phenylethyl, triphenylethyl, 3-phenylbromo, 2-phenylbromo, 4-phenylbutyl, 3-phenylbutyl, 5-phenylpentyl, 4-phenylpentyl, 6-phenylhexyl, 5-phenylhexyl, 7-phenylhexyl, 6-phenylhexyl, naphthylmethyl 2-, (5-naphthyl) ethyl, 3- (hynaphthyl) ) Proville,
  • Examples of cycloalkyl represented by Q include those having 3 to 7 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl and the like can be mentioned.
  • Examples of the alkyl and aryl selected as the substituent of the cycloalkyl include those exemplified for R above.
  • Examples of the alkyl moiety of the alkoxy selected as the substituent include the alkyls exemplified for R above.
  • Halogens selected as substituents include fluorine, chlorine, bromine, and iodine.
  • examples of the alkyl represented by RR 2 , R 3 , R 4 , or Y include the alkyls exemplified for R above.
  • Halogen includes fluorine, chlorine, bromine, and iodine.
  • the compound of the present invention in which ⁇ is —CH ( ⁇ ) is one having two asymmetric carbons, and thus has two optically active compounds.
  • the compound [I] of the present invention includes, for example, the following first to fourth group compounds.
  • ⁇ is —CH ( ⁇ ) —
  • ⁇ is Q—0—CH 2 —
  • Q is C 3 -C cycloalkyl substituted with C ⁇ -C 7 alkyl.
  • B is - CO- or one CH (0H) is one
  • A is of the formula [II]
  • X is - a 0-
  • Y ⁇ 1
  • Zeta 2 is One is CH2, RR 2 , R 3 , or R 4 Wherein any one of is a C i -C 7 alkyl and the remaining three are hydrogen.
  • B gar CH (OH) is one
  • A is of the formula [II]
  • X gar CH 2 - and is, Z 1 and Z 2 is in which its Re hydrogen
  • B gar CH (0H) is one
  • A is of the formula [II]
  • X gar 0-, Z 1 and Z 2 be it that water containing , Y, R 1 R 2 , R 3 , or R 4 is hydrogen, and the remaining two are the same or different and are hydrogen or Ci-C 7 alkyl;
  • Preferred compounds among the compounds of the present invention [I] are the following compounds:
  • the compound of the present invention may be a free carboxylic acid, but may be converted into a pharmacologically acceptable salt by a known method.
  • 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 calcium salt.
  • Examples of the compound of the present invention include the following compounds in addition to the compounds described as examples according to the production method described below. These are listed to exemplify some of the compounds of the present invention, and the compounds of the present invention are not limited thereto.
  • the compound [I] of the present invention can be produced, for example, by the following method.
  • R 0 represents the same alkyl or arylalkyl as R described above, and T represents halogen (such as chlorine, bromine, and iodine), alkylsulfonyloxy (such as methanesulfonyloxy), or arylsulfonyloxy. It represents a leaving group such as xy (P-toluenesulfonyloxy, etc.).
  • Compound [Ia] is a compound of the present invention [I], wherein B is —CO— and R is alkyl or arylalkyl.
  • a compound of the formula [Ib] is a compound of the present invention [I], wherein B is -CH (0H)-and R is alkyl or arylalkyl.
  • Compound [I c] is a compound of the present invention [I], wherein B is —CO— and R is hydrogen.
  • Ridge [Id] is a compound of the present invention [I], wherein B is one CH (0H) — and R is hydrogen.
  • Compound [Ia] can be produced by reacting compound [III] with compound [IV] in the presence of a base.
  • This reaction is usually carried out in an aprotic solvent (for example, polar solvents such as acetonitrile and N, N-dimethylformamide), ether solvents such as tetrahydrofuran and getyl ether, and halogenated hydrocarbons such as chloroform and methylene chloride.
  • aprotic solvent for example, polar solvents such as acetonitrile and N, N-dimethylformamide
  • ether solvents such as tetrahydrofuran and getyl ether
  • halogenated hydrocarbons such as chloroform and methylene chloride.
  • a base for example, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, pyridine, triethylamine, etc.
  • a solvent such as benzene, toluene, or a hydrocarbon solvent such as n-hexane
  • reaction time varies depending on the type of the compound [III] or the compound [IV] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • the amount of compound [IV] to be used is generally 1- to 1.2-fold the molar amount of compound [III].
  • Compound [Ib] can be produced by reducing compound [Ia]. This reaction should be carried out in a suitable solvent at ⁇ 20 to 10 G ° C using a metal hydride complex compound (eg, sodium borohydride, sodium cyanoborohydride, etc.) or diporane as the reducing agent.
  • a metal hydride complex compound eg, sodium borohydride, sodium cyanoborohydride, etc.
  • diporane e.g, sodium borohydride, sodium cyanoborohydride, etc.
  • a solvent for example, when sodium borohydride or sodium cyanoborohydride is used as a reducing agent, water, methanol, ethanol, isopropanol, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, etc.
  • ether solvents such as tetrahydrofuran, dimethyl ether, and dimethyl glycol dimethyl ether are preferable (the reaction time varies depending on the type of the compound [Ia], the reducing agent, and the reaction temperature).
  • the amount of the reducing agent varies depending on the type of the reducing agent, but is generally 0.5 to 2.4 times the molar amount of the compound [Ia]. is there.
  • the compound [Ic] of the present invention can be produced by hydrolyzing the compound [Ia]. This hydrolysis reaction is usually carried out in water, methanol, ethanol or a mixed solvent thereof in the presence of a base such as potassium carbonate, sodium hydroxide, potassium hydroxide or the like, usually at Q to 15 Q ° C, preferably 20 to 10 G. ° C.
  • a base such as potassium carbonate, sodium hydroxide, potassium hydroxide or the like
  • Q to 15 Q ° C preferably 20 to 10 G. ° C.
  • the amount of the alkali to be used is 1 to 5 mol, preferably 2 to 3 mol, per 1 mol of compound [Ia].
  • the hydrolysis reaction is carried out in a suitable solvent (for example, aqueous alcohol such as aqueous methanol or aqueous ethanol, acetic acid, etc.) in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., at room temperature to 80 ° C. Can also be done.
  • a suitable solvent for example, aqueous alcohol such as aqueous methanol or aqueous ethanol, acetic acid, etc.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the amount of acid used is Q.! Per mole of compound [Ia]. ⁇ 10 mol, preferably 0.2-3 mol.
  • the compound [Id] of the present invention can be produced by hydrolyzing the compound [Ib] in the same manner as described above.
  • This catalytic hydrogenation is carried out in the presence of a catalyst (for example, palladium carbon, etc.) in a suitable solvent (for example, an alcoholic solvent such as methanol or ethanol, a hydroalcoholic solvent, an ethereal solvent such as dioxane or tetrahydrofuran). Under normal temperature and normal pressure.
  • the reaction time varies depending on the type of catalyst, but is usually 30 minutes to 24 hours.
  • the amount of the catalyst used varies depending on the type of the catalyst, but is generally ⁇ 20% by weight based on the compound [Ia].
  • the compounds [Ia :) and [Ib] of the present invention the compounds [Ia,;], and [Ib,] wherein A is the formula [II] and X is -0- It can also be manufactured by the method described below.
  • R 1 R 2 , R 3 , R 4 , R 0 , A, and T are the same as above.
  • Y 1 is formyl, or the same hydrogen as the above ⁇ , hydroxy, Represents alkyl and halogen.
  • Compound [VIII] can be produced by reducing compound [VII]. This reaction can be carried out in the same manner as in the above-mentioned reaction from compound [Ia] to compound [Ib].
  • Compound [Ia,] can be produced by reacting compound [VII] with compound [IX] in the presence of a base. This reaction is usually carried out in the presence of a base (eg, sodium hydride, metal sodium, sodium methoxide, potassium carbonate, etc.) in the presence of 12 D to 1 GO.
  • a base eg, sodium hydride, metal sodium, sodium methoxide, potassium carbonate, etc.
  • the solvent to be used depends on the type of base.
  • reaction time is preferably as long as the compound [VII]
  • the compound [IX] is generally used in a molar amount of 1 to 1.7 times the amount of the compound [VII], although it depends on the kind of the compound and the reaction temperature.
  • Compound [Ib '] can be produced using compound [VIII] in the same manner as in the above-mentioned reaction from compound [VII] to compound [Ia,].
  • Compound [Ia,] can also be produced by the method shown below.
  • Compound [XI] can be produced by reacting compound [X] with compound [IX] in the presence of a base. This reaction can be carried out in the same manner as in the above-mentioned reaction from compound [VI I] to compound [I a,].
  • Compound [XII] can be produced by oxidizing compound [XI].
  • dimethylsulfoxide monoacetic anhydride, dimethylsulfoxide, ⁇ '-dicyclohexylcarbodiimide, chlorochromate pyridine, sodium dichromate, or the like can be used as an oxidizing agent.
  • the reaction time varies depending on the compound [XI], the type of the oxidizing agent, and the reaction temperature, but is usually appropriate for 3 to 24 hours.
  • the reaction can be carried out in a dimethylsulfoxide solvent at G to 100 ° C. Benzene, getyl ether and the like can also be used as an auxiliary solvent.
  • the reaction can be performed at 0 to 10 ° C. in the presence of celite in a solvent such as toluene.
  • reaction can be carried out in an aqueous medium in the presence of acetic acid and sulfuric acid at Q to 10 () ° C.
  • Compound [Ia,] can be produced using compound [XII] in the same manner as in the above-mentioned reaction for obtaining compound [Ia] from compound [III] and compound [IV].
  • the compounds [Ic] and [Id] of the present invention obtained by the above method are free carboxylic acids, and can form salts with pharmacologically acceptable bases by a conventional method.
  • the compound [Ia:] or the compound [Ib] produced by the above method is the same as above using sodium hydroxide or potassium hydroxide in an alcohol or a hydrous alcohol. It can be obtained by hydrolysis in a method. Further, to the compound (Ic) or the compound (Id), preferably by adding i equivalent of sodium hydroxide, hydroxylating power or metal sodium in an alcoholic solvent, a corresponding metal salt is added to form a corresponding metal salt. Obtainable.
  • the alkaline earth metal salt produced by the above method can be dissolved in water, and one equivalent of calcium chloride or the like can be added to obtain the corresponding alkaline earth metal salt.
  • the compound [I] thus obtained or a salt thereof can be separated and purified from the reaction mixture by a conventional means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. Can be isolated and purified.
  • the compounds [I] of the present invention the compounds [I b] and [I d] of the present invention in which B is —CH (OH) — have two asymmetric carbons because they have one asymmetric carbon.
  • each optically active substance, and mixtures thereof are also included in the present invention.
  • the reaction rate of one optically active substance is high, but the reaction rate of the other optically active substance is low.
  • An optically active form can be obtained from a racemic form.
  • R 10 represents alkyl
  • R 11 represents alkyl, haloalkyl, or alkenyl
  • c P and M represent that these marked carbons are asymmetric carbons that are mirror images of one another.
  • compound [Id-P] and compound [Id-M] are enantiomers. ]
  • compound (Ib) is converted to compound (XXX) in the presence of lipase.
  • the compound [Ib-M] can be selectively acylated to produce the compound [XX-M].
  • Examples of the compound [XXX] include alkenyl esters such as vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, isoprobenyl propionate, and isobrodinyl butyrate, or 2,2,2-trifluoroethyl acetate and brobion Active esters such as haloalkyl esters such as 2,2,2-trifluoroethyl acid, 2,2,2-trichloroethyl acetate, and 2,2,2-trichloromethyl brobionic acid can be used. You. Inert esters such as ethyl acetate, brovir acetate, methyl propionate and ethyl propionate can be used in a large excess. Preference is given to vinyl acetate, isobromopropyl acetate, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroethyl acetate.
  • the solvent used depends on the type of compound [Ib], but examples thereof include polar solvents such as acetonitrile, N, N-dimethylformamide, ether solvents such as tetrahydrofuran, getyl ether, diisopropyl ether, and the like. Examples include halogenated hydrocarbon solvents such as chloroform and methylene chloride, and hydrocarbon solvents such as benzene, toluene, and n-hexane. Diisopropyl ether is preferable.
  • the reaction temperature can be 20 to 40 ° C, and preferably 30 ° C.
  • the reaction time varies depending on the type of the compound [Ib] and the compound [XXX] and the reaction temperature, but is usually 30 minutes to hours.
  • reaction rate can be increased by adding molecular sieves 4A to the reaction solution to reduce the water content of the reaction solution.
  • the resulting mixture was subjected to column chromatography to obtain compound [Ib-P] [XX-M] can be isolated and purified.
  • Compound [Id-M] can be obtained by hydrolyzing compound [XX-] as described above.
  • an optically active substance can be obtained from a mixture of the compound [Ib-P] and the compound [XX-M] obtained by the above reaction.
  • a mixture of the compound [Ib-P] and the compound [XX-M] obtained above is dissolved in a solution of benzene, toluene or the like in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • succinic anhydride in a medium, only the compound [Ib-P] having a hydroxyl group can be acylated without reacting the compound [XX-M].
  • Compound [XXI-P] can be produced by treating with a base such as dicyclohexylamine or benzylamine in a solvent such as propyl ether.
  • glutaric anhydride, adibic anhydride, and fluoric anhydride may be used instead of succinic anhydride.
  • Compound [XXI-P] forms a salt and is insoluble in the solvent used, so that it can be precipitated as crystals.
  • the compound [XXI-P] can be isolated and purified by filtering the reaction solution.
  • Compound [XX-M] can be isolated and purified from the filtrate using column chromatography or the like.
  • Compound [Id-P] can be obtained by hydrolyzing compound [XXI-P] as described above.
  • compound [Id-M] can be obtained from compound [XX-M].
  • the optically active form of the compound of the present invention can also be produced using an asymmetric reduction reaction. That is, the optical activity of compound (Ib) is obtained by asymmetric reduction of compound (Ia) using a catalyst such as a rhodium complex or a ruthenium complex using an asymmetric ligand such as MCCPM, BINAP, or BPPF0H. Body can be manufactured. In these reactions, the (R) -form or the (S) -form optically active form can be arbitrarily produced by appropriately selecting the enantiomer of the asymmetric ligand. In the same manner as described above, an optically active compound of the compound [Id] can be produced from the compound [Ic].
  • asymmetric reduction reaction That is, the optical activity of compound (Ib) is obtained by asymmetric reduction of compound (Ia) using a catalyst such as a rhodium complex or a ruthenium complex using an asymmetric ligand such as MCCPM, BINAP, or BPPF
  • a reductase can also be used for asymmetric reduction.
  • the light of The biologically active substance can be produced arbitrarily.
  • the optically active compound is obtained by converting a racemic mixture into an optically active resolving reagent (cis-benzamidocyclohexanecarbonyl chloride, trans-benzamidocyclohexanecarbonyl chloride, trans-cyclohexanedicarboxylic anhydride, etc.). ) To give a diastereomer, separated by fractional crystallization or means such as chromatography, and then hydrolyzed. When the obtained diastereomer is a carboxylic acid, the diastereomer can be further reacted with an appropriate base to be used as a diastereomer salt having good crystallinity.
  • an optically active resolving reagent cis-benzamidocyclohexanecarbonyl chloride, trans-benzamidocyclohexanecarbonyl chloride, trans-cyclohexanedicarboxylic anhydride, etc.
  • the optically active substance can be obtained from the racemic mixture by high-performance liquid chromatography using an optically active substance-separating ram (Daisernet ⁇
  • optically active substance-separating ram Daisernet ⁇
  • optically active bases such as brucine, quinine, and monomethylbenzylamine
  • the compound [III], compound [IV:], compound [VII], compound [IX], and compound [X] used as a starting material in the production of the compound of the present invention are known compounds, or according to known methods. It can be produced, for example, as shown in Reference Example by using the above method.
  • the compound of the present invention is effective for treating hyper-Lp (a) blood disease and diseases caused by the same.
  • the compound of the present invention has an Lg (a) lowering action and a TC lowering action, and also has an Fg lowering action that is not known in known compounds.
  • the compound of the present invention is expected to be a particularly excellent therapeutic agent for arterial sclerosis as compared with known compounds.
  • the pharmaceutical composition of the present invention is effective for the treatment and prevention of arterial sclerosis caused by hyperlipidemia, and can be effectively applied for the treatment of the following symptoms, for example.
  • Myocardial infarction coronary artery disease including re-occlusion after PTCA treatment, angina pectoris and ischemic heart disease caused by coronary artery disease, cerebral infarction including cortical and perforating infarcts, thrombosis and its causes Applicable for arteriosclerosis.
  • the compound of the present invention is administered as a medicament
  • the compound of the present invention is used as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1 to 99.5%, preferably 0.5 to 9%. It is administered to animals including humans as a pharmaceutical composition containing 90%.
  • the pharmaceutical compositions are preferably administered in dosage unit forms.
  • the pharmaceutical composition of the present invention can be administered intravenously, orally, intraosseously, topically (such as transdermally), or rectally. Needless to say, it 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) blood disease is preferably determined in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc.
  • the amount of the active ingredient of the present invention for an adult is generally in the range of 50 to 600 nig / human, preferably 10 (! To 300 mgZ human) per day.
  • lower doses may be sufficient, and 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.
  • Step 2 Methyl 2-bromoacetyl-5-benzofurancarboxylate 3 g of methyl 2-acetyl-5-benzofurancarboxylate 31 g was dissolved in 440 ml of chloroform, and 20 ml of a solution of 22.74 g of bromine in chloroform was added dropwise with stirring at room temperature over 2 hours. After the completion of the dropwise addition, the mixture was stirred for 1.5 hours, the reaction solution was poured into ice water, the pore layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 6 Gml of ether was added to the residue, and the crystals were collected by filtration. I got
  • Step 2 1- (4-tert-Butylphenoxy) -3-chloro-2--2-propanone
  • Step 1 4- (2-tert-butylphenoxy) -3- (2-formyl-4-methoxycarbonylphenoxy) -2-propanol Dissolve 3.04 g of methyl 4- (2,3-epoxypropoxy) -3-formylbenzoate and 4.32 g of 4-tert-butylphenol obtained in Reference Example 3 in 70 ml of acetonitrile, and stir at room temperature with anhydrous potassium carbonate. The reaction solution to which 3,98 g was added was immersed in an oil bath at 8 G to 85 ° C. and heated and stirred for 14 hours.
  • Step 3 2- i2.- (4-tert-butyl phenoxy)-i-oxoethyl 1-5-ben Methyl zofurancarboxylate
  • the reaction solution was poured into ice water, made weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 5 As in Example 5, using 4 g of methyl 2-[(5-tert-butylbenzofuran-2-yl) carbonyl] -5-benzofurancarboxylate obtained in Example 1 was reacted. The precipitated crystals were washed with water, dried and recrystallized from acetone to obtain 15.6 g of white crystals.
  • Example 10 The reaction was carried out in the same manner as in Example 5 using 21.8 g of methyl 2- [3- (4-tert-butylphenyl) -trihydroxybutanol] -5-benzofurancarboxylate obtained in Example 10. After concentration, the resulting residue was recrystallized from toluene. As a result, 18.ig white crystals were obtained.
  • Step 1 (2,5-Dimethylphenoxy) -3- (2-formyl-4-methoxycarbonylpropoxy) -2-propanol
  • Step 2 (2,5-Dimethylphenoxy) -3- (2-formyl-4-methoxycarbonylpropoxy) -2-propano
  • Step 1 ( ⁇ ) -2- [2- (4-tert-Butylphenoxy) -triacetoxethyl] -5-Methyl benzofurancarboxylate.
  • Step 2 (-)-2- [2-M-tert-Butylphenoxy) -trihydroxyethyl ⁇ ]-5-benzofurancarboxylic acid Using 8.58 g of the colorless oil obtained in Step 1, the reaction was carried out in the same manner as in Example 5 to obtain 32 g of white crystals.
  • Step 1 (-)-2-i2- (4-tert-butylphenyloxy) -1- (2-carboxyethylcarbonyloxy) ethyl 2-methyl 5-benzofurancarbonate dicyclohexylamine salt
  • Activated carbon (lQg) was added to the mother liquor, and after heating, filtration and partial concentration under reduced pressure were performed to obtain 45 g of secondary crystals.
  • the primary crystals and the secondary crystals were combined and recrystallized from 1.5 L of acetonitrile and 10 g of activated carbon to obtain 271 g of white crystals.
  • mice 7- to 8-week-old male ddY mice (5 mice per group) were orally administered the compound of the present invention of Example 3 or Example 5 suspended in 0.5% methylcellulose solution at a dose of lg / kg. After administration, general symptoms were observed until one week later. As a result, there were no deaths and no abnormal findings were found.
  • each administration group received 0.1% of the control compound, the compound of the present invention of Example 3, or the compound of the present invention of Example 5 in 0.1%.
  • APF monokey bait, Oriental Yeast Co., Ltd.
  • APF was given to the control group at a rate of 20 g / kg each day for 4 weeks.
  • 4- [2- (5-tert-butylbenzofuran-2-yl) -2-hydroxyethoxy] benzoic acid described in WO93 / 01180 was used as a reference compound.
  • Plasma Blood was collected every two weeks from two weeks before the start of dosing to the second week after the end of dosing. Plasma was prepared by adding 1/10 volume of 3.8% aqueous sodium citrate to blood, and TC and Lp (a) and blood clotting time (Fg and APTT) were determined by enzyme method, ELISA method and ratio, respectively. It was measured by a turbidity method (a fully automatic blood coagulation analyzer: Coagmas Yuichi, manufactured by Sankyo).
  • Example 5 4 71 ⁇ 4 74 ⁇ 23 F: P ⁇ 0.05, **: P ⁇ 0.01 Table 5 Effects on APTT Test substance No. of subjects Dosing 4 weeks Dosing completed 2 weeks Control 4 100 Sat 2 1 ( ⁇ Sat 1
  • Formulation 1 tablet in 180 mg of the compound of the present invention of Example 5 1 G Omg Lactose 45 mg Corn starch 20 mg Low-substituted hydroxybutyric cellulose 9 mg Polyvinyl alcohol (partially saponified) 5 mg Magnesium stearate Img After mixing the above components except polyvinyl alcohol and magnesium stearate uniformly, manufacture granules for tableting by wet granulation using aqueous polyvinyl alcohol as a binder did. Magnesium stearate was mixed with the mixture, and the mixture was formed into an oral tablet using a tableting machine to form a tablet with an 8-dragon diameter and a tablet weight of 180 mg.
  • Hard capsule hard capsule
  • Example 5 The compound of the present invention of Example 5 l O Omg lactose? 90mg Low-substituted hydroxybutene bil cellulose 70mg Hydroxybutyl pill cellulose 40 mg The above components were uniformly mixed, kneaded, and then granulated with a diameter of 0.7 using a granulator to obtain granules.

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Abstract

Composé représenté par la formule générale [I], sel de ce composé acceptable en pharmacologie, et composition pharmaceutique le contenant comme ingrédient actif. Dans la formule, R représente hydrogène, alkyle, etc.; B représente -CO- ou -CH(OH)-; A représente un groupe de formule [II], etc., où R?1, R2, R3, R4¿ et Y représentent chacun hydrogène, alkyle, etc.; X représente -O-, etc.; et Z1 et Z2 représentent chacun hydrogène, ou Y, Z1 et Z2 sont combinés ensemble pour représenter -CH=. Cette composition pharmaceutique est efficace dans la prévention et le traitement de l'artériosclérose, des maladies cardiaques d'origine ischémique, de l'infarctus cérébral et dans la reconstruction après une angioplastie coronarienne transluminale percutanée (PTCA).
PCT/JP1994/000664 1993-04-22 1994-04-22 Derive de l'acide benzofurancarboxylique et composition pharmaceutique WO1994024117A1 (fr)

Priority Applications (1)

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AU65810/94A AU6581094A (en) 1993-04-22 1994-04-22 Benzofurancarboxylic acid derivative and pharmaceutical composition

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JP12054693 1993-04-22
JP5/120546 1993-04-22

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WO1994024117A1 true WO1994024117A1 (fr) 1994-10-27

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057117A3 (fr) * 1998-05-04 2001-04-12 Asta Medica Ag Derives indoliques et leur utilisation pour le traitement de maladies malignes et autres induites par des proliferations cellulaires pathologiques
JP2007536226A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 選択的アンドローゲン受容体モジュレーター（ｓａｒｍｓ）としての新規インドール化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60112783A (ja) * 1983-10-31 1985-06-19 メルク　フロスト　カナダ，インコーポレーテツド リポキシゲナーゼ阻害剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60112783A (ja) * 1983-10-31 1985-06-19 メルク　フロスト　カナダ，インコーポレーテツド リポキシゲナーゼ阻害剤

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057117A3 (fr) * 1998-05-04 2001-04-12 Asta Medica Ag Derives indoliques et leur utilisation pour le traitement de maladies malignes et autres induites par des proliferations cellulaires pathologiques
US6407102B1 (en) 1998-05-04 2002-06-18 Zentaris Ag Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation
US6812243B2 (en) 1998-05-04 2004-11-02 Zentaris Ag Indole derivatives and their use for the treatment of malignant and other diseases based on pathological proliferation
JP2007536226A (ja) * 2004-05-03 2007-12-13 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 選択的アンドローゲン受容体モジュレーター（ｓａｒｍｓ）としての新規インドール化合物
US7678926B2 (en) * 2004-05-03 2010-03-16 Janssen Pharmaceutica Nv Indole derivatives as selective androgen receptor modulators (SARMS)
JP4917018B2 (ja) * 2004-05-03 2012-04-18 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 選択的アンドローゲン受容体モジュレーター（ｓａｒｍｓ）としての新規インドール化合物
US8394971B2 (en) 2004-05-03 2013-03-12 Janssen Pharmaceutica N.V. Indole derivatives as selective androgen receptor modulators (SARMS)

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