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WO1994018191A1 - Nouveau derive d'amine - Google Patents

Nouveau derive d'amine Download PDF

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Publication number
WO1994018191A1
WO1994018191A1 PCT/JP1994/000175 JP9400175W WO9418191A1 WO 1994018191 A1 WO1994018191 A1 WO 1994018191A1 JP 9400175 W JP9400175 W JP 9400175W WO 9418191 A1 WO9418191 A1 WO 9418191A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
group
methyl
dimethyl
compound
Prior art date
Application number
PCT/JP1994/000175
Other languages
English (en)
Japanese (ja)
Inventor
Akira Suga
Koyo Matsuda
Yuichi Iizumi
Hirotoshi Kakuta
Original Assignee
Yamanouchi Pharmaceutical 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
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU59795/94A priority Critical patent/AU5979594A/en
Publication of WO1994018191A1 publication Critical patent/WO1994018191A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel amide derivative having squalene 'epoxidase inhibitory activity or a pharmaceutical composition containing the derivative.
  • Mortality due to ischemic heart disease caused by coronary atherosclerosis is the second highest in Japan after cancer, and is increasing further due to the aging of the population and westernization of diet.
  • arteriosclerosis As a major risk factor for arteriosclerosis, a degenerative disease of the arteries, an increase in blood cholesterol is regarded as important.
  • An increase in cholesterol in the blood first causes the deposition of lipids in the intima of large blood vessels, which increases in extent and extent with age, and finally in ischemic hearts such as myocardial infarction and angina. It presents clinical symptoms such as illness, cerebral arteriosclerosis such as cerebral infarction or aneurysm. Therefore, suppressing the increase in blood cholesterol and lowering it to a normal value is considered to be extremely effective in treating or preventing the above-mentioned various diseases caused by arteriosclerosis.
  • HMG-CoA reductase 3 -hydroxymethylglutaryl lucenzam A reductase
  • enzyme inhibition due to the administration of the above drugs may also inhibit synthesis of other physiologically important metabolites such as alcohol-ubiquinone.
  • triparanol which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, accumulates desmosterol, which causes cataracts.
  • squalene epoxidase inhibitors which target squalene epoxidase, which is an enzyme located in the middle stage of the cholesterol synthesis system, inhibit the synthesis of other metabolites or inhibit harmful substances in vivo. It is expected to provide a safer cholesterol agent with no risk of accumulation.
  • squalene epoxidase is a rate-limiting enzyme, and it is thought that cholesterol can be more efficiently reduced by selectively inhibiting squalene epoxidase.
  • squalene epoxidase inhibitors have been known to date. For example, in Example 1 of Japanese Patent Laid-Open Publication No.
  • the compound represented by is described as a substituent of the phenyl group, which is a 4- (3-thenyl) 1-2-thenylmethyloxy group. In that it has the following.
  • European Patent Publication No. 448,078 describes compounds having a wide range of general formulas as compounds having squalene epoxidase inhibitory activity. Compounds that are structurally related to can be exemplified as in the following formula.
  • this compound is required to have 5 atoms between the phenyl ring and the terminal heterocyclic group R, and the compound between the phenyl ring and the terminal heterocyclic ring.
  • This is structurally different from the compound of the present invention, which is required to have 6 atoms.
  • an object of the present invention is to provide a compound having a squalene epoxidase inhibitory activity without the above-mentioned adverse effects. Disclosure of the invention
  • R hydrogen atom or lower alkyl group
  • the present invention provides a pharmacologically effective amount of the above amide derivative, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable solvate thereof. Or a stereoisomer compound thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a squalene 'epoxidase inhibitor or a cholesterol lowering agent.
  • the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Therefore, the “lower alkyl group” is specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group.
  • Pentyl (amyl) group isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2—methylbutyl group, 1,2—dimethylpropyl group, hexyl group, isohexyl group , 1 —methylpentyl group, 2 —methylpentyl group, 2,2 —dimethylbutyl group, 1,3 —dimethylbutyl group, 2,3 —dimethylbutyl group, 3,3 —dimethylbutyl group, 1 —ethylbutyl group , 2-Ethylbutyl group, 1,1,2—Trimethylpropyl group, 1,2,2—Trimethylpropyl group, 1-Ethyl-1—Methylpropyl group, 1—Ethyl-2 Methyl propyl group and the like are preferable, and among them, a linear lower alkyl group is preferable, and specific examples thereof include a linear lower
  • the compound of the present invention has a double bond and may contain an asymmetric carbon atom depending on the type of the substituent. Therefore, the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, and optical isomers, and an isolated compound.
  • the compound (I) of the present invention may form an acid addition salt.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Acids organic acids such as fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and acidic amino acids such as aspartic acid, glutamic acid, etc. And acid addition salts thereof.
  • the present invention includes various hydrates, solvates and polymorphic substances of the compound (I) of the present invention.
  • particularly preferred compounds are those wherein the group R 1 is hydrogen Compounds in which the group R 2 is an atom or a methyl group, and the group R 2 is an ethyl group or a propyl group.
  • the compound of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • the typical production method is shown below. l manufacturing method
  • reaction formula, R 1 , R 2 , and X have the above-mentioned meanings, and Y 1 means a halogen atom or an organic sulfonic acid residue.
  • the compound (1) of the present invention can be produced by reacting the amide derivative (II) with a halide or a sulfonate represented by the general formula (II).
  • examples of the halogen atom include an iodine atom, a bromine atom and a chlorine atom.
  • examples of the organic sulfonic acid residue include sulfonic acid residues such as methansulfonate 3 ⁇ 43 ⁇ 4 and ethanesulfonic acid residues, and toluene sulfonic acid residues (for example, p-toluenesulfonyloxy group). ), Aromatic sulfonic acid residues such as benzenesulfonic acid residues, etc .;
  • reaction proceeds in the absence of solvent but usually does not participate in the reaction.
  • compounds (II) and (II) in an organic solvent such as ether, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, hexane, etc. III) means almost ⁇ mol 3 ⁇ 4 or one of them slightly excess mol: ft, and it is usually advantageous to carry out the reaction at room temperature or under heating. In some cases, it is advantageous to carry out this reaction in the presence of a base. Examples of such a base include butyllithium, sodium hydroxide, potassium hydroxide, and sodium hydride. Umm, Bases such as sodium metal and sodium carbonate are preferred.
  • the compound (III) and the compound (III) are reacted with an equimolar to slightly excessive molar amount of the compound (II) by an organic solvent inert to the reaction, for example, ether, It is advantageous to carry out the reaction at room temperature or under heating in toluene, tetrahydrofuran, etc.
  • the reaction time is appropriately set in consideration of various reaction conditions. And may be carried out in the presence of an organic or inorganic base as described above.
  • R 1 R 2 and X have the above-mentioned meanings, Y 2 represents a halogen atom, M represents a hydrogen atom or an alkali metal.
  • lithium is lithium
  • Examples of the compound (I) include a halide represented by the general formula (IV) and a phenol or an aluminum metal represented by the general formula (V). It can also be produced by reacting with a phenol.
  • the reaction proceeds in the absence of a solvent but usually does not participate in the reaction.
  • compounds (IV) and (IV) in an organic solvent such as ether, tetrahydrofuran, dimethylformamide, dichloromethan, toluene, hexane, etc. V) and approximately equimolar amounts, or one of them is used in a slightly excessive molar amount. It is advantageous to work under warm to warm conditions.
  • phenol where M is a hydrogen atom
  • the reaction is carried out in the presence of a base, such as butyllithium, sodium hydroxide, Bases such as potassium hydroxide, sodium hydride, sodium metal, and sodium carbonate are suitable.
  • D 1 is a group represented by CH 3
  • D 1 is a halogen atom or an organic sulfonic acid residue
  • E 1 is a group represented by the formula
  • the compound (Factory) of the present invention comprises an amide derivative or a halide or sulfonate derivative represented by the general formula (VI) and a (6,6-dimethyl-1-yl) derivative represented by the general formula (VII).
  • —Hepten 1-41) One halide Is prepared by reacting with sulfonate or lower alkyl halide or sulfonate or N- (6,6-dimethyl-2-hepten-4-yl) -1N-lower alkylamine You can do it.
  • the reaction can be carried out in almost the same manner as in the first production method.
  • the compound (I) of the present invention can also be produced by reductive condensation in which a benzaldehyde represented by the general formula (VIII) and an amine represented by the general formula (IX) are reacted in the presence of a reducing agent. it can.
  • the reaction is carried out by reacting the compound (VIII) in the presence of a reducing agent in an organic solvent inert to the reaction, for example, an organic solvent such as tetrahydrofuran, methanol, ethanol, acetonitrile or water or a mixed solvent thereof.
  • a reducing agent for example, an organic solvent such as tetrahydrofuran, methanol, ethanol, acetonitrile or water or a mixed solvent thereof.
  • the compound (IX) and the compound (IX) are used in an equimolar amount or an excess amount of either, and the reaction is carried out at room temperature or under heating, or the compound (VIII) and the compound (IX) are dissolved in a solvent-free solvent or benzene.
  • the compound (I) of the present invention can also be synthesized by a condensation reaction of a carboxylic acid represented by the general formula (X) with an amine derivative represented by the formula (XI).
  • This reaction can be carried out using a commonly used condensing reagent (dicyclohexylcarbodiimide, diphenylphosphorylazide, 1,1'-carbyldiimidazole, etc.), or a method using ethyl chloroformate chloroformate.
  • the mixed acid anhydride method using isobutyl or the like, or the compound (X) is converted to an acid halide with a halogenating reagent such as thionyl chloride or chloride and then reacted with the compound (XI). Is also possible.
  • This reaction is usually carried out in a solvent such as tetrahydrofuran, dimethylformamide, or dichloromethane, and, if necessary, in the presence of a base such as triethylamine or potassium carbonate.
  • a solvent such as tetrahydrofuran, dimethylformamide, or dichloromethane
  • a base such as triethylamine or potassium carbonate.
  • under cooling preferably at 15 to 0 ° C
  • room temperature preferably at about 0 ° C
  • Each product synthesized by each of the above-mentioned first to fifth production methods is isolated and purified as a free compound, its salt, hydrate or various solvates.
  • the salt can be produced by subjecting it to a usual salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration recrystallization, and various types of chromatography. Industrial applicability
  • the compound (I) of the present invention a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, a solvate or various isomers thereof have excellent squalene and epoxidase inhibitory activity. It has been confirmed that it has an excellent in vivo cholesterol biosynthesis inhibitory action based on this activity. Furthermore, since it is effective in a system using cultured cells derived from humans, it can be used in humans and warm-blooded animals caused by the action of cholesterol, especially in humans with arteriosclerosis, myocardial infarction, angina pectoris, etc. It is useful for the prevention and treatment of ischemic heart disease, cerebral arteriosclerosis such as cerebral infarction and aneurysms.
  • the compound of the present invention selectively inhibits squalene 'epoxidase, which is an enzyme located at the middle stage of the cholesterol biosynthesis system, so that an enzyme inhibitor located at the early or late stage of the cholesterol biosynthesis system may have. No side effects.
  • the compounds of the present invention do not have side effects such as gastrointestinal tract disorders in the stomach and small intestine, diarrhea, loose stool, and weight loss, which have conventionally been obstacles to commercialization of this series of compounds.
  • HepG2 cells human hepatoma cells
  • FBS fetal bovine serum
  • LPDS Human lipoprotein deficient serum
  • Dithiothreitol and Triton X—100 were adjusted to ImM and 0.1%, respectively, and the protein amount was adjusted to 1.5 mg ml, and this was used for Hep G2 squalene 'epoxidase. Fractions.
  • a solution of the test suspension was prepared by adding a dimethyl sulfoxide solution of the test agent to a solution consisting of 80 suspensions, making the total volume 0.3 ml, and shaking at 37 ° C for 90 minutes. The reaction was stopped by adding 0.3 ml of a 15% aqueous hydroxide-methanol solution, and the mixture was heated at 75 for 1 hour.
  • the unsaponifiable substances were extracted with petroleum ether, concentrated to dryness, and dissolved in a small amount of black-mouthed form. One-fourth of this was measured with a liquid scintillation counter as a total petroleum ether extract, and one-half was spotted on a precoated Silicagel TLC. 5: 0. 5.) did.
  • concentration (IC5 () value) at which the compound of the present invention inhibits squalene epoxidase by 50% was calculated.
  • Hep-G2 Human Hepatoma
  • 1 ml of the culture medium is replaced, and 1 ⁇ Ci of 14 C sodium acetate and the test agent.
  • Add 1 ⁇ 1 of dimethylsulfoxide solution and incubate at 37 ° C for 6 hours in 5% carbon dioxide mixed air.
  • the cells obtained are scraped with rubber policeman and collected by centrifugation. After lysing the collected cells with 0.3 N sodium hydroxide 500/1, use 492/1/1 for extraction and 81 as a sample for protein quantification.
  • the TLC strip is immersed in a toluene scintillator, and the radioactivity is measured using a liquid scintillation counter. The results are corrected using the protein amount measured by the dye method (BI0-RAD PROTEIN ASSAY KIT). The concentration (IC CQ value) at which the compound of the present invention inhibited cholesterol biosynthesis by 50% in Hep-G2 cultured cells was determined. (C) Gastrointestinal disorders and weight fluctuation tests using rats
  • F344 (Fisher strain) rats male weight 180-250 g, female weight 120-160 g were used. Animals were housed in a laboratory with constant control of temperature, humidity and lighting. Animals were fed a normal diet (CE-2 Nippon Clear) and water ad libitum. The drug was prepared by uniformly suspending the drug to a concentration of 50 and 200 mg / kg in 0.5% methylcellulose solution adjusted to pH 2 with hydrochloric acid. The drug was administered by gavage at a rate of 10 mlkg once a day at 9: 00 using an oral sonde into the stomach for 3 days. Body weight was measured daily before dosing and before dissection. Animal behavior and fecal status were observed daily at 3, 6, 9, and 24 hours after drug administration, and 24 hours after final administration, the animals were dissected under ether anesthesia and the internal organs were observed.
  • the Ic5 () value of squalene epoxidase inhibitory activity was determined by the above experimental method (A), and the results are shown in the following table.
  • the compound of the present invention exhibited a squalene 'epoxidase inhibitory activity which was equal to or higher than that of the control compound.
  • the cholesterol biosynthesis inhibitory activity IC5Q value was determined by the above experimental method (B), and the results are shown in the table below.
  • Compound IC 50 value was determined by the above experimental method (B), and the results are shown in the table below.
  • the compound of the present invention showed as strong a cholesterol biosynthesis inhibitory activity as the control compound.
  • the control compound showed a remarkable weight loss in rats following continuous administration of 50 mg / kg for 3 days, whereas the compound of the present invention administered 200 mg Z kg However, no weight loss was observed.
  • the control compound was observed from the third day.
  • the compound of the present invention was not observed even at a dose of 200 mg / kg.
  • compositions containing one or more of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrate as an active ingredient are: Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, tablets, powders, fine granules, It is prepared into a patch or the like and administered orally (including sublingual administration) or parenterally (including administration to the joints).
  • the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the patient's symptoms, weight, age, sex, etc., and is usually 10 to 500 mg orally per adult per day. Preferably 100 to 500 mg, parenterally 1 to: LOO mg, preferably 10 to:! O O mg, given once or in several divided doses. Since the dose varies under various conditions, a smaller dose than the above range may be sufficient.
  • the one or more active substances comprise at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystals. It is mixed with cellulose, starch, polyvinylpyrrolidone, and magnesium aluminate.
  • the composition may be formulated in a conventional manner with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and lactose.
  • Such stabilizers and solubilizers such as glumic acid or aspartic acid may be included.
  • Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsifying and dissolving agents. Includes solutions, suspensions, syrups, and elixirs, and includes commonly used inert diluents, such as purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate. 8 0 (product name).
  • Such compositions may further include additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. .
  • Example 2 Compound of Example 2 10 mg Lactose 81.4 Constarch 20 Hydroxypropylcellulose 4 Carboxymethylcellulose Calcium 4 Magnesium stearate 0.6 Total 120 mg 50 g of Example 2 , Lactose 407 g, constarch 100 g The mixture was uniformly mixed using a granulation coating device (Okawara Seisakusho). This was sprayed with 200 g of a 10% aqueous solution of hydroxypropylcellulose and granulated.
  • a granulation coating device Okawara Seisakusho
  • the starting compounds of the compound of the present invention also include novel compounds, and the production methods of these compounds will be described with reference to reference examples.
  • Reference example 1
  • (E) 12_ [3— [N- (6,6—dimethyl-2—heptene-14-ynyl) -1-N-ethylamino] methyl] phenoxicetylamine 1 g of methylene chloride To the solution (20 ml), under ice cooling, add 0.4 g of triethylamine and 0.5 g of ethyl ethyl chloroformate, gradually bring to room temperature, and stir for 3 hours at the same temperature. The reaction solution is washed with water (30 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Tetrahydrofuran (10 ml) is added dropwise to 0.23 g of lithium aluminum hydride at room temperature.
  • a solution of 1.2 g of quichetilamine in tetrahydrofuran (10 ml) is dropped at room temperature, and the mixture is refluxed for 3 hours. Water (20 ml) is added dropwise to the reaction mixture under ice-cooling, and the mixture is filtered.
  • Benzene (20 ml) is added to 0.5 g of thiophene-3-acetic acid, 0.45 g of oxalyl chloride is added dropwise at room temperature, and the mixture is stirred at 60 for 1 hour.
  • the solvent is distilled off under reduced pressure, and the residue is dissolved in methylene chloride (20 ml).
  • R 1 represents a hydrogen atom or a lower alkyl group
  • R 2 represents a lower alkyl group
  • X represents an oxygen atom or a sulfur atom, respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Nouveau dérivé d'amine représenté par la formule générale (I), ou sel dérivé de ce produit, (où R1 représente hydrogène ou alkyl inférieur, R2 est un alkyle inférieur et X l'oxygène ou le soufre), utile comme médicament, notamment comme agent inhibiteur de l'époxidase de squalène pour le traitement de l'hypercholestérolémie, etc.
PCT/JP1994/000175 1993-02-05 1994-02-04 Nouveau derive d'amine WO1994018191A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59795/94A AU5979594A (en) 1993-02-05 1994-02-04 Novel amine derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/41965 1993-02-05
JP4196593 1993-02-05

Publications (1)

Publication Number Publication Date
WO1994018191A1 true WO1994018191A1 (fr) 1994-08-18

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WO (1) WO1994018191A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2745573A1 (fr) * 1996-02-29 1997-09-05 Pf Medicament Nouveaux amides derives de benzylamines acetyleniques, leurs sels, ainsi que leurs procedes de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1998008838A1 (fr) * 1996-08-27 1998-03-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'amines substitues

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0318860A2 (fr) * 1987-11-27 1989-06-07 Banyu Pharmaceutical Co., Ltd. Dérivés substitués d'alkylamine
EP0448078A2 (fr) * 1990-03-20 1991-09-25 Banyu Pharmaceutical Co., Ltd. Dérivés d'amines substitués ayant une activité anti-hyperlipémique
WO1993012069A1 (fr) * 1991-12-16 1993-06-24 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'alcool amine ou son sel
JPH05213923A (ja) * 1992-02-06 1993-08-24 Yamanouchi Pharmaceut Co Ltd 新規なチオアミド誘導体またはその塩

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0318860A2 (fr) * 1987-11-27 1989-06-07 Banyu Pharmaceutical Co., Ltd. Dérivés substitués d'alkylamine
EP0448078A2 (fr) * 1990-03-20 1991-09-25 Banyu Pharmaceutical Co., Ltd. Dérivés d'amines substitués ayant une activité anti-hyperlipémique
WO1993012069A1 (fr) * 1991-12-16 1993-06-24 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive d'alcool amine ou son sel
JPH05213923A (ja) * 1992-02-06 1993-08-24 Yamanouchi Pharmaceut Co Ltd 新規なチオアミド誘導体またはその塩

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2745573A1 (fr) * 1996-02-29 1997-09-05 Pf Medicament Nouveaux amides derives de benzylamines acetyleniques, leurs sels, ainsi que leurs procedes de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1998008838A1 (fr) * 1996-08-27 1998-03-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'amines substitues

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