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WO1998035939A1 - Derives de diamide malonique et utilisation de ces derniers - Google Patents

Derives de diamide malonique et utilisation de ces derniers Download PDF

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Publication number
WO1998035939A1
WO1998035939A1 PCT/JP1997/003863 JP9703863W WO9835939A1 WO 1998035939 A1 WO1998035939 A1 WO 1998035939A1 JP 9703863 W JP9703863 W JP 9703863W WO 9835939 A1 WO9835939 A1 WO 9835939A1
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WO
WIPO (PCT)
Prior art keywords
diisopropylphenyl
dihydro
quinolinepropanamide
oxo
methyl
Prior art date
Application number
PCT/JP1997/003863
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English (en)
Japanese (ja)
Inventor
Tomoo Suzuki
Shigeyoshi Nakamura
Masato Fukushima
Kouji Mineta
Masahiro Fuchigami
Koji Maeda
Hiromoto Kimura
Katsushi Yamaguchi
Takahiko Mitani
Original Assignee
Sanwa Kagaku Kenkyusho Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP3356797A external-priority patent/JPH09301953A/ja
Application filed by Sanwa Kagaku Kenkyusho Co., Ltd. filed Critical Sanwa Kagaku Kenkyusho Co., Ltd.
Publication of WO1998035939A1 publication Critical patent/WO1998035939A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to a novel malonic acid diamide derivative having a potent acyl-Co: A cholesterol acyltransferase (ACAT) inhibitory activity and thus effective for the prevention and treatment of hypercholesterolemia and arteriosclerosis. And its non-toxic salts.
  • ACAT cholesterol acyltransferase
  • Arteriosclerosis is an important disease that causes ischemic injury such as cerebral infarction and myocardial infarction and is the leading cause of death in developed countries.
  • Atherosclerosis is a chronic disorder of the vascular endothelial cells, and its onset and progression involves hyperlipidemia, LDL degeneration, monocyte adhesion and entry, macrophage generation and foaming, etc. I have.
  • ACAT esterifies cholesterol in each organ, and is involved in the absorption of cholesterol in the intestinal tract, the accumulation of cholesterol in the liver, and the foaming of denatured LDL into macrophages under vascular endothelial cells. Inhibiting ACAT leads to the treatment and prevention of hyperlipidemia and arteriosclerosis.
  • ACAT inhibitors can be classified into amide derivatives (for example, JP-A-3-218340), urea derivatives (for example, JP-A-5-92950), imidazole derivatives (for example, TO 91/18885), and the like.
  • amide derivatives for example, JP-A-3-218340
  • urea derivatives for example, JP-A-5-92950
  • imidazole derivatives for example, TO 91/18885)
  • an object of the present invention is to provide a malonic acid diamide derivative which has a stronger ACAT inhibitory action than conventional compounds and is particularly effective for arteriosclerosis. Disclosure of the invention
  • the present inventors have conducted intensive studies to develop malonic acid derivatives which are highly effective in the prevention and treatment of hypercholesterolemia and arteriosclerosis.
  • R1, R2 and R3 represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R4 and R5 represent a hydrogen atom or a lower alkyl group
  • R6 and R7 represent a hydrogen atom and a lower alkyl group.
  • R8, R9 and R10 represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group which can be substituted with a halogen atom,
  • X represents an amino group substituted with a lower alkyl group, a cyclic amino group, a lower alkylthio group or a nitro group,
  • X represents a bond or a methylene group,
  • Y represents a bond, 0, S, NR11, CHR1U or CIKH.
  • R11 represents a lower alkyl group or a phenyl group
  • n means an integer of 0, 1, 2 or 3
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the lower alkyl group means a methynole group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group and the like.
  • the lower alkoxy group which can be substituted with a halogen atom means a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a trifluoromethoxy group and the like.
  • the phenyl group which may have a substituent means a phenyl group, a 2-methylphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, or the like.
  • the amino group substituted with a lower alkyl group means a dimethylamino group, a getylamino group, a di-n-propylamino group, a diisopropylamino group, or the like.
  • the cyclic amino group means a pyrrolidinyl group, a piperidinyl group, a morpholino group, a 4-methylpiperazinyl group, a 4-phenylbiperazinyl group or the like, and the lower alkylthio group means a methylthio group, an ethylthio group or the like.
  • the compound according to the present invention can be produced by various methods and is not particularly limited. For example, it can be synthesized by the following routes.
  • the above synthetic routes 1 and 2 will be described in more detail.
  • DCC dicyclohexyl carpoimide
  • WSC triethyl-3- (3-dimethylaminopropyl) carbodiimide
  • CDI carbodyl midazole
  • About 0.5-2 mol can be used for (II).
  • the reaction can be carried out at a temperature of about -50 to 150 ° C in the presence or absence of a solvent.
  • Solvents include water, acetic acid, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, getyl ether, tetrahydrofuran, dioxane, ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide (DMF), N, N-dimethylacetamide (DMA), benzene, toluene, xylene, hexane and mixtures thereof can be used.
  • DMF dimethylformamide
  • DMA N-dimethylacetamide
  • 4-dimethylaminopyridine, N-hydroxysuccinimide, hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, etc. can also be added.
  • Separation and purification of the target compound from the obtained reaction mixture can be performed by a method known per se such as filtration, concentration, extraction, column chromatography, distillation, and recrystallization.
  • the type and molar ratio of the condensing agent, the solvent used, and the replacement paper (Rule 26) Additives and separation / purification methods are the same as in Route 1.
  • the compounds according to the present invention can also be synthesized by the methods of Routes 3 and 4 below.
  • R1-RIO, X and Y have the above-mentioned meanings, and ⁇ means a chlorine atom, a bromine atom or an iodine atom.
  • the reaction can be carried out at a temperature of about -50 to 100 ° C in the presence or absence of a solvent.
  • Solvents include ethyl acetate, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, dimethyl ether, tetrahydrofuran, dioxane, DMF, DMA, benzene, toluene, xylene, hexane, hexane, pyridine and mixtures thereof. Can be used.
  • Organic additives such as triethylamine, and inorganic bases such as sodium hydroxide and sodium hydrogen carbonate can be added as additives. Separation and purification of the target compound from the obtained reaction mixture can be carried out in the same manner as in Synthesis Route 1.
  • the starting compound (Va) can also be the corresponding hydrochloride or bromate.
  • the type of condensing agent, molar ratio, solvent used, additives, separation and purification method, etc. are the same as those in Route 1.
  • the compound according to the present invention and its non-toxic salt have a strong ACAT inhibitory activity, they are useful as an active ingredient of a therapeutic agent for hyperlipidemia, arteriosclerosis and the like.
  • the compounds according to the invention and the non-toxic salts thereof are administered orally or parenterally.
  • the dose varies depending on symptoms, age, sex, body weight, dosage form, etc. For example, when administered orally to adults, it is usually 0.1-100 mg / day.
  • the dosage form when the compound of the present invention and its non-toxic salt are formulated and solid preparations such as tablets, pills, capsules, powders, and granules, liquid forms such as solutions, suspensions, and emulsions It can be made into preparations, suppositories, and patches; in the case of solid preparations and liquid preparations, it can be administered orally; in the case of solution preparations, it can be injected intravenously, intramuscularly, subcutaneously Can be administered.
  • excipients such as starch, lactose, glucose, calcium phosphate, magnesium stearate, carboxymethyl cellulose can be used, and if necessary, lubricants, disintegrants, coatings, coloring Agents and the like can also be used.
  • stabilizers, solution auxiliaries, suspending agents, emulsifiers, buffering agents, preservatives and the like can be added.
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1, 19 g, 4.52 mmol), 1, 2,3,4-Tetrahydroquinoline (500 mg, 3.75 mmol) and DCC (775 mg, 3.75 mmol) were dissolved in dichloromethane (25.0 ml) and stirred at room temperature for 1 day. Thereafter, the generated precipitate was removed by filtration, and concentrated under reduced pressure. Then, the obtained concentrated solution is separated and purified by silica gel column chromatography (developing solution: n-hexane / ethyl acetate), and recrystallized from n-hexane / dichloromethane to obtain a desired compound as colorless crystals. (1.09 g, yield: 76.7%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (807 mg, 3.0 bandol), 1,2,3,4 tetrahydro 6-methoxyquinoline (500 mg, 3.0 bandol) and DCC (631 mg, 3.06 ol) was dissolved in dichloromethane (10.0 ml) and stirred at room temperature for 14 hours. Then, the resulting precipitate was removed by filtration, and a saturated aqueous sodium hydrogen carbonate solution, a 2M aqueous solution of citric acid, and then The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired compound as colorless crystals (703 mg, yield: 56.2%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (478 mg, 1.82 mmol), 6-fluoro 1,2,3,4 tetrahydro-2-methylquinoline (300 mg, 1.82 bandol) and DCC (375 mg) , 1.82 mmol) was dissolved in dichloromethane (5.0 ml) and stirred at room temperature for 17 hours. Thereafter, the resulting precipitate was removed by filtration, washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the concentrate obtained is crystallized with 11-hexane to obtain the desired solution. The compound was obtained as colorless crystals (690 mg, quantitative).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.79 g, 6.79 dragonol), 1,2,3,4-tetrahydro-2-methylquinoline (1.00 g, 6. 79mmol) and DCC (1.40g, 6.79inraol) were dissolved in dichloromethane (40.0ml) and stirred at room temperature for 16 hours. Thereafter, the formed precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then, the obtained concentrate was crystallized from ether to give the desired compound as colorless crystals (2.60 g, yield: 97.3%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.41 g, 5.37IMO1), 1,2,3,4-tetrahydro-6,7,8-trimethoxyquinoline (1.20 g, 5 37 marl ol) and DCC (1.16 g, 5.62 mmol) were dissolved in dichloromethane (50 ml) and stirred at room temperature for 16 hours. Thereafter, the generated precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, an aqueous solution of dicarboxylic acid, and subsequently with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained concentrated solution was fractionated and purified by silica gel column chromatography (developing solution: ethanol), and then crystallized with ⁇ -hexane / ethyl acetate to obtain the desired compound as colorless crystals ( 630 mg, yield: 25.7%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.39 g, 5.28 liter), 6-methoxy-2,2-dimethyl 1 (2H) -quinoline (l.OOg, 5.23MIO1) and DCC (1.09 g, 5.28 mmol) was dissolved in dichloromethane (40.0 ml), and the mixture was stirred at room temperature for 30 hours. Thereafter, the formed precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from ether / n-hexane to give the desired compound as colorless crystals (2.20 g, yield: 95.6%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (527 mg, 2.0 mmol).
  • 1,2,3,4-tetrahydroisoquinoline (267 mg, 2.00 ol) and DCC (423 mg, 2.5) mmol) was dissolved in dichloromethane (25.0 ml) and stirred at room temperature for 4 days.
  • the resulting precipitate is removed by filtration, concentrated under reduced pressure, and purified by silica gel column chromatography (developing solution: ethyl acetate / n-hexane) to give the desired compound in colorless form. Obtained as crystals (580 mg, yield: 76.6%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (3.67 g, 14.0 mmol), 2, 3,4,5-tetrahydro-7 methoxy-1H-trobenzazepine (2.06 g, 11.6 mmol), 1-hydroxybenzotriazol (1.88 g, 14.Ommol) and WSC (2.68 g, 14.Ommol) ) was added to dichloromethane (60 ml) and stirred at room temperature for 16 hours. Thereafter, the mixture was concentrated under reduced pressure, ethyl acetate and 1N-hydrochloric acid were added, and the insoluble material was removed by filtration.
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (1.47 g, 5.58 ol), 2,3,4,5-tetrahydro-2-methyl-1H-benzazepine (900 mg, 5,58 Marauder ol) and DCC (1.15 g, 5.58 marauder ol) were dissolved in dichloromethane (30 ml) and stirred at room temperature for 20 hours. Thereafter, the resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, a 2M aqueous solution of citric acid, and then with a saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrate was recrystallized from ethanol / ether to give the desired compound as colorless crystals (1.25 g, yield: 55.1%).
  • the obtained concentrate was separated and purified by silica gel column chromatography (developing solution: n-hexane / ethyl acetate), and crystallized with ether to give the desired compound as colorless crystals (216 mg, quantitative ).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (157 mg, 0.598 marl ol), 1,4-benzoxazine (80.8 mg, 0.598 marl ol) and DCC (124 mg, 0.598 ol) was dissolved in dichloromethane (5.0 ml) and stirred at room temperature for 25 hours. Thereafter, the generated precipitate was removed by filtration, and concentrated under reduced pressure. The concentrated solution obtained is silica gel The desired compound was obtained as colorless crystals by separation and purification by column chromatography (developing solution: dichloromethane) and crystallization with ether (220ing, yield: melting point: 232-235 ° C)
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (274 mg, 1.04 raiol), 1,4-benzothiazine (157 mg, 1.04 mmol) and DCC (216 mg, 1.04 mmol) were added to dichloromethane (5 mg). .0 ml) and stirred at room temperature for 14 hours. Thereafter, the resulting precipitate was removed by filtration, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated solution was separated and purified by silica gel column chromatography (developing solution: n-hexane / ethyl acetate), and crystallized with ether to obtain the desired compound as colorless crystals (420 mg). , quantitative).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (176 mg, 0.67 marl), 3,4-dihydro-1,5benzoxazepine (100 mg, 0.67 mmol) and DCC (138 mg,
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (884 mg, 3.36 bandol), 3,4-dihydro-1,5-benzothiazepine (555 mg, 3.36 mmol) and DCC (693 mg, 3.36 mmol) ) was dissolved in dichloromethane (10 ml) and stirred at room temperature for 17 hours. Thereafter, the formed precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from n-hexane / ethyl acetate to give the desired compound as colorless crystals (1.18 g, yield: 85.6%).
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (l.Olg, 3.84MIO1), 3,4-dihydro-7-methoxy-1,5-benzothiazepine (750 mg, 3.84 mmol) and DCC ( 792 mg, 3.8 mol) was dissolved in dichloromethane (20 ml) and stirred at room temperature for 16 hours. Thereafter, the generated precipitate was removed by filtration, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, a 2M aqueous solution of citric acid, and then with a saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was recrystallized from ethanol / ether to give the desired compound as colorless crystals (1.37 g, yield: '81 .03 ⁇ 4).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.44 g, 5.48 bandol)
  • 6,8 dimethoxy-2,2 dimethyl-1,2,3,4-tetrahydroquinoline (1.21 g, 5.48 Dragonol)
  • DCC (1.13 g, 5.48 mmol)
  • the resulting precipitate was removed by filtration, washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the concentrate was crystallized from ethanol to give the desired compound as colorless crystals (1.60 g, yield: 59.0%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (442 mg, 1.68 mmol), 1,2,3,4-tetrahydro-2-methyl-6 ditroquinoline (323 mg, 1.68 mmol) and DCC (347 mg , 1.68 bandol) was dissolved in dichloromethane (15.0 ml) and stirred at room temperature for 21 hours. The resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrate was crystallized from dichloromethane / ether to give the desired compound as colorless crystals (520 mg, yield: 71%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.25 g, 4.74 ol), 6,8 dimethyl 2,2 dimethyl-1 (2H) quinoline (1.04 g, 4.74 ol) and DCC (0.98 g, 4.74 mmol) was dissolved in dichloromethane (40 ml) and stirred at room temperature for 41 hours. The resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, a 2M aqueous solution of citric acid, followed by water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained concentrated solution was fractionated and purified by silica gel column chromatography (developing solution: n-hexane / ethyl ether), and crystallized with ethanol to obtain the desired compound as colorless crystals (442 mg). , Yield: 20%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.53 g, 5.81 mmol), 8-methoxy-2,2-dimethyl-K2H) -quinoline (1.10 g, 5.81 1)
  • DCC (1.20 g, 5.81 mmol) were dissolved in dichloromethane (30 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous sodium hydrogen carbonate solution, a 2M aqueous solution of citric acid, and subsequently with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained darkness The condensed liquid was fractionated and purified by silica gel column chromatography (developing liquid: n-hexane / ether) to obtain the desired compound as colorless crystals (390 mg, yield: 15.4%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (606mg, 2.30IMO1), 8-ethoxy-2,2,4-trimethyl-1 (2H) quinoline (500mg, 2.30 bandages) ol) and DCC (475 mg, 2.30 ol) were dissolved in dichloromethane (10.0 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, and the solution was washed with saturated aqueous sodium hydrogen carbonate, 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Was. The concentrate was crystallized from ethanol to give the desired compound as colorless crystals (752 mg, yield: 70.6%).
  • N- (2,6-difluorophenyl) malonic acid monoamide (l.OOg, 4.56IMIO1), 1,2,3,4-tetrahydro-6-methoxy-2-methylquinoline (809 mg, 4.56 mmol) and DCC (941 mg, 4.56 band01) was dissolved in dichloromethane (20.0 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, and the solution was washed with saturated aqueous sodium hydrogen carbonate, 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Was. The obtained concentrate was recrystallized from ethanol to give the desired compound as colorless crystals (1.21 g, yield: 70.8%).
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (l.OOg, 3.80 mmol), 1,2,3,4-tetrahydro-6-methoxy-4-methylquinoline (673 mg, 3.80 mmol) and DCC (784 mg, 3.80 bandol) was dissolved in dichloromethane (0.0 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, dichloromethane was additionally added, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentrated. The obtained concentrate was recrystallized from n-hexane / ethanol to give the desired compound as colorless crystals (1.22 g, yield: 76.0%).
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (961 mg, 3.65 mmol), 6-ethoxy 3,4 dihydro-2,2,4 trimethylquinoline (800 mg, 3.65 bandol), DCC (753 mg
  • the desired compound was obtained as colorless crystals by performing the same operation as in Production Example 24 except that dichloromethane (20.0 ml) and dichloromethane (20.0 ml) were used (766 mg, yield: 45.2%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.3 g, 5.1 bandol), 6-chloro-1,2,3,4-tetrahydro-2,2-dimethylquinoline (l Og, 5. lmmol) and DCC (1. lg, 5.2 mmol) were dissolved in dichloromethane (30 ml) and stirred at room temperature for 19 hours. The resulting precipitate was removed by filtration, and the solution was washed with saturated aqueous sodium hydrogen carbonate, 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained concentrated solution was fractionated and purified by silica gel column chromatography (developing solution: dichloromethane / diethyl ether), and crystallized from ethanol to obtain the desired compound as colorless crystals (1.38 mg, Yield: 61%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (280 mg, 1.1 marl), (-)-1,2,3,4 tetrahydro-8-methoxy-2-methylquinoline (180 mg, 1.0 bandol) and DCC (250 mg, 1.2 mmol) were dissolved in dichloromethane (10.0 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrate is subjected to silica gel column chromatography (developing solution: dichlorometh The desired compound was obtained as colorless crystals by preparative purification using -Tel (390 mg, yield: 91%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide 165 mg, 80.6 mmol
  • (+) 1,2,3,4-tetrahydro-8-methoxy-2-methylquinoline 110 mg, 0.1 mg 6 marol ol
  • DCC 153 mg, 0.7 mmol
  • dichloromethane 8.0 ml
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (678 mg, 2.57 bandol), 1,2,3,4-tetrahydro-6-methoxy-2-phenylquinoline (615 mg, 2.57 mmol) and DCC (531mg, 2.57mmol) in dichloromethane (30.0ml)
  • dichloromethane 30.0ml
  • the resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained concentrate was separated and purified by silica gel column chromatography (eluent: n-hexane / getyl ether) to give the desired compound as colorless crystals (589 mg, yield: 47.3%).
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (797 mg, 3.03 ol), (-)-6-Fluoro 1,2,3,4-tetrahydro-2-methylquinoline (500 mg, 3 .03 bandol) and DCC (625 mg, 3.03 mmol) were dissolved in dichloromethane (7.0 ml) and stirred at room temperature for 16 hours. The resulting precipitate was removed by filtration, washed with a saturated aqueous sodium bicarbonate solution, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrate was crystallized from n-hexane to give the desired compound as colorless crystals (802 mg, yield: 64.5 64.
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (3. lg, 12 mmol)
  • 1,2,3,4-tetrahydro-2,2-dimethyl 6-trifluoromethoxyquinoline (2.9 g, 12 mmol)
  • Marauder ol) and DCC (3. Og, 14 marauder ol) were dissolved in dichloromethane (70 ml) and stirred at room temperature for 19 hours.
  • the resulting precipitate was removed by filtration, washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained concentrated solution was fractionated and purified by silica gel column chromatography (developing solution: n-hexane / dichloromethane), and then recrystallized from ethanol to obtain a desired compound as colorless crystals (1.88 g). , Yield: 32.0%).
  • the obtained concentrated liquid was fractionated and purified by silica gel column chromatography (developing liquid: getyl ether / dichloromethane), and recrystallized with ethanol to obtain a desired compound as colorless crystals (302 mg, yield). : 44.0%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide 1.4 g (5.4IMO1), 1,2,3,4-tetrahydro-2,2-dimethyl-6-dimethylaminoquinoline 1.lg (5.4 mmol), DCC (1.4 g, 6.8 mraol) and dichloromethane (55 ml), except that the desired compound was obtained as colorless crystals by performing the same operation as in Production Example 39 (1.1 yield: 45.0%). Melting point: 217-218 ° C
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (440 mg, 1.67 liters), (+)-1,2,3,4-tetrahydro-2-methyl-6 nitroquinoline (321 mg , 1.67 mmol) and DCC (345 mg, 1.67 mmol) were dissolved in dichloromethane (15.0 ml) and stirred at room temperature for 24 hours. The resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from n-hexane / dichloromethane to give the desired compound as colorless crystals (518 mg, yield: 70.9%).
  • N-(2-isopropylphenyl) malonic acid monoamide (1.21 g, 4.59I IO1), 1,2,3,4 tetrahydro-2,2,6-trimethylquinoline (804 mg, 4. 59 mmol) and DCC (946 mg, 4.59 mmol) were dissolved in dichloromethane (25.0 ml), and the mixture was stirred at room temperature for 24 hours. The resulting precipitate was removed by filtration, and the solution was washed with saturated aqueous sodium hydrogen carbonate, 2M aqueous solution of citric acid, and then with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By crystallizing the obtained concentrated liquid with ethanol, the desired compound was obtained as a colorless compound B (1.21 g, yield: 62.7%).
  • the obtained concentrate was separated and purified by silica gel column chromatography (developing solution: dichloromethane / diethyl ether), and crystallized from ethanol to obtain the desired compound as colorless crystals (170 mg, yield Rate: 25.0%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (580 mg, 2.20 bandol), (+) 1,2,3,4-tetrahydro-2-methyl-6-trifluoromethoxyquinoline (500 mg, 2 I61M0I) and DCC (480 mg, 2.33 mmol) were dissolved in dichloromethane (20 ml) and stirred at room temperature for 15 hours. The resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By crystallizing the obtained concentrate with ethanol, The desired compound was obtained as colorless crystals (621 mg, yield: 60.4%).
  • N- (2,6 diisopropylphenyl) malonic acid monoamide (888 mg, 3.37 bandol), (-) 1,2,3,4-tetrahydro-5,6,7-trimethoxy-2-methylquinoline (800 mg,
  • the desired compound was obtained as colorless crystals by performing the same operation as in Production Example 36 except that 3.37 mmol), DCC (696rag, 3.37 mmol) and dichloromethane (15.0 ml) were used (975 mg, yield: 84.8). %).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (888 mg, 3.37 mmol), (+)-1,2,3,4-tetrahydro-5,6,7-trimethoxy 2-methylquinoline (800 mg , 3.37 mmol), DCC (696 mg, 3 ⁇ 37 bandol) and dichloromethane (15.0 ml), except that the desired compound was obtained as colorless crystals (1.02 g). , Yield: 80.5%).
  • N- (2,6-diisopropylphenyl) malonic acid monoamide (1.23 g, 4.67 nmol)
  • 1,2,3,4-tetrahydro-6-methoxy-2-propylquinoline (956 mg, 4.66 marauder) ol)
  • DCC (1.02 g, 4.94 ol)
  • dichloromethane 30.0 ml
  • the resulting precipitate was removed by filtration, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, a 2M aqueous solution of citric acid, followed by brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the concentrate was crystallized from methanol / water to give the desired compound as colorless crystals (1.33 g, yield: 63.3%).
  • the compounds produced by the Production Examples were tested for their ability to inhibit ACAT, an enzyme involved in the intracellular synthesis of cholesteryl ester, as follows.
  • 0.154 M phosphate buffer pH 6.2, containing 0.5 mM EDTA, 2. OmM dithiothreitol, 0.25 M sucrose. Then, the mixture was centrifuged at 15000 G for 15 minutes, and the obtained supernatant was further centrifuged at 100,000 G for 1 hour to obtain a pellet of microsomal. The resulting pellet was suspended in 0.154M phosphate buffer (pH 7.4), isolated again by centrifugation, and stored at -80 ° C.
  • Cholesterol esterification was measured using the mouse 'macrophage-like cell line J774.A1.
  • Cells were seeded at 35 mm wells in Dulbecco's Eagle's medium (MEM, 2ral) supplemented with 10% fetal serum at a density of 300,000 cells / well. Under the conditions of cells is 37 ° C, 5% CO 2 /95% air, the culture medium Asechiru of human low density lipoprotein (ac-LDL, 50 ⁇ g ) containing 10% FBS-DMEM (lml) 24 hours instead I caught it.
  • MEM Dulbecco's Eagle's medium
  • test compound (10 // 1) and lOmM 14 C oleic acid (0.1 mg / ml, 100 ⁇ 1) complexed with serum albumin were added, and the mixture was incubated at 37 ° C for 5 hours. Thereafter, the reaction was stopped, and intracellular lipids were extracted with hexane: propanol (3: 2).
  • the obtained hexane layer was evaporated to dryness under reduced pressure, fractionated by silica gel thin layer chromatography using petroleum ether: ethyl ether: acetic acid (80: 20: 1) as a developing solution, and then cholesteryl ester was extracted.
  • the radiation activity of the spots was measured with a liquid scintillation counter. From the measured values, the concentration at which ACAT activity was inhibited by 50% by the test compound (IC 5 ) was determined.

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Abstract

L'invention concerne des dérivés de diamide malonique représentés par la formule générale (I), et des sels non toxiques de ces derniers, présentant une activité inhibant la transférase d'acyle de cholestérole. R1, R2 et R3 représentent chacun un atome d'hydrogène, un atome d'halogène, un groupe alkyle inférieur ou un groupe alcoxy inférieur. R4 et R5 représentent chacun un atome d'hydrogène ou un groupe alkyle inférieur; R6 et R7 représentent chacun un atome d'hydrogène, un groupe alkyle inférieur ou un groupe phényle éventuellement substitué; R8, R9 et R10 représentent chacun un atome d'hydrogène, un atome d'halogène, un groupe alkyle inférieur, un groupe alcoxy inférieur éventuellement substitué par de l'halogène, un groupe aminé substitué par de l'alkyle inférieur, un groupe aminé cyclique, un groupe alkylthio inférieur, ou un groupe nitro; X représente une liaison ou un groupe de méthylène; Y représente une liaison, O, S, NR11, CHR11 ou CH=CH, où R11 représente un groupe alkyle inférieur ou un groupe phényle; et n est un nombre entier de 0, 1, 2 ou 3.
PCT/JP1997/003863 1997-02-18 1997-10-24 Derives de diamide malonique et utilisation de ces derniers WO1998035939A1 (fr)

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JP3356797A JPH09301953A (ja) 1996-03-12 1997-02-18 マロン酸ジアミド誘導体及びその用途
JP9/33567 1997-02-18

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
WO2014146494A1 (fr) * 2013-03-20 2014-09-25 中国科学院上海药物研究所 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors

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Publication number Priority date Publication date Assignee Title
JPH03220164A (ja) * 1989-11-16 1991-09-27 Warner Lambert Co Ａｃａｔ阻害剤
JPH04236268A (ja) * 1991-01-18 1992-08-25 Fuji Photo Film Co Ltd アゾメチン系化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03220164A (ja) * 1989-11-16 1991-09-27 Warner Lambert Co Ａｃａｔ阻害剤
JPH04236268A (ja) * 1991-01-18 1992-08-25 Fuji Photo Film Co Ltd アゾメチン系化合物

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
WO2014146494A1 (fr) * 2013-03-20 2014-09-25 中国科学院上海药物研究所 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants
CN105051046A (zh) * 2013-03-20 2015-11-11 中国科学院上海药物研究所 β-氨基羰基类化合物、其制备方法、药物组合物及其用途
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors

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