WO1995004025A1 - Derive d'acide tricarboxylique a activite d'inhibition de la squalene-synthetase - Google Patents

Derive d'acide tricarboxylique a activite d'inhibition de la squalene-synthetase Download PDF

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WO1995004025A1
WO1995004025A1 PCT/JP1994/001249 JP9401249W WO9504025A1 WO 1995004025 A1 WO1995004025 A1 WO 1995004025A1 JP 9401249 W JP9401249 W JP 9401249W WO 9504025 A1 WO9504025 A1 WO 9504025A1
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phenyl
hydroxy
succinate
substituent
synthesis
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PCT/JP1994/001249
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English (en)
Japanese (ja)
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Takamitsu Kobayashi
Kunio Tamura
Mitsutaka Yoshida
Hiroshi Koga
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU72383/94A priority Critical patent/AU7238394A/en
Publication of WO1995004025A1 publication Critical patent/WO1995004025A1/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
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms

Definitions

  • Tricarboxylic acid derivatives having squalene synthetase inhibitory action having squalene synthetase inhibitory action
  • the present invention relates to a carboxylic acid derivative, and more particularly, to a novel tricarboxylic acid derivative which has a squalene synthetase inhibitory activity and suppresses squalene production, thereby suppressing cholesterol biosynthesis.
  • Cholesterol-lowering agents have been used for drug treatment of hyperlipidemia and arteriosclerosis. Possible mechanisms for lowering serum cholesterol include inhibition of cholesterol biosynthesis, inhibition of cholesterol absorption, and promotion of bile acid excretion, and cholesterol biosynthesis inhibitors are considered to be rational. Among them, HMG-C0A reductase inhibitors such as lovastatin are widely used clinically because of their strong cholesterol lowering action and relatively few side effects.
  • HMG-C0A reductase inhibitors which are used for drug treatment of hyperlipidemia and arteriosclerosis, are enzymes located upstream in the cholesterol biosynthesis pathway and are one of the rate-limiting enzymes. Because it inhibits certain HMG-COA reductases, it also inhibits the biosynthesis of mevalonic acid-derived products other than cholesterol, such as isopentenyl tRNA, ubiquinone, and dolichol. Ubiquinone acts as an antioxidant in vivo, and dolichol acts as a lipid intermediate that transports sugars in cell membranes.HMG-C0A reductase inhibitors reduce non-sterol products derived from mevalonic acid. Side effects are also a concern.
  • the present invention relates to a tricarboxylic acid derivative having a squalene synthetase inhibitory activity for inhibiting the production of a non-sterol product derived from mevalonic acid and more selectively inhibiting cholesterol biosynthesis.
  • natural products having squalene synthetase inhibitory activity have been discovered (S qualestatins: MJD aws on, etc. J. Antibio t.45.639—647, 19 ⁇ 2 and Zarago nicacids: Proc. Nat 1. A cad. Sci. USA, 90, 80—84.1993). Synthetic compounds have also been reported (J. Med. Chem, 20, 243-249, 1977.J. Am. Chem.
  • pyrophosphates Most of them are pyrophosphates, and their efficacy is not sufficient. Such pyrophosphates are of concern for their chemical and enzymatic instability against allylic C-0 cleavage and susceptibility to metabolism by phosphatases. Bisphosphonate derivatives are also known, but have high affinity for bone and have an effect on the bone metabolic system, and their evaluation as a squalene synthetase inhibitor has not yet been determined.
  • the present inventors have conducted intensive studies with the aim of developing an efficient squalene synthetase inhibitor with higher reaction specificity. As a result, the compound represented by the general formula (1) achieved the first object. And completed the present invention.
  • R 2 has the general formula (2)
  • R 3 represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms which may have a substituent
  • R 4 and R 5 represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms which may have a substituent;
  • R 6 represents a hydrogen atom or a linear or branched saturated or unsaturated alkyl group having 1 to 25 carbon atoms which may have a substituent;
  • n 1 or 2)
  • R 3 , R 4 and R 5 represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms which may have a substituent:
  • R 6 represents a hydrogen atom or a hydroxyl group, and when it is a hydroxyl group, it may be condensed with COOR 3 to form a cyclic ester
  • R 3 represents a lower alkyl group having 1 to 6 carbon atoms which may have a substituent) or a general formula (5) R 6 ⁇ C ⁇ R S
  • R 3 and R 5 represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms;
  • R 6 represents a hydrogen atom or a linear or branched C 1 to C 25 optionally having substituent (s); Represents a saturated or unsaturated alkyl group)
  • A is 0, S, indicates the member selected from the group consisting of S 0 and NR 7, wherein indicating the R 7 is a hydrogen atom or an optionally substituted alkyl group)
  • the substituent of the saturated or unsaturated alkyl group which may have a substituent includes 3-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-isomyroxyphenyl, 4- (1-ethylpropoxy) phenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3,4- Difluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-methylphenyl, 4-phenylphenyl, 4- (phenylthio) phenyl, 4- (3-methylphenylthio) phenyl, 4- (3-methyl Phenylsulfinyl) phenyl, 4- (3-methylphenylsulfonyl) phenyl, 4- (2-methylphenyloxy) phenyl, 4- (3-methylphenoxy) phenyl, 4- (3-methylphenoxy) phen
  • the saturated or unsaturated alkyl group of a saturated or unsaturated alkyl group which may have a substituent means a linear or branched saturated or unsaturated alkyl group having 3 to 25 carbon atoms.
  • n-pentyl, n-heptyl and 8-nonenyl are preferred.
  • Examples include: 5- (4-phenyloxyphenyl) pentyl, 5- (4-phenylthiophenyl) pentyl, 5- (4- (3-fluorophenyloxy) phenyl) pentyl, 5- (4— (3 —Methylphenyloxy) pentyl, 5- (4- (3-chlorophenyloxy) pentyl) pentyl, 5- (4- (3,4-dimethylphenyloxy) phenyl) pentyl, 5 -— (3-methyl-14-1- (3— Methylphenoxy) phenyl) pentyl, 7- (4-fluorophenyl) heptyl, 7- (3,4-dichlorophenyl) heptyl, 9-phenyl-18-nonenyl, 4- (4-phenyloxybutyl) butyl, 5- (4-biphenyl) pentyl, 5- (4-phenyloxy) 1-3-methylpentyl, 5- (4
  • Nil) pliers 5— (4-phenylthiophenyl) pentyl, 5— (4- (3-fluorophenoxy) phenyl) pentyl, 5— (4- (3-methylphenyloxy) phenyl) pentyl, 5 — (4— (3—Chloropheno Quin) .phenyl) pentyl, 5- (4- (3,4-dimethylphenoxy) phenyl) pentyl, 5- (3-methyl-4-1 (3-methylphenoxy) phenyl) pentyl, 7— (4 —Fluorophenyl) heptyl, 7— (3,4-dichlorophenyl) heptyl and 9-phenyl-8-nonenyl are preferred.
  • a lower alkyl group having 1 to 6 carbon atoms which may have a substituent means an alkyl group having 1 to 6 carbon atoms which may have a linear or branched substituent.
  • R 3 is preferably a methyl group or an ethyl group.
  • R 4 is preferably a methyl group or an ethyl group.
  • R 5 is preferably a methyl group or an ethyl group.
  • alkyl group include a methyl group, an ethyl group, an n-propyl group, a t-butyl group-phenylesyl group, a dodecanyl group, and a 3,7,11-trimethyldodecanyl group.
  • R 6 is preferably a hydrogen atom, a methyl group, or a phenylesyl group.
  • ⁇ is preferable.
  • the compounds of the present invention are all novel compounds not described in the literature, and can be produced, for example, as follows.
  • R 8 represents a lower alkyl group
  • Z is a member selected from the group consisting of 0, S and NR 7, wherein indicating the R 7 is hydrogen atom or optionally substituted alkyl group)
  • R 9 and R 1 () represent a lower alkyl group.
  • Examples of the inert solvent used in the reaction c obtained by reacting the compound of the formula (1) in an inert solvent in the presence of a base include tetrahydrofuran and getyl ether, with tetrahydrofuran being particularly preferred.
  • Examples of the base include lithium diisopropylamide, lithium getylamide, lithium tetramethylpiperazide, lithium hexamethyldisilazide, and the like, with lithium diisopropylamide being particularly preferred.
  • the reaction temperature is in the range of 100 to 0 ° C, preferably 178 to 0 ° C, and the reaction time is in the range of 0.5 to 20 hours, preferably 0.5 to 3 hours.
  • the compound represented by the general formula (15) obtained by reacting the general formula (9) with the general formula (14) is converted into a compound represented by the general formula (16)
  • reaction temperature is in the range of 0 to 150 ° C, preferably room temperature to 80 ° C.
  • Rn represents a linear or branched C1-C25 saturated or unsaturated alkyl group which may have a substituent
  • X represents a chlorine, bromine or iodine atom
  • the reaction is performed under a nitrogen stream, and examples of the inert solvent used in the reaction include tetrahydrofuran and dimethylformamide.
  • examples of the base include sodium hydride, potassium hydride, n-butyllithium and the like.
  • the reaction temperature is in the range of 0 to 80 ° C, preferably at room temperature.
  • the conjugate salt of the compound represented by the general formula (1) is obtained by hydrolyzing the compound represented by the general formula (1).
  • the hydrolysis is carried out at 0 ° C to room temperature in a solvent such as ethanol, tetrahydrofuran or dioxane, or a mixed solvent thereof with water using 3 to 4 equivalents of a base such as sodium hydroxide or potassium hydroxide.
  • the reaction is carried out at a reaction temperature for a reaction time of 1 to 20 hours.
  • E represents an oxygen atom or a zeo atom
  • a base such as N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane or a two-phase solvent such as water and benzene using a phase transfer catalyst.
  • the base used include n-butyllithium, sodium amide, sodium hydride, potassium t-butoxide, hydroxide hydroxide, sodium hydroxide, and the like, and preferably sodium hydride is used.
  • E is an iodo atom
  • the reaction is carried out in a solvent such as N, N-dimethylformamide, tetrahydrofuran, acetone, methylene chloride, etc., in the range of 0 to 120. Performed in the range of C.
  • the base to be used include organic bases such as pyridine and inorganic bases such as sodium hydride and lithium carbonate. Preferably, sodium hydride is used.
  • oxidizing a compound represented by the general formula (9) wherein Z is iodo a compound represented by the general formula (9) wherein Z is a sulfoxide is produced. can do.
  • the oxidation reaction is carried out in an organic solvent such as methylene chloride or chloroform using an oxidizing agent such as perbenzoic acid or hydrogen peroxide in acetic acid at a temperature in the range of o ° C to room temperature.
  • those in which Z is oxygen can be obtained by converting the compound represented by the general formula (20) into paratoluenesulfonyl in the presence of a base such as pyridine. After treatment with chloride, mesyl chloride, trifluoromethanesulfonic anhydride, etc. to convert to the sulfonate, the general formula (24)
  • reaction By reacting with a compound represented by the formula in the presence of a base.
  • the reaction may be carried out in a solvent such as N, N-dimethylformamide, tetrahydrofuran, or dimethoxetane, using n-butyllithium, sodium amide, sodium hydride, potassium tert-butoxide, etc. as a base, or
  • the reaction is carried out in a solvent such as methylene chloride or chloroform using an organic base such as triethylamine or an inorganic base such as lithium carbonate.
  • E represents an oxygen atom or a zeo atom
  • a compound represented by the formula And o ° c to the reflux temperature of the reaction mixture.
  • the reaction is performed at room temperature.
  • In general formula (1) is a saturated alkyl group which may have a substituent.
  • In general formula (1) is a unsaturated alkyl group which may have a substituent. It can be obtained by subjecting a certain substance to a usual reduction reaction such as catalytic reduction.
  • Gn represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an acyloxy group, a phenyloxy group which may have a substituent, a fujylthio group which may have a substituent, Represents an aralkyl group which may have a group; n represents an integer of 0 to 4)
  • R 8 has the same meaning as described above; X represents a chlorine atom or a bromine atom; m represents an integer of 3 to 9)
  • a compound represented by the general formula (32) is obtained by subjecting the compound to a Wit tig reaction with a Wit tig reagent represented by the following formula.
  • the double bond of the compound represented by the general formula (32) is reduced by catalytic reduction or the like to obtain the compound represented by the general formula (33). Also, the general formula (32)
  • a compound represented by the formula (30) is represented by the general formula (34)
  • the compound represented by the general formula (35) is obtained by reacting with a Grignard reagent represented by the following formula.
  • a dialcohol represented by the general formula (36) can be obtained.
  • ketoester derivative may be reduced with hydrazine, triethylsilane, etc. to obtain the compound represented by the general formula (44), and then further reduced with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, diborane, or the like.
  • a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, diborane, or the like.
  • the alcohol represented by the general formula (40) can be obtained.
  • the alcohol represented by the general formula (54) is obtained by reacting with the dialcohol represented by the following formula.
  • the crude product was purified by silica gel column chromatography (n-hexane containing 10% ethyl acetate) to obtain 2.22 g of 5- (4- (2-ethylbutyryl) phenyl) pentyl acetate as a colorless oil.
  • 4-Nitro 3 '— trifluoromethyldiphenyl ether 2.4 g was dissolved in 80 ml of methanol, and a small amount of 10% palladium / carbon was added as a catalyst to this solution, and stirred under a hydrogen atmosphere for a short time. did. After removing the catalyst by filtration, the filtrate was concentrated to give 2.0 g of 4-amino-3'-trifluoromethyldiphenyl ether as a colorless oil. Next, this was dissolved in 30.1 ml of 10% hydrochloric acid, and an aqueous solution (2.5 ml) of 0.57 g of sodium nitrite was added dropwise so that the temperature of the solution did not exceed 0 ° C.
  • Oily sodium hydride 0.23 is suspended in 10 ml of ⁇ , N-dimethylformamide, and 0.5 ml of ethyl glycolate is added to this suspension under ice-cooling with 5 ml of N , N-dimethylformamide, and added dropwise, followed by stirring for 30 minutes. Then, the reaction solution was returned to room temperature, and 1.56 ml of funesyl bromide was added dropwise. After stirring at room temperature overnight, 15 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with getyl ether, and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate.
  • L-bromo-5-phenylpentane (4.54 g) and ethyl glycolate (3.12 g) were prepared and treated in the same manner as for L-1a to give 5-ethylpentyloxyethyl ester (511). 3.00 g was obtained as a colorless oil.
  • Example 1-1a 0.5 g of 1-promo 7-phenyl-1-heptene and 0.23 g of ethyl ethyl glycolate were treated in the same manner as in Example 1-1a, and 7-phenyl 4-heptenyloxyethyl acetate was converted into a colorless oil. 0.13 g was obtained.
  • Jetyl succinate 0.198 was hydrolyzed in the same manner as in Example 1-lc, and the cis-trans mixture of 2-carboxylate 12-hydroxy-3- (7-phenyl 6- Heptenyloxy) 0.12 g of trisodium succinate was obtained as a white powder.
  • Jetyl succinate 0.80 g was treated in the same manner as in Example 1-2a to give 2-ethoxycarbonyl 2--2- 0.62 g of acetyl succinate was obtained as a colorless oily product of hydroxy-3- (9-phenylnonyloxy).
  • Jetyl succinate 0.42 g was treated in the same manner as in Example 11-1c (Z 0.31 g of trisodium succinate was obtained as a white powder of))-2-carboxylate-2-hydroxy-3- (6- (2-naphthyl) -15-hexenyloxy).
  • Jetyl succinate 1.04 was catalytically reduced in the same manner as in Example 1-2a. —Ethokinecarbonyl-1-2-hydroquinine-3 -— (7- (3.4-dichlorophenyl) heptyloxy) 1.01 g of getyl succinate was obtained as a colorless oil.
  • Example 7 By treating 0.78 g of 1- (2-biphenyl) -ethyl 6-heptenyloxyacetate 0.78 g in the same manner as in Example 1 1b, 2-ethoxyethoxycarbonyl 2-hydroxy 3- (7- (2-biphenyl) 0.93 g of 1-6-heptenyloxy) getyl succinate was obtained as a colorless oil.

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Abstract

Composé répondant à la formule générale (1): R1-A-R2 ses stéréoisomères et isomères optiques, et ses sels pharmaceutiquement acceptables. Ce composé présente une puissante activité d'inhibition de la squalène-synthétase et est utilisable comme agent de réduction du taux de cholestérol. Dans ladite formule, R1 représente alkyle saturé ou insaturé éventuellement substitué; R2 représente un groupe répondant à la formule générale (2) (dans laquelle R3, R4 et R5 indépendamment les uns des autres, représentent hydrogène ou alkyle inférieur; R6 représente hydrogène ou alkyle, et n vaut 1 ou 2), à la formule générale (3) (dans laquelle R3, R4 et R5, indépendamment les uns des autres représentent hydrogène ou alkyle inférieur; et R6 représente hydrogène ou hydroxy), à la formule générale (4) (dans laquelle R3 représente alkyle inférieur), ou à la formule générale (5) (dans laquelle R3, R4 et R5, indépendamment les uns des autres, représentent hydrogène ou alkyle inférieur; et R6 représente hydrogène ou alkyle); et A représente O, S, SO ou NR7.
PCT/JP1994/001249 1993-07-29 1994-07-29 Derive d'acide tricarboxylique a activite d'inhibition de la squalene-synthetase WO1995004025A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783593A (en) * 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase
EP1618086A4 (fr) * 2003-04-22 2007-05-09 Wellstat Therapeutics Corp Composes pour le traitement de troubles metaboliques
US10532124B2 (en) 2012-12-27 2020-01-14 Kimberly-Clark Worldwide, Inc. Water soluble farnesol analogs and their use
US10717946B2 (en) 2012-12-27 2020-07-21 Kimberly-Clark Worldside, Inc. Water soluble essential oils and their use

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JPH04217986A (ja) * 1990-03-21 1992-08-07 Merck & Co Inc 抗高コレステロール血症薬
JPH04221327A (ja) * 1990-03-30 1992-08-11 Merrell Dow Pharmaceut Inc スクアレンエポキシダーゼの抑制剤としてのスクアレンのジ−及びテトラ−フルオロ類似体類

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US5783593A (en) * 1993-11-04 1998-07-21 Abbott Laboratories Inhibitors of squalene synthetase and protein farnesyltransferase
EP1618086A4 (fr) * 2003-04-22 2007-05-09 Wellstat Therapeutics Corp Composes pour le traitement de troubles metaboliques
US7361686B2 (en) 2003-04-22 2008-04-22 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
US10532124B2 (en) 2012-12-27 2020-01-14 Kimberly-Clark Worldwide, Inc. Water soluble farnesol analogs and their use
US10717946B2 (en) 2012-12-27 2020-07-21 Kimberly-Clark Worldside, Inc. Water soluble essential oils and their use

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