CN1042910A - The allylamine derivatives that replaces, their production method and application thereof - Google Patents

Abstract

The invention discloses a substituted allylamine derivative represented by the following general formula or a non-toxic salt thereof and a preparation method thereof,

Wherein, A ¹ , A ² , Q ¹ , Q ² , X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in the specification. The above compounds are used for inhibiting squalene epoxidase in mammals and for treating hypercholesterolemia. Hyperlipidemia and arteriosclerosis.

Description

The present invention relates to new substituted allylamine derivatives, more specifically substituted allylamine derivatives and their salts used in the field of pharmacy, especially for the treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis , their production methods and their applications.

Atherosclerosis is a degenerative arterial disease closely related to age and diet, and is believed to be the cause of coronary and cerebral artery disease, by far the leading cause of death. Arteriosclerosis begins at a young age due to lipid deposition on the endothelium of large vessels, increases with age and eventually manifests as clinical symptoms of ischemic heart disease, such as myocardial infarction and angina pectoris, cerebral arteriosclerosis , such as cerebral infarction, and aneurysm. It has been known that the increase of various blood lipids is related to the deposition of this lipid, especially the increase of blood cholesterol is the most important risk factor, and reducing the blood cholesterol level to a normal value is the most effective means of treating and preventing arteriosclerosis. It is said that more than 50% of the cholesterol in the human body comes from do novo biosynthesis. Currently, lovastatin and eptastatin, which are enzyme inhibitors during de novo biosynthesis, are clinically used as hypocholesterolemic agents [see, for example, A.W.Alberts et al., proc.Natl.Acad.Sci., 773957 (1980) and Tsujita et al., Biochim. Biophs. Acta, 877 50 (1986)]. However, the target enzyme of these inhibitors, 3-hydroxy-3-methylglutaryl-CoA reductase, is early in cholesterol biosynthesis, so the use of these drugs also inhibits other important biological metabolites dolichol and coenzyme Q. Furthermore, it has been reported that triparnol, an inhibitor of the late stage of the cholesterol biosynthesis process, is the cause of cataracts due to the accumulation of streptosterols. Since squalene epoxidase is in the middle stage of cholesterol biosynthesis, inhibitors of this enzyme are expected to solve this problem and be used as highly safe blood cholesterol-lowering agents.

Certain compounds are known to be inhibitors of squalene epoxidase [see G. Petranyi et al., Science, 224 1239 (1984)]. However, all of these have been developed as antifungal agents which selectively inhibit fungal squalene epoxidase. So far, there are no inhibitors that inhibit mammalian enzymes, nor are they useful as blood cholesterol-lowering agents.

The primary object of the present invention is to provide a blood lipid-lowering agent, as well as a therapeutic and preventive agent for arteriosclerosis, which is better and safer than the presently used blood-lipid-lowering agents.

In order to develop new anti-arteriosclerotic agents, the present inventors have studied squalene epoxidase inhibitors with hypocholesterolemic activity, and have found that substituted allylamine derivatives of the general formula (I) have an inhibitory effect on mammals. Selective inhibition of squalene epoxidase, and has strong hypocholesterolemic activity.

The present invention provides substituted allylamine derivatives represented by the following general formula, their non-toxic salts, their production methods, and their application in the treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis,

in

^A1 and ^A2 are the same or different, each representing a methine group or a nitrogen, oxygen or sulfur atom;

Q ¹ and Q ² are the same or different, and each represents a group containing 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, the group is connected to an adjacent carbon atom and A ¹ or A ² together form a 5-membered or 6-membered aromatic ring;

X and Y are the same or different, each representing an oxygen or sulfur atom, a carbonyl group, a group of the formula -CHR ^a -, wherein R ^a represents a hydrogen atom or a lower alkyl group, or a group of the formula -NR ^b -, wherein R ^b represents a hydrogen atom Or lower alkyl, or X and Y together form 1,2-vinylene or ethynylene;

R ¹ represents a 5-membered or 6-membered heterocyclic group containing 1-4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;

R ² represents lower alkyl, allyl, propargyl or cyclopropyl;

^R3 and ^R4 are the same or different, each representing a lower alkyl group, or together with adjacent carbon atoms to form a cycloalkyl group;

^R represents a hydrogen atom, lower alkyl or lower alkoxy; and

^R6 and ^R7 are the same or different, each representing a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group;

Provided that when one of X and Y represents an oxygen atom, a sulfur atom or a -NR ^b - (where R ^b is as defined) group, the other represents a carbonyl group or a -CHR ^a - (where R ^a is as defined) group.

The present invention is described in detail below.

known to have the following structural formula

The allylamine derivatives represented by naftifine and terbinafine showed strong inhibitory activity on squalene epoxidase of fungi, and as a result were used as antifungal agents [see G. Petranyi et al., Science, 244 1239 (1984)]. However, these compounds show little inhibitory activity against squalene epoxidase in mammals including humans, and cannot act as inhibitors of cholesterol synthesis [see N.S. Ryder et al., Biochemical, Journal, 230765 (1985)].

The inventors conducted extensive studies in order to develop a drug that selectively acts on mammalian squalene epoxidase and exhibits hypocholesterolemic activity. As a result, the inventors have found that when the naphthalene rings of the above-mentioned naftifine and terbinafine are replaced by 5-membered or 6-membered aromatic ring groups of the following formula 1,3-substituted 5-membered or 6-membered aromatic ring groups can be obtained to show a strong effect on mammalian squalene-epoxidase. compounds that inhibit activity,

Wherein R ⁷ , A ² and Q ² are as defined, and its 3-position is of the formula

The group substitution, wherein R ¹ , R ⁶ , A ¹ , Q ¹ , X and Y are as defined.

The present inventors have also found that the squalene-epoxidase inhibitory activity of the compound of general formula [I] is very selective, and shows almost no activity on fungal enzymes. Drugs for polycythemia and arteriosclerosis are very valuable.

Now, definitions and specific examples of various terms mentioned in the description of this specification are explained.

The term "lower", used to qualify a group or compound, means that the defined group or compound has not more than 6, preferably not more than 4 carbon atoms.

Correspondingly, for example, lower alkyl groups include linear or branched alkyl groups with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, neopentyl and hexyl. Examples of lower alkoxy preferably include linear or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy and tert-butoxy. The cycloalkane means a cycloalkane having 3 to 6 carbon atoms, specific examples of which are cyclopropane, cyclobutane, cyclopentane and cyclohexane. The halogen atom means a fluorine, chlorine, bromine or iodine atom.

To disclose more specific compounds represented by the general formula [I] of the present invention, various symbols used in the general formula [I] will be explained in detail when enumerating preferred examples.

Examples of 5-membered or 6-membered heterocyclic groups that can be represented by R ¹ and contain 1-4 heteroatoms selected from nitrogen, oxygen and sulfur include aromatic heterocyclic groups, such as pyrrolyl, furyl, thienyl, oxa Azolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl , pyrimidinyl, pyrazinyl and triazinyl groups; non-aromatic heterocyclic groups such as dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, iso Oxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1 , 2-dithiolanyl, 1,3-dithiolanyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4- Dithiinyl (1,4-dithiinyl) 1,4-oxathiinyl (1,4-oxathiinyl) and thiomorpholinyl groups. Among these groups, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl and dihydrothienyl are preferred. Particularly preferred are 3-thienyl, 1-pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl and 2,5-dihydro-3-thiophene groups.

As mentioned above X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula -CHR ^a - (where R ^a represents a hydrogen atom or a lower alkyl group) or a group of the formula -NR ^b - ( wherein R ^b represents a hydrogen atom or a lower alkyl); or X and Y together represent 1,2-vinylene or ethynylene, provided that one of X and Y represents an oxygen atom, a sulfur atom or the formula -NR ^b - group, the other represents a carbonyl group or a group of formula -CHR ^a -. Specifically, the group represented by -XY- may be, for example, -(CHR ^a ) ₂ -, -CHR ^a O-, -OCHR ^a -, -CHR ^a S-, -SCHR ^a -, -CHR ^a NR ^b -, -NR ^b CHR ^a , -CHR ^a CO-, -COCHR ^a -, -COO-, -OCO-, -COS-, -SCO-, -CONR ^b -, -NR ^b CO-, -CH= CH- and -C≡C- (wherein R ^a and R ^b are as defined above). Among them, 1,2-ethylene, (E)-1,2-vinylidene, -CH ₂ O-group, -CH ₂ S-group and -CH ₂ NH-group are preferred of.

R ² represents lower alkyl, allyl, propargyl or cyclopropyl. Examples of preferred lower alkyl groups are linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl. Methyl, ethyl, propyl, allyl or propargyl are preferably selected as substituents on ^R , most preferably methyl, ethyl and propyl.

^R3 and ^R4 are the same or different, and each represents a lower alkyl group, or when bonded together, they represent a cycloalkyl group formed with adjacent carbon atoms. Preferred lower alkyl groups are straight-chain lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl and butyl. Examples of preferred cycloalkanes are cycloalkanes having 3 to 6 carbon atoms such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

As substituents on ^R3 and ^R4 , preferred are methyl, ethyl, propyl and groups which together with adjacent carbon atoms form a cyclopropane ring, most preferably methyl.

R ⁵ represents a hydrogen atom, lower alkyl or lower alkoxy. Preferred lower alkyl groups are linear or branched lower alkyl groups with 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl base and pentyl. Examples of preferred lower alkoxy groups are linear or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyl Oxygen, sec-butoxy and tert-butoxy, of which methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropoxy are preferred, methyl , ethyl and methoxy are most preferred.

The aromatic rings represented can be the same or different, and preferably include aromatic rings containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, such as benzene, pyrrole, furan, thiophene, oxazole, iso Oxazole, thiazole, isothiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine rings. Use the following formula

The aromatic ring indicated is particularly preferably a benzene or thiophene ring.

Of the above aromatic rings, unsubstituted is most preferred. They may have substituents such as halogen atom, hydroxyl group, cyano group, lower alkyl group or lower alkoxy group, if necessary. Examples of substituents are hydroxyl group, fluorine atom, chlorine atom, methyl group, ethyl group and methoxy group.

Thus, preferred examples of compounds provided by the present invention are substituted allylamine derivatives of general formula [I], wherein ^R is pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, iso Thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, Dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazole Linyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolanyl, 1,3-dithiolanyl Dienyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithianyl, 1,4-oxathianyl or thiomorpholinyl; Use the following formula

The 5-membered or 6-membered aromatic rings can be the same or different, and each represents benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, 1,3,4-oxadiazole, 1, 3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring; X and Y are the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula -CHR ^a - (R ^a represents hydrogen atom or lower alkyl) or a group of formula -NR ^b - (R ^b represents hydrogen atom or lower alkyl), or X and Y together represent 1,2-vinylidene or ethynylene [provided that X and Y When one of them is an oxygen atom, a sulfur atom or a -NR ^b - group (R ^b is as defined), the other is a carbonyl group or a -CHR ^a - group (R ^a is as defined)]; R ² is a lower alkyl, alkenyl Propyl, propargyl or cyclopropyl; R ³ and R ⁴ are the same or different, each represents a lower alkyl group, or the two are bonded together to represent a cycloalkyl group formed together with adjacent carbon atoms; R ⁵ is a hydrogen atom, lower alkyl or lower alkoxy; ^R6 and ^R7 are the same or different, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group or a lower alkoxy group.

More preferred groups of compounds of general formula [I] include those of the formula

The aromatic ring is benzene or thiophene ring.

More preferred groups of compounds of general formula [I] are those wherein ^R is thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl or dihydrothienyl; The following formula

wherein the aromatic ring is a benzene or thiophene ring; and an aromatic ring represented by the formula

Benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.

A further preferred group of compounds of general formula [I] is wherein R is 3-thienyl, ¹ -pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4- Thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro- 3-thienyl; with the following formula

The aromatic ring represented is a benzene or thiophene ring; and the following formula

The aromatic ring represented is benzene, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine ring.

A particularly preferred group of compounds of general formula [I] is wherein R ^is 3-thienyl, 1-pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl , 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3- Thienyl; X is a methylene group; Y is a methylene group, an oxygen atom, a sulfur atom or an imine group, or X and Y together represent (E)-1,2-vinylidene; an aromatic ring represented by the following formula

Is a benzene or thiophene ring; the aromatic ring represented by the following formula

is benzene, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine ring; R ² is lower alkyl, allyl, propargyl or cyclopropyl; R ³ and R ⁴ are the same or different, each represents a lower alkyl group or the two are bonded together to represent a ring formed with adjacent carbon atoms Alkyl; R ⁵ represents a hydrogen atom, lower alkyl or lower alkoxy; and R ⁶ and R ⁷ are the same or different, each representing a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl or a lower alkoxy.

The most preferred group of the compound of general formula [I] is wherein ^R is 3-thienyl, 1-pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl , 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3- Thienyl; by the following formula

The aromatic ring represented is benzene or thiophene ring, with the following formula

The aromatic ring represented is benzene, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine ring; ^R2 is methyl, ethyl or propyl; ^R3 and ^R4 are methyl; ^R5 is methyl, ethyl or methoxy; and ^R6 and ^R7 are hydrogen atoms.

The substituted allylamine derivatives of the formula [I] may exist in the form of acid addition salts. Examples of such acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, perchloride and phosphate; and organic acid salts such as p-toluenesulfonate, benzene Sulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate and maleate. Those pharmaceutically acceptable non-toxic salts are preferred. The compound of formula [I] provided by the present invention may include stereoisomers such as geometric isomers and optical isomers. The present invention includes all such stereoisomers and mixtures thereof.

A general method for producing the compounds of the present invention is described below.

The compound of the present invention represented by the general formula [I] can be produced by any one of the following methods A, B, C, D, E and F.

In the formula, Z represents a leaving group; X ^a and Y ^b represent a carbonyl group or a formula -CHR ^a - (wherein R ^a is as defined above) group; X ^b and Y ^a represent an oxygen atom, a sulfur atom or a formula -NR ^b - (wherein R ^b is as defined above) group; and A ¹ , A ² , Q ¹ , Q ² , R ¹ , R ² , R ³ , R ⁴ , R ⁵ R ⁶ and R ⁷ are as defined above.

Methods A, B and C are well known in the field of synthetic organic chemistry for the alkylation of amines and can thus be accomplished by ordinary methods known per se. Each reaction in these methods can be carried out with a solvent which does not adversely affect the reaction. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; alcohols such as ethanol and isopropanol ; dimethylformamide, acetonitrile and dimethylsulfoxide; and mixtures thereof. Usually, in Process A, compounds [II] and [III] are reacted in an approximately equimolar ratio. In Process B, compounds [IV] and [V] are reacted in an approximately equimolar ratio. In Process C, compounds [VI] and [VII] are reacted in an approximately equimolar ratio. In addition, one of the reactants may be in slight excess. The reaction conditions used at this time are that the reaction temperature is generally -20 to 150°C, preferably from room temperature to the boiling point of the solvent, and the reaction time is usually 5 minutes to 10 days, preferably 1 to 24 hours. In order to make the reaction proceed smoothly, it is more favorable to carry out the above reaction in the presence of a base. Examples of the base used at this time are alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal carbonates , such as potassium carbonate and sodium bicarbonate; organic amines, such as triethylamine and pyridine. The amount of base is not standard and can vary widely, but generally at least 1 mole, preferably 1-2 moles of base is used per mole of starting compound.

Methods D and E are used for the synthesis and where the -XY- groups are -COO-, -OCO-, -CONR ^b -, -NR ^b CO-, -CHR ^a O-, -OCHR ^a -, -CHR ^a S - or -SCHR ^a - (where R ^a and R ^b are as defined) is the compound [I ^a ] or [I ^b ] corresponding to the compound of formula [I]. Methods D and E are carried out in a solvent which does not adversely affect the reaction, such as tetrahydrofuran, dioxane, chloroform, benzene, acetone, dimethylformamide or dimethylsulfoxide, and in the case of method D is compound [VIII] and [IX] Reaction, in the case of method E, compound [X] and [XI] are reacted in an approximately equimolar ratio or a slight excess of one of the reactants used. The reaction conditions at this time such as the temperature and time used differ depending on the raw materials used. Generally, the reaction temperature is -70 to 100°C, preferably -20 to 50°C, and the reaction time is 1 minute to 24 hours, preferably 30 minutes to 5 hours. In order to make the reaction proceed smoothly, the reaction is preferably carried out in the presence of a base. Examples of the base used at this time include inorganic bases such as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; and organic bases such as pyridine, triethylamine and Dimethylaminopyridine. The amount of the base to be used is not strictly limited, usually at least 1 mole, preferably 1-2 moles, per mole of the starting compound.

Process F is the production of a compound of formula [I ^c ] corresponding to a compound of formula [I] wherein the -XY- group is a -CH ₂ NH- group.

Process F is accomplished by condensing compound [XII] and compound [XIII] in benzene or alcohol to form an imine, and then reducing the product. The reagent used in the reduction may be, for example, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. The reaction can be carried out, for example, in methanol, ethanol or tetrahydrofuran at 0°C to room temperature for 1 to 6 hours. If formula [Ⅱ], [Ⅲ], [Ⅳ], [Ⅴ], [Ⅵ], [Ⅶ], [Ⅷ], [IX], [Ⅹ], [Ⅺ], [Ⅻ] and [ⅩⅢ] The initial compound has active functional groups such as hydroxyl or amino groups. Except for the hydroxyl, mercapto or amino groups participating in the reaction, the active functional groups can be protected when necessary, and the protective groups can be separated after the reaction. The protecting group used here is a group that is easily removed by hydrolysis under acidic or basic conditions, and examples include methoxymethyl, tetrahydropyranyl, trityl, dimethyl-(tert-butyl)methyl Silyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl groups.

The object compound of the formula [I] thus obtained can be isolated and purified by methods such as column chromatography, solvent extraction, precipitation, recrystallization alone or in combination. The compound [I] in the form of a free base can be converted into an acid addition salt thereof, or an acid addition salt can also be converted into a free base, when desired. The step of converting the free base into its acid addition salt, and the step of converting the acid addition salt into the free base, are easily accomplished by the usual methods using the corresponding acid or base.

The leaving group represented by Z may be, for example, a halogen atom such as chlorine, bromine or iodine atom, or an organic sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy.

The starting compound of formula [Ⅱ] to [ⅩⅢ] is commercially available or can be according to the method described in literature, [J.Med.Chem.27 1539 (1984), the same, 29 112 (1986), Japanese publication Patent specifications 32440/1981, 123177/1982, 208252/1983, 45/1986, 201850/1987 and 5059/1988], and the common methods listed below or the corresponding methods substantially with these methods.

The starting compounds used in the present invention can be prepared by synthetic methods such as listed below.

production route[a]

Production route[c]

Production route[d]

Production route[e]

Production route [f]

[In the formula, X ^c and Y ^c are the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula -CHR ^a - (where R ^a is as defined above), or a group of formula -NR ^b - (where R ^b as defined above); R ⁸ represents a lower alkyl group; R ⁹ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group; B represents a hydrogen atom or a protecting group; and A ¹ , A ² , Q ¹ , Q ² , X, Y, X ^a , X ^b , Y ^a , Y ^b , Z, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above; with the proviso that when X ^c and Y ^c Where one represents an oxygen atom, a sulfur atom or a group of formula -NR ^b - (wherein R ^b is as defined), the other represents a carbonyl group or the formula -CHR ^a - (wherein R ^a is as defined above). ]

Production route (a)

The step of making compound [XIV] react with compound [VIII] to produce compound [XVI] is at -20 to 100°C in a solvent such as tetrahydrofuran, chloroform or dimethylamide, in a solvent such as sodium hydride, sodium hydroxide or carbonic acid This is accomplished by reacting approximately equimolar compounds [XIV] and [VIII] in the presence of a potassium base for 2 to 3 hours.

The step of reacting compound [XV] and [X] to produce compound [XVI] can be carried out in the same manner as the step of reacting compound [XIV] and [VIII].

The step of making compound [XVI] and [XVIII] react to produce compound [ ^IIa ] can be performed, for example, by condensing compound [XVI] and [XVIII] in benzene or alcohol to form an imine, and then reducing the product, or by making excess compound [ XVIII] is reacted with compound [XVI] and reduced simultaneously. The reagent used in the reduction at this time may be, for example, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. The reaction can be carried out in methanol, ethanol or tetrahydrofuran at, for example, 0°C to room temperature for 1 to 6 hours.

The step of reducing the compound [XVI] to produce the compound [XVII] is carried out, for example, by subjecting the compound [XVI] to a reducing agent such as sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride in a solvent such as methanol, ethanol or tetrahydrofuran. 0°C to room temperature for 1 to 5 hours to complete.

The step of converting the compound [XVII] into the compound [IV ^a ] is carried out, for example, with a sulfonating agent such as methanesulfonyl chloride and trichloromethane in a solvent such as chloroform or dichloromethane or in the absence of a solvent at -20°C to room temperature. Treatment with ethylamine or a halogenating agent such as thionyl chloride or phosphorus tribromide for 1 to 5 hours is accomplished.

production route (b)

The step of reacting compounds [XXIX] and [XII] to produce compound [XX] can be carried out, for example, by treating these compounds with a base such as n-butyllithium or sodium hydride in a solvent such as tetrahydrofuran at 0°C to room temperature for 1 to 6 hours. Finish.

The step of reducing compound [XX] to compound [ ^XVIIa ] can be carried out by treating compound [XX] with a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran for 1 to 5 hours.

The step of reducing compound [XX] or oxidizing compound [XVII ^a ] to compound [XVI ^a ] can be carried out, for example, by reducing compound [XX] with diisobutylaluminum hydride in toluene or by oxidation with pyridinium chlorochromate in methylene chloride Compound [ ^XVIIa ] to complete.

The step of converting compound [XVII ^a ] into compound [IV ^b ] and the step of making compound [XVII ^a ] and [XVIII] react to generate compound [II ^b ] can be converted into compound [XVII] in the production route (a) The step of compound [ ^IVa ] is carried out in the same manner as the step of reacting compound [XVI] with compound [XVIII] to produce compound [ ^IIa ].

production route (c)

The step of making compound [XXI] react with compound [XXII] or making compound [XXIII] react with compound [XII] to generate compound [ ^XVIIa ] can be produced by reacting compound [XXX] with compound [XII] in the production route (b) Compound [XX] can be carried out by the same route.

The step of reducing compound [XVII ^a ] to compound [XVII ^b ] can be accomplished, for example, by carrying out catalytic reduction at room temperature under normal pressure for 1 to 10 hours in a solvent such as methanol or ethanol in the presence of a catalyst such as palladium-carbon. .

The step of converting compound [ ^XVIIa ] into [ ^XVIIc ] can be accomplished by the following reaction: in an organic solvent such as dichloromethane, chloroform or ether, compound [ ^XVIIa ] at 0 to 60°C; form, or react with bromine for 0.5-3 hours after being protected with an appropriate protecting group, the resulting solution is concentrated to dryness, and then dissolved in a base such as methanol, ethanol or isopropanol in the presence of a base such as sodium hydroxide or potassium hydroxide In an alcoholic solution, the residue is treated at the boiling point of the solvent for 1-10 hours.

The step of converting compound [XVII ^b ] into compound [IV ^c ] and the step of converting compound [XVII ^c ] into compound [IV ^d ] can be carried out in the same manner as the step of converting compound [XVII] into compound [IV ^a ].

production route (d)

The step of making compound [ ^XVIb ] react with compound [ ^Va ] to generate compound [VI] is carried out in the same route as the step of making compound [XVI] react with compound [XVIII] to generate compound [II ^a ] in the production route (a) .

The compound [V ^a ] used here can be produced, for example, by the Gabriel's method, which comprises, in the presence of a base such as sodium hydroxide or potassium carbonate, in a solvent such as tetrahydrofuran or dimethylformamide at 10 to 100 Compound [III] is reacted with phthalimide to give compound [XXIV], which is then reacted with hydrazine in e.g. ethanol or dimethylformamide to give compound [ ^Va ].

Production route (e)

The step of reacting compound [ ^XIVa ] with compound [XVIII] to produce compound [XXVII] can be carried out in the same manner as the step ^{of reacting compound [XVI] with compound [XVIII] to produce compound [IIa]} . The step of reducing compound [XIV ^a ] to generate compound [XXV] and then converting it into compound [XXVI] can produce compound [XVI] in the production route (a) by reducing compound [XVI] and then converting it into compound [IV ^a ] in the same way as the steps.

Compound [XXVI] is reacted with compound [V] to produce compound [IX], or compound [XXVII] is reacted with compound [III] to produce compound [XXVIII], and then, when necessary, the step of deprotecting the product may be the same as the above Carried out in the same way as method A or B described herein.

The protecting group represented by B in the starting compound used in the production route (e) may be any one of various protecting groups used as protecting groups for hydroxyl, mercapto or amino groups in the field of organic synthetic chemistry. Specific examples include methoxymethyl, tetrahydropyranyl, trityl, tert-butoxycarbonyl and dimethyl(tert-butyl)silyl groups.

production route (f)

The step of reducing the compound [XXIX] to produce the compound [XXX] is a partial reduction which utilizes the difference in reactivity of the coexisting carbonyl groups in the reduction. It can be accomplished, for example, by reducing compound [XXIX] at -20°C to room temperature for 1 to 5 hours with 1 to 2 equivalents of a reducing agent such as sodium borohydride or diisobutylaluminum hydride in a solvent such as ethanol or tetrahydrofuran , or by catalytic reduction in the presence of a catalyst, such as palladium-carbon, for 1 to 5 hours. Compound [XXX] is converted into compound [XXXI], and then the step of reacting it with compound [V] to generate compound [XXXII] can be converted into compound [XXVI] from compound [XXV] in the production route (e), and then made It is carried out in the same manner as the step of reacting compound [V] to produce compound [XXVIII].

The step of converting compound [XXXII] to compound [XXXIII], wherein Y ^b is the alcohol product [XXXIII] of the formula -CHR ^a - group (wherein R ^a is as defined above), is accomplished by reduction, or in In the case of the carboxylic acid product [XXXIII] in which Y ^b is a carbonyl group, it is completed by hydrolysis. The step of reducing compound [XXXII] to generate alcohol product [XXXIII] can be accomplished in the same way as the step of reducing compound [XVI] to compound [XVII] in the production route (a), or by reducing the compound in the production route (b) [XX] It can be carried out in the same manner as the step of producing compound [XVII ^a ]. The step of hydrolyzing the compound [XXXII] to produce the corresponding carboxylic acid compound [XXXIII] can be carried out, for example, by dissolving the compound [XXXII] in a solvent such as aqueous ethanol or aqueous tetrahydrofuran containing an equimolar or excess molar base such as sodium hydroxide, in This is accomplished by maintaining the solution at a temperature ranging from room temperature to 100°C for 1 to 10 hours.

The step of converting compound [XXXIII] to compound [XI] can be carried out by using a halogenating agent such as thionyl chloride or tribromophosphorus in a solvent such as chloroform or dichloromethane or without a solvent at -20°C to room temperature Compound [XXXIII] is treated for 1 to 5 hours to complete.

If necessary, the products obtained in the above respective stages can be purified or isolated by methods such as chromatography, recrystallization, solvent extraction, precipitation, and distillation, which may be used alone or in combination as appropriate.

Compounds that can be used as starting materials for intermediates are readily available commercially or as described in the literature [e.g., J. Med. Chem. 27 1539 (1984); ibid., 29 112 (1986); And Japanese published patent specifications NOS.32440/1981, 123177/1982, 208252/1983, 45/1986, 201850/1987 and 5059/1988] and synthetic methods known in organic synthetic chemistry.

The compounds of the present invention represented by the general formula [I] are useful compounds which highly selectively and strongly inhibit mammalian squalene epoxidase, and are expected to be useful as hypolipidemic agents or antiarteriosclerotic agents.

In order to prove this point, a drug test example and an acute toxicity test example will be given below.

Pharmacological Test Example 1

Squalene epoxidase inhibitory activity

(1) Preparation of squalene epoxidase

Rat squalene epoxidase was prepared as described in J. Biol. Chem. 245 1670 (1970); and supra, 250 1572 (1975).

Kill SD strain female rats by bloodletting, extract and homogenize the liver in 2 volumes of 0.1M tris-hydrochloric acid (Tris-Hcl) buffer solution (PH7.5), and centrifuge the homogenate at 9750Xg for 10 minute. The supernatant was centrifuged again at 105000Xg for 1 hour. The sediment was washed with 0.1M Tirs-Hcl buffer solution (pH 7.5), and then centrifuged at 105000Xg for 1 hour. Suspend the obtained microsomes in 0.1M Tris-Hcl buffer solution (PH7.5), so that the amount of protein is 40mg/ml, under ice cooling, stir the suspension in the presence of 2% Triton X-100 to dissolve the enzyme . After dissolving, dilute the solution into 0.5% Triton X-100 containing 1mM EDTA and 1mM dithiothreitol, and centrifuge at 105000Xg for 1 hour. The resulting supernatant fraction was used as the squalene epoxidase fraction in the following experiments.

(2) Method for measuring squalene epoxidase activity

Squalene epoxidase activity was determined according to the method described in J. Biol. Chem 245 1670 (1970).

Add 3 microliters of the test drug in dimethyl sulfoxide to a solution with the following composition: 0.2 ml of the squalene epoxidase fraction prepared in (1) [protein 0.4 mg, 0.5% Triton X-100, 20 μM Tris-HCl buffer solution (pH7.5)], 100 μM FAD, 1 mM NADPH, 1 mM EDTA and 8 μM ³ H-squalene-Tween 80 emulsion, and adjust the total volume of the solution to 0.3 ml. The solution was incubated at 37°C for 30 minutes with shaking. Then, 0.3 ml of 10% methanolic potassium hydroxide was added to terminate the reaction, and the reaction mixture was left standing at room temperature for 1 hour. The unsaponifiable was extracted with petroleum ether, and the solvent was evaporated to dryness under nitrogen flow. The obtained residue was dissolved in a small amount of ether, and spotted on a pre-coated silica gel TLC plate, then developed with benzene/ethyl acetate (99.5:0.5), and determined with ergosterol acetate as a marker. The position of the obtained ³ H-squalene-2,3-epoxide, and the ³ H-squalene-2,3-epoxide portion on TLC were excised. Immerse the TLC part in a toluene-type scintillator and measure it with a liquid scintillation counter. As a result, the 50% inhibitory concentration (IC ₅₀ value) of the compound of the present invention to squalene epoxidase was determined. The results are listed in Table 1.

Table 1

Squalene epoxidase inhibitory activity

Test drug 50% inhibitory concentration (IC ₅₀ , nM)

Example 2 compound 7

Example 3 compound 4

Example 8 compound 11

Example 9 compound 6

Example 15 compound 60

Example 19 compound 27

Example 25 compound 33

Example 26 compound 31

Example 31 compound 26

Example 33 compound 26

Example 47 compound 26

Example 48 compound 23

Example 51 compound 34

Example 54 compound 21

Example 56 compound 34

Example 70 compound 11

Example 74 compound 22

Example 78 compound 33

Pharmacological Test Example 2

Inhibitory activity on cholesterol biosynthesis in cultured cells:

Human liver cancer (Hep-G ₂ ) cells were cultured in 10 cm ² dishes until monolayers formed. Remove 1ml of the culture medium, add 1μC; (microcurie) [ ¹⁴ C] sodium acetate and 1μ [test drug in dimethyl sulfoxide solution, and culture the cells at 37°C for 6 hours in an air containing 5% carbon dioxide.

After incubation, the medium was aspirated and the cells were cooled with water and washed with Dulbecco's phosphate-buffered saline. The resulting cells were removed with a rubber sponge and collected by centrifugation. The collected cells were dissolved in 400 µl of 0.3N NaOH. A 200 μl aliquot was used for extraction and the remainder was used for protein determination.

Add 15% ethanol potassium hydroxide to 200 μl of extracted cells, saponify at 75°C for 1 hour. Water (1ml) was then added and the mixture was extracted twice with 2ml of petroleum ether to remove unsaponifiables. The petroleum ether extract was washed with 1 ml of water and evaporated to dryness under a stream of nitrogen. The residue was spotted on a precoated silica gel TLC plate with a small amount of chloroform and developed with hexane/ether/acetic acid (85:15:4). Cholesterol and squalene fractions on TLC plates were detected with iodine and the corresponding TLC fractions were excised. The TLC was immersed in a toluene-type scintillator, and the radioactivity was counted with a liquid scintillation counter. The results were corrected by the amount of protein determined as described in J. Biol. Chem. 193 265 (1951). The 50% inhibitory concentration (IC ₅₀ ) of the compounds of the present invention on cholesterol biosynthesis in cultured Hep-G2 cells was calculated, and the results are listed in Table 2.

Table 2

Inhibitory activity of cholesterol biosynthesis in cultured cells

Test drug 50% inhibitory concentration (IC ₅₀ , nM)

Example 2 compound 53

Example 3 compound 11

Example 8 compound 12

Example 9 compound 11

Example 15 compound 54

Example 19 compound 9

Example 25 compound 6

Compound 5 of Example 26

Example 31 compound 22

Example 33 compound 25

Example 42 compound 30

Example 47 compound 10

Example 48 compound 10

Example 51 compound 33

Example 74 compound 29

Example 78 compound 17

Example 80 compound 52

Pharmacological Test Example 3

In vivo assays for inhibition of cholesterol biosynthesis:

SD female rats, 5 weeks old, were used for in vivo experiments. The rats were kept in the environment of the opposite light cycle (ie, the dark time from 6:00 am to 6:00 pm) for 9 days, and they were allowed to eat solid food and drink water freely. The test drug was orally administered 2 hours before the sixth hour of darkness when cholesterol synthesis was at its maximum. The test drug was dissolved in water containing 5% dimethyl sulfoxide and 2% Tween 80 and administered orally at a dose of 3 mg/Kg (1 ml/100 g body weight).

The control group was dosed with the same volume of vehicle as above. One hour after taking the test drug, [ ¹⁴ C]-labeled sodium acetate (56mCi/mmol) was intraperitoneally administered to the rats, with a dose of 20μCi/100g body weight. Six hours in the dark, blood samples were taken from the abdominal artery under ether anesthesia, and the plasma was separated by centrifugation.

Mix 1ml of plasma with 2ml of 15% methanolic potassium hydroxide and heat to 75°C for saponification for 3 hours. The resulting sample was extracted twice with 2 ml of petroleum ether. The extract was washed with 2 ml of distilled water and finally evaporated under nitrogen flow. The resulting residue was dissolved in a small amount of diethyl ether and the entire solution was spotted on a pre-coated silica gel TLC plate. The TLC plate was developed in a solvent system consisting of hexane/ether/acetic acid (85:15:4), and iodine was used to generate color, and the radioactivity of the cholesterol moiety was measured with a liquid scintillation counter.

The results are expressed in dpm of ¹⁴ C-cholesterol produced in 1 ml of plasma. The inhibition of cholesterol biosynthesis was calculated by comparing the amount of ¹⁴ C-cholesterol biosynthesized in the test group with that in the control group. The results are listed in Table 3.

Example of Acute Toxicity Test

Various test drugs (compounds 3, 9, 19, 20, 25, 51, free base) were dissolved in medium-chain triglyceride (MCT), and administered orally to mice (ddy, male, body weight 28±2g , 2 per group). Acute toxicity was evaluated by measuring the mortality rate after one week of administration.

The toxicity of the test drug was very low, and no death was observed even at the high dose of 1000mg/kg.

As seen from the previous experiments, the compounds of the present invention strongly inhibit squalene epoxidase, thereby inhibiting the biosynthesis of cholesterol. Accordingly, they can be effectively used for the treatment and prevention of various diseases induced by increased biosynthesis of cholesterol, such as obesity, hyperlipidemia, arteriosclerosis. No inhibitory activity against fungal squalene epoxidase was observed for the compounds of the present invention, but only specific activity against mammals. The compounds of the present invention also have low toxicity, so they are very useful as medicines.

The compound of general formula [I] provided by the present invention can be made into a form suitable for oral and parenteral administration, and can be used for treating hypercholesterolemia, hyperlipidemia and arteriosclerosis. When the compounds of the present invention are used clinically, they can be formulated together with pharmaceutically acceptable auxiliary agents suitable for pharmaceutical forms, and then administered. Various adjuvants commonly used in the pharmaceutical field can be used. Examples of adjuvants include gelatin, lactose, sucrose, titanium dioxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminosilicate, anhydrous Calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone , Magnesium Stearate, Light Anhydrous Silicic Acid, Talc, Vegetable Oil, Benzyl Alcohol, Gum Arabic, Propylene Glycol, Polyalkylene Glycol, Cyclodextrin, or Carboxypropyl Cyclodextrin.

Formulations prepared from mixtures containing these adjuvants include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories, liquid preparations such as syrups, elixirs and injection preparations. These formulations can be prepared by common methods known in the field of pharmaceutical formulations. Liquid preparations may be solutions or suspensions in water or other suitable medium. Preparations for injection may be dissolved in physiological saline or glucose solution, or buffered solutions or preservatives may also be added, if necessary.

These preparations may contain 1.0-100% by weight of the total drug. Preference is given to 1.0% to 60% by weight of the compound of the invention. They may also contain other therapeutically effective compounds.

When the compounds of the present invention are used as hypolipidemic agents, antiarteriosclerotic agents or hypocholesterolemic agents, the dose or frequency of administration may vary depending on sex, age, body weight, severity of symptoms of the patient and type and extent of the expected therapeutic effect. Generally speaking, for oral administration, a dose of 0.01-20 mg/kg is preferred, or administered in several divided doses. For parenteral administration, it is preferred that the dose is 0.001-2 mg/kg in one dose, or divided into several doses.

The following examples and reference examples illustrate the present invention more specifically, but it should be understood that the present invention is not limited by these examples.

Example 1

Preparation of (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-furyl)benzyloxy]benzylamine hydrogen chloride

Dissolve 190mg (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxybenzylamine in 3ml of anhydrous tetrahydrofuran, cool in ice and 31 mg of 60% oily sodium hydride was added with stirring and the solution was stirred for 10 minutes. The ether solution of 3-(2-furyl)-benzyl chloride was added to the resulting solution (160 mg of 3-(2-furyl) benzyl alcohol was reacted with 73 μl of thionyl chloride in anhydrous ether under ice-cooling and stirring for 3 hours, and then washed the resulting solution with saturated aqueous sodium chloride and 5% aqueous sodium bicarbonate (prepared) and 1 ml of dimethylformamide. The mixture was stirred overnight at room temperature. 30 ml of water and 30 ml of ether were added to the reaction solution, and the mixture was separated. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then the solvent was evaporated. The residue was purified by medium pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si 60F (E.Merck Co.); elution solvent: hexane/ethyl acetate=10/1→8/1] to give 63 mg (21% yield) of the free base of the title compound as a colorless oil. The free base was treated with methanol and hydrogen chloride and recrystallized from an ethyl acetate/ether mixture to give the title hydrochloride, m.p. 115-116°C.

IRν ^pure _max cm ^-1 : 2968, 2488, 1605, 1497, 1461, 1266, 789.

NMR ( _CDCl3 ) δ: 1.25 (9H, s), 2.60 (3H, s), 3.50-3.64 (2H, m), 4.00-4.13 (2H, m), 5.20 (2H, s), 5.78-5.84 ( 1H, m), 6.18-6.32 (1H, m), 6.47 (1H, dd, J=3.5Hz, 2.0Hz), 6.70 (1H, d, J=3.5Hz), 7.05-7.11 (2H, m), 7.30-7.47 (5H, m), 7.62 (1H, d, J=7.1Hz), 7.78 (1H, s).

Example 2

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(1-pyrrolyl)benzyloxy]benzylamine:

Dissolve 100mg (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine in 1ml of anhydrous tetrahydrofuran, cool in ice and To the solution was added 20 mg of 60% oily sodium hydride with stirring, and the mixture was stirred for 10 minutes. To the resulting solution was added a solution of 100 mg of 3-(1-pyrrolyl)benzyl methanesulfonate in 1 ml of dimethylformamide, and the mixture was stirred overnight at room temperature. 20ml of water and 30ml of ether were added to the solution for extraction. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-200, 20 g, eluent: hexane/ethyl acetate=10/1-5/1] to give 110 mg (yield 70%) of the title compound as Colorless oil.

IRν ^pure _max cm ^-1 : 2968, 1596, 1506, 1488, 1455, 1341, 1263, 1071, 786, 726.

NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.0Hz), 1.19 (9H, s), 2.45 (2H, q, J = 7.0Hz), 3.03 (2H, dd, J = 6.4Hz, 1.6 Hz), 3.49 (2H, s), 5.06 (2H, s), 5.59 (1H, dt, J=15.9Hz, 1.6Hz), 6.01 (1H, dt, J=15.9Hz, 6.4Hz), 6.30 (2H , t, J=2.1Hz), 6.80 (1H, ddd, J=8.3Hz, 2.6Hz, 0.8Hz), 6.88 (1H, d, J=7.6Hz), 6.96-6.98 (1H, m), 7.06 ( 2H, t, J = 2.1Hz), 7.17 (1H, t, J = 7.8Hz), 7.25-7.32 (2H, m), 7.39 (1H, t, J = 7.8Hz), 7.44-7.45 (1H, m ).

Example 3

Preparation of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)benzyloxy] -Benzylamine hydrochloride

Dissolve 57.5 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxybenzylamine in 0.5 ml of anhydrous tetrahydrofuran , and under a nitrogen atmosphere, 8.1 mg of 60% oily sodium hydride was added thereto. The mixture was stirred at room temperature for 10 minutes, and to this solution was added a solution of 53.7 mg of 3-(3-thienyl)benzyl methanesulfonate in 1 ml of dimethylformamide. The mixture was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E. Merck Co.), eluent: hexane/ethyl acetate = 6/1-1/1] to give 81.6 mg (89% yield) of the free base of the title compound as a colorless oil. Treatment of the free base with hydrogen chloride and methanol and recrystallization from a mixture of ethyl acetate and ether gave the title hydrochloride, m.p. 153-155°C.

IRν ^pure _max cm ^-1 : 3340, 2986, 2932, 1605, 1455, 1266, 1173, 1071, 777.

NMR (CDCl ₃ ) δ: 1.41 (3H, t, J=7.2Hz), 1.47 (6H, s), 2.90-3.20 (2H, m), 3.34 (3H, s), 3.40-3.80 (2H, m) , 4.08 (2H, br.s), 5.22 (2H, s), 5.84 (1H, d, J = 15.9Hz), 6.36 (1H, dt, J = 15.9Hz, 7.9Hz), 7.00-7.20 (2H, m), 7.33 (1H, t, J=7.9Hz), 7.40-7.70 (7H, m), 7.73 (1H, s).

Example 4

Preparation of (E)-N-[6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-isoxazolyl)benzyloxy)benzyl Oxy]benzylamine:

106 mg of 5-(3-methylphenyl)isoxazole, 119 mg of N-bromosuccinimide and 2 mg of benzoyl peroxide were dissolved in 10 ml of carbon tetrachloride, and the solution was refluxed for 3 hours with stirring. After cooling, the precipitate was isolated by filtration and concentrated under reduced pressure to give 5-(3-bromomethylphenyl)isoxazole as a light yellow oily product.

The obtained bromomethyl compound was dissolved in 5 ml of dimethylformamide. This solution was added to a solution of phenoxide in 10 ml of tetrahydrofuran, which was composed of 171 mg of (E)-N-(6,6-dimethyl-2-heptene-4-ynyl)-N-methyl-3-hydroxy Benzylamine and 30 mg of 60% oily sodium hydride were prepared in advance, and the reaction mixture was stirred under ice cooling for 1 hour, and water and diethyl ether were added to the reaction solution to dilute. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, the solvent was evaporated, and the residue was subjected to medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E.Merck Co.]; eluent: hexane/ethyl acetate 10/1- 5/1] and purification by preparative thin-layer chromatography [thin-layer plate Kieselgel 60F ₂₅₄ , Art. 5744 (E. Merck Co.); developing solvent: hexane/ethyl acetate=3/1] gave 19 mg (yield 11 %) the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 2974, 2788, 1584, 1491, 1470, 1266, 786.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.5Hz, 1.4Hz), 3.47 (2H, s), 5.13 (2H, s), 5.65 (1H, dt, J = 15.8Hz, 1.4Hz), 6.08 (2H, dt, J = 15.8Hz, 6.5Hz), 6.55 (1H, d, J = 1.9Hz), 6.88 (1H, ddd, J = 8.1Hz, 2.6Hz, 0.9Hz), 6.70-6.75 (1H, m), 7.00-7.03 (1H, m), 7.24 (1H, t, J=8.1Hz), 7.50-7.55 (2H, m), 7.77 (1H, dt, J=6.7Hz, 1.9Hz), 7.88-7.91 (1H, m), 8.30 (1H, d, J=1.9Hz).

Example 5

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1-imidazolyl)benzyloxy]benzylamine:

90 mg of 1-(3-hydroxymethylphenyl)imidazole was dissolved in 10 ml of chloroform, 100 µl of thionyl chloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of ether and water. The organic layer was separated, washed successively with 5% aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the ether was evaporated to give 1-(3-chloromethylphenyl)imidazole as a pale yellow oil.

The obtained chloromethyl compound was dissolved in 1.5ml of dimethylformamide, and 140mg of (E)-N-(6,6-dimethyl-2-heptene-4-ynyl)-N-methyl A solution of the phenoxide from 3-hydroxybenzylamine in tetrahydrofuran (1.5 ml) and 22 mg of 60% oily sodium hydride. The mixture was reacted as in Examples 1-4 to give 110 mg (57% yield) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 1599, 1506, 1491, 1455, 1311, 1263, 1056, 1026, 786.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.36 (2H, dd, J=6.5Hz, 1.4Hz), 3.47 (2H, s), 5.13 (2H, s), 5.65 (1H, dt, J = 15.8Hz, 1.4Hz), 6.07 (1H, dt, J = 15.8Hz, 6.5Hz), 6.87 (1H, ddd, J = 8.3Hz, 2.7Hz, 1.0Hz), 6.92 ( 1H, d, J = 8.3Hz), 6.99-7.10 (1H, m), 7.22 (1H, t, J = 1.4Hz), 7.24 (1H, t, J = 7.7Hz), 7.31 (1H, t, J =1.4Hz), 7.34-7.45 (2H, m), 7.50 (1H, t, J=7.7Hz), 7.51 (1H, s), 7.88 (1H, t, J=1.4Hz).

Carry out the same reaction as in Example 1-5 to obtain the compound of the following examples 6-44, just to replace the various starting compounds in the examples 1-5, using the corresponding 3-hydroxybenzylamine derivatives and 3-hetero Cyclic benzyl halide derivatives or methanesulfonyl derivatives or their starting materials.

Example 6

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-furyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1458, 1263, 1161, 1059, 1038, 1020, 873, 777.

NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.50 (2H, q, J = 7.1Hz), 3.09 (2H, d, J = 6.4Hz), 3.54 (2H, s), 5.08 (2H, s), 5.64 (1H, dt, J = 15.9Hz, 1.5Hz), 6.07 (1H, dt, J = 15.9Hz, 6.4Hz), 6.71 (1H, dd, J = 1.8Hz, 0.9Hz), 6.87 (1H, dd, J = 7.8Hz, 2.0Hz), 6.92 (1H, d, J = 7.6Hz), 7.02 (1H, br.s), 7.22 (1H, t , J = 7.8Hz), 7.34 (1H, dt, J = 7.4Hz, 1.7Hz), 7.39 (1H, t, J = 7.1Hz), 7.45 (1H, dt, J = 7.4Hz, 1.7Hz), 7.48 (1H, t, J=1.7Hz), 7.57 (1H, br.s), 7.75 (1H, t, J=1.4Hz).

Example 7

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-thienyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1599, 1491, 1455, 1365, 1266, 1152, 1026, 786, 696.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.04 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.10 (2H, s), 5.65 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.6Hz), 6.86-6.93 (2H, m), 7.00 (1H, br.s), 7.23 ( 1H, t, J = 7.8Hz), 7.29 (1H, dd, J = 5.1Hz, 1.1Hz), 7.33 (1H, dd, J = 3.6Hz, 1.1Hz), 7.36-7.39 (1H, m), 7.40 (1H, t, J=7.6Hz), 7.57 (1H, dt, J=7.6Hz, 1.8Hz), 7.68-7.71 (1H, m).

Example 8

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(3-thienyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1599, 1491, 1455, 1365, 1263, 1026, 774.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.10 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.6Hz), 6.86-6.92 (2H, m), 7.00 (1H, br.s), 7.23 ( 1H, t, J = 8.0Hz), 7.36 (1H, dt, J = 7.6Hz, 1.6Hz), 7.39-7.40 (2H, m), 7.41 (1H, t, J = 7.6Hz), 7.46-7.48 ( 1H, m), 7.55 (1H, dt, J = 7.6Hz, 1.7Hz), 7.67 (1H, br.s).

Example 9

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine hydrochloride compound:

m.p.168-169℃

IRν ^pure _max cm ^-1 : 2974, 2500, 1602, 1461, 1266, 1173, 777, 759, 747.

NMR (CDCl ₃ ) δ: 1.25 (9H, s), 1.42 (3H, t, J=7.3Hz), 2.95-3.06 (2H, m), 3.50-3.67 (2H, m), 4.08 (2H, d, J = 5.3Hz), 5.23 (2H, s), 5.80 (1H, d, J = 15.7Hz), 6.22 (1H, dt, J = 15.7Hz, 7.5Hz), 7.06 (1H, ddd, J = 8.3Hz , 2.5Hz, 0.8Hz), 7.09 (1H, d, J = 8.3Hz), 7.33 (1H, t, J = 8.1Hz), 7.37-7.43 (4H, m), 7.51 (1H, dd, J = 2.8 Hz, 1.5Hz), 7.53-7.58 (2H, m), 7.73 (1H, br.s).

Example 10

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[3-(3-thienyl)benzyloxy]benzylamine hydrochloride compounds

m.p.164-166℃

IRν ^pure _max cm ^-1 : 2968, 1605, 1458, 1266, 777.

NMR (CDCl ₃ ) δ: 0.92 (3H, t, J=7.3Hz), 1.25 (9H, s), 1.82-1.98 (2H, m), 2.73-2.92 (2H, m), 3.44-3.78 (2H, m), 4.09 (2H, br.s), 5.23 (2H, s), 5.78 (1H, d, J = 15.6Hz), 6.21 (1H, dt, J = 15.6Hz, 7.8Hz), 7.04-7.09 ( 2H, m), 7.33 (1H, t, J=8.1Hz), 7.35-7.43 (4H, m), 7.50 (1H, dd, J=2.5Hz, 1.5Hz), 7.53-7.57 (2H, m), 7.74 (1H, s).

Example 11

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1-pyrrolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 1596, 1506, 1488, 1458, 1341, 1266, 1029, 786, 726.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.11 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.07 (1H, dt, J = 15.8Hz, 6.6Hz), 6.35 (2H, t, J = 2.2Hz), 6.86 (1H, ddd, J = 10.8Hz, 2.3Hz, 0.8Hz), 6.91 (1H, d, J = 7.8Hz), 6.98-6.99 (1H, m), 7.10 (2H, t, J = 2.2Hz), 7.22 (1H, t, J =7.8Hz), 7.25-7.50 (4H, m).

Example 12

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[3-(1-pyrrolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1596, 1506, 1488, 1455, 1341, 1263, 1071, 723.

NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.4Hz), 1.24 (9H, s), 1.47 (2H, sex., J = 7.4Hz), 2.36 (2H, t, J = 7.4Hz) , 3.06 (2H, dd, J = 6.4Hz, 1.6Hz), 3.53 (2H, s), 5.11 (2H, s), 5.63 (1H, dt, J = 15.9Hz, 1.6Hz), 6.05 (1H, dt , J = 15.9Hz, 6.4Hz), 6.35 (2H, t, J = 2.2Hz), 6.85 (1H, ddd, J = 8.2Hz, 2.6Hz, 0.9Hz), 6.92 (1H, d, J = 7.6Hz ), 7.00-7.03 (1H, m), 7.11 (2H, t, J=2.2Hz), 7.21 (1H, t, J=7.8Hz), 7.28-7.37 (2H, m), 7.44 (1H, t, J=7.8Hz), 7.49 (1H, t, J=1.5Hz).

Example 13

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-pyridyl)-benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1587, 1464, 1365, 1263, 1152, 1026, 768.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (1H, dd, J = 6.5Hz, 1.5Hz), 3.47 (2H, s), 5.15 (2H, s), 5.64 (1H, dt, J = 15.9Hz, 1.5Hz), 6.08 (1H, dt, J = 15.9Hz, 6.5Hz), 6.86-6.92 (2H, m), 7.00 (1H, br.s), 7.22- 7.27 (3H, m), 7.49-7.51 (2H, m), 7.75-7.77 (2H, m), 7.93-7.96 (1H, m), 8.08 (1H, br.s), 8.70 (1H, dt, J = 4.8Hz, 1.5Hz).

Example 14

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(3-pyridyl)-benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1599, 1491, 1458, 1365, 1263, 1152, 1023, 783.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.5Hz, 1.5Hz), 3.47 (2H, s), 5.62 (2H, s), 5.64 (1H, dt, J = 15.9Hz, 1.5Hz), 6.07 (1H, dt, J = 15.9Hz, 6.6Hz), 6.87-6.93 (2H, m), 7.01 (1H, br.s), 7.23 ( 1H, t, J = 7.9Hz), 7.37 (1H, ddd, J = 6.8Hz, 5.0Hz, 0.9Hz), 7.48-7.57 (3H, m), 7.67 (1H, br.s), 7.87-7.91 ( 1H, m), 8.60 (1H, dd, J=4.8Hz, 1.7Hz), 8.86 (1H, dd, J=2.4Hz, 0.9Hz).

Example 15

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-pyridyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1596, 1458, 1263, 786, 711.

NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.1Hz), 1.23 (9H, s), 2.50 (2H, q, J = 7.1Hz), 3.09 (2H, d, J = 6.3Hz), 3.54 (2H, s), 5.14 (2H, s), 5.63 (1H, dd, J = 15.9Hz, 1.4Hz), 6.06 (1H, dt, J = 15.9Hz, 6.3Hz), 6.87 (1H, dd, J = 8.0Hz, 2.7Hz), 6.92 (1H, d, J = 7.6Hz), 7.03 (1H, br.s), 7.22 (1H, t, J = 7.8Hz), 7.36 (1H, ddd, J = 7.6Hz, 4.9Hz, 1.2Hz), 7.48-7.57 (3H, m), 7.66 (1H, d, J = 1.2Hz), 7.87-7.91 (1H, m), 8.60 (1H, dd, J = 5.1Hz , 1.8Hz), 8.85 (1H, dd, J = 2.7Hz, 1.2Hz).

Example 16

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(4-pyridyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2972, 1596, 1490, 1458, 1364, 1266, 1152, 1026, 786.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.04 (1H, dd, J = 6.5Hz, 1.5Hz), 3.47 (2H, s), 5.14 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.9Hz, 1.5Hz), 6.87-6.93 (2H, m), 7.00 (1H, br.s), 7.24 ( 1H, t, J = 8.0Hz), 7.51-7.54 (4H, m), 7.59-7.62 (1H, m), 7.59-7.62 (1H, m), 8.67 (2H, dd, J = 4.5Hz, 1.7Hz ).

Example 17

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-oxazolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2974, 1590, 1491, 1458, 1365, 1266, 1152, 1026, 798, 729.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.30 (2H, dd, J=6.6Hz, 1.5Hz), 3.46 (2H, s), 5.12 (2H, s), 5.63 (1H, dd, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.6Hz), 6.85-6.92 (2H, m), 6.99-7.15 (1H, m), 7.22 ( 1H, t, J = 7.7Hz), 7.24 (1H, d, J = 1.1Hz), 7.48 (1H, t, J = 7.7Hz), 7.54 (1H, d, J = 7.9Hz), 7.72 (1H, d, J=1.1Hz), 8.01 (1H, dt, J=7.9Hz, 1.2Hz), 8.13-8.16 (1H, m).

Example 18

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-oxazolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1596, 1458, 1263, 1152, 1026, 954, 789, 693.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.5Hz, 1.4Hz), 3.47 (2H, s), 5.11 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.4Hz), 6.08 (1H, dt, J = 15.9Hz, 6.5Hz), 6.86-6.93 (2H, m), 7.00-7.02 (1H, m), 7.23 ( 1H, t, J = 7.9Hz), 7.38 (1H, s), 7.42-7.43 (1H, m), 7.45 (1H, t, J = 7.6Hz), 7.60-7.64 (1H, m), 7.74-7.76 (1H, m), 7.93 (1H.s).

Example 19

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(5-oxazolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1491, 1458, 1263, 1107, 954, 789.

NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.50 (2H, q, J = 7.1Hz), 3.09 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.54 (2H, s), 5.11 (2H, s), 5.64 (1H, dt, J=15.8Hz, 1.5Hz), 6.07 (1H, dt, J=15.8Hz, 6.4Hz), 6.84-6.89 (1H, m), 6.93 (1H, d, J=7.7Hz), 7.03 (1H, br.s), 7.23 (1H, t, J=7.7Hz), 7.39 (1H, s), 7.40-7.49 ( 2H, m), 7.62 (1H, dt, J=6.6Hz, 2.1Hz), 7.75 (1H, br.s), 7.93 (1H, s).

Treatment of the free base with hydrogen chloride-methanol in the customary manner gave the hydrochloride, m.p. 160°C (dec.).

Example 20

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[3-(5-oxazolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2968, 1596, 1491, 1455, 1263, 1107, 954, 789.

NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.4Hz), 1.47 (2H, sex, J = 7.4Hz), 2.37 (2H, t, J = 7.4Hz), 3.07 (2H, dd, J = 6.4Hz, 1.5Hz), 3.53 (2H, s), 3.53 (2H, s), 5.10 (2H, s), 5.63 (1H, dt, J = 15.9Hz, 1.5Hz), 6.06 (1H, dt, J=15.9Hz, 6.4Hz), 6.84-6.89 (1H, m), 6.92 (1H, d, J=7.8Hz), 7.02 (1H, br.s), 7.22 (1H, t, J=7.8Hz) , 7.38 (1H, s), 7.40-7.49 (2H, m), 7.62 (1H, dt, J = 6.6Hz, 2.1Hz), 7.75 (1H, br.s), 7.93 (1H, s).

Example 21

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(4-isoxazolyl)benzyloxy]benzylamine :

IRν ^pure _max cm ^-1 : 2974, 1602, 1494, 1458, 1266, 756.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.5Hz, 1.4Hz), 3.48 (2H, s), 5.10 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.4Hz), 6.08 (2H, dt, J = 15.9Hz, 6.5Hz), 6.85-6.95 (2H, m), 7.01 (1H, br.s), 7.24 ( 1H, t, J=8.0Hz), 7.38-7.49 (3H, m), 7.57 (1H, br.s), 8.58 (1H, s), 8.70 (1H, s).

Example 22

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-thiazolyl)benzyloxy]benzylamine:

IRν ^pure _max cm ^-1 : 2972, 1588, 1490, 1456, 1364, 1266, 1148, 1022, 788, 692.

NMR (CDCl ₃ ) δ: 1.19 (9H, s), 2.14 (3H, s), 2.99 (2H, dd, J=6.6Hz, 1.4Hz), 3.42 (2H, s), 5.08 (2H, s), 5.60 (1H, dt, J = 15.8Hz, 1.4Hz), 6.04 (1H, dt, J = 15.8Hz, 6.6Hz), 6.83 (1H, dd, J = 8.1Hz, 1.5Hz), 6.87 (1H, d , J=8.1Hz), 6.95 (1H, d, J=1.5Hz), 7.18 (1H, t, J=7.8Hz), 7.30 (1H, d, J=3.3Hz), 7.42 (1H, t, J = 8.1Hz), 7.47 (1H, d, J = 7.6Hz), 7.83 (1H, d, J = 3.3Hz), 7.87 (1H, d, J = 7.3Hz), 8.01 (1H, s).

Example 23

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(4-isothiazolyl)benzyloxy]benzylamine: -

IRν ^pure _max cm ^-1 : 2968, 1590, 1491, 1458, 1365, 1263, 1152, 1026, 780.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.5Hz, 1.5Hz), 3.47 (2H, s), 5.12 (2H, s), 5.64 (1H, dt, J = 15.9Hz, 1.5Hz), 6.07 (1H, dt, J = 15.9Hz, 6.5Hz), 6.85-6.94 (2H, m), 7.01 (1H, t, J = 2.1Hz) , 7.23 (1H, t, J = 7.9Hz), 7.40-7.50 (2H, m), 7.55 (1H, dt, J = 6.9Hz, 1.9Hz), 8.73 (1H, s), 8.79 (1H, s) .

Example 24

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-isothiazolyl)benzyloxy]benzylamine: -

IRν ^pure _max cm ^-1 : 2968, 1590, 1491, 1458, 1419, 1368, 1266, 1152, 786, 756.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.2Hz, 1.5Hz), 3.48 (2H, s), 5.11 (2H, s), 5.65 (1H, dt, J = 15.6Hz, 1.5Hz), 6.08 (1H, dt, J = 15.6Hz, 6.2Hz), 6.88 (1H, ddd, J = 8.2Hz, 2.8Hz, 1.0Hz), 6.89- 6.90 (2H, m), 7.00-7.03 (1H, m), 7.23 (1H, t, J=7.8Hz), 7.43 (1H, d, J=2.1Hz), 7.45-7.50 (2H, m), 7.54 -7.59 (1H, m), 7.68-7.71 (1H, m), 8.48 (1H, d, J=2.1Hz).

Example 25

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(1-imidazolyl)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1506, 1491, 1458, 1308, 1263, 1056, 789.

NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.49 (2H, q, J = 7.1Hz), 3.08 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.54 (2H, s), 5.13 (2H, s), 5.64 (1H, dt, J=15.9Hz, 1.5Hz), 6.06 (1H, dt, J=15.9Hz, 6.4Hz), 6.85 (1H , ddd, J=8.0Hz, 2.0Hz, 0.9Hz), 6.93 (1H, d, J=7.5Hz), 7.00-7.05 (1H, m), 7.21 (1H, t, J=1.4Hz), 7.23 ( 1H, t, J=8.0Hz), 7.31 (1H, t, J=1.4Hz), 7.33-7.53 (4H, m), 7.88 (1H, t, J=1.4Hz).

Example 26

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[3-(1-imidazolyl)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1599, 1506, 1488, 1455, 1308, 1263, 1152, 1056, 786.

NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.4Hz), 1.24 (9H, s), 1.47 (2H, sex, J = 7.4Hz), 2.37 (2H, t, J = 7.4Hz), 3.06 (2H, dd, J = 6.3Hz, 1.5Hz), 3.53 (2H, s), 5.13 (2H, s), 5.63 (1H, dt, J = 15.6Hz, 1.5Hz), 6.05 (1H, dt, J = 15.6Hz, 6.3Hz), 6.84 (1H, ddd, J = 8.2Hz, 3.4Hz, 0.8Hz), 6.93 (1H, d, J = 7.6Hz), 7.01 (1H, br.s), 7.21 ( 1H, t, J = 1.4Hz), 7.22 (1H, t, J = 8.2Hz), 7.31 (1H, t, J = 1.4Hz), 7.33-7.53 (4H, m), 7.88 (1H, t, J = 1.4Hz).

Example 27

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-pyrimidinyl)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2974, 1584, 1455, 1419, 1266, 786, 756.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, d, J=6.2Hz), 3.47 (2H, s), 5.15 (2H, s), 5.64 (1H , d, J = 15.9Hz), 6.07 (1H, dt, J = 15.9Hz, 6.2Hz), 6.82-6.93 (2H, m), 7.02 (1H, br.s), 7.23 (1H, t, J = 7.5Hz), 7.54-7.55 (3H, m), 7.67 (1H, s), 8.96 (2H, s), 9.22 (1H, s).

Example 28

(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1,2,4-triazol-1-yl) Benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2974, 1599, 1512, 1458, 1266, 1215, 1146, 759.

NMR (CDCl ₃ ) δ: 1.23 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.46 (2H, s), 5.14 (2H, s), 5.64 (1H, dt, J = 15.9Hz, 1.5Hz), 6.06 (1H, dt, J = 15.9Hz, 6.6Hz), 6.85 (1H, ddd, J = 7.9Hz, 2.7Hz, 0.5Hz), 6.92 ( 1H, d, J = 7.9Hz), 6.98-7.05 (1H, m), 7.23 (1H, t, J = 7.9Hz), 7.45-7.49 (1H, m), 7.53 (1H, t, J = 7.8Hz ), 7.64 (1H, dt, J=7.8Hz, 1.8Hz), 7.80 (1H, br.s), 8.11 (1H, s), 8.58 (1H, s).

Example 29

(E)-N-Ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(1-pyrrolyl)benzyloxy]benzyl amine:-

IRν ^pure _max cm ^-1 : 1605, 1506, 1341, 1170, 1149, 1074, 960, 789, 723, 696.

NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 6.9Hz), 1.46 (6H, s), 2.56 (2H, q, J = 6.9Hz), 3.15 (2H, dd, J = 6.5Hz, 1.5 Hz), 3.35 (3H, s), 3.61 (2H, s), 5.12 (2H, s), 5.73 (1H, dt, J=15.9Hz, 1.5Hz), 6.20 (1H, dt, J=15.9Hz, 6.5Hz), 6.37 (2H, t, J=2.1Hz), 6.86 (1H, dd, J=7.8Hz, 1.6Hz), 6.93 (1H, d, J=7.8Hz), 6.99-7.05 (1H, m ), 7.10 (2H, t, J=2.1Hz), 7.23 (1H, t, J=7.5Hz), 7.29-7.46 (3H, m), 7.48-7.50 (1H, m).

Example 30

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2,3-dihydro-4-thienyl)benzyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2788, 1584, 1491, 1455, 1365, 1263, 1152, 1023, 783.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.4Hz), 3.11-3.19 (2H, m), 3.35-3.43 (2H , m), 3.46 (2H, s), 5.04 (2H, s), 5.64 (1H, dt, J=15.9Hz, 1.4Hz), 6.08 (1H, dt, J=15.9Hz, 6.6Hz), 6.59 ( 1H, t, J=2.1Hz), 6.83-6.93 (2H, m), 6.97-7.00 (1H, m), 7.19-7.33 (4H, m), 7.39-7.42 (1H, m).

Example 31

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(2,3-dihydro-4-thienyl)benzyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1587, 1491, 1455, 1365, 1263, 1149, 777.

NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.49 (2H, q, J = 7.1Hz), 3.08 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.15 (2H, dt, J=8.4Hz, 1.8Hz), 3.38 (2H, t, J=8.4Hz), 3.53 (2H, s), 5.04 (2H, s), 5.64 (1H, dt, J=15.8Hz, 1.5Hz), 6.07 (1H, dt, J=15.8Hz, 6.4Hz), 6.59 (1H, t, J=1.8Hz), 6.82-6.87 (1H, m), 6.89-6.94 (1H , m), 6.98-7.02 (1H, m), 7.21 (1H, t, J=7.8Hz), 7.23-7.35 (3H, m), 7.39-7.42 (1H, m).

Example 32

(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(2,3-dihydro-4-thiophene base)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 1452, 1380, 1365, 1254, 1173, 1149, 1077, 819, 777, 693.

NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.0Hz), 1.46 (6H, s), 2.51 (2H, q, J = 7.0Hz), 3.09-3.18 (4H, m), 3.35 (3H , s), 3.35-3.42 (2H, m), 3.54 (2H, s), 5.04 (2H, s), 5.68 (1H, dt, J = 15.7Hz, 1.8Hz), 6.16 (1H, dt, J = 15.7Hz, 6.6Hz), 6.59 (1H, t, J = 1.6Hz), 6.83-6.89 (1H, m), 6.90-6.95 (1H, m), 6.98-7.04 (1H, m), 7.21 (1H, t, J=7.5Hz), 7.25-7.35 (3H, m), 7.39-7.40 (1H, m).

Example 33

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(2,5-dihydro-3-thienyl)benzyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2920, 1587, 1491, 1455, 1365, 1263, 1152, 777.

NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.49 (2H, q, J = 7.1Hz), 3.08 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.53 (2H, s), 3.91-3.96 (2H, m), 4.11-4.15 (2H, m), 5.06 (2H, s), 5.64 (1H, dt, J=15.8Hz, 1.5Hz), 6.05 (1H, dt, J = 15.8Hz, 6.4Hz), 6.26 (1H, quint, J = 2.0Hz), 6.82-6.87 (1H, m), 6.89-6.94 (1H, m), 6.99-7.01 (1H , m), 7.21 (1H, t, J=8.0Hz), 7.34-7.37 (3H, m), 7.47-7.49 (1H, m).

Example 34

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1-pyrrolidinyl)benzyloxy]benzylamine: -

IRν ^pure _max cm ^-1 : 2968, 1608, 1584, 1506, 1491, 1458, 1368, 1266, 1152, 768.

NMR ( _CDCl3 ) δ: 1.24 (9H, s), 1.97-2.02 (4H, m), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.29-3.31 (4H , m), 3.46 (2H, s), 5.01 (2H, s), 5.64 (1H, dt, J=15.9Hz, 1.5Hz), 6.08 (1H, dt, J=15.9Hz, 6.5Hz), 6.51 ( 1H, dd, J=8.3Hz, 2.4Hz), 6.62-6.64 (1H, m), 6.72 (1H, d, J=7.4Hz), 6.85-6.90 (2H, m), 6.98 (1H, t, J =2.1Hz), 7.20-7.22 (2H, m).

Example 35

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[5-(3-thienyl)-2-thienylmethyloxy Base] benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1596, 1446, 1377, 1260, 1017, 852, 801, 771.

NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.0Hz), 1.24 (9H, s), 2.50 (2H, q, J = 7.0Hz), 3.10 (1H, dd, J = 6.3Hz, 1.4 Hz), 3.54 (2H, s), 5.18 (2H, s), 5.64 (1H, dt, J=15.9Hz, 1.4Hz), 6.08 (1H, dt, J=15.9Hz, 6.3Hz), 6.86 (1H , dd, J=8.0Hz, 2.7Hz), 6.93 (1H, d, J=7.6Hz), 7.00-7.04 (2H, m), 7.07 (1H, d, J=3.6Hz), 7.22 (1H, t , J = 8.0Hz), 7.29 (1H, dd, J = 5.2Hz, 1.2Hz), 7.33 (1H, dd, J = 5.2Hz, 4.5Hz), 7.36 (1H, dd, J = 4.5Hz, 1.2Hz ).

Example 36

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-(5-oxazolyl)-4-pyridylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1620, 1491, 1455, 1365, 1266, 1113, 957, 831, 762.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.05 (2H, dd, J=6.5Hz, 1.5Hz), 3.48 (2H, s), 5.14 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.5Hz), 6.09 (1H, dt, J = 15.9Hz, 6.5Hz), 6.86 (1H, ddd, J = 7.9Hz, 2.7Hz, 0.9Hz), 6.94 ( 1H, d, J = 7.9Hz), 7.00-7.01 (1H, m), 7.25 (1H, t, J = 7.9Hz), 7.32 (1H, dt, J = 5.0Hz, 0.8Hz), 7.73 (1H, s), 7.76-7.77 (1H, m), 7.99 (1H, s), 8.64 (1H, dd, J=5.0Hz, 0.8Hz).

Example 37

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[4-(5-oxazolyl)-2-pyridylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1617, 1584, 1494, 1455, 1263, 1155, 1113, 957.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, d, J=6.5Hz), 3.48 (2H, s), 5.24 (2H, s), 5.64 (1H , dt, J=15.9Hz, 1.7Hz), 6.08 (1H, dt, J=15.9Hz, 6.5Hz), 6.88-6.95 (2H, m), 7.04-7.05 (1H, m), 7.19-7.27 (1H , m), 7.46 (1H, dd, J = 5.4Hz, 1.5Hz), 7.59 (1H, s), 7.79 (1H, m), 8.00 (1H, s), 8.65 (1H, d, J = 6.2Hz ).

Example 38

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[5-(5-oxazolyl)furfuryloxy]benzylamine: -

IRν ^pure _max cm ^-1 : 2968, 2926, 1458, 1263, 1107, 1020, 963, 789.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.5Hz, 1.5Hz), 3.47 (2H, s), 5.05 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.5Hz), 6.09 (1H, dt, J = 15.9Hz, 6.5Hz), 6.53 (1H, d, J = 3.4Hz), 6.64 (1H, d, J = 3.4Hz), 6.87 (1H, ddd, J = 8.1Hz, 2.7Hz, 0.8Hz), 6.93 (1H, d, J = 8.1Hz), 7.00 (1H, m), 7.24 (1H, t, J = 8.1 Hz), 7.30 (1H, s), 7.86 (1H, s).

Example 39

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-oxazolyl)-5-furylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1584, 1461, 1269, 1152, 1098, 1041, 1032, 891, 831.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.20 (3H, s), 3.05 (2H, dd, J=6.5Hz, 1.4Hz), 3.48 (2H, s), 4.97 (2H, s), 5.66 (1H, dt, J = 15.8Hz, 1.4Hz), 6.09 (1H, 15.8Hz, 6.5Hz), 6.75 (1H, d, J = 0.8Hz), 6.82-6.88 (1H, m), 6.92 (1H , d, J=7.8Hz), 6.98 (1H, br.s), 7.23 (1H, t, J=7.8Hz), 7.28 (1H, s), 7.54 (1H, d, J=0.8Hz), 7.86 (1H, s).

Example 40

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-(5-oxazolyl)-4-thiazolylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1596, 1491, 1455, 1263, 1158, 1104, 1059, 1017, 966, 894.

NMR (CDCl ₃ ) δ: 1.19 (9H, s), 2.14 (3H, s), 3.00 (2H, dd, J=6.6Hz, 1.4Hz), 3.43 (2H, s), 5.22 (2H, d, J = 0.96Hz), 5.60 (1H, dt, J = 15.8Hz, 1.4Hz), 6.03 (1H, dt, J = 15.8Hz, 6.6Hz), 6.83 (1H, ddd, J = 7.6Hz, 2.6Hz, 0.75 Hz), 6.89 (1H, d, J=7.6Hz), 6.97 (1H, m), 7.19 (1H, t, J=7.6Hz), 7.37 (1H, t, J=0.96Hz), 7.63 (1H, s), 7.92 (1H, s).

Example 41

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[6-(5-oxazolyl)-2-pyridylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1596, 1452, 1365, 1260, 1158, 1107, 804, 786.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.5Hz, 1.4Hz), 3.46 (2H, s), 5.25 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.4Hz), 6.07 (1H, dt, J = 15.8Hz, 6.5Hz), 6.86-6.91 (1H, m), 6.91-6.95 (1H, m), 7.01- 7.04 (1H, m), 7.23 (1H, t, J=8.0Hz), 7.51 (1H, dd, J=7.8Hz, 0.9Hz), 7.59 (1H, dd, J=7.8Hz, 0.9Hz), 7.72 (1H, s), 7.80 (1H, t, J=7.8Hz), 7.99 (1H, s).

Example 42

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[5-(5-oxazolyl)-3-pyridylmethyl Oxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1590, 1491, 1455, 1266, 1152, 1107, 1026, 963, 759.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.05 (2H, dd, J=6.6Hz, 1.4Hz), 3.48 (2H, s), 5.13 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.4Hz), 6.09 (1H, dt, J = 15.9Hz, 6.6Hz), 6.88 (1H, dd, J = 7.8Hz, 2.6Hz), 6.94 (1H, d , J = 7.8Hz), 7.01-7.04 (1H, m), 7.25 (1H, t, J = 7.8Hz), 7.49 (1H, s), 8.00 (1H, s), 8.05 (1H, t, J = 2.0Hz), 8.65 (1H, d, J=2.0Hz), 8.90 (1H, d, J=2.0Hz).

Example 43

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-methyl-3-(1-pyrrolyl)benzyloxy ]Benzylamine hydrochloride:-

m.p.137-139℃

IRν ^pure _max cm ^-1 : 2968, 2500, 1599, 1497, 1458, 1332, 1263, 1038, 723.

NMR ( _CDCl3 ) δ: 1.25 (9H, s), 2.18 (3H, s), 2.65 (3H, s), 3.48-3.61 (1H, m), 3.65-3.78 (1H, m), 3.95-4.08 ( 1H, m), 4.16-4.29 (1H, m), 5.21 (2H, s), 5.85 (1H, d, J=15.6Hz), 6.20-6.36 (1H, m), 6.32 (2H, t, J= 2.1Hz), 6.79 (2H, t, J=2.1Hz), 7.04-7.11 (1H, m), 7.24-7.30 (2H, m), 7.35 (1H, t, J=7.9Hz), 7.51 (1H, t, J = 4.5Hz), 7.63 (1H, br.s).

Example 44

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[6-methyl-3-(1-pyrrolyl)benzyloxy ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1590, 1518, 1488, 1455, 1341, 1266, 1026, 723.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 2.39 (3H, s), 3.04 (2H, dd, J=6.5Hz, 1.5Hz), 3.48 (2H, s), 5.06 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.5Hz), 6.08 (1H, dt, J = 15.9Hz, 6.5Hz), 6.33 (2H, t, J = 2.2Hz), 6.86 -6.95 (2H, m), 6.99-7.02 (1H, m), 7.07 (2H, t, J=2.2Hz), 7.21-7.27 (3H, m), 7.50 (1H, br.s).

Example 45

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(4-thiazolyl)benzyloxy]benzylamine :-

Dissolve 600mg of 2-chloro-4-(3-tolyl)thiazole in a mixture of 8ml of carbon tetrachloride and 2ml of 1,2-dichloroethane, add N-bromosuccinimide (511mg) and 3mg of peroxide Benzoyl was added and the mixture was stirred and refluxed for 3 hours. After cooling, the precipitate was separated from the reaction mixture by filtration. Washing with aqueous sodium bicarbonate, and distilling off the solvent under reduced pressure gave 4-(3-bromomethylphenyl)-2-chlorothiazole as a pale yellow oil.

The obtained bromomethyl compound was dissolved in 2ml of dimethylformamide, and then this solution was added to 8ml containing 388mg (E)-N-(6,6-dimethyl-2-heptene-4- Alkynyl)-N-methyl-3-hydroxybenzylamine and 68 mg of phenoxide prepared from 60% oily sodium hydride in tetrahydrofuran. The mixture was stirred under ice-cooling for 1 hour and then at room temperature for another 2 hours. Water and ether were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 80g, eluent: hexane/ethyl acetate=6/1→4/1) to obtain 396mg (57% yield) of (E)-N- (6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-chloro-4-thiazolyl)benzyloxy]benzylamine, is a light Yellow oil.

The obtained ether compound (92mg) was dissolved in 0.8ml of acetic acid, and the solution was heated to 57-60°C with stirring, and 40mg of zinc powder was added at the same time. After the mixture was stirred for 30 minutes, it was poured into ice water and sodium carbonate was added to adjust the pH to 9.0. The solution was extracted with ethyl acetate, the extract was dried with anhydrous sodium sulfate, and the solvent was evaporated, and the residue was purified by medium-pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si60 (E.Merck Co); Removal agent: hexane/ethyl acetate = 6/1 → 3/1] to obtain 52 mg (60% yield) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 2968, 1587, 1491, 1455, 1365, 1266, 1026, 789.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.5Hz, 1.5Hz), 3.47 (2H, s), 5.13 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.5Hz), 6.86-6.92 (2H, m), 7.00 (1H, br.s), 7.22 ( 1H, t, J = 7.8Hz), 7.44-7.45 (1H, m), 7.57 (1H, d, J = 2.0Hz), 7.64 (1H, t, J = 7.7Hz), 7.87-7.91 (1H, m ), 8.02 (1H, br.s), 8.84 (1H, d, J=2.0Hz).

According to the method of Example 45, 5-(3-bromomethylphenyl)-2-bromothiazole obtained from 5-(3-methylphenyl)thiazole [see J.Org.Chem; 51,3375( 1986); Org. React, 6 381; and Ann, 628 (1981)] in place of 4-(3-bromomethylphenyl)-2-chlorothiazole. Condensation with the corresponding 3-hydroxybenzylamine derivative and dehalogenation yields the compounds of Examples 46 to 48.

Example 46

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-thiazolyl)benzyloxy]benzylamine:-

IRν ^neat _max cm ^-1 : 2974, 1590, 1458, 1266, 873, 789, 693.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.10 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.6Hz), 6.88 (1H, dd, J = 8.1Hz, 1.8Hz), 6.92 (1H, d , J=7.8Hz), 7.00 (1H, t, J=1.8Hz), 7.23 (1H, t, J=7.8Hz), 7.42-7.44 (2H, m), 7.53-7.56 (1H, m), 7.65 -7.66 (1H, m), 8.10 (1H, d, J=0.6Hz), 8.76 (1H, d, J=0.6Hz).

Example 47

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(5-thiazolyl)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2972, 1588, 1490, 1456, 1364, 1264, 1152, 1046, 874, 788.

NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.0Hz), 1.19 (9H, s), 2.46 (2H, q, J = 7.0Hz), 3.04 (2H, d, J = 6.0Hz), 3.50 (2H, s), 5.06 (2H, s), 5.60 (1H, d, J = 15.8Hz), 6.02 (1H, dt, J = 15.8Hz, 6.0Hz), 6.82 (1H, dd, J = 8.1 Hz, 2.1Hz), 6.89 (1H, d, J=8.0Hz), 6.98 (1H, br.s), 7.18 (1H, t, J=8.0Hz), 7.38-7.41 (2H, m), 7.48- 7.52 (1H, m), 7.62 (1H, s), 8.05 (1H, d, J=0.6Hz), 8.71 (1H, d, J=0.6Hz).

Example 48

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[3-(5-thiazole)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1490, 1458, 1364, 1264, 1152, 872, 788, 694.

NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.4Hz), 1.24 (9H, s), 1.46-1.51 (2H, m), 2.37 (2H, t, J = 7.1Hz), 3.07 (2H , dd, J=6.4Hz, 1.3Hz), 3.53 (2H, s), 5.10 (2H, s), 5.63 (1H, dd, J=15.9Hz, 1.3Hz), 6.04 (1H, dt, J=15.9 Hz, 6.4Hz), 6.86 (1H, dd, J = 7.8Hz, 1.8Hz), 6.92 (1H, d, J = 7.4Hz), 7.20 (1H, s), 7.22 (1H, t, J = 7.8Hz ), 7.43-7.44 (2H, m), 7.53-7.55 (1H, m), 7.66 (1H, br.s), 8.10 (1H, s), 8.76 (1H, s).

Example 49

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(3-pyrrolyl)benzyloxy]benzylamine :-

Mix methyl isocyanoacetate (280 µl) and 400 µl 1,8-diazabicyclo[5.4.0]+-alk-7-ene (DBU) under stirring at a temperature of 45 to 50°C Add to 20ml tetrahydrofuran, add 500mg (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-formylbenzyloxy ) benzylamine in tetrahydrofuran (5 ml), and the mixture was stirred at the above temperature for 5 hours. The reaction mixture was cooled and neutralized with acetic acid. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the residue to conduct extraction, the organic layer was separated, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography [Wakogel C-200, 30 g, eluent: hexane/ethyl acetate: 5/1] to obtain 140 mg (yield 20%) of (E)-N-(6 ,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2,4-dimethoxycarbonyl-3-pyrrolyl)benzyloxy]benzylamine , is a pale yellow oil.

The obtained pyrrolyl compound (32 mg) was added to a mixture of 2 g of potassium hydroxide and 6 ml of water, and the mixture was heated and stirred under reflux for 6 hours. After cooling, diethyl ether was added to the reaction mixture for extraction. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The residue was purified by silica gel column chromatography [Wakogel C-200, 30 g; eluent: hexane/ethyl acetate=10/1→2/1] to obtain 12.4 mg (50% yield) of the title compound, which was a Pale yellow oil.

IRν ^neat _max cm ^-1 : 3440, 2972, 2928, 2872, 1610, 1490, 1454, 1364, 1266, 1034, 778.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.08 (2H, s), 5.64 (1H, dt, J = 15.8Hz, 1.5Hz), 6.09 (1H, dt, J = 15.8Hz, 6.6Hz), 6.54-6.57 (1H, m), 6.82-6.92 (3H, m), 6.99- 7.01 (1H, m), 7.10-7.13 (1H, m), 7.22 (1H, t, J=7.6Hz), 7.23-7.28 (1H, m), 7.35 (1H, t, J=7.4Hz), 7.49 (1H, dt, J = 7.4Hz, 1.7Hz), 7.59-7.61 (1H, m), 8.20-8.40 (1H, br).

Example 50

(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1,3,4-oxadiazol-2-yl) ) Preparation of benzyloxy]benzylamine:-

Dissolve 173 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-methoxycarbonylbenzyloxy)benzylamine in 3ml of ethanol, and add 100mg of 98% hydrazine hydrate. The mixture was heated at reflux for 3 hours. After the reaction mixture was evaporated under reduced pressure, water and ethyl acetate were added to the residue to conduct extraction. The organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated. The remaining carbohydrazide was added to 4 ml of trimethyl orthoformate, and the mixture was heated under reflux for 8 hours. After distilling off the excess trimethyl orthoformate, the residue was extracted with a mixture of ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography [Wakogel C-200, 30 g; eluent: hexane/ethyl acetate=2/1] and medium pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si60 (E.Merck Co.); eluent: hexane/ethyl acetate = 3/1 → 2/1] to obtain 18 mg = (yield 10%) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 2974, 1590, 1491, 1455, 1368, 1266, 1152, 960, 726.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.04 (1H, dd, J=6.5Hz, 1.5Hz), 3.47 (2H, s), 5.15 (2H, s), 5.65 (1H, dt, J = 15.8Hz, 1.5Hz), 6.08 (1H, dt, J = 15.8Hz, 6.5Hz), 6.85-6.90 (1H, m), 6.90-6.94 (1H, m), 7.00 ( 1H, br.s), 7.24 (1H, t, J = 7.8Hz), 7.55 (1H, t, J = 7.6Hz), 7.63-7.67 (1H, m), 8.05 (1H, dt, J = 6.3Hz , 1.5Hz), 8.18 (1H, br.s), 8.49 (1H, s).

Example 51

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-[3-(3-thienyl)benzene Base]-vinyl]benzylamine hydrochloride preparation:-

Dissolve 95 mg of (E)-3-[2-[3-(3-thienyl)phenyl]vinyl]benzyl chloride in 2 ml of dimethylformamide. To this solution were added 58 mg of (E)-N-methyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 126 mg of potassium carbonate, and the mixture was stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure, and diethyl ether and water were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-200, 15g; eluent: hexane→hexane/ethyl acetate=10/1] to obtain 88mg (yield 67% ) the free base of the title compound as a colorless oil.

The free base obtained above was treated with hydrochloric acid-methanol solution and recrystallized from a mixture of chloroform and hexane to give the title hydrochloride, m.p. 132-133°C.

IRν ^KBr _max cm ^-1 : 3430, 2968, 2482, 1464, 966, 777, 699.

NMR (CDCl ₃ ) δ: 1.25 (9H, s), 2.61 (3H, s), 3.56-3.61 (2H, m), 4.05-4.10 (2H, m), 5.84 (1H, d, J=15.9Hz) , 6.27 (1H, dt, J = 15.9Hz, 7.3Hz), 7.12-7.29 (2H, m), 7.37-7.53 (8H, m), 7.58 (1H, dt, J = 7.4Hz, 1.9Hz), 7.74 (1H, br.s), 7.79 (1H, br.s).

Except that the starting compound (E)-3-[2-[3-(3-thiophene base) phenyl] vinyl] benzyl chloride and (E)-N-methyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, by the same method as in Example 51 Compounds of Examples 52 to 66 were obtained.

Example 52

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(3-thienyl)benzene [yl]vinyl]benzylamine hydrochloride:-

m.p.174-176℃

IRν ^pure _max cm ^-1 : 3436, 2968, 966, 777, 699.

NMR ( _CDCl3 ) δ: 1.25 (9H, s), 1.40-1.46 (3H, m), 2.98-3.01 (2H, m), 3.57-3.62 (2H, m), 4.07-4.09 (2H, m), 5.83 (1H, d, J = 15.6Hz), 6.25 (1H, dt, J = 15.6Hz, 7.3Hz), 7.12-7.25 (2H, m), 7.30-7.53 (9H, m), 7.56 (1H, d , J=7.5Hz), 7.74-7.75 (1H, m), 7.86 (1H, br.s).

Example 53

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[2-[3-(3-thienyl)benzene [yl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2806, 1605, 963, 774, 696.

NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.2Hz), 1.24 (9H, s), 1.47-1.57 (2H, m), 2.41 (2H, t, J = 7.2Hz), 3.11 (2H , d, J = 6.4Hz), 3.58 (2H, s), 5.66 (1H, d, J = 15.8Hz), 6.11 (1H, dt, J = 15.8Hz, 6.4Hz), 7.16 (2H, s), 7.22-7.26 (1H, m), 7.30 (1H, t, J=7.2Hz), 7.36-7.51 (8H, m), 7.73-7.74 (1H, m).

Example 54

(E), (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[2-[3-(3-thiophene yl)phenyl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2980, 2932, 2818, 1605, 1251, 1170, 1149, 1074, 774, 699.

NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.1Hz), 1.46 (6H, s), 2.55 (2H, q, J = 7.1Hz), 3.15 (2H, dd, J = 6.4Hz, 1.2 Hz), 3.36 (3H, s), 3.59 (2H, s), 5.71 (1H, dt, J=15.9Hz, 1.2Hz), 6.20 (1H, dt, J=15.9Hz, 6.4Hz), 7.16 (2H , s), 7.20-7.25 (2H, m), 7.31 (1H, t, J=7.5Hz), 7.35-7.55 (7H, m), 7.74 (1H, t, J=2.3Hz).

Example 55

(E), (E)-N(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-[3-(1-pyrrolyl)phenyl) ]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1605, 1506, 1341, 1071, 963, 756, 723, 696.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.22 (3H, s), 3.08 (2H, dd, J=6.6Hz, 1.5Hz), 3.51 (2H, s), 5.67 (1H, dt, J = 15.9Hz, 1.5Hz), 6.12 (1H, dt, J = 15.9Hz, 6.6Hz), 6.37 (2H, t, J = 2.1Hz), 7.13 (2H, t, J = 2.1Hz), 7.15 (2H , s), 7.20-7.34 (3H, m), 7.37-7.44 (3H, m), 7.49-7.54 (2H, m).

Example 56

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(1-pyrrolyl)benzene [yl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1608, 1587, 1506, 1341, 1071, 963, 723.

NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 6.8Hz), 1.24 (9H, s), 2.54 (2H, q, J = 6.8Hz), 3.14 (2H, dd, J = 6.5Hz, 1.5 Hz), 3.60 (2H, s), 5.67 (1H, dt, J=15.9Hz, 1.5Hz), 6.10 (1H, dt, J=15.9Hz, 6.5Hz), 6.37 (2H, t, J=2.2Hz ), 7.13 (2H, t, J=2.2Hz), 7.12-7.16 (2H, m), 7.25-7.34 (3H, m), 7.38-7.44 (3H, m), 7.50 (1H, s), 7.52- 7.54 (1H, m).

Example 57

(E), (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[2-[3-(1-pyrrole yl)phenyl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 1605, 1506, 1341, 1170, 1149, 1074, 960, 789, 723, 696.

NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 6.9Hz), 1.46 (6H, s), 2.56 (2H, q, J = 6.9Hz), 3.15 (2H, dd, J = 6.5Hz, 1.5 Hz), 3.35 (3H, s), 3.61 (2H, s), 5.73 (1H, dt, J=15.9Hz, 1.5Hz), 6.20 (1H, dt, J=15.9Hz, 6.5Hz), 6.37 (2H , t, J=2.7Hz), 7.12-7.16 (4H, m), 7.25-7.35 (3H, m), 7.38-7.45 (3H, m), 7.50-7.54 (2H, m).

Example 58

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(3-pyridyl)benzene [yl]vinyl]benzylamine:-

IRν ^neat _max cm ^-1 : 3016, 2974, 1605, 1473, 1365, 1266, 1215, 963, 759, 711.

NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.55 (2H, q, J = 7.1Hz), 3.13 (1H, dd, J = 6.7Hz, 1.5 Hz), 3.60 (2H, s), 5.70 (1H, dt, J=15.9Hz, 1.5Hz), 6.10 (1H, dt, J=15.9Hz, 6.7Hz), 7.19 (2H, s), 7.23-7.59 (8H, m), 7.71 (1H, br.s), 7.89-7.94 (1H, m), 8.61 (1H, dd, J=4.8Hz, 1.6Hz), 8.89 (1H, d, J=1.6Hz) .

Example 59

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(5-oxazolyl) Phenyl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1263, 1107, 960, 798, 756, 696.

NMR (CDCl ₃ ) δ: 1.07 (3H, t, J=7.0Hz), 1.24 (9H, s), 2.51-2.58 (2H, m), 3.12-3.14 (2H, m), 3.58-3.62 (2H, m), 5.68 (1H, d, J = 15.7Hz), 6.10 (1H, dt, J = 15.7Hz, 6.1Hz), 7.15-7.57 (10H, m), 7.81 (1H, t, J = 1.5Hz) , 7.94 (1H, s).

Example 60

(E), (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[2-[3-(5-oxo Azolyl)phenyl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 3128, 2984, 2936, 2820, 1604, 1582, 1506, 968.

NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.0Hz), 1.46 (6H, s), 2.56 (2H, q, J = 7.0Hz), 3.15 (2H, d, J = 6.3Hz), 3.36 (3H, s), 3.60 (2H, s), 5.71 (1H, dt, J = 15.8Hz, 1.5Hz), 6.21 (1H, dt, J = 15.8Hz, 6.3Hz), 7.13 (1H, d, J=16.1Hz), 7.14 (1H, d, J=16.1Hz), 7.32 (1H, t, J=7.5Hz), 7.41 (1H, s), 7.42-7.45 (2H, m), 7.49-7.50 ( 2H, m), 7.51-7.52 (1H, m), 7.55 (1H, dt, J=7.5Hz, 1.6Hz), 7.81 (1H, t, J=1.6Hz), 7.94 (1H, s).

Example 61

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[2-[3-(1-pyrrolyl)benzene [yl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1608, 1506, 1341, 1071, 960, 723, 696.

NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.24 (9H, s), 1.48-1.60 (2H, m), 2.42 (2H, t, J = 7.3Hz), 3.12 (2H , d, J = 6.2Hz), 3.58 (2H, s), 5.66 (1H, d, J = 15.8Hz), 6.10 (1H, dt, J = 15.8Hz, 6.2Hz), 6.37 (2H, t, J =2.2Hz), 7.14 (2H, t, J=2.2Hz), 7.13-7.15 (2H, m), 7.22-7.34 (3H, m), 7.38-7.42 (3H, m), 7.48-7.52 (1H, m), 7.52-7.54 (1H, m).

Example 62

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(1-imidazolyl)benzene [yl]vinyl]benzylamine:-

IRν ^pure _max cm ^-1 : 2972, 2864, 1608, 1588, 1504, 1308, 1060, 962.

NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2Hz), 1.25 (9H, s), 2.57 (2H, q, J = 7.2Hz), 3.18 (2H, dd, J = 6.3Hz, 1.5 Hz), 3.61 (2H, s), 5.64 (1H, dt, J=15.9Hz, 1.5Hz), 6.06 (1H, dt, J=15.9Hz, 6.3Hz), 7.14 (1H, dt, J=16.0Hz ), 7.19 (1H, d, J=16.0Hz), 7.21-7.58 (9H, m), 7.67-7.74 (1H, m), 7.91 (1H, br.s).

Example 63

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-2-[2-[3-(3-thienyl)benzene [yl]vinyl]-4-pyridylmethylamine:-

IRν ^pure _max cm ^-1 : 1602, 1479, 1458, 1365, 1263, 1203, 975, 852, 774.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.34 (3H, s), 3.10 (2H, dd, J=7.0Hz, 1.6Hz), 3.52 (2H, s), 5.68 (1H, dt, J = 15.8Hz, 1.6Hz), 6.10 (1H, dt, J = 15.8Hz, 7.0Hz), 7.14 (1H, d, J = 5.6Hz), 7.23 (1H, d, J = 16.4Hz), 7.41-7.48 (4H, m), 7.49-7.55 (3H, m), 7.68 (1H, d, J=16.4Hz), 7.81 (1H, t, J=1.8Hz), 8.54 (1H, d, J=4.7Hz) .

Example 64

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[2-[3-(3-thienyl)phenyl]ethyl ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1458, 1365, 963, 774, 699.

NMR ( _CDCl3 ) δ: 1.24 (9H, s), 2.16 (3H, s), 2.95 (4H, s), 3.02 (2H, dd, J=6.6Hz, 1.5Hz), 3.45 (2H, s), 5.63 (1H, dt, J=15.9Hz, 1.5Hz), 6.08 (1H, dt, J=15.9Hz, 6.6Hz), 7.07-7.25 (5H, m), 7.27-7.52 (6H, m).

Example 65

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(1-pyrrolyl)phenyl]ethyl ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2928, 2864, 2796, 1610, 1594, 1506, 726.

NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.48 (2H, q, J = 7.1Hz), 2.95 (4H, s), 3.06 (2H, dd , J = 6.2Hz, 2.3Hz), 3.53 (2H, s), 5.62 (1H, dt, J = 15.8Hz, 2.3Hz), 6.06 (1H, dt, J = 15.8Hz, 6.2Hz), 6.33 (2H , t, J=2.2Hz), 7.04 (2H, t, J=2.2Hz), 7.04-7.08 (2H, m), 7.13-7.17 (3H, m), 7.19-7.23 (2H, m), 7.31 ( 1H,t,J=7.8Hz).

Example 66

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(3-pyridyl)phenyl]ethyl ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2932, 2866, 1473, 1458, 1365, 789, 705.

NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.3Hz), 1.24 (9H, s), 2.50 (2H, q, J = 7.3Hz), 2.96-2.99 (4H, m), 3.01 (1H , d, J = 6.4Hz), 3.54 (1H, s), 5.63 (1H, d, J = 16.2Hz), 6.08 (1H, dd, J = 16.2Hz, 6.4Hz), 7.06-7.11 (1H, m ), 7.15-7.27 (4H, m), 7.32-7.42 (4H, m), 7.83 (1H, dt, J = 8.4Hz, 1.8Hz), 8.60 (1H, br.s), 8.80 (1H, br. s).

Example 67

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-5-[2-[3-(3-thienyl)benzene Preparation of [yl]vinyl]furfurylamine:-

Mix 18mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-5-formylfurfuramide and 19mg of dimethyl-3-(3- Thienyl)benzylphosphonate [synthesized by condensation of 3-(3-thienyl)benzyl bromide with trimethyl phosphite] was dissolved in dimethylformamide and 2.6 mg of 60% oily sodium hydride was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography [TLC plate: Kieselgel 60F ₂₅₄ , Art, 5715 (E. Merck Co.); developing solvent: hexane/ethyl acetate = 3/1] , to obtain 15 mg (55% yield) of the title compound as a pale yellow oil.

IRν ^pure _max cm ^-1 : 2968, 1602, 1458, 1365, 1266, 1020, 960, 774.

NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.0Hz), 1.24 (9H, s), 2.58-2.68 (2H, m), 3.25 (2H, d, J = 6.8Hz), 3.77 (2H , s), 5.73 (1H, d, J = 15.9Hz), 6.13 (1H, dt, J = 15.9Hz, 6.8Hz), 6.25-6.35 (2H, m), 6.90 (1H, d, J = 16.4Hz ), 7.04 (1H, d, J=16.4Hz), 7.32-7.52 (6H, m), 7.67 (1H, br.s).

In addition to replacing the starting material (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-5-formylfurfurylamine with the corresponding formyl derivative, Compounds of Examples 68 and 69 can be obtained by carrying out the same reaction as in Example 67.

Example 68

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-4-[2-[3-(3-thienyl)benzene [yl]vinyl]-2-pyridylmethylamine:-

IRν ^pure _max cm ^-1 : 2968, 2868, 1602, 1450, 1266, 966, 777.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.35 (3H, s), 3.20-3.27 (2H, m), 3.74-3.79 (2H, m), 5.72 (1H, d, J=15.7Hz) , 6.18 (1H, dt, J = 15.7Hz, 6.6Hz), 7.19 (1H, d, J = 16.4Hz), 7.19-7.63 (9H, m), 7.76 (1H, m), 8.52 (1H, d, J=5.3Hz).

Example 69

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(3-thienyl)benzene [yl]vinyl]-5-isoxazolylmethylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1440, 1365, 963, 852, 774.

NMR (CDCl ₃ ) δ: 0.88 (3H, t, J=7.1Hz), 1.25 (9H, s), 2.53-2.68 (2H, m), 3.17-3.28 (2H, m), 3.81 (1H, s) , 5.71 (1H, d, J = 15.9Hz), 6.08 (1H, dt,

J=15.9Hz, 6.5Hz), 6.40-6.48 (1H, m), 7.15-7.25 (2H, m), 7.38-7.53 (5H, m), 7.56 (1H, dt, J=7.1Hz, 2.1Hz) , 7.73 (1H, s).

Example 70

Preparation of (E)-N-(6,6-dimethyl-2-octen-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine :-

Dissolve 50 mg of N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine hydrochloride in 1.5 ml of dimethylformamide, and add 30 mg of 1-bromo-6,6-dimethyl - 2-octene-4-yne (mixture of forms E and Z in an approximate 4:1 ratio) and 65 mg of sodium carbonate. The mixture was stirred at room temperature overnight, and the reaction mixture was diluted with water, then extracted with ether. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=7/1] to obtain 39 mg (yield 63%) of the title compound as a colorless oil.

IRν ^neat _max cm ^-1 : 2968, 2926, 2800, 1584, 1491, 1458, 1260, 774.

NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.3Hz), 1.00-1.10 (3H, m), 1.18 (6H, s), 1.44 (2H, q, J = 7.3Hz), 2.45-2.60 (2H, m), 3.05-3.15 (2H, m), 3.50-3.60 (2H, m), 5.11 (2H, s), 5.65 (1H, d, J = 15.9Hz), 6.07 (1H, dt, J =15.9Hz, 6.4Hz), 6.85-6.90 (1H, m), 6.90-6.95 (1H, m), 7.01-7.06 (1H, m), 7.22 (1H, t, J = 8.0Hz), 7.35-7.45 (4H, m), 7.47 (1H, dd, J=2.3Hz, 1.8Hz), 7.55 (1H, dt, J=7.0Hz, 1.8Hz), 7.66-7.69 (1H, m).

Example 71

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-4-hydroxy-3-[3-(3-thienyl)benzyloxy] Preparation of benzylamine hydrochloride:-

A dimethylformamide solution (1 ml) containing 32 mg of 3-(3-thienyl)benzyl bromide was added to 40 mg of (E)-N-(6,6-dimethyl-2-heptene-4-yne phenoxide)-N-methyl-3-hydroxy-4-methoxymethyloxybenzylamine and 5 mg of phenoxide in tetrahydrofuran (1.5 ml) prepared from 60% oily sodium hydride. The mixture was stirred at room temperature for 2 hours, diethyl ether was added to the reaction mixture, and insoluble inorganic salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of 1 ml of 10% hydrochloric acid-methanol and 1 ml of tetrahydrofuran, and the solution was allowed to stand at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 5% aqueous sodium bicarbonate and diethyl ether were added to the residue for extraction. The organic layer was separated, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-200, 5g; eluent: hexane/ethyl acetate=3/1] to obtain 31 mg (yield 56%) of the free base of the title compound as a colorless Oil. The free base was treated with hydrochloric acid-methanol solution and recrystallized from a mixture of diethyl ether and isopropyl ether to give the title hydrochloride salt, m.p. 88-90°C.

IRν ^pure _max cm ^-1 : 2968, 1521, 1464, 1446, 1281, 777.

NMR ( _CDCl3 ) δ: 1.25 (3H, s), 3.39-3.54 (1H, m), 3.59-3.74 (1H, m), 3.83-4.00 (1H, m), 4.01-4.20 (1H, m), 5.31 (2H, s), 5.81 (1H, d, J = 15.6Hz), 5.91 (1H, br.s), 6.21 (1H, dt, J = 15.6Hz, 7.7Hz), 6.80 (1H, d, J =7.8Hz), 6.91 (1H, d, J=7.8Hz), 7.38-7.48 (4H, m), 7.50-7.55 (1H, m), 7.56-7.62 (1H, m), 7.75 (1H, s) , 7.82 (1H, s).

Except that the starting compound (E)-N-(6,6-dimethyl Base-2-hepten-4-ynyl)-N-methyl-3-hydroxy-4-methoxymethyloxybenzylamine and/or 3-(3-thienyl)benzyl bromide, for implementation The same reaction as in Example 71 gave the compounds of Examples 72 and 73.

Example 72

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-2-hydroxy-3-[3-(5-oxazolyl)benzyloxy ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1476, 1365, 1245, 1107, 1035, 954, 789, 750, 693.

NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.0Hz), 1.23 (9H, s), 2.63 (2H, q, J = 7.0Hz), 3.20 (2H, d, J = 7.0Hz), 3.78 (2H, s), 5.18 (2H, s), 5.62 (1H, d, J=15.7Hz), 6.08 (1H, dt, J=15.7Hz, 7.0Hz), 6.59-6.64 (1H, m), 6.67 (1H, t, J = 8.0Hz), 6.84 (1H, dd, J = 8.0Hz, 1.8Hz), 7.37 (1H, s), 7.38-7.50 (2H, m), 7.60 (1H, dt, J = 7.0Hz, 1.8Hz), 7.77 (1H, s), 7.91 (1H, s).

Example 73

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-4-hydroxy-3-[3-(5-oxazolyl)benzyloxy ]Benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1518, 1461, 1365, 1275, 1200, 1119, 795, 759.

NMR ( _CDCl3 ) δ: 1.24 (9H, s), 2.19 (3H, s), 2.96-3.12 (2H, m), 3.44 (2H, s), 5.16 (2H, s), 5.65 (1H, d, J = 16.1Hz), 6.08 (1H, dt, J = 16.1Hz, 6.7Hz), 6.80 (1H, dt, J = 8.0Hz, 1.7Hz), 6.89 (1H, d, J = 8.0Hz), 7.02 ( 1H, br.s), 7.39 (1H, s), 7.39-7.42 (1H, m), 7.48 (1H, t, J = 7.6Hz), 7.65 (1H, dt, J = 7.6Hz, 1.6Hz), 7.73 (1H, s), 7.93 (1H, s).

Example 74

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzylamino]benzylamine: -

Dissolve 90mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and 63mg of 3-(3-thienyl)benzaldehyde In 2.5 ml of dry methanol, the solution was stirred overnight at room temperature in the presence of molecular sieves 3A. The molecular sieves were separated from the reaction mixture by filtration. Then, 12.5 mg of sodium borohydride was added, and the mixture was stirred at room temperature for another 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of dichloromethane and water. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-2005g; eluent: hexane/ethyl acetate=10/1→5/1] to obtain 80 mg (yield 55%) of the title compound as a pale yellow oil things.

IRν ^pure _max cm ^-1 : 2968, 2926, 1608, 1491, 774.

NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.49 (2H, q, J = 7.1Hz), 3.08 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.48 (2H, s), 4.37 (2H, s), 5.63 (1H, dt, J=15.9Hz, 1.5Hz), 6.06 (1H, dt, J=15.9Hz, 6.4Hz), 6.51-6.56 (1H, m), 6.66-6.69 (1H, m), 7.11 (1H, t, J=8.0Hz), 7.31 (1H, dt, J=7.8Hz, 1.7Hz), 7.35-7.40 (3H, m) , 7.45 (1H, t, J = 2.2Hz), 7.51 (1H, dt, J = 7.8Hz, 1.7Hz), 7.61 (1H, br.s).

In addition to replacing the starting compound (E)-N-(6,6-dimethyl-2-hepten-4-ynyl with the corresponding 3-aminobenzylamine derivative and/or 3-substituted benzaldehyde derivative )-N-ethyl-3-aminobenzylamine and/or 3-(3-thienyl)benzaldehyde, the same reaction as in Example 74 can give the compounds of Examples 75 to 80.

Example 75

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(3-thienyl)benzylamino]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1608, 1491, 1458, 1365, 774.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.18 (3H, s), 3.02 (2H, dd, J=6.5Hz, 1.4Hz), 3.42 (2H, s), 4.37 (2H, s), 5.63 (1H, dt, J = 15.8Hz, 1.4Hz), 6.07 (1H, dt, J = 15.8Hz, 6.5Hz), 6.52-6.56 (1H, m), 6.65-6.68 (2H, m), 7.11 ( 1H, t, J = 7.9Hz), 7.30 (1H, dt, J = 7.5Hz, 1.4Hz), 7.35-7.40 (3H, m), 7.45 (1H, t, J = 2.1Hz), 7.51 (1H, dt, J = 7.5Hz, 1.7Hz), 7.61 (1H, br.s).

Example 76

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(1-pyrrolyl)benzylamino]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 1608, 1506, 1338, 1071, 783, 726.

NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.47 (2H, q, J = 7.1Hz), 3.07 (2H, dd, J = 6.5Hz, 1.5 Hz), 3.48 (2H, s), 4.39 (2H, s), 5.62 (1H, dt, J=15.8Hz, 1.5Hz), 6.05 (1H, dt, J=15.8Hz, 6.5Hz), 6.33 (2H , t, J=2.2Hz), 6.49-6.53 (1H, m), 6.66-6.69 (2H, m), 7.08 (2H, t, J=2.2Hz), 7.10 (1H, t, J=8.1Hz) , 7.24-7.32 (2H, m), 7.36-7.42 (2H, m).

Example 77

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(5-oxazolyl)benzylamino]benzylamine:-

IRν ^pure _max cm ^-1 : 2974, 1611, 1506, 1494, 1458, 1107, 954, 696.

NMR (CDCl ₃ ) δ: 1.20 (9H, s), 2.14 (3H, s), 3.05 (2H, dd, J=6.6Hz, 1.5Hz), 3.42 (2H, s), 4.38 (2H, s), 5.59 (1H, dt, J = 15.9Hz, 1.5Hz), 6.03 (1H, dt, J = 15.9Hz, 6.6Hz), 6.52 (1H, dt, J = 8.0Hz, 1.0Hz), 6.67-6.69 (2H , m), 7.11 (1H, t, J=8.0Hz), 7.35-7.42 (3H, m), 7.57 (1H, dt, J=7.4Hz, 1.6Hz), 7.68 (1H, br.s), 7.91 (1H, s).

Example 78

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(5-oxazolyl)benzylamino]benzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 1611, 1506, 1494, 1476, 1266, 1107, 954, 789, 759, 696.

NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.48 (2H, q, J = 7.1Hz), 3.07 (2H, dd, J = 6.4Hz, 1.5 Hz), 3.48 (2H, s), 4.38 (2H, s), 5.62 (1H, dt, J=15.9Hz, 1.5Hz), 6.05 (1H, dt, J=15.9Hz, 6.4Hz), 6.50-6.54 (1H, m), 6.67-6.69 (2H, m), 7.11 (1H, t, J=7.9Hz), 7.36 (1H, s), 7.37-7.44 (2H, m), 7.57 (1H, dt, J = 7.2Hz, 1.7Hz), 7.68 (1H, br.s), 7.91 (1H, s).

Example 79

(E)-N-Ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[3-(3-thienyl)benzylamino]benzylamine :-

cm^-1：3412，3100，2980，2932，2818，1608，1491，1473，1365.IRν

cm ^-1 : 3412, 3100, 2980, 2932, 2818, 1608, 1491, 1473, 1365.

NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.0Hz), 1.46 (6H, s), 2.50 (2H, q, J = 7.0Hz), 3.13 (2H, d, J = 6.0Hz), 3.52 (2H, s), 4.37 (2H, s), 5.67 (1H, d, J = 16.2Hz), 6.16 (1H, dt, J = 16.2Hz, 6.0Hz), 6.52-6.57 (1H, m), 6.66-6.72 (2H, m), 7.12 (1H, t, J=7.8Hz), 7.29-7.40 (4H, m), 7.45 (1H, t, J=2.2Hz), 7.51 (1H, dt, J= 7.5Hz, 2.1Hz), 7.61 (1H, br.s).

Example 80

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-2-[3-(3-thienyl)benzylamino]-4-pyridyl Methylamine:-

IRν ^pure _max cm ^-1 : 2968, 1611, 1569, 1515, 1464, 1368, 1269, 774.

NMR (CDCl ₃ ) δ: 0.81 (3H, t, J = 7.3Hz), 1.24 (9H, s), 1.40 (2H, sex, J = 7.3Hz), 2.32 (2H, t, J = 7.3Hz), 3.03 (2H, dd, J = 6.4Hz, 1.4Hz), 3.42 (3H, s), 4.53 (2H, s), 5.59 (1H, dt, J = 15.9Hz, 1.4Hz), 5.99 (1H, dt, J=15.9Hz, 6.4Hz), 6.48 (1H, d, J=1.6Hz), 6.58 (1H, dd, J=5.4Hz, 1.6Hz), 7.27-7.31 (1H, m), 7.34-7.40 (3H , m), 7.45 (1H, t, J=1.8Hz), 7.50 (1H, dt, J=7.6Hz, 1.7Hz), 7.59 (1H, br.s), 7.96 (1H, dt, J=7.6Hz , 1.7Hz).

Example 81

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[N′-methyl-3-(3-thienyl)benzylamino ] Preparation of Benzylamine:-

100 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl) obtained in Example 74 ) benzylamino] benzylamine was dissolved in 3 ml of acetonitrile, 0.1 ml of 35% aqueous formaldehyde and 22.7 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in a mixture of ethyl acetate and water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-200, 5g; eluent: hexane/ethyl acetate=10/1→6/1] to obtain 55 mg (yield 53%) of the title compound as a dilute Yellow crystalline solid, m.p.51～52℃.

IRν ^pure _max cm ^-1 : 2974, 2926, 1605, 1500, 1368, 1218, 762.

NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.0Hz), 1.23 (9H, s), 2.47 (2H, q, J = 7.0Hz), 3.02 (3H, s), 3.06 (1H, dd , J = 6.3Hz, 1.4Hz), 3.51 (2H, s), 4.56 (2H, s), 5.61 (1H, dt, J = 15.8Hz, 1.4Hz), 6.05 (1H, dt, J = 15.8Hz, 6.3Hz), 6.63-6.71 (2H, m), 6.78-6.79 (1H, m), 7.12-7.19 (2H, m), 7.31-7.38 (3H, m), 7.41 (1H, dd, J=2.7Hz , 1.5Hz), 7.46-7.49 (2H, m).

Example 82

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-5-[2-[3-(3-thienyl)benzene Preparation of [yl]vinyl]-(1,3,4-oxadiazol-2-yl)methanamine:-

57 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethylaminoacetylhydrazide [via (E)-N-ethyl-6,6 -Dimethyl-2-hepten-4-ynylamine and methyl bromoacetate were condensed in the presence of sodium bicarbonate, and then the product was reacted with hydrazide to synthesize] and 20 mg of sodium bicarbonate was added to 1 ml of dioxin to the mixture was added a solution of 3-(3-thienyl)cinnamoyl chloride in dioxane (1 ml). 3-(3-thienyl)cinnamoyl chloride is prepared from 50 mg of 3-(3-thienyl)cinnamic acid [by condensation of 3-(3-thienyl)benzaldehyde and malonic acid in the presence of piperidine/pyridine and heating Synthesis] and 0.3ml of thionyl chloride were prepared. The above reaction mixture was stirred at room temperature for 30 minutes. Inorganic salts were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 0.8 ml of phosphorus oxychloride, and the solution was stirred at 65°C for 16 hours. The reaction mixture was poured into ice water and neutralized by adding sodium bicarbonate. The solution was then extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-200, 10 g; eluent: hexane/ethyl acetate = 3/1] to obtain 37 mg (yield 36%) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 2972, 1648, 1364, 1266, 964, 854, 778.

NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.65 (2H, q, J = 7.1Hz), 3.26 (2H, dd, J = 6.8Hz, 1.5 Hz), 3.95 (2H, s), 5.73 (1H, dt, J=15.9Hz, 1.5Hz), 6.07 (1H, dt, J=15.9Hz, 6.8Hz), 7.09 (1H, dt, J=16.3Hz ), 7.39-7.50 (4H, m), 7.51 (1H, dd, J = 3.1Hz, 1.7Hz), 7.60 (1H, d, J = 16.3Hz), 7.62 (1H, dt, J = 7.4Hz, 1.8 Hz), 7.76 (1H,t,J=1.8Hz).

Example 83

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(1-pyrrolyl)benzamido]benzylamine preparation:-

Dissolve 83mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and 100mg of 3-(1-pyrrolyl)benzoic acid In a mixture of 1 ml of dichloromethane and 2 ml of tetrachlorofuran, 92 mg of N,N'-dicyclohexylcarbodiimide (DCC) was added. The mixture was stirred at room temperature for 3 hours, the reaction mixture was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The insoluble matter was removed by filtration, and washed successively with 5% aqueous sodium bicarbonate, 5% hydrochloric acid and saturated aqueous sodium chloride. Dry over anhydrous sodium sulfate, and distill off the solvent. The residue was purified by silica gel column chromatography [Wakogel C-200, 20g; eluent: hexane/ethyl acetate=10/1→3/1] to obtain 98mg (yield 61%) of the title compound as a dilute Yellow oil.

IRν ^neat _max cm ^-1 : 2968, 1653, 1593, 1554, 1503, 1443, 1341, 723.

NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.1Hz), 1.23 (9H, s), 2.52 (2H, q, J = 7.1Hz), 3.10 (2H, dd, J = 6.7Hz, 1.6 Hz), 3.56 (2H, s), 5.65 (1H, dt, J = 15.8Hz, 1.6Hz), 6.08 (1H, dt, J = 15.8Hz, 6.7Hz), 6.37 (2H, t, J = 2.5Hz ), 7.11-7.15 (3H, m), 7.31 (1H, t, J=7.8Hz), 7.48-7.58 (3H, m), 7.62-7.70 (2H, m), 7.91-7.94 (2H, m).

Example 84

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(1,3,4-triazol-1-yl) The preparation of benzyloxy]benzylamine:

430 mg of ethyl 3-(1,3,4-triazol-1-yl)benzoate [synthesized essentially according to the method described in J. Med. Chem, 5 383 (1962)] was dissolved in 20 ml of tetrahydrofuran and 20 ml of dioxane To the mixture, add 100 mg lithium aluminum hydride. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g; eluent: chloroform/methanol = 20/1] to obtain 240 mg (69% yield) of 1-(3-hydroxymethylphenyl)-1 , 3,4-triazole.

220 mg of the obtained alcohol compound was dissolved in 20 ml of chloroform, and 2 ml of thionyl chloride was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and partitioned between chloroform and water. The organic layer was separated and washed with 5% aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 143 mg (59% yield) of 1-(3-chloromethylphenyl)-1,3,4-triazole.

38 mg of the obtained chloromethyl compound was dissolved in 2 ml of dimethylformamide, and the solution was added to a solution containing 60 mg of (E)-N-(6,6-dimethyl-2-heptene-4 -alkynyl)-N-methyl-3-hydroxybenzylamine and 14 mg of phenoxide salt in tetrahydrofuran (2 ml) prepared from 60% oily sodium hydride. The mixture was stirred at room temperature for 5 hours. Diethyl ether and water were added to the reaction mixture to separate. The separated organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=1/1→1/5] to obtain 48 mg (59% yield) of the title compound as a pale yellow oil.

IRν ^neat _max cm ^-1 : 2968, 1599, 1518, 1491, 1452, 1368, 1269, 1152, 1092, 1032, 786, 762.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.19 (3H, s), 3.03 (2H, dd, J=6.6Hz, 1.5Hz), 3.48 (2H, s), 5.15 (2H, s), 5.64 (1H, dt, J = 15.3Hz, 1.5Hz), 6.05 (1H, dt, J = 15.3Hz, 6.6Hz), 6.87 (1H, ddd, J = 7.8Hz, 2.7Hz, 1.2Hz), 6.93 ( 1H, d, J = 7.8Hz), 6.99-7.02 (1H, m), 7.24 (1H, t, J = 7.8Hz), 7.35 (1H, dt, J = 6.9Hz, 2.4Hz), 7.50-7.59 ( 3H, m), 8.50 (2H, s).

Example 85

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzylthio]benzylamine :-

10 mg of 3-[3-(3-thienyl)benzylthiobenzaldehyde was dissolved in 1 ml of ethanol, and 1.8 mg of sodium borohydride was added. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and diethyl ether and water were added to the residue to conduct extraction. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was distilled off. The residue was dissolved in 1 ml of ethyl acetate, and 4.4 mg of methanesulfonyl chloride and 5.9 mg of triethylamine were added. The mixture was stirred at room temperature for 10 minutes. Precipitated triethylamine hydrochloride was removed by filtration, and the solvent was distilled off. The residue was dissolved in 1 ml of dimethylformamide, and (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 10 mg of potassium carbonate were added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ether. Insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography [TLC plate: Kieselgel 60F ₂₅₄ , Art, 5744 (E. Merck Co.); developing solvent: hexane/ethyl acetate = 5/1] to obtain 7.5 mg (yield 51% ), the title compound is a colorless oil.

IRν ^pure _max cm ^-1 : 1478, 1363, 1265, 844, 777.

NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.44 (2H, q, J = 7.1Hz), 3.03 (2H, d, J = 6.5Hz), 3.49 (2H, s), 4.15 (2H, s), 5.62 (1H, d, J=15.9Hz), 6.04 (1H, dt, J=15.9Hz, 6.5Hz), 7.13-7.42 (8H, m), 7.45 (1H, t, J=1.7Hz), 7.46-7.51 (2H, m).

Example 86

(E), (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[2-[3-(5-thienyl)benzene Preparation of [yl]vinyl]benzylamine:-

116 mg of (E)-3-[2-[3-(5-thiazolyl)phenyl]vinyl]benzoic acid methyl ester [by adding 3-methoxycarbonylbenzyl phosphate dimethyl ester with 3-bromo Synthesis of (E)-3-[2-(3-bromophenyl)vinyl]benzoic acid methyl ester obtained by condensation of benzaldehyde with 5-trimethylstannylthiazole: see "Synthesis" 757 (1986 )] was dissolved in 3ml of tetrahydrofuran, and 14mg of lithium aluminum hydride was added under ice cooling. The mixture was stirred for 30 minutes. It was poured into water, and ether was added for extraction. The extract was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off. The residue was dissolved in a mixture of 3 ml of ethyl acetate and 3 ml of dichloromethane, and 31 µl of methanesulfonyl chloride and 70 µl of triethylamine were added. The mixture was stirred at room temperature for 30 minutes. Triethylamine hydrochloride was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 3 ml of dimethylformamide, and 81 mg of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 42 mg of sodium carbonate were added . The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and ether and water were added to the residue to conduct extraction. The separated organic layer was collected and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off. The residue was purified by medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprop Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=8/1→6/1] to obtain 63 mg (36% yield) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 2968.2872, 1605, 1458, 1392, 1365, 1266, 963, 876, 795.

NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.54 (2H, q, J = 7.1Hz), 3.11 (1H, d, J = 6.7Hz), 3.59 (2H, s), 5.67 (1H, d, J = 15.9Hz), 6.11 (1H, dt, J = 15.9Hz, 6.7Hz), 7.15 (2H, s), 7.29-7.57 (7H, m), 7.69 (1H, dd, J = 3.6Hz, 1.7Hz), 8.12 (1H, s), 8.77 (1H, s).

Example 87

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(3-tetrahydrothienyl)benzyloxy]benzylamine Preparation of:-

25 mg of 3-(3-tetrahydrothienyl)benzyl alcohol was dissolved in 5 ml of ether, and 15 µl of methanesulfonyl chloride and 30 µl of triethylamine were added. The mixture was stirred under ice-cooling for 1 hour. Precipitated triethylamine hydrochloride was removed by filtration, and the solvent was distilled off. The residue was dissolved in 1ml of dimethylformamide, and this solution was added to 10ml of -Methyl-3-hydroxybenzylamine and 30 mg of phenoxide prepared from 60% oily sodium hydride in dimethylformamide. The mixture was stirred at room temperature for 3 hours, and diluted with water and ether. The organic layer was separated and dried over magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated. The residue was purified by medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E.Merck Co); eluent: hexane/ethyl acetate=20/1→10/1] to obtain 42 mg (75% yield) of the title compound as a colorless oil.

IRν ^pure _max cm ^-1 : 1446, 1365, 1272, 1152, 1026, 885, 786, 693.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 2.07 (1H, ddt, J = 12.2Hz, 10.6Hz, 8.5Hz), 2.19 (3H, s), 2.42 (1H, dq, J = 12.2Hz, 4.6Hz), 2.88-3.01 (3H, m), 3.04 (2H, dd, J = 6.6Hz, 1.5Hz), 3.17 (1H, dd, J = 10.2Hz, 6.7Hz), 3.29-3.41 (1H, m ), 3.47 (2H, s), 5.04 (2H, s), 5.64 (1H, dt, J=15.8Hz, 1.5Hz), 6.07 (1H, dt, J=15.8Hz, 6.6Hz), 6.86 (1H, ddd, J=8.2Hz, 2.6Hz, 1.4Hz), 6.91 (1H, d, J=7.5Hz), 6.99 (1H, br.s), 7.19-7.35 (4H, m), 7.37 (1H, br. s).

Except that starting material 3 was replaced by the corresponding benzyl alcohol derivative and (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine -(3-tetrahydrothienyl)benzyl alcohol and (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxybenzylamine, Compounds of Examples 88 and 89 can be obtained by carrying out the same reaction as in Example 87.

Example 88

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3,4-dihydro-2H-thiopyran-5 -yl)benzyloxybenzylamine:-

IRν ^pure _max cm ^-1 : 2968, 2926, 2866, 1599, 1491, 1455, 1263, 777.

NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.14-2.23 (1H, m), 2.50 (2H, q, J = 7.1Hz), 2.46-2.58 (2H, m), 2.88-2.93 (2H, m), 3.09 (2H, dt, J=6.5Hz), 3.54 (2H, s), 5.04 (2H, s), 5.64 (1H, dt, J=15.9 Hz, 1.5Hz), 6.06 (1H, dt, J = 15.9Hz, 6.5Hz), 6.45 (1H, s), 6.85 (1H, dd, J = 8.4Hz, 2.0Hz), 6.92 (1H, d, J =7.2Hz), 7.00 (1H, br.s), 7.19-7.36 (4H, m), 7.39 (1H, br.s).

Example 89

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(5,6-dihydro-2H-thiopyran-3 -yl)benzyloxy]benzylamine:-

IRν ^pure _max cm ^-1 : 3034, 2968, 2926, 1740, 1602, 1491, 1458, 1263.

NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.1Hz), 1.24 (9H, s), 2.45-2.59 (4H, m), 2.77 (2H, t, J = 5.7Hz), 3.09 (2H , d, J = 6.5Hz), 3.50 (2H, dd, J = 3.9Hz, 2.1Hz), 3.55 (2H, br.s), 5.05 (2H, s), 5.65

(1H, d, J = 15.9Hz), 6.07 (1H, dt, J = 15.9Hz, 6.5Hz), 6.11-6.17 (1H, m), 6.83-6.89 (1H, m), 6.92 (1H, d, J=7.5Hz), 7.01 (1H, br.s), 7.19-7.36 (4H, m), 7.40 (1H, br.s).

Example 90

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethoxy ] Preparation of benzylamine hydrochloride:-

Suspend 100 mg of 2-hydroxymethyl-4-(3-thienyl)thiophene in 5 ml of chloroform, stir and under ice-cooling, add 2 μl of dimethylformamide and 80 μl of thionyl chloride, and stir the mixture for 30 minute. Under ice-cooling, the solution was neutralized with an excess of saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the chloroform was distilled off to obtain 2-chloromethyl-4-(3-thienyl)thiophene as a pale yellow powder.

The dimethylformamide solution (3ml) of the obtained chloromethyl compound was added to the -Ethyl-3-hydroxybenzylamine was dissolved in 3 ml of anhydrous tetrahydrofuran, and 26 mg of 60% oily sodium hydride was added with stirring under ice cooling, and the mixture was stirred for 10 minutes to prepare the phenoxide solution. The mixture was stirred at room temperature for 3 hours, then extracted with 20 ml of water and 30 ml of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by medium-pressure liquid chromatography [column: Lobar column, size B, Lichroprep Si 60F (E.Merck Co.); eluent: hexane/ethyl acetate=20/1→10/ 1], and recrystallized from methanol to give 179 mg (78% yield) of the free base of the title compound as white needles (m.p. 67-68°C). The free base was treated with hydrochloric acid-methanol solution and recrystallized from ethyl acetate to give the hydrochloride salt of the title compound, m.p. 128-129°C.

IRν ^pure _max cm ^-1 : 2974, 2926, 2608, 1602, 1458, 1266, 1179, 786

NMR ( _CDCl3 ) δ: 1.25 (9H, s), 1.34-1.41 (3H, m), 2.90-3.05 (2H, m), 3.45-3.60 (2H, m), 4.00-4.08 (2H, m), 5.35 (2H, s), 5.78 (1H, dt, J = 15.9Hz, 2.1Hz), 6.18 (1H, dt, J = 15.9Hz, 6.9Hz), 7.00-7.10 (2H, m), 7.15-7.40 ( 5H, m), 7.49-7.65 (2H, m).

Example 91

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethoxy ] Preparation of benzylamine maleate:-

100 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[4-(3-thienyl) obtained in Example 90 -2-Thienylmethoxy]benzylamine was dissolved in 1 ml of dichloromethane, and to this solution was added a solution containing 26 mg of maleic acid in 1 ml of dichloromethane. The solvent was evaporated, and the residue was recrystallized from ether. 115 mg (90% yield) of the maleate salt of the title compound were obtained, melting at 100-102°C.

IRν ^pure _max cm ^-1 : 3466, 2974, 1584, 1497, 1389, 1371, 1266, 1185, 786

NMR (CDCl ₃ ) δ: 1.26 (9H, s), 1.30 (3H, t, J=4.1Hz), 3.02 (2H, q, J=4.1Hz), 3.62 (2H, br.s), 4.09 (2H , s), 5.23 (2H, s), 5.82 (1H, d, J = 15.6Hz), 5.95 (1H, dt, J = 15.6Hz, 7.3Hz), 6.99 (1H, d, J = 7.5Hz), 7.25 (1H, dd, J=7.5HZ, 2.1Hz), 7.12-7.16 (1H, m), 7.29-7.39 (6H, m)

Examples 92-96

Except that (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3 used in Example 90 was replaced by the corresponding 3-hydroxybenzylamine derivative -Hydroxybenzylamine, repeat the method in Example 90 to obtain the compounds of Examples 92 to 96.

Example 92

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-3-[4-(3-thienyl)-2-thienylmethoxy ]Benzylamine:-

：2974，2788，1584，1488，1455，1269，1026，783.

: 2974, 2788, 1584, 1488, 1455, 1269, 1026, 783.

NMR (CDCl ₃ ) δ: 1.24 (9H, s), 1.60 (3H, s), 3.04 (2H, dd, J=6.6Hz, 1.5Hz), 3.47 (2H, s), 5.22 (2H, s), 5.65 (1H, dt, J = 15.9Hz, 1.5Hz), 6.01 (1H, dt, J = 15.9Hz, 6.6Hz), 6.85-6.94 (2H, m), 6.99-7.01 (1H, m), 7.23 ( 1H, t, J=7.8Hz), 7.29-7.36 (5H, m).

Example 93

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-[4-(3-thienyl)-2-thienylmethoxy ]Benzylamine:-

: 2968, 2872, 1584, 1455, 1263, 1029, 783.

NMR (CDCl ₃ ) δ: 0.86 (3H, t, J=7.3Hz), 1.24 (9H, s), 1.46-1.52 (2H, m), 2.36-2.40 (2H, m), 3.07 (2H, dd, J = 6.3Hz, 1.4Hz), 3.53 (2H, s), 5.21 (2H, s), 5.63 (1H, dt, J = 15.9Hz, 1.4Hz),

6.06 (1H, dt, J = 15.9Hz, 6.3Hz), 6.86 (1H, ddd, J = 7.8Hz, 2.6Hz, 0.9Hz), 6.93 (1H, d, J = 7.8Hz), 7.01-7.03 (1H , m), 7.21 (1H, t, J=7.8Hz), 7.28-7.35 (5H, m).

Example 94

(E)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-N-methyl-3-[4-(3-thienyl)-2-thienyl Methoxy]benzylamine:-

: 2986, 1455, 1365, 1251, 1170, 1152, 1074, 1023, 783

NMR (CDCl ₃ ) δ: 1.46 (6H, s), 2.20 (3H, s), 3.06 (2H, dd, J=7.8Hz, 1.5Hz), 3.35 (3H, s), 3.48 (2H, s), 5.22 (2H, s), 5.69 (1H, dt, J = 15.8Hz, 1.5Hz), 6.18 (1H, dt, J = 15.8Hz, 7.8Hz), 6.87-6.94 (2H, m), 6.99-7.01 ( 1H, m), 7.21-7.36 (6H, m)

Example 95

(E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-[4-(3-thienyl)-2-thienyl Methoxy]benzylamine:-

: 1455, 1377, 1365, 1254, 1173, 1149, 1074, 1032, 837, 783

NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.1Hz), 1.46 (6H, s), 2.50 (2H, q, J = 7.1Hz), 3.10 (2H, dd, J = 6.4Hz, 1.4 Hz), 3.35 (3H, s), 3.54 (2H, s), 5.22 (2H, s), 5.69 (1H, dt, J=15.8Hz, 1.4Hz), 6.16 (1H, dt, J=15.8Hz, 6.4Hz), 6.86 (1H, ddd, J=7.9Hz), 2.7Hz, 1.0Hz), 6.93 (1H, d, J=7.9Hz), 7.00-7.10 (1H, m), 7.23 (1H, t, J=7.9Hz), 7.29 (1H, dd, J=4.6Hz, 1.3Hz), 7.33-7.39 (4H, m).

Example 96

(E)-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-N-propyl-3-[4-(3-thienyl)-2-thienyl Methoxy]benzylamine:-

：1455，1365，1254，1173，1152，1077，1032，783.

: 1455, 1365, 1254, 1173, 1152, 1077, 1032, 783.

NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.3Hz), 1.39-1.58 (2H, m), 2.38 (2H, t, J = 7.3Hz), 3.09 (2H, dd, J = 6.4Hz , 1.4Hz), 3.35 (3H, s), 3.54 (2H, s), 5.22 (2H, s), 5.68 (1H, dt, J=15.9Hz, 1.4Hz), 6.16 (1H, dt, J=15.9 Hz, 6.4Hz), 6.87 (1H, dd, J = 7.9Hz, 2.9Hz), 6.93 (1H, d, J = 7.9Hz), 7.00-7.03 (1H, m), 7.22 (1H, t, J = 7.9Hz), 7.30 (1H, dd, J = 4.5Hz, 1.4Hz), 7.32-7.36 (4H, m).

Example 97

Preparation of powder containing the compound of Example 19 as active ingredient:-

25 parts of the compound of Example 19 (hydrochloride salt) were dissolved in a mixture of 500 parts of ethanol and 500 parts of chloroform, and 75 parts of polyvinylpyrrolidone K-30 were added. The mixture was evaporated to dryness under reduced pressure by conventional means. The resulting solid was ground into fine powder and uniformly mixed with 250 parts of lactose, 145 parts of cornstarch and 5 parts of magnesium stearate to form a powder containing 25 mg of the active ingredient per 500 mg.

Example 98

Preparation of capsules containing the compound of Example 19 as active ingredient:-

25 parts of the compound of Example 19 (hydrochloride salt) were dissolved in a mixture of 500 parts of ethanol and 500 parts of chloroform, and 72.5 parts of polyvinylpyrrolidone K-30 and 2.5 parts of Tween 60 (nonionic active agent) were added. The mixture was evaporated to dryness under reduced pressure by conventional means. The resulting solid was ground into a fine powder and mixed well with 50 parts of lactose, 45 parts of cornstarch and 5 parts of magnesium stearate. The powder is filled into hard gelatin capsules in an amount of 200 mg per capsule to prepare capsules containing 25 mg of the active ingredient per capsule.

Example 99

Preparation of capsules containing the compound of Example 19 as active ingredient:-

25 parts of the compound of Example 19 (hydrochloride salt) were suspended in 1000 parts of water, and 150 parts of β-cyclodextrin were added. The mixture was stirred at room temperature for 12 hours, 1000 parts of water were added, and the mixture was stirred at room temperature for a further 3 hours. The mixture was freeze-dried by a conventional method, and the resulting cotton wool-like solid was lightly ground, and the granules were filled into hard gelatin capsules in an amount of 70 mg per capsule to prepare capsules containing 10 mg of the active ingredient per capsule.

The following Reference Examples illustrate the general synthesis of the starting compounds used in the preceding Examples.

Reference Example 1

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxybenzylamine:-

10.0 g of 3-hydroxybenzaldehyde and 9.55 g of a 40% methanol solution of methylamine were mixed, and the solvent was distilled off. The obtained Schiff's base was dissolved in 50 ml of ethanol, and 10.0 g of sodium borohydride was added under ice cooling with stirring. The mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium chloride solution were added thereto for extraction. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-100, 100g; eluent: dichloromethane/methanol=10/1→5/1] to obtain 8.88g (yield 79%) of N- Methyl-3-hydroxybenzylamine is a pale yellow crystal, m.p.138-140°C.

The resulting N-methylamine compound (8.88g) and 18.0g of potassium carbonate were added to 30ml of dimethylformamide, stirred at room temperature, and 13.0g of 1-bromo-6,6-dimethyl-2- Hepten-4-yne (3:1 mixture of E-form and Z-form) in dimethylformamide (10 ml). The mixture was stirred overnight at room temperature. After the reaction was completed, the solvent was distilled off. The residue was extracted with a mixture of ethyl acetate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 300g; eluent: hexane/ethyl acetate=10/1] to obtain 7.94g (total yield 39%) of the title compound as a pale yellow crystal , m.p. 76-77°C.

In addition to replacing the starting methylamine-methanol solution with ethylamine or propylamine or a methanolic solution of propylamine, and, if desired, with 1-bromo-6-methoxy-6-methyl-2-heptene-4-yne Except for 1-bromo-6,6-dimethyl-2-hepten-4-yne, the same reaction as in Reference Example 1 can give the 3-hydroxybenzylamine derivative used in Examples 1 to 48 , such as (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine, (E)-N-(6,6- Dimethyl-2-hepten-4-ynyl)-N-propyl-3-hydroxybenzylamine or (E)-N-ethyl-N-(6-methoxy-6-methyl-2 -hepten-4-ynyl)-3-hydroxybenzylamine.

Reference Example 2

Preparation of 3-(2-furyl)benzyl chloride:-

3-(2-furyl) ethyl benzoate [J.Chem.Soc, (B), 1971, 2305] was dissolved in 5ml of anhydrous ether, stirred and under ice cooling, 23mg of lithium aluminum hydride was added, and The mixture was stirred for 40 minutes. After the reaction, water and ether were added to the reaction mixture for extraction. The extract was treated in a conventional manner to obtain 170 mg (yield 83%) of 3-(2-furyl)benzyl alcohol.

Reference Example 3

Preparation of 3-(1-pyrrolyl)benzyl methanesulfonate:-

1.6 g of ethyl m-aminobenzoate was dissolved in 10 ml of glacial acetic acid, and 1.3 g of 2,5-dimethoxytetrahydrofuran was added, the mixture was heated under reflux for 2 hours, the solvent was evaporated, and the residue was dissolved in In ethyl acetate and water. The organic layer was separated, treated in a conventional manner, and finally recrystallized from hexane to obtain 1.7 g (82% yield) of pure ethyl 3-(1-pyrrolyl)benzoate as colorless needles, m.p.64-65°C.

1.1 g of the obtained pyrrolyl compound was dissolved in 30 ml of diethyl ether, and with stirring, 0.2 g of lithium aluminum hydride was added under ice-cooling, and the mixture was stirred for 1 hour. Water and ether were added to the reaction mixture for extraction. The extract was treated in the usual way and then recrystallized from a mixture of ethyl acetate and hexane to give 0.80 g (91% yield) of 3-(1-pyrrolyl)benzyl alcohol as colorless needles, m.p.66 -68°C.

170 mg of the obtained alcohol compound was dissolved in 10 ml of dichloromethane, 120 mg of methanesulfonyl chloride and 150 mg of triethylamine were added, and the mixture was stirred under ice cooling for 1 hour. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 230 mg (yield 92%) of the title compound as a pale yellow oil.

Reference Example 4

Preparation of 3-(3-thienyl)benzyl methanesulfonate:-

Suspend 790 mg of magnesium in 1 ml of anhydrous tetrahydrofuran, and add a small amount of 1,2-dibromoethane. After the occurrence of bubbles was detected, a tetrahydrofuran solution (12 ml) containing 5 g of 3-bromobenzaldehyde dimethyl acetal was added dropwise at room temperature over a period of 1.5 hours with stirring. The mixture was stirred at 45 to 55°C for 30 minutes, then 80 mg of bis(diphenylphosphine)ethane nickel(II) chloride and a tetrahydrofuran solution (6 ml) of 3-bromothiophene were added. The mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and insoluble materials were removed by filtration. Ethyl acetate was added to extract the reaction mixture, the extract was processed by conventional methods, and purified by silica gel column chromatography [Wakogel C-100, 70g; eluent: hexane/ethyl acetate=50/1→10/1], to obtain 1.35 g (27% yield) of 3-(3-thienyl)benzaldehyde dimethyl acetate, m.p. 45-46°C.

The obtained thienyl compound (1.35 g) was dissolved in a mixture of 4 ml of 1N hydrochloric acid and 8 ml of tetrahydrofuran. The solution was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and water. The extract was worked up in the usual manner to give 1.05 g (96% yield) of 3-(3-thienyl)benzaldehyde, m.p. 44-45°C.

1.05 g of the obtained aldehyde compound was dissolved in 15 ml of ethanol, and 250 mg of sodium borohydride was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The extract was treated in a conventional manner, and purified by silica gel column chromatography [Wakogel C-100, 20g; eluent: hexane/ethyl acetate=5/1] to obtain 960mg (yield 86%) of 3-(3- Thienyl) benzyl alcohol, m.p. 89-90°C.

300 mg of the obtained alcohol compound was dissolved in 7 ml of ethyl acetate, and to the solution, 320 mg of triethylamine and an ethyl acetate solution (1 ml) containing 270 mg of methanesulfonyl chloride were added under ice cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The precipitated salt was removed by filtration, and the reaction mixture was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow powder.

In Reference Example 4, when the starting material 3-bromothiophene was replaced with the corresponding bromine-substituted heterocyclic derivative, the 3-(3-furyl)benzyl derivative, 3-(2-thienyl Benzyl derivatives, 3-(2-pyridyl)benzyl derivatives, 3-(3-pyridyl)benzyl derivatives and 3-(4-pyridyl)benzyl derivatives.

Reference Example 5

Preparation of 5-(3-methylphenyl)isoxazole:-

1.56g of 3-ethynyltoluene was dissolved in 20ml of diethyl ether, and at -70°C, 8.5ml of 1.5M n-butyllithium-hexane solution and 1.2ml of ethyl formate were added with stirring. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water, and the organic layer was separated. The solvent was evaporated to obtain 900 mg (47% yield) of 3-(3-methylphenyl)-2-propynal as a colorless oil.

130 mg of the obtained aldehyde was dissolved in 20 ml of ethanol, and 5 ml of an aqueous solution containing 70 mg of bromehydrochloride was added. The solvent was distilled off under reduced pressure, and the residue was purified by medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=10/1 ] to obtain 122 mg (85% yield) of 3-(3-methylphenyl)-2-propylyl aldoxime as a pale yellow oil.

122 mg of the obtained oxime compound was dissolved in 20 ml of ethanol, and 1 drop of 1N aqueous sodium hydroxide solution was added. The solution was left for 3 minutes and quenched by adding 3 drops of 1N HCl. The solvent was distilled off under reduced pressure, and the residue was extracted with a mixture of water and ether. The organic layer was separated and the solvent was evaporated to give 106 mg (87% yield) of the title compound as a pale yellow oil.

Reference Example 6

Preparation of 1-(3-hydroxymethylphenyl)imidazole:-

230mg of 1-(3-ethoxycarbonylphenyl) imidazole [see J.Am.Chem.Soc., 79, 4922 (1957)] was dissolved in 10ml of ether, and 50mg of lithium aluminum hydride was added, and the mixture was stirred at room temperature 2 hours. The reaction mixture was poured into ice water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-200, 20g; eluent: chloroform/methanol=20/1] to obtain 160 (yield 92%) of the title compound, It is a colorless oil.

Reference Example 7

Preparation of 3-(2-oxazolyl)benzyl bromide:-

200 mg of 2-(3-methylphenyl) oxazole [synthesized essentially as described in Ang. Chem, 75, 165 (1963)] was dissolved in 5 ml of carbon tetrachloride, and 231 mg of N-bromo-succinyl imine and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 2 hours with stirring. After completion of the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound.

In a similar manner, 3-(2-thiazolyl)benzyl bromide can be synthesized.

Reference Example 8

Preparation of 3-(5-oxazolyl)benzyl alcohol:-

400 mg of 3-(hydroxymethyl)benzaldehyde (prepared by reduction of isophthalaldehyde with equimolar sodium borohydride, 574 mg of p-toluenesulfonylmethyl isocyanide and 406 mg of potassium carbonate were added to 10 ml of methanol. Stirring and reflux The mixture was heated for 1 hour under reduced pressure. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The extract was processed in a conventional manner and purified by silica gel column chromatography [Wakogel C-200, 50g; Eluent: hexane /ethyl acetate=1/1] to obtain 375 mg (yield 73%) of the title compound as a white powder.

When the above alcohol compound was mesylated in the same manner as in Reference Example 3, 3-(5-oxazolyl)benzyl methanesulfonyl ester was obtained as a colorless oil.

Reference Example 9

Preparation of 3-(4-isoxazolyl)benzyl bromide:-

Dissolve 185mg of 4-(3-methylphenyl)isoxazole [see: J.Heterocyclic Chem, 11, 51 (1974); and J.Chem.Soc, Perkin II, 1121 (1977)] in 8ml of carbon tetrachloride , and 206 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added. The mixture was refluxed for 3 hours with stirring. Insoluble materials were removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography [Wakogel C-200, 30 g; eluent: hexane/ethyl acetate = 10/1] to obtain 210 mg (yield 76%) of the title compound as a colorless powder.

When carrying out the same reaction as in Reference Example 9, except for using 4-(3-methylphenyl)isothiazole [see J.Prakt.Chem, 318,507 (1976)], 5-(3-methylphenyl) ) isothiazole [see J.Heterocyclic Chem., 11,55 (1974); Heterocyclic, 19,1080 (1982)], or 1-(3-methylphenyl)-1,2,4-triazole [see J.Org, Chem., 21, 1037 (1956), and Japanese Patent Laid-Open No.4173/1976] when replacing the starting material 4-(3-methylphenyl) isoxazole, 3-(4- Isothiazolyl)benzyl bromide, 3-(5-isothiazolyl)benzyl bromide, 3-(5-pyrimidinyl)benzyl bromide, or 3-(1,2,4-triazol-1-yl) Benzyl bromide.

Reference Example 10

Preparation of 3-(2,3-dihydro-4-thienyl)benzyl alcohol and 3-(2,5-dihydro-3-thienyl)benzyl alcohol:-

Under ice-cooling, tetrahydrothiophene-3-one tetrahydrofuran solution (10ml) was added dropwise with stirring to the tetrahydrofuran solution (15ml )middle. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, ether was added to extract the product, and the extract was processed by conventional methods to obtain 1.20 g (yield 47%) of crude product 3-(3-hydroxytetrahydro-3-thienyl)benzaldehyde dimethyl acetal.

1.20 g of the obtained alcohol compound was dissolved in a mixture of 20 ml of tetrahydrofuran and 3 ml of 10% HCl. After standing at room temperature for 2 hours, diethyl ether and water were added to the solution for dilution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of dichloromethane, and 1.0 ml of methanesulfonyl chloride and 2.0 ml of triethylamine were added. The mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was poured into ice water, the organic layer was separated, and the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in 10 ml of ethanol, and 0.2 g of sodium borohydride was added. The solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ether and water were added to the residue to conduct extraction. The extract was processed by conventional methods, and the product was purified by medium-pressure liquid chromatography [Lobar column, size B, Lichroprep Si60 (E.Merck Co.); eluent: hexane → hexane/ethyl acetate 10/1], 0.45 g (50% yield) of 3-(2,3-dihydro-4-thienyl)benzyl alcohol and 0.20 g (22% yield) of 3-(2,5-dihydro-3-thienyl) were obtained ) benzyl alcohol.

Reference Example 11

Preparation of 3-(1-pyrrolidinyl)benzyl alcohol:-

Dissolve 0.25g of N-(3-ethoxycarbonylphenyl)succinimide [synthesized by heating condensation of m-aminobenzoic acid ethyl ester and succinic anhydride in acetic acid] in 5ml of anhydrous tetrahydrofuran, stir and Under ice cooling, 0.17 g of lithium aluminum hydride was added. The mixture was kept at room temperature for 30 minutes and then heated to reflux for 4 hours. After the reaction was complete, ethyl acetate and water were added. The organic layer was separated, then worked up by conventional methods, and purified by medium-pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=10/1 ] to obtain 84 mg (yield 47%) of the title compound as a colorless oil.

When the obtained alcohol compound was mesylated in the same manner as in Reference Example 4, 3-(1-pyrrolidinyl)benzyl methanesulfonate was obtained as a colorless oil.

Reference Example 12

Preparation of 5-(3-thienyl)thienylmethanol:-

Dissolve 5g of 3-bromothiophene in 35ml of anhydrous ether, stir and add 19ml of 15% n-butyllithium-hexane solution and 10.5g of tributyl tin chloride, and the mixture was stirred at the above temperature for 1 hour, then at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, then the solvent was distilled off, and the residue was purified by distillation under reduced pressure to obtain 8.5 g (74% yield) of tributyl(3-thienyl)tin, b.p.150-158°C /2mmHg.

1.19 The above-mentioned tin compound and 0.56g of 5-bromothiophene-2-formaldehyde were dissolved in 3ml of toluene, 20mg of tetrakis(triphenylphosphine) palladium was added, the mixture was heated and stirred under reflux for 7 hours, and 10% potassium fluoride aqueous solution and 5% aqueous potassium carbonate solution to wash the reaction mixture. The solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel L-200, 50g; eluent: hexane/ethyl acetate=10/1] to obtain 0.36g (yield 63%) of 5-(3- Thienyl) Thiophene-2-carbaldehyde.

In 4 ml of tetrahydrofuran, 144 mg of the obtained aldehyde compound was reduced with 15.6 mg of lithium aluminum hydride and then treated in a conventional manner to obtain 134 mg (yield 92%) of the title compound as a colorless oil.

Reference Example 13

Preparation of 2-(5-oxazolyl)-4-pyridinemethanol:-

Dissolve 1.07g of dimethyl pyridine-2,4-dicarboxylate in 20ml of toluene, stir and add 6.04ml of 1M diisobutylaluminum hydride dropwise over 2.5 hours under cooling at -80 to -70°C solution in toluene, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water, and diethyl ether was added. The organic layer was separated, worked up by conventional methods, and then purified by medium-pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=4/1 →3/1] to obtain 0.27 g (yield 30%) of methyl 2-formylisonicotinate as a colorless crystalline powder.

203 mg of the obtained formyl compound was dissolved in 8 ml of methanol, and 240 mg of p-toluenesulfonylmethyl isocyanide and 170 mg of potassium carbonate were added. The mixture was heated to reflux for 10 minutes, and the reaction mixture was evaporated to dryness under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was treated in a conventional manner to obtain 224 mg (91% yield) of methyl 2-(5-oxazolyl)isonicotinate as a pale yellow powder.

102 mg of the obtained oxazolyl compound was dissolved in 2 ml of anhydrous tetrahydrofuran, stirred and 14 mg of lithium aluminum hydride was added under ice cooling. The mixture was stirred at the same temperature for 30 minutes, the reaction mixture was poured into ice water, and dichloromethane was added for extraction. The extract was treated conventionally and purified by silica gel column chromatography [Wakogel C-200, 5, 5 g; eluent: dichloromethane/methanol = 50/1 → 20/1] to obtain 49.5 mg (yield 56%) The title compound is a pale yellow crystalline powder.

Reference Example 14

Preparation of 5-(5-oxazolyl)-3-pyridinemethanol:-

1.67g of pyridine-3,5-dicarboxylic acid dimethyl ester was dissolved in 30ml of anhydrous tetrahydrofuran, stirred and under ice cooling, 162mg of lithium aluminum hydride was added, the mixture was stirred at this temperature for 30 minutes, and the reaction mixture was poured Into ice water, and add ether for extraction. The extract was treated in a conventional manner to obtain crude methyl 5-hydroxymethylnicotinate. The crude product was dissolved in 20 ml of dichloromethane, 2.2 g of pyridinium chlorochromate was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, the organic layer was separated, treated with a conventional method, and purified by silica gel column chromatography [Wakogel C-200, 80g; eluent: chloroform/methanol=20/1] to obtain 0.37g (produced 5-formyl nicotinic acid methyl ester, m.p.96-97℃.

Using 110 mg of the obtained formyl compound as a starting material, the oxazolylation reduction in Reference Example 13 was carried out to obtain 77 mg (yield 64%) of the title compound as a colorless oil.

When using pyridine-2,6-dicarboxylate instead of starting material pyridine-3,5-dicarboxylate dimethyl ester to carry out the same reaction in Reference Example 14, 6-(5-oxazolyl )-2-pyridinemethanol.

Reference Example 15

Preparation of 5-(5-Hydroxymethyl-2-furyl)oxazole:-

300 mg of 5-formylfurfuryl alcohol [Ref: Japanese Laid-Open Publication No. 154758/1979] was dissolved in 10 ml of methanol, and 502 mg of p-toluenesulfonylmethyl isocyanide and 329 mg of potassium carbonate were added. The mixture was heated to reflux for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of water and ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [Wakogel C-200, 45g; eluent: hexane/ethyl acetate=3/2→1/1] to obtain 260mg (yield 66%) of the title compound as a dilute Yellow crystalline powder.

Reference Example 16

Preparation of 4-Hydroxymethyl-2-(5-oxazolyl)thiazole:-

1.5 g of diethyl thiazole-2,4-dicarboxylate were suspended in 15 ml of ethanol, and at -10°C, 0.16 g of sodium borohydride and 3 ml of an ethanol solution containing 0.58 g of calcium chloride were added. The mixture was stirred at the above temperature for 2 hours, the excess reducing agent was decomposed by adding acetone, and the solvent was distilled off under reduced pressure. Dilute sulfuric acid was added to the residue, and insoluble calcium sulfate was removed by filtration. The pH of the filtrate was adjusted to 10 with an aqueous potassium carbonate solution, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure, and the residue was treated with isopropyl ether to obtain 0.78 g (yield 64%) of ethyl 2-hydroxymethylthiazole-4-carboxylate, It is a colorless crystalline powder.

0.78 g of the obtained hydroxymethyl compound was dissolved in 40 ml of chloroform, and 25 g of active magnesium dioxide was added, and the mixture was stirred at room temperature for 5 days. The precipitate was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to give 0.67 g (87% yield) of ethyl 2-formylthiazole-4-carboxylate as colorless needles.

60 mg of ethyl 2-(5-oxazolyl)thiazole-4-carboxylate (prepared by 80 mg of the formyl compound obtained above, 91 mg of p-toluenesulfonylmethyl isocyanate and 60 mg of potassium carbonate according to the reaction described in Reference Example 13] Be dissolved in 3ml ethanol, add 6.6mg sodium borohydride and 24mg calcium chloride in this solution.The mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid was added in the residue.Filter separation The generated precipitate, potassium carbonate was added to the filtrate to adjust its pH value to 10. Chloroform was added to extract the product, the extract was dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by preparative thin-layer chromatography. Thin-layer plate: Kieselgel 60 F254, Art.5744 (E.Merck.Co.); developing solvent: hexane/ethyl acetate = 1/4] to obtain 20 mg (yield 25%) of the title compound as a white crystalline powder.

Reference Example 17

Preparation of 5-(5-Hydroxymethyl-3-furyl)oxazole:-

408 mg of dimethyl furan-3,5-dicarboxylate [see J. Chem. Soc. Perkin I, 1130 (1973) for reference] was dissolved in 4 ml of anhydrous tetrahydrofuran, and 59 mg of lithium aluminum hydride was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and ethyl acetate was added for extraction, the extract was processed by conventional methods, and purified by silica gel column chromatography [Wakogel C-200, 20g; eluent: hexane/ethyl acetate=2/1 ] to obtain 44 mg (yield 13%) of methyl 5-hydroxymethyl-furan-3-carboxylate as a colorless oil.

44 mg of the obtained alcohol compound was dissolved in 2 ml of chloroform, and pyridinium chlorochromate was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, the organic layer was separated, processed by conventional methods, and purified by silica gel column chromatography [Wakogel C-200, 20g; eluent: hexane/ethyl acetate=3/1] to obtain 28 mg of pure formyl compounds. This was dissolved in 2 ml of methanol, and 35 mg of p-toluenesulfonylmethyl isocyanide and 25 mg of potassium carbonate were added. The mixture was refluxed for 30 minutes and worked up in the usual manner to give 30 mg of methyl 5-(5-oxazolyl)-furan-3-carboxylate. The obtained compound was dissolved in 2 ml of tetrahydrofuran, and 6 mg of lithium aluminum hydride was added under ice-cooling. The mixture was stirred at the above temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with diethyl ether. The extract was treated in a conventional manner to obtain 22 mg (yield 48%) of the title compound as a pale yellow oil.

Reference Example 18

Preparation of 6-methyl-3-(1-pyrrolyl)benzyl alcohol:-

158 mg of methyl 3-amino-6-methylbenzoate were dissolved in 3 ml of acetic acid, and 2.5-dimethoxytetrahydrofuran was added. The mixture was heated at reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [Wakogel C-200, 10 g; eluent: hexane/ethyl acetate=10/1] to obtain 185 mg (yield 87%) of 3-(1-pyrrolyl)-6 - Methyl methylbenzoate, m.p. 56-57°C.

180 mg of the obtained pyrrolyl compound was dissolved in 2 ml of diethyl ether, and 24 mg of lithium aluminum hydride was added. The mixture was stirred at room temperature for 30 minutes. Water and ether were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was evaporated to give 155 mg (quantitative yield) of the title compound as a colorless crystalline powder, m.p. 70-71°C.

When carrying out the same reaction of Reference Example 18 with 3-amino-2-methylbenzoic acid methyl ester instead of starting material 3-amino-6-methylbenzoic acid methyl ester, 2-methyl-3-( 1-pyrrolyl)benzyl alcohol.

Reference Example 19

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-formylbenzyloxy)benzylamine:-

A solution of 90 mg of 3-chloromethylbenzaldehyde in dimethylformamide (1.5 ml) was added to 150 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N -Methyl-3-hydroxybenzylamine, 23.2 mg of 60% oily sodium hydride and 1 ml of tetrahydrofuran in a phenoxide solution, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate-water, processed by conventional methods, and purified by silica gel column chromatography [Wakogel C-200, 15g; eluent: hexane/ethyl acetate=10/1 → 5/1], 85 mg (yield 39%) of the title compound were obtained as a colorless oil.

When the same reaction of Reference Example 19 is carried out with methyl 3-bromomethylbenzoate instead of the starting material 3-chloromethylbenzaldehyde, (E)-N-(6,6-dimethyl-2 -hepten-4-ynyl-N-methyl-3-(3-methoxycarbonylbenzyloxy)benzylamine.

Reference Example 20

Preparation of (E)-3-[2-[3-(3-thienyl)phenyl]vinylbenzyl chloride:-

2.40 g of 3-(3-thienyl)benzyl chloride were dissolved in 40 ml of toluene, and 3.62 g of triphenylphosphine were added, and the mixture was heated under reflux for 50 hours. The reaction mixture was cooled, and the precipitated crystals were collected by filtration to obtain 3.60 g (66% yield) of 3-(3-thienyl)benzyltriphenylphosphonium chloride.

1.21 g of the obtained phosphonium salt was dissolved in 45 ml of ethanol, and 0.35 g of 3-formylbenzyl alcohol and 0.27 g of sodium ethoxide were added. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and water, processed by a conventional method, and purified by silica gel column chromatography [Wakogel C-300, 100 g; eluent: hexane/ethyl acetate=10 /1→5/1] to obtain 0.34 g (yield 46%) of E-type 3-[2-[3-(3-thienyl)phenyl]vinyl]benzyl alcohol and 0.34 g of Z-type compound.

0.20 g of the obtained (E)-type alcohol was dissolved in 6 ml of chloroform, 0.15 ml of thionyl chloride and a drop of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water, treated with conventional methods, and purified by silica gel column chromatography [Wakogel C-100, 20 g; eluent: hexane/ethyl acetate=20/1 ] to give 0.19 g (87% yield) of the title compound as a colorless crystalline powder, m.p. 79-81°C.

When the same reaction as in Reference Example 20 is carried out except that the starting material 3-(3-thienylbenzyl chloride is replaced by the corresponding 3-substituted benzyl chloride or bromine, (E)-3-[2- [3-(5-oxazolyl)phenyl]vinyl]benzyl chloride, (E)-3-[2-[3-(5-thiazolyl)phenyl]vinyl]benzyl chloride and (E )-3-[2-[3-(1-imidazolyl)phenyl]vinyl]benzyl chloride.

Reference Example 21

(E)-3-[2-[3-(1-Pyrrolyl)phenyl]vinylbenzyl alcohol:-

560 mg of 3-(dimethoxymethyl)benzyltriphenylphosphonium bromide [by brominating 3-hydroxymethylbenzaldehyde with phosphorus tribromide, and then dissolving the product in anhydrous methanol, in the presence of p- Acetalization was carried out in the presence of toluenesulfonic acid, which was then reacted with triphenylphosphine to synthesize] phosphonium and 180 mg of 3-(1-pyrrolyl)benzaldehyde [by oxidation of 3- (1-pyrrolyl) benzyl alcohol to synthesize] dissolved in 20ml of methanol. 110 mg of sodium methoxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue for extraction, and the organic layer was treated in a conventional manner and purified by medium pressure liquid chromatography [Lobar column, size B, Lichroprep Si60 (E.Merck Co.) ;Eluant: hexane/ethyl acetate=10/1], to obtain 135 mg (yield 42%) of E-type 3-[2-[3-(1-pyrrolyl)phenyl]vinyl]benzene Formaldehyde dimethyl acetal and 127 mg of its Z-type compound.

135 mg of the obtained (E)-form acetal was dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of 2N HCl, the solution was stirred at room temperature for 3 hours, then the solvent was distilled off under reduced pressure, and the residue was worked up in a conventional manner. The obtained formyl compound was dissolved in 10 ml of ethanol, and 40 mg of sodium borohydride was added. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, processed in a conventional manner, and purified by silica gel column chromatography [Wakogel C-100, 20 g; eluent: hexane/ethyl acetate=5/1] to obtain 78 mg (produced Yield 67%) of the title compound as a colorless crystalline powder, m.p. 108-110°C.

When using 3-(3-pyridyl)benzaldehyde instead of the starting material 3-(1-pyrrolyl)benzaldehyde for the same reaction as in Reference Example 21, (E)-3-[2-[3- (3-pyridyl)phenyl]vinyl]benzyl alcohol.

Reference Example 22

Preparation of 3-[2-[3-(3-thienyl)phenyl]ethyl]benzyl alcohol:-

Dissolve 81mg (Z)-3-[2-[3-(3-thienyl)phenyl]vinyl]benzyl alcohol in 3ml ethanol, and in the presence of 15mg10% palladium-carbon, at normal temperature and pressure Under catalytic reduction for 15 hours. The catalyst was removed by filtration and the solvent was evaporated to give the title compound as a colorless oil in quantitative yield.

When using (Z)-3-[2-[3-(1-pyrrolyl)phenyl)vinylbenzyl alcohol or (Z)-3-[2-[3-(3-pyridyl)phenyl]ethylene Base] benzyl alcohol instead of the starting material (Z)-3-[2-[3-(3-thienyl) phenyl] vinyl] benzyl alcohol when carrying out the same reduction reaction in Reference Example 22, 3- [2-[3-(1-Pyrrolyl)phenyl]ethyl]benzyl alcohol and 3-[2-[3-(3-pyridyl)phenyl]ethyl]benzyl alcohol.

Reference Example 23

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-5-formylfurfurylamine:-

100 mg of 5-hydroxymethylfurfural was dissolved in 2 ml of anhydrous diethyl ether. With stirring, a diethyl ether solution (1 ml) containing 30 l of phosphorus tribromide was added under ice cooling, and the mixture was stirred at the above temperature for 10 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate, then, 183 mg of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 136 mg of potassium carbonate and 3ml of dimethylformamide, the mixture was stirred at room temperature overnight and the reaction mixture was concentrated under reduced pressure, the residue was partitioned between ether and water, treated with conventional methods, and purified by silica gel column chromatography to obtain 132mg (yield 53% ) as the title compound as a pale yellow oil.

Reference Example 24

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-4-formyl-2-pyridylmethylamine:-

160 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-4-ethoxycarbonyl-2-pyridylmethylamine [by using p -Tosyl chloride and triethylamine tosylate 4-ethoxycarbonyl-2-pyridinemethanol, then react the tosylated product with (E)-N-methyl-6,6-dimethyl -Condensation of 2-heptene-4-ynylamine to synthesize] Dissolve in 2ml of toluene, stir and add 0.56ml of 1M toluene solution of diisobutylaluminum hydride under cooling at a temperature of -75 to -70°C. The mixture was stirred at the above temperature for 40 minutes. The reaction mixture was poured into ice water, and diethyl ether was added. The organic layer was separated, processed by conventional methods, and purified by medium-pressure liquid chromatography [Lobar column, size A, Lichroprep Si 60 (E.Merck Co.); eluent: hexane/ethyl acetate=4/1] , to obtain 15 mg (yield 11%) of the title compound as a pale yellow oil.

When using (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-ethoxycarbonyl-5-isoxazolylmethylamine [via Bromination of ethyl 5-methylisoxazole-3-carboxylate with N-bromosuccinimide, followed by reaction of the brominated product with (E)-N-ethyl-6,6-dimethyl -2-hepten-4-ynylamine condensation to synthesize] instead of starting material (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl- When 4-ethoxycarbonyl-2-pyridylmethylamine is subjected to the same reaction as in Reference Example 24, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl) can be obtained -N-Ethyl-3-formyl-5-isoxazolylamine.

Reference Example 25

Preparation of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxy-4-methoxymethyloxybenzylamine:-

Suspend 3g of 3.4-dihydroxybenzaldehyde and 0.87g of 60% oily sodium hydride in 13ml of tetrahydrofuran, and add dimethylformamide solution (10ml) containing 3.3ml of methoxymethyl chloride, and place the mixture at room temperature Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the organic layer was processed by conventional methods, and then purified by silica gel column chromatography [Wakogel C-200, 150 g; eluent: hexane/ethyl acetate =4/1] to obtain 1.78 g (yield 45%) of 3-hydroxy-4-methoxymethyloxybenzaldehyde.

360 mg of the obtained methoxymethyloxy compound was dissolved in 6 ml of a 40% methanol solution of methylamine, 151 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the organic layer was separated, and the solvent was distilled off. The residue was dissolved in 10ml of dimethylformamide, and 361mg of 1-bromo-6,6-dimethyl-2-heptene-4-yne (3:1 mixture of E-form and Z-form) and 276mg potassium carbonate, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ether and water. The organic layer was separated, processed by conventional methods, and purified by silica gel column chromatography [Wakogel C-200, 30 g; eluent: hexane/ethyl acetate=3/1] to obtain 140 mg (yield 22%) of the title compound , is a pale yellow oil.

When the starting material 3,4-dihydroxybenzaldehyde is replaced by 2,3-dihydroxybenzaldehyde, and 3-hydroxy-2-methanol is synthesized by selective alkylation with methoxymethyl chloride and triethylamine in chloroform Oxymethyloxybenzaldehyde, and then carry out the same reaction of Reference Example 25 to obtain (E)-N-(6,6-dimethyl-2-heptene-4-ynyl)-N-form -3-hydroxy-2-methoxymethyloxybenzylamine.

Reference Example 26

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine:-

Add 6.0 g of N-(3-bromomethylphenyl)phthalimide [by using N-bromosuccinimide in carbon tetrachloride to p-N-(m-tolyl)phthalimide imide was synthesized by bromination] was dissolved in 100ml of dimethylformamide, and 3.82g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine was added hydrochloride and 7.87 g of potassium carbonate, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was extracted with ethyl acetate-water, the organic layer was separated, the solvent was evaporated, and the residue was washed with a small amount of ether to obtain 5.5 g (yield 72%) of (E)-N -(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-phthalimidobenzylamine, m.p. 96-98°C.

150 mg of the obtained benzylamine compound was dissolved in 5 ml of ethanol, and 23 mg of hydrazine was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was removed by filtration. and distill off the solvent. The residue was partitioned between dichloromethane and water. The organic layer was treated in a conventional manner and purified by silica gel column chromatography [Wakogel C-100, 5 g; eluent: hexane/ethyl acetate = 10/1 → 3/1] to obtain 95 mg (yield 95%) of the title The compound is a pale yellow crystalline powder, m.p.65-66°C.

Reference Example 27

Preparation of 3-[3-(3-thiophene)benzylthio]benzaldehyde:-

0.3 g of sulfur was added to a tetrahydrofuran solution (20 ml) of Grignard's reagent prepared from 1.0 g of 3-bromobenzaldehyde dimethyl acetal and 0.4 g of magnesium, and the mixture was stirred at room temperature for 2 hours. 0.3 g of lithium aluminum hydride was added, and the mixture was stirred at 40°C for 3 hours. The reaction mixture was poured into ice water, acidified by adding hydrochloric acid, and extracted by adding ether. The extract was treated in a conventional manner, and the solvent was distilled off to obtain 0.36 g (60% yield) of 3-mercaptobenzaldehyde.

60 mg of the obtained mercapto compound was dissolved in 5 ml of dimethylformamide, 50 mg of 3-(3-thienyl)benzyl bromide and 30 mg of 60% oily sodium hydride were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, processed by conventional methods, and purified by medium-pressure liquid chromatography [column: Lobar column, size A, Lichroprep Si60 (E.Merck Co.); eluent: hexane/ethyl acetate = 30/1→10/1], 2.3 mg (yield 4%) of the title compound were obtained as a colorless oil.

Reference Example 28

Preparation of 3-(3-tetrahydrothienyl)benzyl alcohol:-

30 mg of 3-(2,5-dihydro-3-thienyl) benzyl alcohol obtained in Reference Example 10 was dissolved in 25 ml of ethanol, and in the presence of 50 mg of 10% palladium-carbon, 3.5 Kg/ ^cm hydrogen Catalytic reduction under pressure for 8 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 25 mg (yield 82%) of the title compound as a colorless oil.

Reference Example 29

Preparation of 3-(3,4-dihydro-2H-thiopyran-5-yl)benzyl alcohol and 3-(5,6-dihydro-2H-thiopyran-3-yl)benzyl alcohol:-

With 534 mg of 3-(tetrahydro-3-hydroxyl-3-thiocyanate prepared by the same reaction as in Reference Example 10, using 3-bromobenzaldehyde dimethyl acetal and tetrahydrothiopyran-3-one as starting materials Fyl)benzaldehyde dimethyl acetal was dissolved in 5 ml of ethyl acetate, with stirring, 187 µl of methanesulfonyl chloride and 553 µl of triethylamine were added under ice-cooling, and the mixture was stirred for 30 minutes. Triethylamine hydrochloride was removed by filtration, and the solvent was distilled off. The residue was dissolved in 20 ml of benzene, and 373 mg of 90% potassium tert-butoxide was added, and the mixture was stirred at room temperature for 15 hours. Diethyl ether and water are added to the reaction mixture, and the mixture is worked up in a conventional manner. The obtained 3-dihydrothiopyranylbenzaldehyde dimethyl acetal was dissolved in a mixture of 3 ml of 1N HCl and 6 ml of tetrahydrofuran, and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ether and water and worked up in the usual way. The obtained formyl compound was dissolved in 20 ml of tetrahydrofuran, and 380 mg of lithium aluminum hydride was added, and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into ice water, treated with conventional methods, and purified by silica gel column chromatography [Wakogel C-200, 20 g; eluent: hexane/ethyl acetate=2/1] to obtain 7 mg (yield 2%) The title compound 3-(3,4-dihydro-2H-thiopyran-5-yl)benzyl alcohol and 4 mg (yield 1%) of 3-(5,6-dihydro-2H-thiopyran-3-yl ) benzyl alcohol.

The compound of the present invention inhibits the biosynthesis of cholesterol by inhibiting squalene epoxidase in mammals, and reduces the content of blood cholesterol. In addition, they are expected to be effective agents for the treatment and prevention of diseases caused by excess cholesterol, such as obesity, hyperlipidemia, arteriosclerosis and heart disease as well as concurrent brain diseases.

Claims (16)

1, the allylamine derivatives and the non-toxic salt thereof of the replacement represented of following general formula,

Wherein

A ¹And A ²Identical or different, each represents methyne or nitrogen, oxygen or sulphur atom;

Q ¹And Q ²Identical or different, each expression contains 1 or 2 heteroatomic group that is selected from a group that nitrogen, oxygen and sulphur atom form, this group and adjacent carbon atom and A ¹Or A ²Form five yuan or hexa-atomic aromatic ring together;

X and Y are identical or different, and each represents oxygen or sulphur atom, carbonyl, formula-CHR ⁸-group, wherein R ^aExpression hydrogen atom or low alkyl group or formula-NR ^b-group, wherein R ^bExpression hydrogen atom or low alkyl group, perhaps X and Y form vinylene or ethynylene together;

R ¹Expression contains 1-4 heteroatomic five yuan or the hexa-member heterocycle base that are selected from one group that is made up of nitrogen, oxygen and sulphur atom;

R ²Expression low alkyl group, allyl group, propargyl or cyclopropyl;

R ³And R ⁴Identical or different, each represents low alkyl group, perhaps forms naphthene group jointly with adjacent carbon atom together;

R ⁵Expression hydrogen atom, low alkyl group or lower alkoxy; With

R ⁶And R ⁷Identical or different, each represents hydrogen atom, halogen atom, hydroxyl, cyano group, low alkyl group or lower alkoxy;

Condition be in X and Y expression Sauerstoffatom, sulphur atom or-NR ^b-(R wherein ^bAs definition) during group, another expression carbonyl or-CHR ^a-(R wherein ⁸As definition) group.

2, the allylamine derivatives of the described replacement of claim 1 and non-toxic salt thereof, wherein R ¹Be pyrryl, furyl, thienyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, the furazan base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, the dihydro-thiophene base, tetrahydro-thienyl, pyrrolinyl, pyrrolidyl oxazolinyl oxazolidinyl isoxazoline-3-yl isoxazole alkyl, thiazolinyl, thiazolidyl, the isothiazoline base, the isothiazole alkyl, 1,2-dithiolane base, 1,3-dithiolane base, 1,2-dithiole base, 1,3-dithiole base, dihydro thiapyran base, tetrahydro thiapyran base, 1,4-dithiane base, 1,4-dithia English base (1,4-dithiinyl), 1,4-oxa-sulphur English base (1,4-oxathiinyl), or thio-morpholinyl; Use formula

They are identical or different for five yuan of expression or hexa-atomic aromatic ring, and each represents benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.

3, the allylamine derivatives of the described replacement of claim 2 and non-toxic salt thereof, its Chinese style

The aromatic ring of expression is benzene or thiphene ring.

4, the allylamine derivatives of the described replacement of claim 1 and non-toxic salt thereof, wherein R ¹Be thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyridyl or dihydro-thiophene base; Formula

The aromatic ring of expression is benzene or thiphene ring; Following formula

The expression five yuan or hexa-atomic aromatic ring be benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.

5, the described allylamine derivatives of claim 4 and non-toxic salt, wherein R ¹Be 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl.

6, the allylamine derivatives and the non-toxic salt thereof of claim 4 or 5 described replacements, its Chinese style

The expression five yuan or hexa-atomic aromatic ring be benzene, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring.

7, the allylamine derivatives of the described replacement of claim 4,5 or 6 and non-toxic salt thereof, wherein X is a methylene radical, Y is methylene radical, Sauerstoffatom, sulphur atom or imido grpup, or X and Y represent (E)-vinylene together.

8, the allylamine derivatives of the described replacement of claim 7 and non-toxic salt thereof, wherein R ²Be methyl, ethyl or propyl group, R ³And R ⁴Be methyl, and R ⁵Be methyl, ethyl or methoxyl group.

9, the allylamine derivatives of the replacement of the described general formula of production claim 1 [I] and the method for non-toxic salt thereof comprise the substituted amine derivatives or its protected compound that make general formula [II] expression,

A wherein ¹, A ², Q ¹, Q ², X, Y, R ¹, R ², R ⁶And R ⁷As claim 1 definition,

With the compound reaction of general formula [III] expression,

Wherein Z represents leavings group, R ³, R ⁴And R ⁵As claim 1 definition,

Then, if desired, remove blocking group;

Perhaps make compound or its protected derivative of general formula [IV] expression,

A wherein ¹, A ², Q ¹, Q ², X, Y, R ¹, R ⁶, R ⁷Define as mentioned with Z, with the replacement amine reaction of general formula [V] expression,

R wherein ², R ³, R ⁴And R ⁵Definition as mentioned,

Then, if desired, remove blocking group;

Then, when needed compound is converted into its non-toxic salt.

10, the allylamine derivatives that replaces of the general formula [I] that provides of production claim 1 and the method for non-toxic salt thereof comprise allylamine derivatives or its protected derivative of the replacement that makes general formula [VI],

A wherein ¹, A ², Q ¹, Q ², X, Y, R ¹, R ³, R ⁴, R ⁵, R ⁶And R ⁷As claim 1 definition,

With the compound reaction of general formula [VII],

R wherein ²As claim 1 definition, Z is a leavings group, then, if desired, removes blocking group, when needed product is changed into non-toxic salt then.

11, produce general formula [I ^a] expression the replacement allylamine derivatives and the method for non-toxic salt,

A wherein ¹, A ², Q ¹, Q ², X ^a, Y ^a, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷As hereinafter definition, it comprises compound or its protected derivative that makes general formula [VIII] expression,

X wherein ^aExpression carbonyl or formula-CHR ^a-group (R wherein ^aExpression hydrogen atom or low alkyl group), Z represents leavings group, and A ¹, Q ¹, R ¹And R ⁶As claim 1 definition, with substituted amine derivatives or its protected compound reaction of general formula [IX] expression,

Y wherein ^aThe expression Sauerstoffatom, sulphur atom, or formula-NR ^b-group (R wherein ^bExpression hydrogen atom or low alkyl group), and A ², Q ², R ², R ³, R ⁴, R ⁵And R ⁷As claim 1 definition,

Then, if desired, remove blocking group; When needed product is converted into non-toxic salt then.

12, produce general formula [I ^b] expression the replacement allylamine derivatives and the method for non-toxic salt,

A wherein ¹, A ², Q ¹, Q ², X ^b, Y ^b, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷As hereinafter definition, comprise the compound or its protected derivative that make general formula [X] expression,

X wherein ^bExpression Sauerstoffatom, sulphur atom or formula-NR ^b-group (R wherein ^bExpression hydrogen atom or low alkyl group), and A ¹, Q ¹, R ¹And R ⁶As claim 1 definition,

With substituted amine derivatives or its protected radical reaction of general formula [XI] expression,

Y wherein ^bExpression carbonyl or formula-CHR ^a-group (R wherein ^aExpression hydrogen atom or low alkyl group), Z represents leavings group, and A ², Q ², R ², R ³, R ⁴, R ⁵And R ⁷As claim 1 definition,

Then, if desired, remove blocking group; When needed product is converted into non-toxic salt then.

13, produce general formula [I ^c] expression the replacement allylamine derivatives and the method for non-toxic salt,

A wherein ¹, A ², Q ¹, Q ², R ¹, R ², R ³, R ⁴, R ⁵, R ⁶And R ⁷As hereinafter definition,

Comprise the compound that makes general formula [XII] expression

A wherein ¹, Q ¹, R ¹And R ⁶As claim 1 definition,

With the compound reaction of general formula [X III] expression,

A wherein ², Q ², R ², R ³, R ⁴, R ⁵And R ⁷As claim 1 definition, then, reduzate,

14, treat hypercholesteremic medicament, it contains allylamine derivatives or its non-toxic salt that the described general formula of claim 1 [I] replaces.

15, the medicament of treatment hyperlipoidemia, it contains allylamine derivatives or its non-toxic salt of the replacement of the described general formula of claim 1 [I].

16, treat arteriosclerotic medicament, it contains allylamine derivatives or its non-toxic salt of the replacement of the described general formula of claim 1 [I].