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WO1995018121A1 - Nouveau derive de benzylamine - Google Patents

Nouveau derive de benzylamine Download PDF

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Publication number
WO1995018121A1
WO1995018121A1 PCT/JP1994/002164 JP9402164W WO9518121A1 WO 1995018121 A1 WO1995018121 A1 WO 1995018121A1 JP 9402164 W JP9402164 W JP 9402164W WO 9518121 A1 WO9518121 A1 WO 9518121A1
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WIPO (PCT)
Prior art keywords
ring
group
propynyl
chenyl
benzylamine
Prior art date
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PCT/JP1994/002164
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English (en)
Japanese (ja)
Inventor
Akira Suga
Kenichi Kazuta
Koichiro Morihira
Koyo Matsuda
Hirotoshi Kakuta
Hiroshi Moritani
Yuichi Iizumi
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU12799/95A priority Critical patent/AU1279995A/en
Publication of WO1995018121A1 publication Critical patent/WO1995018121A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel benzylamine derivative having a squalene-epoxidase inhibitory activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these as an active ingredient.
  • 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 blood cholesterol first causes the deposition of lipids in the intima of large blood vessels, which increases in extent and extent with aging, and finally ischemic heart disease such as myocardial infarction and angina. It exhibits clinical symptoms such as 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-coenzyme A reductase
  • the enzyme inhibition by the administration of the above drug may also cause the inhibition of the synthesis of other physiologically important metabolites such as dolichol and ubiquinone.
  • triparanol which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, accumulates desmosterol, which causes cataract.
  • squalene and epoxidase inhibitors which target squalene epoxidase, an enzyme located in the middle stage of the cholesterol synthesis system, have a risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the body. No, it is expected to provide a more safe anticholesterol agent.
  • squalene-epoxidase is a rate-limiting enzyme, it is thought that cholesterol can be more efficiently reduced by selectively inhibiting squalene-epoxidase.
  • European Patent Application Publication No. 448,078 describes compounds having a wide range of general formulas as compounds having squalene 'epoxidase inhibitory activity.
  • the compound can be exemplified as in the following formula. RCDEFG
  • Ring A a benzene ring or one or more of one or two or three or more hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms.
  • R ' lower alkyl group
  • Ring B an aromatic carbocycle, or a 5- or 6-membered unsaturated ring having one or two or one or two hetero atoms selected from the group consisting of a sulfur atom and a nitrogen atom,
  • R 2 and R 3 same or different, hydrogen atom, 'halogen atom, hydroxyl group, lower group
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a benzylamine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in particular, squalene epoxide. And cholesterol-lowering agents.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof includes a 2-propyne-1,3-diyl group (—CH 2 —C ⁇ C—) which binds to an amino amino atom of a benzylamine derivative.
  • a 2-propyne-1,3-diyl group —CH 2 —C ⁇ C—
  • Substituted or unsubstituted aromatic carbocyclic ring or 5- or 6-membered unsaturated heterocyclic ring having one or two heteroatoms selected from the group consisting of sulfur and nitrogen atoms Has a characteristic in chemical structure.
  • the “lower alkyl group” specifically includes, 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, a pentyl (amyl) group , Isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,
  • Examples thereof include a propyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group.
  • a linear lower alkyl group is preferable.
  • Specific examples thereof include a methyl group, an ethyl group, Examples thereof include a propyl group, a butyl group, a pentyl group, and a hexyl group. Particularly preferred specific examples are a methyl group, an ethyl group, and a propyl group.
  • lower alkoxy group examples include, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group and a pentyloxy group (amyloxy group) , Isobe Nchiruokishi group, sec - Penchiruokishi group, tert - Penchiruokishi group, ne Openchiruokishi group, to Kishiruokishi group, Kishiruokishi group and the like isohexane, especially C, - C 4 alkoxy groups, especially main butoxy group, an ethoxy group, Propoxy groups and isopropoxy groups are preferred.
  • the "lower Arukanoiru group” specifically, for example, formyl group, Asechiru group, a propionyl group, Puchiriru group, Isobuchiriru group, valeryl group, Isobareriru groups, C such as pivaloyl group, - C 6 Arukanoiru group.
  • the “lower alkoxycarbonyl group” is a (C, -C 6 alkoxy) carbonyl group in which a straight-chain or branched alkoxy group having 1 to 6 carbon atoms is bonded to carbonyl, and specifically, for example, methoxy Carbonyl group, ethoxyquincarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group (amyloxycarbonyl group), isopentyloxy group Examples thereof include a carbonyl group, a hexyloxycarbonyl group, and an isohexyloxycarbonyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • a 5- or 6-membered unsaturated hetero ring having 1 to 3 or 1 or 2 or more hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom '' represented by ring A Specifically, for example, a 5- or 6-membered unsaturated having one to three nitrogen atoms such as a pyrrole ring, a pyrazole ring, an imidabule ring, a triazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring.
  • Sulfur source such as heterocyclic ring and tiophene ring
  • Unsaturated heterocyclic ring having an oxygen atom such as an unsaturated heterocyclic ring having an oxygen atom, a furan ring, etc., a thiazole ring, an isothiazole ring, a thiadiazole ring, a dithiazolyl ring, an oxazole ring, an isoxazole ring, an oxaziazolone.
  • preferred hetero rings include a furan ring, a thiophene ring, a thiazole ring, an isothiazole ring, an oxaziazole ring and a pyridine ring.
  • Examples of the aromatic carbon ring represented by the ring B include a benzene ring, a naphthalene ring, a phenanthrene ring, an anthracene ring and the like, and a benzene ring and a naphthalene ring are particularly preferable examples.
  • a 5- or 6-membered unsaturated hetero ring having one or two or one or two hetero atoms selected from the group consisting of a sulfur atom and a nitrogen atom '' represented by ring B Specifically, for example, a 5- or 6-membered unsaturated heterocyclic ring having one or two nitrogen atoms such as a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridin ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, etc.
  • Unsaturated heterocyclic groups having a nitrogen atom and a sulfur atom such as an unsaturated hetero ring having a sulfur atom such as a sulfur ring, a thiabour ring, and an isothiazol ring, and the like. Particularly preferred examples thereof include a thiophene ring. , A thiazole ring and a pyridine ring.
  • B rings can have substituents of R 2 and R 3 as long as they can be bonded.
  • C The compound (I) of the present invention can form an acid addition salt or an ammonium salt.
  • R 2 and R 3 are phenolic hydroxyl groups, they may form salts with bases.
  • the present invention includes pharmaceutically acceptable salts of compound (I), such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and formic acid Organic acids such as acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, glutamic acid, aspartic acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid Acid addition salts, lower alkyl halides, lower alkyl triflates, lower alkyl tosylates, quaternary ammonium salts with benzyl halides, etc., inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc., methylamine, ethylamine, mono Ethanolamine, diethanolamine, triethanolamine, cyclohexane
  • the compound of the present invention may contain an asymmetric carbon atom depending on the type of the substituent, and such a compound has an optical isomer.
  • the present invention includes a mixture of isomers and an isolated one. Further, the compound of the present invention may be isolated as various solvates such as hydrates and ethanol solvates or as polymorphic substances.
  • compound (I) or a pharmaceutically acceptable compound thereof is acceptable. Hydrates, solvates and polymorphs of such salts.
  • Particularly preferred compounds among the compounds of the present invention are those wherein the A ring is a benzene ring, a furan ring, a thiophene ring, a thiazole ring, an isothiazole ring, an oxadiazole ring or a pyridine ring, and the B ring is a benzene ring, a naphthalene ring, a thiophene ring, A compound having a thiazole ring or a pyridin ring, particularly a compound having a ring A as a thiophene ring and a ring B as a benzene ring or thiophene ring.
  • more preferred compounds include the following.
  • 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.
  • the compound (I) of the present invention can be produced by reacting a halide or a sulfonate represented by the general formula (H) with a phenol or an alkali metal phenolate represented by the general formula (II).
  • the halogen atom includes an iodine atom, a bromine atom and a chlorine atom
  • the organic sulfonic acid residue includes an alkanesulfonic acid residue such as a methanesulfonic acid residue and an ethanesulfonic acid residue, and a toluenesulfonic acid residue.
  • Acid residues for example, p-toluenesulfonyloxy group
  • aromatic sulfonic acid residues such as benzenesulfonic acid residues are used.
  • the alkali metal represented by M 1 include lithium, sodium, potassium, and the like.
  • reaction proceeds without solvent, but usually does not take part in the reaction, such as organic solvents such as ether, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dichloromethane, chloroform, benzene, toluene, and hexane.
  • organic solvents such as ether, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dichloromethane, chloroform, benzene, toluene, and hexane.
  • organic solvents such as ether, tetrahydrofuran, dioxane, ethyl acetate, dimethylformamide, dichloromethane, chloroform, benzene, toluene, and hexane.
  • (I) and (H) are almost equimolar or one of them is in a slightly excessive molar amount, and is usually carried out at room
  • the starting compound (I) can be easily obtained by applying the method described in Reference Example or a method analogous thereto, as shown in the following reaction formula.
  • a 3-substituted 1-2-propyn-1-ol when used as a raw material, it is reacted with a halogenating agent such as an organic sulfonyl halide, a sulfonium halide, or a sulfonic acid ester to form a corresponding halide (V).
  • a halogenating agent such as an organic sulfonyl halide, a sulfonium halide, or a sulfonic acid ester to form a corresponding halide (V).
  • a secondary amine (VI) secondary amine
  • a ring, R ', B ring, R 2 and R 3 have the meanings given above, M 2 and X 3 one of formula one SnR 4 3 (wherein R 4 is meant a lower alkyl group ) Represents an organic tin group or a boron group represented by the formula B (OH) 2, and the other represents a halogen atom or an organic sulfonic acid residue. ]
  • Compound (I) is a compound of the formula (VI), which is obtained by reacting a chenylsamine or boronic acid derivative with a halide or a sulfonate represented by the formula (W), or vice versa.
  • the organotin group examples include a trimethylstannyl group and a tributylstannyl group.
  • a palladium-tertiary phosphine complex such as tetrakis (triphenylphosphine) palladium or a combination of a palladium salt and a tertiary phosphine such as palladium chloride and triphenylphosphine is used.
  • the reaction is usually carried out by making the compounds (YD and (VE) equimolar or one in a slight excess) and using an organic solvent which does not participate in the reaction, such as benzene, toluene, quinylene or tetrahydrofuran. It is advantageous to carry out the reaction in drofuran, dioxane, dimethoxetane, etc., usually at room temperature or under heating, or by heating to reflux.
  • the starting compound (W) can be easily obtained by N-alkylation in the same manner as in the production method of the starting compound (II).
  • the compound (I) of the present invention comprises an acetylene compound represented by the formula (H) and a compound represented by the formula (K
  • the c reaction which can be produced by reacting aryl halide or aryl sulfonate represented by the general formula (1) is usually carried out in the presence of a palladium catalyst and a copper catalyst using a lower alkylamine such as getylamine, triethylamine or the like as a solvent. It is advantageous to carry out the reaction from room temperature to heating, or heating to reflux.
  • the palladium catalyst tetrakis (triphenylphosphine) nordium, bis (triphenylphosphine) palladium chloride or the like is used, and as the copper catalyst, cuprous iodide, cuprous bromide, or the like is preferable. No. 4th manufacturing method
  • a ring, R ′, B ring, R 2 and R 3 have the above-mentioned meaning, and D ′ and E ′ are
  • the compound (I) is composed of a benzylamine derivative or a benzyl halide or a benzylsulfonate derivative represented by the formula (X) and a propargyl halide or a sulfonate represented by the formula (XI) or an N-propargyl-N-lower alkylamine derivative.
  • the reaction using halide as the starting compound (X) or (XI) is carried out in the absence of a solvent or in an organic solvent that does not participate in the reaction of benzene, toluene, quinylene, dimethylformamide, acetonitrile, dichloromethane, dichloroethane, methanol, ethanol, etc. It is advantageous that the compound (X) and (XI) are used in a solvent in an equimolar amount or one of them in a slight excess, at room temperature or under heating, or by heating to reflux.
  • tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, trimethylamine and triethylamine
  • inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate are used.
  • the addition is advantageous for smoothly proceeding the reaction.
  • the compound (X) and the compound (XI) are used in an equimolar amount or in a slightly excessive amount, and an organic solvent inert to the reaction, for example, ether, It is advantageous to carry out the reaction in dimethylformamide, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, etc. under cooling or at room temperature.
  • the reaction time is appropriately set in consideration of various reaction conditions. This reaction is preferably carried out in the presence of an organic or inorganic base as in the reaction using a halide.
  • Compound (I) can also be produced by reductive condensation of benzaldehyde represented by formula (XIT) and amine represented by formula (XII) in the presence of a reducing agent.
  • compounds (XI) and (xm) are equimolarly dissolved in an organic solvent inert to the reaction, for example, an organic solvent such as tetrahydrofuran, methanol, ethanol, or acetonitrile, or water or a mixed solvent thereof in the presence of a reducing agent.
  • an organic solvent such as tetrahydrofuran, methanol, ethanol, or acetonitrile, or water or a mixed solvent thereof in the presence of a reducing agent.
  • compound (XE) and (XI) without solvent, in benzene, toluene, etc., azeotropically or dried After condensing while removing water in the presence of the agent to synthesize a Schiff base, it may be reduced in ethanol, methanol or the like.
  • hydrides such as sodium borohydride and sodium cyanoborohydride are preferably used. Further, an acid catalyst such as hydrochloric acid or acetic acid may be used. When other groups which are susceptible to reduction are present, they can be selectively obtained by selecting reaction conditions and the like. 6th manufacturing method
  • R 1 , B ring, R 2 and!? 3 has the above-mentioned meaning
  • one of D 2 and E 2 represents a group represented by the formula —COCH 2 X 2 (wherein X 2 has the above-mentioned meaning)
  • the other represents one group (where Z 2 represents Is represented by the formula NH, ⁇ or S
  • the 1,3-abour compound (la) in which the ring A is oxazole, thiazole or imidazole is the compound (XIV) in which one is an octaloketone and the other is an amide, thioamide or amidine. It can be produced by reacting (XV).
  • reaction proceeds without solvent, but compounds (XIV) and (XV) are almost the same in organic solvents that do not normally participate in the reaction, such as tetrahydrofuran, ethyl acetate, dimethylformamide, ethanol, isopropanol, and toluene. It is advantageous to carry out the reaction usually under heating or heating to reflux with the molar amount or one of them being a slight molar excess.
  • the halogenoacetylthiophene compound in the starting compound (XIV) is obtained by treating acetylthiophene with a halogenating agent such as a perhalide such as a quaternary ammonium salt.
  • a halogenating agent such as a perhalide such as a quaternary ammonium salt.
  • thiophene carboxamide hydrolyzes the corresponding nitrile
  • thiofenthio carboxamide by treating the corresponding carboxamide with a sulphidating agent such as dithiophosphoramide, thereby obtaining amidinothithiol.
  • a conventional method such as a method of adding an ammonium salt such as ammonium chloride to the corresponding nitrile.
  • the starting compound (XV) can be synthesized and obtained in substantially the same manner as the starting compound (XIV).
  • R 1 , B ring, R 2 and R 3 have the above-mentioned meaning, and one of D 3 and E 3 is ⁇ -OH
  • One C is the other C OR 6 (where R s is a hydroxyl group, a halogen atom, a lower alkoxy group or an acid residue, W 2 and Z 3 are one a nitrogen atom and the other is an oxygen atom .]
  • compounds having a 1,2,4-oxazidazole ring as ring A include compounds (XVI) and (XVII) in which one is amidoxime and the other is carboxylic acid, acid halide, ester, or acid anhydride. It can be produced by reacting.
  • the reaction is usually carried out in the presence of a base in an organic solvent that does not affect the reaction, such as tetrahydrofuran, dimethylformamide, ether, benzene, toluene, hexane, etc. It is advantageous to use the compound (XVI) and the compound (XVII) in an equimolar amount or one of them in a slightly excessive amount, under heating or under heating to reflux.
  • Suitable bases include sodium hydride, sodium methoxide, sodium hydroxide, potassium carbonate and the like.
  • a compound having an amino group on an aromatic ring as a substituent can be produced by reducing the corresponding nitro compound.
  • catalytic reduction using a catalyst such as palladium carbon is also possible, but chemical reduction using a metal such as zinc or iron and an acid such as hydrochloric acid is advantageously used.
  • a reducing agent commonly used for the reduction of nitrile such as lithium aluminum hydride, is used.
  • the compound having a hydroxy lower alkyl group as a substituent can be produced by reducing the corresponding formyl or formyl C, mono C 5 alkyl compound when used as a raw material.
  • the compound of the present invention having a formyl group as a substituent can be produced by subjecting the corresponding cyclic acetal as a raw material to acid hydrolysis.
  • the compound of the present invention thus produced is isolated as a free compound, various solvates such as salts, hydrates, and enol solvates, or as polymorphic substances, Purified.
  • a pharmaceutically acceptable salt of compound (I) 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.
  • Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physicochemical properties between the isomers.
  • the optical isomers can be obtained by selecting appropriate starting compounds or by the racemic resolution method of racemic compounds.
  • the compound (I) of the present invention a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable hydrate thereof, a solvate thereof or various isomers thereof have excellent squalene-epoxidase inhibitory activity.
  • ischemic heart diseases such as arteriosclerosis, myocardial infarction and angina in humans and warm-blooded animals caused by the action of cholesterol, especially humans It is useful for prevention and treatment of cerebral arteriosclerosis such as cerebral infarction or aneurysm.
  • the compound of the present invention selectively inhibits squalene epoxidase, which is an enzyme located at the middle stage of the cholesterol biosynthesis system. Does not have. Furthermore, 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 practical use of this series of compounds.
  • the squalene epoxidase inhibitory activity was measured according to the method described in Journal of Biological Chemistry, Vol. 245, p. 1670 (1970). After culturing human hepatoma cells (He pG 2 cells) in DMEM containing 10% FBS to a monolayer, change the medium to DMEM supplemented with 10% Human lipoprotein deficient serum (LP DS) for another 24 hours. Cultured. This was washed twice with PBS, rubber policeman cells were collected and centrifuged. The precipitate was suspended in a solution of 10 OmM Tris-HC1, 1 mM EDTA, and the cells were sonicated on ice.
  • LP DS Human lipoprotein deficient serum
  • Triton X—100 (trade name) having a final concentration of 0.4%, and the mixture was solubilized on ice for 1 hour.
  • the concentrations of dithiothreitol and triton X-100 were adjusted to 1 mM and 0.1%, respectively, and the amount of protein was adjusted to 1.5 mg / m1, and this was used as the He PG 2 squalene / epoxidase fraction. .
  • the reaction was stopped by adding 0.3 ml of a 15% potassium hydroxide-methanol solution, and the mixture was heated at 75 for 1 hour.
  • the unsaponifiable substance was extracted with petroleum ether, concentrated to dryness, and dissolved in a small amount of chloroform. Of these, 1/4 was measured as a total petroleum ether extract with a liquid scintillation counter, and 1Z2 was spotted on Pre-coated Silicagel TLC and developed with ethyl benzene monoacetate (99.5: 0.5).
  • F344 (Fisher system) rats male weight 170-230 g, female weight 110-150 Og were used in the experiments. Animals were housed in a laboratory with constant control of temperature, humidity and lighting. Animals were fed a normal diet (CE-2 CLEA Japan) and water ad libitum. The drug was uniformly suspended and prepared in a 0.5% methylcellulose solution adjusted to pH 2 with hydrochloric acid so as to be 50 and 20 OmgZkg. The drug was administered by gavage at a rate of 10 ml / Zkg once a day into the stomach using an oral probe at 9:00, and continued for 3 days. Body weight was measured daily before administration and also before dissection. Animal behavior and fecal condition were observed daily at 3, 6, 9, and 24 hours after drug administration, and dissected under ether anesthesia 24 hours after the final administration, and the internal organs were observed.
  • the compound of the present invention exhibited a squalene ′ epoxidase inhibitory activity that was at least as strong as the control compound.
  • the control compound showed a remarkable weight loss in rats after continuous administration at 50 mg / kg for 3 days, whereas the compound of the present invention showed a decrease of 50 mg / kg, 3 mg. No body weight loss was observed with continuous dosing for days.
  • control compound was observed from the third day, whereas the compound of the present invention was not observed even at 50 mg / kg for 3 consecutive days.
  • 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 include: Tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, using commonly used pharmaceutical carriers and excipients and other additives Orally (including sublingual administration) or parenterally.
  • the clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied.
  • the dose is 0 to 500 mg, parenterally, 1 to 100 mg, preferably 10 to 100 mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a smaller dose than the above dose range may be sufficient.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolid. It is mixed with lithium and magnesium metasilicate aluminate.
  • the compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium fiber glycolate, and stabilizing agents such as lactose.
  • Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, solubilizing agents, solubilizing agents, 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, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • water-insoluble solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and ethanol.
  • compositions such as alcohol, Bolisorbate 80 (trade name), etc.
  • Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents.
  • These can be sterilized, for example, by filtration
  • Reference example 1 3-[3— [N- (3-hydroxybenzyl) 1-N-propylamino] 1 1-propynyl] benzaldehyde
  • Raw material compound 1- (4-tert-butylphenyl) 1-propyne-3-ol
  • N-ethyl-1-hydroxy-1-N- (3-phenyl-1-propynyl) benzylamine A 50% solution of 50 mg of DMF (20 ml) was added with 105 mg of 60% sodium hydride and stirred for 30 minutes. . Thereto, 142 mg of chloroacetonitrile was slowly added, and the mixture was stirred at room temperature for 1 hour. After adding an appropriate amount of water and methanol to the reaction solution and stirring for 10 minutes, the solvent was distilled off under reduced pressure, and extraction was performed using ethyl acetate. After washing sequentially with water and saturated saline, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Table 3 below shows the physicochemical properties of the compounds obtained in Reference Examples 1 to 36 described above.
  • a solution of 720 mg of benzonitrile in THF (2 ml) was added dropwise, and the mixture was stirred at the same temperature for 3 hours.
  • water (1 Oml) was added to the reaction solution at 0 ° C
  • ethyl acetate (20 ml) was added, followed by filtration. After the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and the organic layer was dried over anhydrous magnesium sulfate.
  • Table 4 shows the chemical structural formulas and physicochemical properties of the compounds obtained in Examples 1 to 45.
  • the free base is shown at the top, and the physical properties of the salt are shown at the bottom.
  • IR (cm ' 1 , neat): 2972, 2948, 2888, 1588, 1490, 1456, 1376, 1328, 1258, 1162, 1074, 1028, 942, 840, 786, 756
  • IR (cm—i, neat): 2972, 2944, 2884, 2832, 1592, 1560, 1490, 1474, 1452, 1372, 1324, 1260, 1168, 1032, 840, 782, 748,
  • IR (cm— 1 , neat): 2972, 1606, 1588, 1490, 1452, 1320, 1288, 1258, 1202, 1174, 1164, 1042, 840, 784, 750, 688
  • IR (cm- 1 , neat): 2972, 2944, 1622, 1602, 1492, 1450, 137/1.
  • Me represents a methyl group
  • Et represents an ethyl group
  • n—Pr represents a normal propyl group
  • i—Pr represents an isopropyl group
  • n—Bu represents a normal butyl group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un dérivé de benzylamine représenté par la formule (I) suivante ou un sel pharmaceutiquement acceptable de ce dernier, qui présente une puissante activité d'inhibition de la squalène époxydase sans être accompagné d'effets néfastes pour la santé, ceci permettant de l'utiliser comme un médicament approprié pour faire baisser le cholestérol. Dans la formule, le noyau A représente un cycle benzène ou un hétérocycle non saturé à 5 ou 6 membres comprenant de 1 à 3 hétéroatomes d'un ou de plusieurs types sélectionnés dans le groupe formé par oxygène, soufre et azote; R1 représente alkyle inférieur; le noyau B représente un carbocycle ou un hétérocycle non saturé à cinq ou six membres comprenant un ou deux hétéroatomes d'un ou de deux types sélectionnés dans le groupe formé par soufre et azote; et R2 et R3 représentent chacun indépendamment hydrogène, halogène, hydroxy, alcoxy inférieur, alcanoyle inférieur, alcoxycarbonyle inférieur, cyano, nitro, amino, dioxolanyle ou alkyle inférieur pouvant être remplacés par halogène, hydroxy ou amino.
PCT/JP1994/002164 1993-12-24 1994-12-21 Nouveau derive de benzylamine WO1995018121A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU12799/95A AU1279995A (en) 1993-12-24 1994-12-21 Novel benzylamine derivative

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JP5/326358 1993-12-24
JP32635893 1993-12-24

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Cited By (3)

* 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
WO1998056757A1 (fr) * 1997-06-11 1998-12-17 Sankyo Company, Limited Derives de benzylamine
JP2008505138A (ja) * 2004-07-01 2008-02-21 エフ．ホフマン−ラ　ロシュ　アーゲー アセチレン基を含むフェニル誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03193746A (ja) * 1987-11-27 1991-08-23 Banyu Pharmaceut Co Ltd 置換アルキルアミン誘導体
JPH04261168A (ja) * 1991-02-14 1992-09-17 Banyu Pharmaceut Co Ltd ４−アルケン−２−イニルアミン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03193746A (ja) * 1987-11-27 1991-08-23 Banyu Pharmaceut Co Ltd 置換アルキルアミン誘導体
JPH04261168A (ja) * 1991-02-14 1992-09-17 Banyu Pharmaceut Co Ltd ４−アルケン−２−イニルアミン誘導体

Cited By (3)

* 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
WO1998056757A1 (fr) * 1997-06-11 1998-12-17 Sankyo Company, Limited Derives de benzylamine
JP2008505138A (ja) * 2004-07-01 2008-02-21 エフ．ホフマン−ラ　ロシュ　アーゲー アセチレン基を含むフェニル誘導体

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