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WO1997001533A1 - Derives d'acide thiocarbamique - Google Patents

Derives d'acide thiocarbamique

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Publication number
WO1997001533A1
WO1997001533A1 PCT/JP1996/001776 JP9601776W WO9701533A1 WO 1997001533 A1 WO1997001533 A1 WO 1997001533A1 JP 9601776 W JP9601776 W JP 9601776W WO 9701533 A1 WO9701533 A1 WO 9701533A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
methyl
general formula
nmr
Prior art date
Application number
PCT/JP1996/001776
Other languages
English (en)
Japanese (ja)
Inventor
Naomichi Ishida
Maki Goda
Yasunari Yamaura
Yoshihisa Inoue
Norifumi Nakamura
Takumi Tokunaga
Kenichi Haga
Kenji Tokuhisa
Kimio Katsuura
Yasuaki Hanasaki
Original Assignee
The Green Cross Corporation
Tosoh Corporation
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 The Green Cross Corporation, Tosoh Corporation filed Critical The Green Cross Corporation
Publication of WO1997001533A1 publication Critical patent/WO1997001533A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen 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
    • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—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 genomic rubamic acid derivative having squalene epoxidase inhibitory activity or a salt thereof, a stereoisomer thereof, a pharmaceutical composition containing them, and a method for producing them.
  • Blood cholesterol lowering agents are said to be effective.
  • inhibitors of cholesterol metabolism in vivo are highly evaluated for their clear mechanism of action and strong drug efficacy.
  • cholesterol biosynthesis inhibitors include oral basin, Epps Yutin and Pravas Yutin have already been used clinically (
  • HMG-CoA reductase HMG-CoA reductase
  • the enzyme is located at a relatively early stage in the cholesterol biosynthesis system. For this reason, the enzyme inhibition by the administration of the above-mentioned drug may also cause the inhibition of the synthesis of other physiologically important metabolites such as dolicholubiquinone. Also, it has been reported that triparanol, which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, can accumulate desmosterol, which causes cataract.
  • squalene epoxidase inhibitors targeting squalene epoxidase which is located in the middle stage of the cholesterol biosynthesis system, have no risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the living body It is expected to provide more safe anticholesterol drugs.
  • Such squalene epoxidase inhibitors include (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) _N-ethyl-1 3- [4- (3-Chenyl) -12-che Nylmethyloxy] benzylamine (NB-598) and other arylamine-based compounds (for example, Japanese Unexamined Patent Publication No. 3-114241, WO93 / 12069, WO94Z188) 91), dibenzylamine-based compounds (for example, WO 94Z18167, etc.), and allyl alcohol-based compounds (for example, JP-A-6-49023).
  • thiocarbamic acid ester derivatives are known to be useful as antifungal agents or agricultural chemicals.
  • An object of the present invention is to provide an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and a therapeutic or prophylactic agent for arteriosclerosis, which are safer and have an excellent anti-cholesterol effect as compared with existing drugs. It is to provide. Disclosure of the invention
  • the present inventors have conducted intensive studies and found that a thiocarbamate derivative having a certain substituent has a high inhibitory activity against squalene epoxidase derived from mammals, and completed the present invention.
  • R 5 and R 6 are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkoxy group and a lower alkyl group or a lower alkoxy group which may be substituted with Z or a cyano group, or 5 and R 6 may be taken together to form a ring with a carbon chain represented by one (CH 9 ) ⁇ K (CH 2) no 3) or a phenyl group represented by the formula: 111]
  • R 7 represents a lower alkoxy group and a lower alkyl group which may be substituted with Z or a cyano group.
  • R 1 and R represent a hydrogen atom, a formyl group or a lower alkyl group, and Z represents a nitrogen atom or a CH group.
  • R 2 is a hydrogen atom, a lower alkyl group, a lower acryl group, a lower alkyl group of a hydroquinine, a lower alkyl group of a lower alkoxy group, a lower alkyl group of a carboxyl substituent, a lower alkyl group of a carboxyl-substituted lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group
  • R 4 is a phenyl group having an optional substituent or a 5- or 6-membered heterocyclic ring containing one or more oxygen, nitrogen, or sulfur atoms or two or more atoms in combination. Represent. Any substituent may be substituted on the heterocycle ⁇ ]
  • the thiocarbamic acid derivative and its salt characterized by being represented by these.
  • Another one of the present invention is a compound represented by the general formula [V]:
  • ⁇ R 8 represents a hydrogen atom or a formyl group. It is a derivative.
  • Still another aspect of the present invention provides a compound represented by the general formula [VI]:
  • One of the production methods of the present invention is a method represented by the following general formula [IV]:
  • Another one of the production methods of the present invention has a general formula as shown in the following reaction formula.
  • Still another one of the production methods of the present invention is a compound represented by the general formula [la] as shown in the following reaction formula.
  • R 2 Y is an alkylating agent having the aforementioned R 2 or acylation Shows the agent.
  • the present invention also provides a squalene epoxidase inhibitor comprising the compound of the above general formula [I] or a salt thereof.
  • the term "lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, specific examples of the lower alkyl group include 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 and an isopentyl group.
  • Examples of the lower alkoxy group include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butyne, pentyloxy, 1-methylbutyl Oxy, 2-methylbutyloxy, 3-methylbutyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, hexyloxy, 1-methylpentyloxy, 1- Tylpropyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1,1-dimethylbutyi group Roxy group, 2,2-dimethylbutyloxy group, 3,3-dimethylbutyloxy group are preferred, and methoxy group, ethoxy group, propoxy group, ishipropoxy group, butoxy group, ter
  • lower alkoxy group and the lower alkyl group which may be substituted with Z or a cyano group include, for example, a methoxymethyl group, a 1-methoxyl group, a 1-methoxy-1-methylethyl group, and a 1-ethoxy group.
  • a methoxymethyl group a 1-methoxyl group, a 1-methoxy-1-methylethyl group, and a 1-ethoxy group.
  • 1 1-Methylethyl group, 2-Methoxy-1 1-Methylethyl group, 2-Methoxy-1,1-dimethylethyl group, 1-Methoxypropyl group, 1-Methoxy-1 1-Methylpropyl group, 2-Methoxy-1 1, 1- Dimethylpropyl group, etc.
  • 1-cyanoethyl group 1-cyano-1-methylethyl group, 2-cyano-1-methylethyl group, 2-cyano1-1,1-dimethylethyl group, 2-cyano-1-methylpropyl group, 2-cyano-1, 1-dimethylpropyl group and the like.
  • 1-methoxy-1-methylethyl group, 1-ethoxy-11-methylethyl group, 2-methoxy-1,1-dimethylthioethyl group, 1-methoxy-1-methylpropyl group, etc. and 1-cyanoethyl group, 1 —Cyan-1-methylethyl group, 2-cyan-1,1-dimethylethyl group and the like.
  • Lower acetyl groups include formyl group, acetyl group, ethylcarbonyl group, propylcarbonyl group, 1-methylethylcarbonyl group, butylcarbonyl group, 1-methylpropylcarbonyl group, 2-methylpropylcarbonyl group, pentylcarbonyl group Examples thereof include a 1-methylbutylcarbonyl group, a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, a 1-ethylpropylcarbonyl group, and a 2-ethylpropylpyrucarbyl group.
  • it is a formyl group, an acetyl group, an ethylcarbonyl group or the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a fluorine atom a chlorine atom, or a bromine atom.
  • unsubstituted or substituted phenyl groups include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl.
  • a 5- or 6-membered heterocyclic ring containing one or more oxygen atoms, nitrogen atoms and sulfur atoms or a combination of each atom is 2-furyl, 3-furyl, 2 —Chenyl group, 3-Chenyl group such as phenyl group, 1-pyrrolyl group, 2-pyrrolyl group, pyrrolyl group such as 3-pyrrolyl group, 1-birazolyl group, 3-virazolyl group, 4-birazolyl group , 5 -Bilazolyl group such as virazolyl group, 2 1 year old xazolyl group, 4 year old xazolyl group, 5 year old oxazolyl group such as xazolyl group, 3 isoxazolyl group, 4 isoxazolyl group such as 4 isoxazolyl group-5-isoxazolyl group , 2-thiazolyl- 5-membered heterocycles such as thiazolyl groups such as 4 thiazolyl group and 5 thi
  • the substituent is not particularly limited, but specifically, a lower alkyl group such as a methyl group and a lower alkoxycarboxy group such as a methoxycarbonyl group. And a benzyl group.
  • a lower alkyl group such as a methyl group
  • a lower alkoxycarboxy group such as a methoxycarbonyl group.
  • a benzyl group Preferably 3-furyl, 2-phenyl, 3-phenyl, 1-pyrrolyl, 1-pyrazolyl, 4-thiazolinole, 3-isothiazolyl, 4-isothiazolyl, 2-methyl-3
  • It is a 5-membered heterocyclic ring such as —thenyl group, 2-methoxycarbonyl-3-enyl group.
  • Examples of the compound represented by the formula [1] include a 4-methoxyphenyl group, a 4-ethoxyphenyl group, a 4-tert-butyloxyphenyl group, a 3-tert-butyloxyphenyl group, and a 4-tert-butyl group.
  • Lower alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, (2-methoxyethoxy) methyl, 2- (2-methoxyethoxy) ethyl, 2- (2-methoxyethoxy) An ethoxymethyl group and the like can be mentioned.
  • hydroxy lower alkyl group examples include a methylol group, a 2-hydroxyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group, and a 2-hydroxybutyl group. And the like.
  • the substitution position in the carboxyl-substituted lower alkyl group is preferably at the ⁇ -position.
  • the ⁇ -hydroxyl-substituted alkyl group include a hydroxycarboxymethyl group, an ⁇ -hydroxycarbonylethyl group, an ⁇ -hydroxycarbonylpropyl group, an ⁇ -hydroxycarbonylcarbonylbutyl group and an ⁇ -hydroxycarbonylpentyl group.
  • ⁇ -hydroxycarbonylhexyl group Preferred are an ⁇ -hydroxycarbonylmethyl group, an ⁇ -hydroxycarbonylylethyl group, an ⁇ -hydroxycarbonylpropyl group and the like.
  • the substitution position in the carboxyl-substituted lower acyl group must be Is preferred.
  • the ⁇ -carboxyl-substituted acetyl group include a hydroxycarbonylacetyl group, an ⁇ -hydroxycarbonylpropanol group, an ⁇ -hydroxycarbonylbutanoyl group, and an ⁇ -hydroxycarbonyloxycarbonyl group.
  • ⁇ -hydroxycarbonylhexanoyl groups Preferred are a hydroxycarbonyl acetyl group, an ⁇ -hydroxycarbonylpropanoyl group and the like.
  • the lower alkylsulfonyl group includes a methyl sulfonyl group, a trifluorosulfone methanesulfonyl group, and the arylsulfonyl group includes a paratoluenesulfonyl group.
  • the compounds of the present invention represented by the general formulas [I], [V], and [VI] contain an asymmetric carbon. Accordingly, the compounds of the present invention include mixtures of various optical isomers such as optically active isomers, racemates, diastereomers and the like, and isolated compounds thereof.
  • These compounds of the present invention represented by the general formulas [I], [V], and [VI] have an amide residue, and thus may form an acid adduct.
  • salts include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid, formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, maleic acid, lactic acid, and lactic acid.
  • Examples thereof include acid adduct salts with organic acids and the like such as cornic acid, tartaric acid, citric acid and methanesulfonic acid.
  • R 8 is a hydrogen atom
  • the compound represented by the formula [V] is used as the compound [V-a] for the synthesis of the compound [I].
  • R 8 is a formyl group
  • the compound represented by the formula [V] is deprotected or reduced to form a compound [Va], which is used for the synthesis of the compound [I].
  • the compound represented by the formula [V] is a novel compound, and typical examples thereof are shown in Tables 13 to 16, but the present invention is not limited thereto.
  • the compound represented by the formula [VI] is used for the synthesis of the compound [I].
  • the compound represented by the formula [VI] is a novel compound, and typical examples thereof are shown in Tables 17 and 18, but the present invention is not limited thereto.
  • the compound of the present invention can be produced by various methods, and typical production methods are shown below.
  • the halogenated thioformate represented by the formula [IV] and the amine represented by the formula [Va] are subjected to quantification in the presence or absence of a base, in the absence of a solvent or in a solvent at room temperature to 150 ° C. It can be manufactured by reacting for minutes to hours.
  • Examples of the base include sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate.
  • organic bases such as pyridine, triethylamine and trimethylenediamine.
  • Solvents include methanol, ethanol, propanol, isopropanol, acetone, Solvents such as methylethyl ketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, and toluene can be used.
  • the compound [IV] is not particularly limited as long as it is at least equimolar to the compound [Va].
  • the halogenated thioformate of the formula V] can be prepared by reacting the corresponding alcohol or phenolic compound with a halogenothiocarbinating agent such as thiophosgene in the presence or absence of a base in a solvent or in a solvent.
  • a halogenothiocarbinating agent such as thiophosgene
  • Examples of the c- base that can be produced by reacting at 0 ° C for several minutes to 24 hours include sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, and sodium hydrogencarbonate.
  • Inorganic bases such as hydrogen carbonate and lime, alkaline metal hydrides such as sodium hydride and lithium hydride, alkaline hydrides such as calcium hydride, earth metal or pyridine, triethylamine, etc.
  • the solvent examples include water or an organic solvent such as n-hexane, cyclohexane, methyl ether, tetrahydrofuran, dichloromethane, chlorophonolene, benzene, toluene, and dimethylformamide. Further, a mixed solvent of water and the above organic solvent may be used.
  • the alcohol or phenolic compound and the halogenothiocarbonylating agent such as thiophosgene are preferably used in the reaction in an equimolar amount or in one molar excess of one.
  • the compound represented by the formula [V] can be produced, for example, as follows.
  • R 9 represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and examples thereof include those having 1 to 5 carbon atoms among the above-mentioned examples of lower alkyl groups.
  • the amino alcohol 1c can be produced, for example, by reacting a two-port compound la having an epoxy group with an amino lb in a solvent such as methanol under heating and refluxing for several hours. .
  • the amino ester form 1d is prepared by subjecting the amino alcohol form 1c and an alkylating agent having an R 2 such as alkyl iodide or dialkyl sulfate to hydroxylation in a solvent such as tetrahydrofuran or dimethylformamide. It can be produced by reacting in the presence of a basic catalyst such as sodium, hydrogenated sodium, sodium carbonate, carbonated carbonate, etc., on ice or in the boiling range of the solvent.
  • a basic catalyst such as sodium, hydrogenated sodium, sodium carbonate, carbonated carbonate, etc.
  • the imide 1e can be produced by reacting the amide 1d in a solvent such as ethanol in the presence of a hydrogen reduction catalyst such as platinum oxide or palladium carbon in a hydrogen atmosphere.
  • a hydrogen reduction catalyst such as platinum oxide or palladium carbon
  • the amine 1e is reacted with, for example, formic acid or acetic acid or a derivative thereof to form an amide, and then the amide is reacted with a reducing agent such as lithium aluminum hydride in tetrahydrofuran.
  • a reducing agent such as lithium aluminum hydride in tetrahydrofuran.
  • Compound [V] can also be produced by the following method using amide compound 2a as a starting material.
  • the amino alcohol 2c is composed of an amide compound 2a having an epoxy group and an amide compound 2a.
  • the compound can be produced by reacting min 1b according to the method for producing the amino alcohol 1c.
  • ⁇ Mi Noe one ether body 2 d is the ⁇ Mi Roh alcohol derivative 2 c and R 2
  • the alkylating agent can be produced by reacting the alkylating agent according to the method for producing the amino alcohol derivative 1d described above.
  • the desired novel amine compound LVc] can be produced.
  • Compound V can also be produced by the method shown below.o
  • the epoxy compound 3b is obtained by combining a phenol compound 3a with a glycidyl chloride (epichlorohydrin), glycidyl bromide (epipromohydrin) or other glycidyl halide (epihalohydrin) compound.
  • a glycidyl chloride epichlorohydrin
  • glycidyl bromide epipromohydrin
  • epihalohydrin glycidyl halide
  • amino alcohol 3c is converted to epoxy 3b and amine lb. It can be produced by reacting in a solvent such as methanol under reflux for several hours.
  • Amino ether compound 3d is obtained by reacting an amino alcohol compound 3c with an alkylating agent having R 1 and then reacting the obtained product with an alkylating agent having R 2. Can be manufactured.
  • the desired novel amine compound [Vd] can be produced by reacting the aminoester 3d in, for example, hydrochloric acid at room temperature or under heating for several minutes to 24 hours.
  • the desired novel amide compound [V e] is obtained by reacting the amino alcohol 3c with a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran or ether. It can be manufactured.
  • the compound represented by [la] in which R 2 is a hydrogen atom in the compound [I] of the present invention includes a compound having an epoxy group represented by the formula [VI] and an amine represented by the formula [VII] Can be produced in the absence of a solvent, in the presence of a solvent or in the presence of a catalyst, by reacting at room temperature or under heating for several minutes to 24 hours.
  • This reaction may proceed without solvent, but usually a solvent is used (such solvents as methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylethyl acetate, tetrahydrofuran, and acetatetonite).
  • Solvents such as ril, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, and toluene can be used.
  • This reaction proceeds without a catalyst, but a catalyst may be used if necessary. it can.
  • a catalyst include lithium perchlorate, magnesium perchlorate, itttrium triflate, anhydrous cobalt chloride (II) n-butyllithium, lithium diisopropylamide and the like.
  • the compound represented by the formula [VI] is a phenolic compound.
  • glycidyl chloride epichlorohydrin
  • glycidyl bromide epipromohydrin
  • epihalohydrin glycidyl halide
  • Solvents used in the reaction include tetrahydrofuran, ether, acetone, methylethylketone, ethylethyl acetate, acetonitril, benzene, toluene, xylene, chloroform, methylene chloride, methylene chloride, dimethylformamide, and dimethylsulfoform. Solvents such as oxides can be used o
  • inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, hydrogen carbonate carbonate, etc., and hydrogenated sodium Hydride, alkaline metal hydride such as lithium, and alkaline earth metal hydride such as calcium hydride.
  • the compound of the present invention [I] in which R 2 is other than hydrogen can also be obtained by reacting an alcohol compound represented by the formula [la] with a compound represented by the formula [IX] usually in a solvent in the presence of a base. Can be manufactured.
  • alkylating agent represented by the formula [] examples include methyl iodide, chloro iodide, chilled bromide, propyl bromide, and isopropyl bromide.
  • Butyl bromide, s-butyl bromide, and bromide Alkyl halides such as isoptyl, t-butyl bromide, chloromethyl methyl ether, 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, 1-bromoacetic acid and 1-chloroacetic acid Sulphates such as dimethylsulphate and getylsulphuric acid, ⁇ -toluenesulfonic acid methyl ester, p-toluenesulfonic acid ethyl ester, D-toluenesulfonic acid propylate Methyl ester, methane sulfonic acid methyl ester, methane sulfonic acid ethy
  • epoxy compounds such as ethylene oxide and propylene oxide.
  • the acylating agent include acid halides such as acetyl chloride and propionyl chloride, and acid anhydrides such as acetic anhydride, propionic anhydride and butyric anhydride.
  • Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylacetate, getylether, tetrahydrofuran, acetonitrile, dimethylformamide, Solvents such as dimethylsulfoxide, dichloromethane, hexane, toluene, pyridine, zoletidine, N, N-dimethylaniline and the like can be mentioned.
  • the base examples include inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogencarbonate, hydrogen carbonate carbonate, and the like; Metal hydrides such as lithium and lithium hydride, alkaline earth metals such as calcium hydride, and organic bases such as pyridine, triethylamine, diisopropylethylamine, trimethylenediamin, etc. Can be.
  • inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogencarbonate, hydrogen carbonate carbonate, and the like
  • Metal hydrides such as lithium and lithium hydride, alkaline earth metals such as calcium hydride
  • organic bases such as pyridine, triethylamine, diisopropylethylamine, trimethylenediamin, etc. Can be.
  • the compounds [Ia] and [] are preferably used in the reaction in substantially equimolar amounts, or one in a slight excess. Manufacturing method 4
  • the compound [I] of the present invention is usually produced by reacting a phenolic compound [X] with an amide compound [XI] in a solvent in the presence of a base at room temperature or under heating for several minutes to 24 hours. Can be.
  • Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, Examples include solvents such as dichloromethane, hexane, toluene, pyridine, lutidine, and N, N-dimethylaniline.
  • Inorganic bases such as potassium hydrogencarbonate, sodium hydride, lithium hydride and other alkali metal hydrides, calcium hydride and other alkaline earth metals or pyridine and triethylamine
  • organic bases such as trimethylene diamine.
  • the compounds [X] and [XI] are subjected to the reaction in substantially equimolar amounts, or one in a slight excess.
  • the compound [I] of the present invention can be produced usually by reacting a funinol compound [XII] with a halogenated thiocarbamate compound [XI] in a solvent in the presence of a base at room temperature or under heating for several minutes to 24 hours.
  • Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethyl acetate, tetrahydrofuran, acetate, dimethylformamide, and dimethylsulfoxide.
  • solvents such as dichloromethane, dichloromethane, hexane, hexane, toluene, pyridine, lutidine and N, N-dimethylaniline.
  • the base examples include inorganic bases such as sodium hydroxide, hydroxylated lime, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogen hydride, sodium hydrogen hydride, and the like; sodium hydride, lithium hydride, and the like.
  • examples include hydrogenated alkaline earth metals such as metal hydrides and calcium hydrides, and organic bases such as pyridine, triethylamine, trimethylenediamine and the like.
  • the compounds [ ⁇ ⁇ ] and [XI ⁇ ] are used in the reaction in substantially equimolar amounts or one of them is in a slight excess.
  • the compound of the formula [I] extremely selectively and strongly inhibits squalene epoxidase in vivo, it is used as an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and an anti-atherosclerotic agent. It is a useful compound that is expected to be used.
  • the compound [I] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, hypercholesterolemia, hyperlipidemia and arteriosclerosis can be obtained. It can be used for treatment and prevention of diseases.
  • the compound of the present invention When the compound of the present invention is used clinically, it is possible to add a pharmaceutically acceptable excipient in accordance with the dosage form and then administer the compound after formulating various preparations.
  • a pharmaceutically acceptable excipient in accordance with the dosage form and then administer the compound after formulating various preparations.
  • various additives commonly used in the field of pharmaceutical preparations can be used, for example, gelatin, hydroxypropylmethylcellulose, carboxymethylcellulose, and the like.
  • Corn starch microcrystalline starch, white cellulose, magnesium metasilicate aluminate, calcium phosphate anhydrous, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester , Polysorbate, Sucrose fatty acid ester, Polyoxyethylene hydrogenated castor oil, Polyvinyl viridone, Magnesium stearate, Light gay anhydride, Talc, Vegetable oil, Benzine alcohol, Arabic gum, Propylene glycol And hydroxypropyl cyclodextrin, etc.
  • Dosage forms formulated as a mixture with these excipients include, for example, solid preparations such as tablets, capsules, granules, powders or suppositories, or mouthwashes, elixirs or
  • liquid preparations such as injections, which can be prepared according to a usual method in the field of preparations.
  • liquid preparations they may be dissolved or suspended in water or other appropriate medium before use.
  • an injection solution it may be dissolved or suspended in a physiological saline or glucose solution as necessary, and a buffer or a preservative may be added.
  • the preparation of the present invention can contain the compound of the present invention at a ratio of 1. (! To 100% by weight, preferably 1.0 to 6% by weight, based on the whole drug. It may also contain other therapeutically effective compounds.
  • the dosage and frequency of administration depend on the sex, age, weight, degree of symptoms and purpose of the patient. Although it depends on the type and range of therapeutic effects to be used, in general, oral administration is performed by dividing 0.01 to 20 nig Z kg per day into 1 to several times per adult, and In the case of administration, it is preferable to administer 0.1 to 0.2 mg of () () in 1 to several portions.
  • IR (a C 1, cm— 1 ) 3450, 3360, 2930, 1620, 1600, 1550, 1495, 1460, 1410, 1190, 1160
  • the organic layer was washed twice with water, washed with saturated saline, and dried over anhydrous magnesium sulfate.
  • IR N a C 1, cm 1
  • IR (KB r, cm- 1 ) 3370, 1680, 1605, 1520, 1500, 1310, 1275, 1165, 1040
  • IR N a C 1, cm— 1 ) 3300, 2930, 2880, 1690, 1600, 1558, 1440, 1290, 1210, 1100, 1040
  • IR N a C 1, crT 1 3560, 3410, 2940, 1600, 1500, 1200, 1170, 995, 760
  • IR N a C 1, cm- 1 3520, 3410, 2930, 1615, 1595, 1500, 1200, 1165, 810
  • I R (Na C 1, cm—up) 3400, 2930, 1625, 1550, 1510, 1497, 1200, 1162
  • P- (tert-butylphenyl) 1- (3-aminophosphonyl) -3- (N-methyl-N-phenylamino) 1-2-propanol in 5 ml of acetonitrile solution of 330 mg of cloform thioformate 282 mg of 2-propanol 5 ml of acetonitrile solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours, and then a saturated sodium hydrogen carbonate solution was added to the reaction solution.
  • IR N a C 1, cm -1 3420, 2960, 1600, 1520, 1480, 1380, 1235, 1210, 1175, 1120, 1105
  • IR (NaC1, cm- 1 ) 2760, 1600, 1500, 1480, 1380, 1210, 1175, 1120, 840, 745, 695
  • IR N a C 1, cm “ 1 ) 2970, 2930, 1600, 1555, 1490, 1470, 1380, 1220, 1170, 1110
  • IR N a C 1, cm— 1 ) 2980, 2930, 1600, 1550, 1485, 1380, 1235, 1205, 1175, 1120
  • IR reflective aluminum plate, em- 1 ) 2960, 1726, 1601, 1508, 1487, 1380, 1211, 1 ⁇ 6, 1124
  • 2998, 2904, 2804 1598, 1591, 1550, 1506, 1484, 1413, 1378, 1321, 1282,
  • IR N a C 1, cm “ 1 ) 2960, 1600, 1590, 1480, 1380, 1235, 1210, 1175, 1120, 1055, 1040
  • IR microwavereflective aluminum plate, cm “ 1 ) 2960, 2900, 2865, 2825, 1596, 1571, 1548, 1504, 1461, 1454, 1427, 1367, 1328, 1270, 1218, 1186, 1151, 1130, 1112, 1074 , 1056, 1012, 1074, 1056, 1012, 985, 941, 885, 860, 835, 800, 738
  • IR microwave reflective aluminum plate, cm “ 1 ) 3083, 2927, 2856, 1598, 15 T3, 1556, 1496, 1471, 1419, 1365, 1326, 1263, 1238, 1222, 1195, 1178, 1151, 1122, 1074, 1054, 1022, 989, 943, 917, 908, 865, 829, 802, 794, 740
  • I R (N a C 1, cm -1 2930, 1595, 1505, 1490, 1260, 1235, 1220, 1150, 730
  • IR N a C 1, cm— 1 ) 2960, 1735, 1600, 1505, 1480, 1380, 1210, 1170
  • the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate.
  • the squalene-epoxidase inhibitory activity and the cholesterol biosynthesis inhibitory activity of the compound of the present invention were confirmed by the following methods.
  • the reaction was stopped by adding 3 ml of a 10% potassium hydroxide / methanol solution Q. The reaction was carried out at 37 ° C for 30 minutes. The extracted substance was extracted with petroleum ether and concentrated to dryness. The obtained residue was dissolved in a small amount of ethyl ether, spotted on a thin layer gel, and developed with ethyl benzene monoacetate (99.5: 0.5). Generate A portion of the 3H-squalene-2,3-epoxide thus obtained was cut out and measured with a liquid scintillation counter. Thus, the inhibition rate of the compound of the present invention with respect to squalene epoxidase was determined.
  • the compound of the present invention potently inhibits squalene epoxidase and inhibits cholesterol biosynthesis, and thus enhances the cholesterol biosynthesis mechanism and / or enhances cholesterol biosynthesis. It is effective for treating and preventing various diseases caused by overdose, such as hypercholesterolemia, hyperlipidemia, and arteriosclerosis.
  • the compound of the present invention is a novel substance having a thiocarbamate skeleton completely different from conventionally known amide-based or arylamine-based compounds, and furthermore, squalene-epoxy derived from mammals. It has high inhibitory activity against dase. Further, the compound of the present invention can be suitably produced by the production method of the present invention.

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

Abstract

Cette invention concerne des dérivés d'acide thiocarbamique, ainsi que leurs sels, les dérivés correspondant à la formule générale (I) où m est égal à 0 ou 1; A représente 4,4-diméthyl-2-pentynyle ou similaire; R1 et R3 représentent chacun hydrogène, formyle ou alkyle inférieur; Z représente azote ou CH; R2 représente hydrogène, alkyle inférieur, acyle inférieur ou similaire; R4 représente un groupe phényle possédant un substituent choisi arbitrairement ou un hétérocycle à 5 ou 6 éléments qui comporte au moins un atome d'oxygène, d'azote ou de soufre, ou encore une combinaison d'au moins deux de ces derniers, ledit hétérocycle étant éventuellement substitué par un groupe choisi arbitrairement. Ces dérivés permettent d'obtenir un agent anti-hypercholestérolémique, un agent anti-hyperlipémique, ainsi qu'un remède ou un agent de prévention contre l'artériosclérose, chacun de ces agents étant plus sûr que les médicaments classiques et possédant une excellente activité contre le cholestérol.
PCT/JP1996/001776 1995-06-27 1996-06-27 Derives d'acide thiocarbamique WO1997001533A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/183560 1995-06-27
JP18356095 1995-06-27

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WO1997001533A1 true WO1997001533A1 (fr) 1997-01-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072800A1 (fr) 2001-03-01 2002-09-19 Centro De Investigaciones Energeticas Medioambientales Y Tecnologicas (C.I.E.M.A.T.) Derme artificiel et procédé de production
WO2003051842A3 (fr) * 2001-12-14 2004-06-03 Novo Nordisk As Utilisation de composes pour reduire l'activite de la lipase hormono-sensible
CN103232723A (zh) * 2012-12-31 2013-08-07 上海安诺其纺织化工股份有限公司 一种酯类化合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0193569A (ja) * 1987-07-02 1989-04-12 Warner Lambert Co アシル‐ＣｏＡ：コレステロールアシルトランスフエラーゼのＮ‐〔（２，６‐ジ置換）フエニル〕尿素およびカルバメート阻害剤
JPH03218345A (ja) * 1989-11-06 1991-09-25 Warner Lambert Co Ａｃａｔ阻害剤
JPH04224554A (ja) * 1990-04-19 1992-08-13 Abbott Lab リポキシゲナーゼ抑制化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0193569A (ja) * 1987-07-02 1989-04-12 Warner Lambert Co アシル‐ＣｏＡ：コレステロールアシルトランスフエラーゼのＮ‐〔（２，６‐ジ置換）フエニル〕尿素およびカルバメート阻害剤
JPH03218345A (ja) * 1989-11-06 1991-09-25 Warner Lambert Co Ａｃａｔ阻害剤
JPH04224554A (ja) * 1990-04-19 1992-08-13 Abbott Lab リポキシゲナーゼ抑制化合物

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072800A1 (fr) 2001-03-01 2002-09-19 Centro De Investigaciones Energeticas Medioambientales Y Tecnologicas (C.I.E.M.A.T.) Derme artificiel et procédé de production
WO2003051842A3 (fr) * 2001-12-14 2004-06-03 Novo Nordisk As Utilisation de composes pour reduire l'activite de la lipase hormono-sensible
WO2003051841A3 (fr) * 2001-12-14 2004-06-24 Novo Nordisk As Composes ralentissant l'activite de la lipase hormono-sensible
US7067517B2 (en) 2001-12-14 2006-06-27 Nero Nordisk A/S Use of compounds for decreasing activity of hormone-sensitive lipase
US7279470B2 (en) 2001-12-14 2007-10-09 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
CN103232723A (zh) * 2012-12-31 2013-08-07 上海安诺其纺织化工股份有限公司 一种酯类化合物及其制备方法
CN103232723B (zh) * 2012-12-31 2015-07-01 上海安诺其集团股份有限公司 一种酯类化合物及其制备方法

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