WO2000071502A1 - Derives d'hydrazide - Google Patents

Derives d'hydrazide Download PDF

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Publication number
WO2000071502A1
WO2000071502A1 PCT/JP2000/003289 JP0003289W WO0071502A1 WO 2000071502 A1 WO2000071502 A1 WO 2000071502A1 JP 0003289 W JP0003289 W JP 0003289W WO 0071502 A1 WO0071502 A1 WO 0071502A1
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Prior art keywords
lower alkyl
optionally substituted
methyl
atom
phenyl
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PCT/JP2000/003289
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English (en)
Japanese (ja)
Inventor
Akira Suga
Naoki Imanishi
Hideki Kubota
Masanori Miura
Kenji Umemoto
Hiroshi Moritani
Koyo Matsuda
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU46162/00A priority Critical patent/AU4616200A/en
Publication of WO2000071502A1 publication Critical patent/WO2000071502A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel hydrazide derivative or a salt thereof having an inhibitory action on apo B-related lipoprotein secretion, and a medicament containing the same as an active ingredient.
  • Hyperlipidemia is one of the risk factors for atherosclerotic diseases such as ischemic heart disease as well as diabetes, hypertension, smoking, etc., and its improvement is effective in the treatment of such diseases [1, 2, 3] .
  • Hypercholesterolemia causes coronary artery disease as a risk factor for arteriosclerosis, and hypertriglyceridemia is also considered as one of the causes of ischemic heart disease such as myocardial infarction. Therefore, it is desirable to lower blood cholesterol and triglyceride for the treatment of hyperlipidemia.
  • HMG-CoA reductase inhibitors As treatments for hyperlipidemia, HMG-CoA reductase inhibitors, anion-exchange resin preparations, and propriol have been used mainly as drugs to lower blood cholesterol, whereas fibrates and nicotinic acid preparations Is mainly used clinically as a drug to reduce triglyceride in blood.
  • Cholesterol absorbed in the small intestine forms a chylomicron complex with apoprotein B (apoB), phospholipids and triglyceride in the rough endoplasmic reticulum of small intestinal epithelial cells, and enters the blood via the lymphatic vessels. Secreted and transported to tissues such as the liver. In addition, cholesterol synthesized in the liver forms a VLDL complex with apo B, phospholipids and triglyceride in the rough endoplasmic reticulum of hepatocytes, is secreted into the blood, and changes its form into LDL. [4]
  • Apo B has two molecular species, Apo B-100 and Apo B-48, which are synthesized on the rough endoplasmic reticulum in the cell.
  • Apo B-100 is synthesized in liver cells and apo B-48 is synthesized in small intestinal cells by apo B mRNA editing, and each is VLD to become a structural apoprotein of chiromiclone.
  • Cholesterol esters and triglycerides synthesized in the smooth endoplasmic reticulum are transferred by MTP, and bind to apo B in the endoplasmic reticulum to form immature lipoproteins. This immature lipoprotein is secreted out of the lipoprotein as a mature lipoprotein through processes such as further lipid loading and sugar chain loading in the Golgi apparatus [5, 6].
  • apo B-related liposome containing apo B as a constituent into the blood from the small intestine and / or liver By inhibiting the secretion of proteins (chylomicrons, collectively called VLD and LDL), it is possible to lower cholesterol and triglyceride in the blood.
  • chylomicrons collectively called VLD and LDL
  • Such compounds can be used in hyperlipidemia, arteriosclerosis, etc. It is useful as a remedy for obesity and inflammation.
  • compounds for inhibiting the production and / or secretion of apoB-related lipoproteins various compounds such as cycloalcoholic noindole and cycloalcoholic norazindole derivatives are reported in JP-A-8-225526. Is not sufficient, and there is a need for a compound having even better effects.
  • An object of the present invention is to provide a novel hydrazide derivative or a salt thereof, which has an excellent inhibitory effect on secretion of apoB-related popoprotein and is useful as an agent for lowering cholesterol and triglyceride in blood.
  • the present inventors have conducted intensive studies to find a compound having a novel apoB-related lipoprotein secretion inhibitory action, and surprisingly found that the compounds described in JP-A No. 8-225525 By converting a substituted amide group to acetic acid (substituted hydrazide group), the present inventors have found that they have strong apo B-related lipoprotein secretion inhibitory activity, have strong cholesterol and triglyceride lowering effects, and complete the present invention. Reached.
  • the present invention relates to a hydrazide derivative represented by the following general formula (I) or a salt thereof, and a medicament containing these as an active ingredient.
  • a hydrazide derivative represented by the following general formula (I) or a salt thereof is represented by the following general formula (I) or a salt thereof.
  • R 7 , R 8 and R 9 H, optionally substituted hydrocarbon, — Z 2 — Q
  • R 8 and R 9 can form a nitrogen-containing hetero ring which may be substituted
  • R 10 H, or optionally substituted lower alkyl
  • Ring A optionally substituted benzene, optionally substituted pyridine, or optionally substituted cyclohexene ring
  • X and Y same or different nitrogen atom, carbon atom or CH
  • a hydrazide derivative represented by the following general formula (I) or a salt thereof.
  • R ⁇ R 2 and R 3 same or different H, lower alkyl, or halogen
  • R 4 , R 6 , R and R 1 Q — R 12 same or different, H or lower alkyl
  • R 5 lower alkyl or cycloalkyl
  • R 8 and R 9 same or different, H, one Z 2 —Q, or R 8 and R 9 in a nitrogen-containing saturated heterocycle
  • Ring A optionally substituted benzene, optionally substituted pyridine, or optionally substituted hexene ring
  • X and Y same or different nitrogen atom, carbon atom or CH
  • Another object of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrazide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for lowering blood lipids, comprising a hydrazide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for lowering blood lipids comprising a hydrazide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention will be further described as follows.
  • “Lower alkyl” is C 6 alkyl, preferably 4 alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl, and more preferably C 3 alkyl.
  • hydrocarbon group which may be substituted means the following.
  • C is a 2 _ 6 alkenyl, preferably vinyl, Purobe alkenyl, C 2 such as 1 Mechirueparu - 4 alkenyl, more preferably C 2 _ 3 alkenyl,
  • Ariel A 6- to 14-membered aromatic hydrocarbon ring group as a whole, preferably phenyl, naphthyl or
  • a saturated or unsaturated C31 () alicyclic group which may be condensed or crosslinked with a benzene ring. More specifically,
  • a C 3 8 cycloalkyl, cycloheptyl and the like preferably cyclopropyl, cyclopentyl, cyclohexylene cyclohexyl, cyclohexylene.
  • tetrahydronaphthyl Preferably tetrahydronaphthyl and the like.
  • dihydronaphthyl Preferably dihydronaphthyl and the like.
  • Nonrogen-containing saturated heterocycle means a 3- to 6-membered saturated heterocycle having a nitrogen atom as a ring atom, and preferably a 5- or 6-membered nitrogen-containing saturated heterocycle.
  • Heterocycle J means “saturated heterocycle” and “heteroaryl”.
  • Heteroaryl means a heteroatom selected from nitrogen, oxygen or sulfur
  • a “saturated heterocycle” is a heteroatom selected from nitrogen, oxygen, and sulfur.
  • Halogen includes, for example, fluorine, chlorine, bromine or iodine atom. “Optionally substituted” may be substituted with 1 to 3 substituents.
  • the substituent means a usual substituent commonly used in the art for the group to be substituted, and includes halogen, lower alkyl, halogeno lower alkyl, lower alkenyl, lower alkynyl, and cycloalkyl.
  • lower alkylene is _ 6 alkylene, preferably methylene, E Ji Ren, propylene, isopropylene, C, such as t- butylene, - 4 alkylene, more preferred properly C, _ 3 alkylene It is.
  • Lower alkenylene is C 2 _ 6 alkenylene, which has one or more double bonds at any position of the above lower alkylene.
  • the substituent of the lower alkyl which may be substituted is a group other than the substituent bonded via lower alkylene, lower alkenylene, lower alkynylene or the like among the above substituents.
  • halogeno lower alkyl means the above lower alkyl substituted by one or more of the above halogens, and is preferably trifluromethyl.
  • the compound (I) of the invention has an asymmetric carbon depending on the type of the substituent, and there are (R) -form, (S) -form optical isomer and racemic form based on this. Further, depending on the type of the substituent, the compound may have a plurality of asymmetric carbon atoms, and there are diastereomers based on this.
  • the present invention includes all such isomers separated or mixtures thereof.
  • the compound (I) of the present invention may form a salt with an acid.
  • salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propyl succinic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleic acid.
  • Acid addition salts of organic acids such as acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned.
  • hydrates of the compound (I) of the present invention solvates such as ethanol, and polymorphic substances are also included.
  • the compounds of the present invention also include pharmacologically acceptable prodrugs.
  • the group that forms a pharmacologically acceptable prodrug of the compound of the present invention include the group described in Prog. Med. 5: 2157-2161 (1985) and “Development of Drugs” published by Hirokawa Shoten, 1990. Vol. 7 Molecular Design 16 Groups from 163 to 198. Specifically, it is a group that can be converted to the primary amine or secondary amine of the present invention, OH, COOH, or the like by hydrolysis, solvolysis or under physiological conditions.
  • Examples of the drug include: one OCO—an optionally substituted lower alkylene—COOR (R represents H or lower alkyl, the same applies hereinafter), —OCO—an optionally substituted lower alkenylene—COOR, —OCO—substituted ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ — — — 0 CO — lower alkylene O — lower alkylene — CO OR, OCO -COR, -OCO- optionally substituted lower alkyl, - OS0 2 - optionally substituted lower grade alkylene one COOR, -0- phthalidyl, 5-methyl - 1, 3-di old Kisoren one-2-one one 4-yl-methyloxy and the like.
  • the compound of the present invention can be produced by applying various synthetic methods.
  • the typical production method is illustrated below.
  • the compound (I) of the present invention can be produced by a condensation reaction between the carboxylic acid represented by (II) and the hydrazine derivative represented by (III).
  • This reaction can be carried out using a commonly used condensation reagent (such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1,1'-carbonyldiimidazole, etc.)
  • a mixed anhydride method using ethyl formate / isobutyl chloroformate can be used.
  • (II) into an acid halide with a halogenating reagent such as thiocyanyl chloride, quizalyl chloride or phosphorus oxychloride and then react with (II).
  • a halogenating reagent such as thiocyanyl chloride, quizalyl chloride or phosphorus oxychloride
  • the reaction is usually carried out in a solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, chloroform and the like, if necessary, in the presence of a base such as triethylamine, potassium carbonate and the like, while cooling (preferably -15 to 0 ° C) to room temperature. It is appropriate to do below.
  • Z 3 represents a CH 2 or S0 2 group, a halogen atom or an organic scan when the Z 3 is CH 2
  • (Ia) can be produced by reacting the amide compound represented by (IVa) with the halide or sulfonate represented by (Va) or the sulfonyl halide.
  • the halogen atom include a bromine atom, a chlorine atom and an iodine atom.
  • the organic sulfonyl group include alkane sulfonyloxy groups such as methanesulfonyl group, toluene sulfinyl groups (for example, P-toluenesulfonyl group), and benzenesulfonyl groups. An aromatic sulfonyl group is used.
  • the compounds (IVa) and (Va) are almost equimolar or slightly excessive molar amounts in an organic solvent not usually involved in the reaction, for example, dimethylformamide, tetrahydrofuran or the like. Performed at room temperature. This reaction is usually carried out in the presence of a base, and suitable bases such as potassium t-butoxide, sodium hydride, potassium carbonate and potassium hydroxide are preferred.
  • a base such as potassium t-butoxide, sodium hydride, potassium carbonate and potassium hydroxide are preferred.
  • Z 4 represents NH or 0, and represents a halogen atom.
  • the compound (Ib) in the invention compound can be produced by reacting the aromatic halide represented by (IVb) with the adiline or phenolic derivative represented by (Vb).
  • the octogen atom is the same as described above.
  • the reaction is usually performed in the presence of a base, and such a base is preferably a base such as sodium hydride, potassium t-butoxide, potassium carbonate, sodium hydroxide, and the like.
  • the reaction is usually carried out in an organic solvent not involved in the reaction, for example, dimethylformamide, tetrahydrofuran, etc., in a substantially equimolar amount with respect to each of the compounds (IVb) and (Vb), or a slight excess in amount. It is usually advantageous to carry out the reaction at room temperature or under heating. When a base is not used, the reaction can be carried out with phenol as a solvent under heating.
  • (Ic) can be produced by a condensation reaction of a carboxylic acid compound represented by (IVc) and an amine compound represented by (Vc). This reaction can be carried out by using a commonly used condensing reagent (dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1,1′-carbonyldiimidazole, etc.), or by using ethyl chloroformate.
  • a commonly used condensing reagent dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1,1′-carbonyldiimidazole, etc.
  • a mixed acid anhydride method using isoptyl chloroformate can be used, or (IV c) is converted to an acid halide with a halogenating reagent such as thionyl chloride, quinoxalyl chloride, or phosphorus oxychloride; It is also possible to react with.
  • the reaction is usually carried out in a solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, chloroform and the like, if necessary, in the presence of a base such as triethylamine, potassium carbonate and the like, while cooling (preferably -15 to 0 ° C) to room temperature. It is appropriate to do below.
  • (Id) represents an aromatic water represented by (IV d) It can be produced by reacting an oxide with a halide or a sulfonate represented by (Vd).
  • the halogen atom is the same as described above.
  • organic sulfonyl group examples include alkane sulfonyl groups such as methanesulfonyl group, and aromatic sulfonyl groups such as toluenesulfonyl group (for example, P-toluenesulfonyl group) and benzenesulfonyl group. Is used.
  • the reaction is generally carried out in an organic solvent not involved in the reaction, for example, dimethylformamide, tetrahydrofuran or the like, in which the conjugates (IV d) and (V d) are almost equimolar or one in a slight excess. Under cooling Or at room temperature. This reaction is usually carried out in the presence of a base, and a suitable base such as potassium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide and the like is preferable.
  • a suitable base such as potassium t-butoxide, sodium hydride, potassium carbonate, potassium hydroxide and the like is prefer
  • the N atom in the hydrazide moiety is a Boc group or the like which is usually used as a protecting group for an amino group. Preferably it is protected by a substituent.
  • Protecting groups can be deprotected under the conditions commonly used by those skilled in the art after performing the desired reaction.
  • the reaction is performed in a halogen solvent such as form and dichloroethane in the presence of hydrogen chloride at room temperature or under heating.
  • R 15 represents a lower alkyl group.
  • the compound (I) of the present invention can be produced by reacting an ester compound represented by (V) with a hydrazine compound represented by (III).
  • the reaction is usually carried out in an organic solvent which does not participate in the reaction, for example, toluene, tetra In hydrofuran, dichloromethane, chloroform, etc., or in the absence of a solvent, the conjugates (V) and (III) are almost equimolar or slightly excess (III), respectively, at room temperature or under reflux with heating.
  • This reaction may be carried out in the presence of a base, and such a base is preferably a base such as sodium hydride, ethylmagnesium bromide, dimethylaminopyridine or the like. It is promoted by being carried out in the co-presence of an organic aluminum reagent.
  • Such organic aluminum reagents include trimethylaluminum, lithium aluminum hydride , Hydrogenated Jie isopropyl secondary aluminum ⁇ ⁇ are preferred.
  • the compound of the present invention is isolated and purified as a free compound, a salt, a hydrate, a solvate or a polymorphic substance thereof.
  • a pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.
  • optical isomers can be separated by selecting appropriate starting compounds or by utilizing the difference in physical properties between the isomers.
  • the optical isomers can be stereochemically selected by selecting an appropriate raw material or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active base). Can lead to highly pure isomers.
  • Preparations containing one or more of the compound of the present invention or a salt thereof as an active ingredient are prepared using carriers, excipients and other additives usually used for preparation.
  • the drug can be administered orally in the form of tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous or intramuscular injections, parenteral administrations such as suppositories, skin, etc. Good.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject, gender, etc. However, in the case of oral administration, it is usually about 0.01 to 100 mg per adult per day, parenteral. In the case of administration, the dose is about 0.001 to 5 Omg per day for an adult, and should be administered once or divided into 2 to 4 times.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, It is mixed with starch, polyvinylpyrrolidone, and magnesium aluminate metasilicate.
  • the composition may contain, in a conventional manner, additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium cellulose dalcholate, and stabilizers such as lactose.
  • Solubilizing agents such as glutamic acid or aspartic acid may be included. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a film of gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert diluents, such as purified diluents. Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions Is included.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as crude oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). .
  • the organic layer is washed sequentially with 300 ml each of 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the residue 27.8 g was dissolved in 60 ml of acetate nitrile under heating, left to cool to room temperature and stirred at the same temperature for 2 hours.
  • the precipitated crystals were collected by filtration, washed with acetate and dried, and 25.2 g of the title compound were obtained as colorless crystals.
  • reaction solution was washed successively with 1M hydrochloric acid (20 ml), saturated aqueous sodium hydrogen carbonate solution (20 ml), and saturated saline solution (20 ml), and dried over magnesium sulfate.
  • 1M hydrochloric acid (20 ml)
  • saturated aqueous sodium hydrogen carbonate solution (20 ml)
  • saturated saline solution (20 ml)
  • reaction solution was washed successively with 20 ml of 1M hydrochloric acid, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 20 ml of saturated saline, and dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (form on black) to obtain 670 mg of a pale yellow solid.
  • Example 11 ( ⁇ ) -2-cyclopentyl-2- ⁇ 4-[(2,4-dimethyl-9H-pyrido- [2,3-b] indole-91-yl) methyl] phenyl ⁇ -2 ′-(3-Methoxyxyphenyl) acethydrazide (313 mg) was dissolved in chloroform (6 ml), and under ice-cooling, 4.2 M of a 1.0 M solution of boron tribromide in methylene chloride was added. Stir for 1 hour.
  • reaction mixture was added with 10 ml of 1 M hydrochloric acid under ice-cooling, extracted with 30 ml of chloroform, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 68 In the same manner as in Example 60, the compounds shown in Table (6) and Examples 61 and 65 and in Table (7), Example 68 were obtained.
  • Example 64 In the same manner as in Example 64, the compounds of Examples 62, 63, 66 and 67 in Table (6) were synthesized.
  • the compound of the present invention has optical isomers based on the configuration of R5.
  • optically active substance is synthesized using optically active (+)-3-methyl-2- (4-methylphenyl) butanoic acid and the like, according to the same method as in Reference Examples 10, 11, 12 and Example 1. it can.
  • the apopin-related lipoprotein secretion inhibitory effect of the compound of the present invention and the blood cholesterol and triglyceride lowering effect in rats were confirmed by the following test methods.
  • Hep G2 cells were transformed with Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (hereinafter referred to as ⁇ containing 10% FBS
  • DMEM medium a DMEM medium containing 10% FBS containing a DMSO solution of the test substance (final concentration of DMSO 0.1%), followed by culturing for 15 hours to obtain a culture supernatant.
  • a culture supernatant obtained from a DMEM medium containing 10% FBS containing only DMSO (final concentration 0.1%) was used as a control.
  • Apo B-related lipoprotein produced in the culture supernatant was quantified by the enzymatic immunoassay method described below.
  • An anti-human polipoprotein B monoclonal antibody solution (1.85 tg / ml) was dispensed at 100 nI into a 96-well immunoplate and allowed to stand at 4 ° C for 18 hours. After washing three times with a phosphate buffer solution (hereinafter referred to as rpBS-T) to which 0.1% Tween 20 had been added, a 4-fold diluted immunoblocking agent “Block AceJ 300 I was added, and the mixture was allowed to stand at 37 ° C. for 1 hour.
  • rpBS-T phosphate buffer solution
  • the above culture supernatant was added and left for 3 hours at 37 ° C After washing three times with PBS-T, 100 l of goat anti-apolipoprotein B polyclonal antibody solution (diluted 2000-fold) was added, and the mixture was incubated at 37 ° C. After washing 3 times with PBS-T, add 100 HI of alkaline phosphatase-labeled anti-goat IgG antibody solution (4000-fold dilution), and let stand for 1 hour at 37 ° C. After washing once with PBS and a carbonate buffer (pH 9.5), the alkaline phosphatase substrate solution was supplemented with 100 I, and allowed to stand at room temperature for 5 minutes. Then, the absorbance at 405 nm was measured, and the absolute amount of apoB-related lipoprotein was determined from a calibration curve using human low-density lipoprotein as a standard.
  • the compound of the present invention may have an inhibitory effect on secretion of apoB-related lipoprotein. confirmed.
  • test substances on VLDL secretion in vivo were studied in rats.
  • a 0.5% methylcellulose suspension of the test substance was orally administered to a male SD rat.
  • Triton WR-1339 physiological saline solution (equivalent to 400 mg / kg) was administered via the tail vein.
  • blood was collected under anesthesia with getyl ether.
  • the measurement of total cholesterol and triglyceride in serum was performed using “Cholesterol C Test Co.” and “Triglyceride G Test Co.” (Wako Pure Chemical Industries, Ltd.), respectively.
  • the difference in total cholesterol and triglyceride in serum between the control group and the normal group was defined as the amount of secretion per hour, and the decrease in secretion due to administration of the test substance was expressed as the inhibition rate.
  • the compound of the present invention has a blood total cholesterol and tridaliceride lowering effect in rats.
  • test substances on blood cholesterol in vivo were studied in high fat diet loading rats.
  • a male SD rat was loaded with a purified feed containing 1.5% cholesterol, 0.5% cholic acid, and 10% coconut oil, and a test substance suspension of 0.5% methylcellulose was orally administered once a day for 7 days.
  • the control group received a 0.5% methylcellulose solution.
  • Serum total cholesterol and HDL cholesterol were measured by Hitachi automatic analyzer 7250. The difference between total cholesterol and HDL cholesterol was defined as nonHDL cholesterol, and the decrease in nonHDL cholesterol due to test substance administration was expressed as a reduction rate.
  • the compound of the present invention which exhibits an apo B-related lipoprotein secretion inhibitory effect, has an excellent blood cholesterol and triglyceride lowering effect, and is used for the treatment of hyperlipidemia, arteriosclerosis, obesity, and inflammation. Useful as an agent.
  • NCEP National Cholesterol Education Program

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

Cette invention se rapporte à des dérivés d'hydrazide représentés par la formule générale (I), où R?1, R2, R3, R4, R5, R6, R7, R8 et R9¿ représentent chacun H, etc.; le cycle A représente benzène éventuellement substitué, etc.; Z¿1? représente alkyle inférieur, etc.; W représente une liaison, oxygène, etc.; et X et Y représentent chacun azote, carbone ou CH; ces dérivés ayant un effet inhibiteur sur la sécrétion des lipoprotéines associées à l'apolipoprotéine B. Ces composés sont utiles comme médicaments pour abaisser le niveau des lipides dans le sang.
PCT/JP2000/003289 1999-05-25 2000-05-23 Derives d'hydrazide WO2000071502A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46162/00A AU4616200A (en) 1999-05-25 2000-05-23 Hydrazide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP14461799 1999-05-25
JP11/144617 1999-05-25

Publications (1)

Publication Number Publication Date
WO2000071502A1 true WO2000071502A1 (fr) 2000-11-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/003289 WO2000071502A1 (fr) 1999-05-25 2000-05-23 Derives d'hydrazide

Country Status (2)

Country Link
AU (1) AU4616200A (fr)
WO (1) WO2000071502A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101983A1 (fr) * 2002-05-31 2003-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derive tetrahydropyrane
WO2005051382A1 (fr) * 2003-11-28 2005-06-09 Astellas Pharma Inc. Agent renforçant l'effet hypolipidemiant

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684014A (en) * 1994-10-04 1997-11-04 Bayer Aktiengesellschaft Cycloalkano-indole and -azaindole derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5684014A (en) * 1994-10-04 1997-11-04 Bayer Aktiengesellschaft Cycloalkano-indole and -azaindole derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101983A1 (fr) * 2002-05-31 2003-12-11 Yamanouchi Pharmaceutical Co., Ltd. Derive tetrahydropyrane
WO2005051382A1 (fr) * 2003-11-28 2005-06-09 Astellas Pharma Inc. Agent renforçant l'effet hypolipidemiant

Also Published As

Publication number Publication date
AU4616200A (en) 2000-12-12

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