JPH03173865A - Substituted allylamine derivative, preparation thereof and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (A<1> and A<2> are CH, N, O, S; Q<1> and Q<2> form together with the adjacent C and A<1> or A<2> a 5-6 membered aromatic ring; X and Y are O, S, CO, etc., or form vinylene or ethylene together; R<1> is 5-6 membered heterocyclic ring group; R<2> is alkyl, allyl, propargyl, etc., R<3> and R<4> are alkyl, or both form a cycloalkane together with C; R<5> is H, alkyl or alkoxy; R<6> and R<7> are R<5>, halogen, OH, or CN) and a salt thereof. EXAMPLE:(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(1-pyrrolyl) benzyloxy]benzylamine. USE:Useful for treating and preventing hypercholesterolemia, hyperlipemia and arterial sclerosis. PREPARATION:For example, a substituted amine derivative of formula II is reacted with a compound of formula III (Z is releasing group) to prepare the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted allylamine derivatives, and more particularly in the field of medicine, particularly in the field of hypercholesterolemia,
The present invention relates to substituted allylamine derivatives and non-toxic salts thereof useful in the field of treatment and prevention of hyperlipidemia and thus arteriosclerosis, a method for producing the same, and uses thereof.

Arteriosclerosis is a degenerative disease of the arteries that is closely related to aging and diet, and is the cause of coronary and cerebral artery disease, which is one of the most major causes of death in modern times. is feared as Arteriosclerosis begins as lipid deposits on the intima of large blood vessels from a young age, and increases in scope and severity with age, leading to myocardial infarction, ischemic heart disease such as angina pectoris, and cerebral artery disease such as cerebral infarction. It exhibits clinical symptoms as sclerosis or aneurysm, and it is known that increases in various blood lipids are involved in this lipid deposition. Among these, increased blood cholesterol is the most major risk factor.
Reducing it to a normal value is the most effective means for treating and preventing arteriosclerosis.

It is said that more than 50% of cholesterol in humans is derived from de novo synthesis.
Lovastatin and nibstatin, which are enzyme inhibitors in the biosynthetic process, are currently used clinically as anticholesterol agents [A. W. Alberts et al., Proceedings. National Academy of Science (Pr.
oc, Natl, Acad, Sci, vol. 77, p. 3957 (1980): Tsujita et al., Biochim, Biophysica Acta
phs.

Acta) Vol. 877, p. 50 (1986), etc.].

However, the target enzyme of these inhibitors, 3-hydroxy-3-methylglutaryleucoenzyme A reductase (H
Since MG-CoA reductase is located at an early stage of the cholesterol biosynthesis system, it has the disadvantage that administration of these drugs suppresses the production of other physiologically important metabolites such as dolichol and ubiquinone. Furthermore, triparanol, which is a late stage inhibitor of the cholesterol biosynthesis system, has been reported to cause cataracts due to the accumulation of desmostyrol. Squalene・
Since epoxidase is located in the middle stage of the cholesterol biosynthesis system, inhibitors of epoxidase are expected to solve these problems and become safer anticholesterol agents.

Several compounds are known to date as squalene epoxidase inhibitors [G. Petranyi et al., Science (S.
science), Volume 244, Page 1239 (1984
All of them were developed as antifungal agents that selectively act on fungal enzymes, and only those that inhibit mammalian enzymes and have been touted for their usefulness as anticholesterol agents are known. It has not been done.

One of the main objects of the present invention is to provide an anti-hyperlipidemic drug that is safer and has superior anti-cholesterol effects compared to conventional anti-hyperlipidemic drugs. The purpose of this invention is to provide an agent for treating and preventing arteriosclerosis.

The present inventors searched for squalene epoxidase inhibitors with anticholesterol effects with the aim of developing new anti-arteriosclerotic agents. Substituted allylamine derivatives of squalene and
The present invention was completed based on the discovery that it selectively inhibits epoxidase and has a strong anticholesterol effect.

That is, the present invention relates to the general formula [wherein A' and A2 are the same or different and represent a methine group, a nitrogen atom, an oxygen atom, or a sulfur atom; Ql and Q2 are the same or different and represent a nitrogen atom, an oxygen atom, and may contain one or two heteroatoms selected from the group consisting of sulfur atoms, and adjacent carbon atoms and A1 or A2
Represents a group that together forms a 5- or 6-membered aromatic ring; X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, or
1 represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NRb- (where Rb represents a hydrogen atom or a lower alkyl group), or Both together represent a vinylene group or an ethynylene group; R1 is a 5- or 6-membered heteroatom containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, acids, elementary atoms, and sulfur atoms; Represents a cyclic group; R2 represents a lower alkyl group, allyl group, propargyl group, or cyclopropyl group; Rs and R4 are the same or different and represent a lower alkyl group, or both are bonded together with adjacent carbon atoms. Represents a group forming a cycloalkane, R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; R1 and R7 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy Indicates the group. However, when either one of X and Y represents an oxygen atom, a sulfur atom, or a group represented by the formula NR'- (where Rb has the above meaning), the other represents a carbonyl group or a group represented by the formula Substituted allylamine derivatives represented by CHR"- (where Ro has the above meaning) and non-toxic salts thereof, methods for producing the same, hypercholesterolemia, hyperlipidemia and its use in the treatment of arteriosclerosis.

Furthermore, the present invention will be explained in detail.

It has been known that allylamine derivatives represented by naftifine and tilbinafine, which have the following structural formula: [G, Pe
tranyi et al., Science, Vol. 244, p. 1239 (1984)]. However, these compounds show almost no inhibitory activity against squalene epoxidase in mammals including humans, and cannot act as inhibitors of cholesterol synthesis [N.
N. S. Ryder et al., Biochem, J., Vol. 230, p. 765 (1985)].

Therefore, the present inventors conducted intensive research aimed at developing a drug that selectively acts only on squalene epoxidase in mammals and exhibits anticholesterol effects. : It has been found that when substituted with a group substituted with a group, a compound exhibiting strong inhibitory activity against mammalian squalene epoxidase can be obtained. The present inventors also found that the squalene epoxidase inhibitory effect of the compound represented by the general formula [I] is extremely selective, shows almost no activity against fungal enzymes, and causes hypercholesterolemia,
The present invention was completed based on the discovery that the present invention is extremely valuable as a drug for treating or preventing hyperlipidemia and arteriosclerosis.

Next, definitions of various terms mentioned in the description of this specification and specific examples thereof will be explained.

The term "lower" is used to mean that the group or compound to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms. Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group,
butyl group, isobutyl group, 5ec-butyl group, tert
- Straight or branched alkyl groups having 1 to 6 carbon atoms such as -butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, etc., and as the lower alkoxy group, preferably methoxy group, Examples include straight-chain or branched alkoxy groups having 1 to 4 carbon atoms, such as ethoxy, propoxy, isopropoxy, butoxy, imbutoxy, 5ec-butoxy, or tert-butoxy.

Cycloalkane means a cycloalkane having 3 to 6 carbon atoms, and specifically includes cyclopropane, cyclobutane, cyclopenkune, and cyclobutane. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Next, in order to more specifically disclose the compound of the present invention represented by the general formula [I], the various symbols used in the formula [1] will be described in more detail by giving preferred specific examples thereof. explain.

Examples of the 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms that can be represented by R1 include pyrrolyl group, furyl group, and thienyl group. group, oxasilyl group, isoxasilyl group, thiazolyl group, inthiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group,
Aromatic heterocyclic groups such as pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, such as dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, iso Oxazolidinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1.2-dithiolanyl group, 1.3-dithiolanyl group, 1.2-dithiolyl group, 1.3-dithiolyl group, dihydro Thiopyranyl group, tetrahydrothiopyranyl group, 1,4-dithianyl group, 1
．． Non-aromatic heterocyclic groups such as 4-dithianyl group, l,4-oxathiinyl group or thiomorpholinyl group, etc.
Among these, thienyl group, pyrrolyl group, oxasilyl group, isoxasilyl group, thiazolyl group, isothiazolyl group,
An imidazolyl group, a pyridyl group, a dihydrothienyl group, etc. are preferred, and particularly a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-isoxasilyl group, and 4-thiazolyl group. , 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-inchazolyl group, 3-pyridyl group, 2.3
-dihydro-4-thienyl group, 2,5-dihydro-3-
A thienyl group and the like are preferred.

As described above, X and Y may be the same or different, and each has an oxygen atom, a sulfur atom, a carbonyl group, or a compound of the formula CHR''- (where Ro represents a hydrogen atom or a lower alkyl group). The group or formula represented by 2~NRb (where R
b represents a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or ethynylene group, provided that either X or Y is an oxygen atom, When a sulfur atom or a group of the formula NRb- is represented, the other is a carbonyl group or a group of the formula CHR
"-" refers to a group represented by the formula: -(CHR")r, -
CHR”0-1-0CHR”-1-CHR”S-1-5
CHR"-1-CHR"NR"-1-NRbCHR"-
1-CHR"C0-1-COCHR", -1-COO-
1-OCO-1-CO3-1-SCO-1-C○NR'
-1-NRbCO-1-CH= CH-1-C-C-(
In the formula, Ro and Rb mean a group represented by Knee C
A group represented by H25, a group represented by the formula OCR, -,
A group represented by the formula SCH,-, a group represented by the formula CH2NH-, or a group represented by the formula NHCH,- is preferred.

R2 represents a lower alkyl group, an allyl group, a propargyl group, or a cyclopropyl group, and examples of preferable lower alkyl groups include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a pentyl group. Examples include straight chain or branched lower alkyl groups having 1 to 5 carbon atoms. In addition, particularly as a substituent for R2, a methyl group, an ethyl group, a propyl group, an allyl group, or a propargyl group is preferable, and among these, a methyl group,
Ethyl or propyl groups are most preferred.

R3 and R4 are the same or different and represent a lower alkyl group, or a group in which both are bonded together to form a cycloalkane with adjacent carbon atoms, and preferred lower alkyl groups include, for example, a methyl group, an ethyl group, Examples include straight-chain lower alkyl groups having 1 to 4 carbon atoms such as propyl and butyl groups, and preferred cycloalkanes include 3 to 6 carbon atoms such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane. cycloalkanes can be mentioned. Among these, especially
Substituents for R3 and R4 include methyl group, ethyl group,
A propyl group or a group forming a cyclopropane ring together with adjacent carbon atoms is preferred, and a methyl group is most preferred. R' represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and preferred lower alkyl groups include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
butyl group, isobutyl group, 5ec-butyl group, tert
- Straight or branched lower alkyl groups having 1 to 5 carbon atoms such as butyl group or pentyl group, and preferred lower alkoxy groups include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group,
Examples include straight-chain or branched alkoxy groups having 1 to 4 carbon atoms such as isobutoxy group, 5ec-butoxy group, and tert-butoxy group. Among these, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group are particularly preferred, and a methyl group, an ethyl group, or a methoxy group is most preferred.

Examples of aromatic rings that are the same or different include a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring,
imidazole ring, 1,3.4-oxadiazole ring, 1
, 3.4-Thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. The h+ aromatic ring is preferably an aromatic ring which may be a benzene ring or a thiophene ring.

Further, the aromatic ring is usually most preferably unsubstituted, but in some cases, it may be substituted with a substituent such as a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. Examples of the group include, for example, a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a methoxy group, and the like.

Thus, in the compound provided by the present invention, preferred examples include R1 being a pyrrolyl group, a furyl group, a thienyl group, an oxasilyl group, an isoxasilyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group. , thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group, pyridyl group,
Pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, inoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group , isothiazolinyl group, isothiazolidinyl group, 1.
2-dithianyl group, ■, 3-dithiolanyl group, l, 2-
a dithiolyl group, l,3-dithiolyl group, dihydrothiopyranyl group, tetrahydrothiopyranyl group, 1,4-dithianyl group, 1,4-dithianyl group, 1,4-oxathiinyl group or thiomorpholinyl group; benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, inoxazole ring, thiazole ring, inthiazole ring, imidazole ring, 1,3,4-oxadi an azole ring, a 1.3.4-thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring or a triazine ring; Carbonyl group, formula: CHR”
- (wherein R8 represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NR"- (wherein R8 represents a hydrogen atom or a lower alkyl group) or, alternatively, both X and Y together form a vinylene group or an ethynylene group [provided that one of X and Y is an oxygen atom, a sulfur atom, or a compound of the formula NRb- (here, Rb
has the abovementioned meaning), the other is a carbonyl group or a group of the formula CHR"- (wherein R" has the abovementioned meaning);
R2 is a lower alkyl group, allyl group, propargyl group, or cyclopropyl group, and R1 and R4 are the same or different lower alkyl groups, or both combine to form a cycloalkane with adjacent carbon atoms. R6 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and Ra and R7 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group; Substituted allylamine derivatives of Monna [I] are mentioned. Among these groups, those having the formula: offene ring are preferred, and furthermore, R
1 is a thienyl group, a pyrrolyl group, an oxasilyl group, an inoxasilyl group, a thiazolyl group, an inthiazolyl group, an imidazolyl group, a pyridyl group, or the dihydro aromatic ring is a benzene ring or a thiophene ring, and the formula: furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, 1,3.4
-oxadiazole ring, 1,3,4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring, among which,
In particular, R1 is a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3
-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-4
-thienyl group or 2.5-dihydro-3-thienyl group; Formula: aromatic ring is benzene ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, 1,3.4 -Oxadiazole ring, 1,3,4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring is preferred.

More preferable compound groups include R1 being a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3- Isothiazolyl group, 4-
isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2.3-dihydro-4-thienyl group or 2.5-dihydro-3-thienyl group; X is a methylene group: Y is a methylene group, an oxygen atom , a sulfur atom or an imino group, or Y is a methylene group: X is a methylene group, an oxygen atom, a sulfur atom or an imino group, or X and Y
Both together are an (E)-vinylene group; Formula: The aromatic ring is a benzene ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a 1,3.4- Oxadiazole ring, 1
, 3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring, R2 is a lower alkyl group, allyl group, propargyl group or cyclopropyl group, and R1 and R4 are the same or different lower is an alkyl group, or a group in which both of them combine to form a cycloalkane with adjacent carbon atoms; R5
is a hydrogen atom, a lower alkyl group, or a lower alkoxy group; R'' and R7 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. , especially R1
is a 3-thienyl group, l-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-ynoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-4-thienyl group, 2,5-dihydro-3-thienyl group; Formula/Object: aromatic ring is benzene ring, furan ring, thiophene ring, Oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, 1,3.4-oxadiazole ring, 1,3
．． 4-thiadiazole ring, pyridine ring, pyridazine ring,
pyrimidine ring or pyrazine ring; R'' is a methyl group, ethyl group or propyl group, Ra and R'' are a methyl group, R8 is a methyl group, ethyl group or methoxy group; R8 and Compounds in which R7 is a hydrogen atom are preferred.

The substituted allylamine derivative of formula [I] can exist in the form of an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, etc. , nitrates, perchlorates or phosphates; or, for example, p-toluenesulfonates, benzenesulfonates, methanesulfonates, oxalates, cono\
Examples include organic acid salts such as phosphates, tartrates, citrates, fumarates, and maleates, and pharmaceutically acceptable non-toxic salts are particularly preferred. Furthermore, the formula [I
The compound of I may have stereoisomers such as geometric isomers and optical isomers depending on the form of its substituents, but the present invention also includes all these stereoisomers and mixtures thereof. .

Next, a general method for producing the compound according to the present invention will be explained.

The compound of formula [II of the present invention can be prepared, for example, by the following manufacturing method ASB
It can be manufactured using any of SCSD, E and F methods.

[Manufacturing method A] [Manufacturing method B] [Manufacturing method C] [Manufacturing method D] [Manufacturing method E] [Manufacturing method F] [Wherein, Z represents a leaving group: X1 and Yb are carbonyl groups or , Ro represents a group represented by the above-mentioned meaning); A1, A2,
Ql, Ql, RISRl, R"SR', R5, R'
and H R' has the meaning of 17) above] The above production methods A, B and C are all well-known alkylation reactions of amines in the field of organic synthetic chemistry, and therefore, they are per se well-known ordinary methods. This can be done using means. The reaction is usually carried out in either case with a solvent which does not have an adverse effect on the reaction; for example aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane; e.g. methylene chloride, chloroform or dichloroethane; In the case of a compound [I[
] and compound [II[], in the case of production method B, compound [I
V] and compound [V], and in the case of production method C, compound [
VI] and compound [■] in an equimolar ratio, or
Alternatively, it may be carried out by reacting either one in slight excess. Regarding the reaction conditions employed at this time, the reaction temperature is generally from -20'C to the boiling point of the solvent, preferably from room temperature to 150°C, and the reaction time is usually from 5 minutes to IO
It can be for days, preferably 1 to 24 hours.

In addition, in this reaction, it is advantageous to conduct it in the presence of a base in order to proceed smoothly. Examples of the base used in this case include alkali hydrides such as sodium hydride, lithium hydride, or potassium hydride. Metals; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate; or triethylamine or pyridine, etc. Examples include organic amines. The amount of these bases to be used is equimolar to each raw material compound or an excess amount, preferably 1 to 2
It can be a mole.

The above manufacturing method and E are such that in the compound of the present invention represented by -Momonana [I], the group of formula N-X-Y- is of formula N-COO-1
-OCO-1-CONR'-1-NR"C○-1-CH
R・0-1-0CHR"-1-CHR"S-1-3CH
R''- (wherein R1 and Rb have the meanings given above)
This is a manufacturing method for synthesizing a compound of formula [I"l or [I"], which is a group represented by. For the manufacturing process and E, compound [■] and compound [IX] are usually mixed in a solvent that does not adversely affect the reaction, such as tetrahydrofuran, dioxane, chloroform, benzene, acetone, dimethylformamide or dimethyl sulfoxide. In the case of production method E, compound [XI] and compound [XI] are reacted in an equimolar ratio, or either one is reacted in slight excess. The reaction conditions adopted at this time are:
Although it varies depending on the raw materials used, the reaction temperature is generally in the range of -70 to 100°C, preferably -20 to 50°C, and the reaction time is 1 minute to 24 hours, preferably 30 minutes to It is 5 hours. In addition, in order to proceed with the reaction smoothly, this reaction is preferably carried out in the presence of a base. Examples of bases used in this case include sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, carbonate Examples include inorganic bases such as sodium, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, and organic bases such as pyridine, triethylamine, and dimethylaminopyridine.Although the amount used is not strictly limited, usually, It can be used in an equimolar amount or in excess of each raw material compound, preferably within a range of 1 to 2 moles.

In production method F, among the compounds of the present invention represented by -Momonana [I], the group represented by the formula
This is a manufacturing method for synthesizing the compound [Ic] represented by H.

Production method F can be carried out, for example, by condensing compound [X[I] with compound [XI[] in advance to form an imine in benzene or alcohol, and then reducing the mixture.

Examples of reagents used for the reduction include sodium borohydride, sodium cyanoborohydride, and lithium aluminum hydride. The reaction conditions at this time include, for example, a method in which the reaction is carried out in methanol, ethanol or tetrahydrofuran at 0° C. to room temperature for 1 to 6 hours.

In addition, in the above manufacturing method, the formula [I
If a reactive functional group such as a hydroxyl group or an amino group is present in the compound of [I] to [X[Il] in addition to the hydroxyl group, mercapto group, or amino group that participates in the reaction, these reactions can be carried out if necessary. The reaction can be carried out after appropriately protecting the functional groups, and these protective groups can be removed after the reaction. Protective groups used in this case include those that are easily eliminated by hydrolysis under acidic or alkaline conditions, such as methoxymethyl group, tetrahydropyranyl group, trityl group, dimethyl(tert-butyl)silyl group, formyl group, etc. group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, or tert-butoxycarbonyl group.

The target compound of formula [I] of the present invention obtained in the above steps can be isolated and purified by, for example, column chromatography, solvent extraction, precipitation, recrystallization, etc. alone or in an appropriate combination. . Furthermore, if necessary, the free base of the compound of the present invention represented by -Momonena [I] can be converted into its acid addition salt, and vice versa, the acid addition salt can be converted into its free base. Step 1 of converting the free base of the compound of formula [I] into its acid addition salt. Further, the step of converting an acid addition salt into its free base can be easily carried out by a conventional method using the corresponding acid or base.

Note that the leaving group represented by Z includes, for example, a chlorine atom,
Examples include halogen atoms such as bromine atoms and iodine atoms, and organic sulfonyloxy groups such as methanesulfonyloxy groups and p-)luenesulfonyloxy groups.

The raw material compounds [I] to [Hyaku] used in the above production methods A-F can be purchased as commercially available products or prepared according to the production method described in the literature [Journal of Medicinal Chemistry (J,
Med, Chem, Volume 27, Page 1539 (19
1984); Journal of Medicinal Chemistry (J, Med, Chem,) Volume 29, No. 11
Page 2 (1986): JP-A No. 56-32440, No. 5
No. 7-123177, No. 58-208252, No. 61
-45, No. 62-201850, No. 63-5059
[Refer to Publications, etc.], and can be manufactured and obtained by the one-boat fishing method shown below or a method similar thereto.

The raw material compound used in the present invention can be produced, for example, by the following synthesis method.

Manufacturing route (a) Manufacturing route (b) Manufacturing route (C) Manufacturing route (d) [I] 1] Manufacturing route (e) Manufacturing route (f) In formula E, X6 and Yo may be the same or different. often,
Oxygen atom, sulfur atom, carbonyl group, formula ``CHR'' (
where R1 has the above meaning) or a group represented by the formula NRb- (wherein Rb has the above meaning)
represents a group represented by; R1 represents a lower alkyl group; R
11 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group; B represents a hydrogen atom or a protective group; and A1, A
2, Ql, Q2, x, ySx", Xb, Y", Y"S
Z, R', R2, R3, R4, R6, R6 and R7 have the above meanings.

However, if either Xo or Yo represents an oxygen atom, a sulfur atom, or a group represented by the formula NR''- (where Rb has the above meaning), the other represents a carbonyl group or a group represented by the formula NR''- (where Rb has the above meaning). represents a group represented by "- (in the formula, R" has the above meaning)] Mugiori Nigoko 0 Compound [XIV] is reacted with compound [■] to form compound [
XVI], for example, sodium hydride,
In the presence of a base such as sodium hydroxide or potassium carbonate,
For example, this can be carried out by reacting Compound [] and Compound [■] in a substantially equimolar ratio at -20 to 100°C for 2 to 3 hours in a solvent such as tetrahydrofuran, chloroform or dimethylformamide.

Compound [X] is reacted with compound [XV] to form compound [X].
The step of producing compound [VI] is to add compound [■] to compound [W].
It can be carried out in the same manner as the step of reacting.

The step of producing compound [■-] by reacting compound [XVI] with compound [X■] can be carried out by, for example, condensing compound [XVI] with compound [X■] in advance in benzene or alcohol to form an imine. This can be carried out by reducing the reaction mixture after the reaction is carried out, or by reacting excess compound [X■] with compound [XVI] and reducing it at the same time. Examples of reagents used for the reduction include sodium borohydride, sodium cyanoborohydride, and lithium aluminum hydride. The reaction conditions at this time include, for example, a method in which the reaction is carried out in methanol, ethanol or tetrahydrofuran at 0° C. to room temperature for 1 to 6 hours.

The step of reducing compound [XVI] to produce compound [X This can be carried out by treating with a reducing agent such as aluminum lithium for 1 to 5 hours.

The step of converting compound [X This can be carried out by treating with a sulfonylating agent such as triethylamine at a temperature of 0° C. to room temperature for 1 to 5 hours.

The step of producing compound [X] by reacting compound [X] with compound [X - This can be carried out by treatment with a base such as butyllithium or sodium hydride for 1 to 6 hours.

The step of reducing compound [XXl to produce compound [X■°] can be carried out by treating for 1 to 5 hours with a reducing agent such as lithium aluminum hydride in a solvent such as ethyl ether or tetrahydrofuran. .

Also, reducing the compound [XXl or reducing the compound [XVI[
”] to produce compound [XVI'l,
For example, compound [X
] in methylene chloride with pyridinium chlorochromate.

The step of converting compound [XVI[''] into compound [■1] and the step of reacting compound [XVI'l with compound [X■] to produce compound [I]'l are each carried out by the above-mentioned production route ( It can be carried out in the same manner as a), the step of converting compound [X■] into compound [■"] and the step of reacting compound [XVI] with compound [X■] to produce compound [■°].

The step of producing compound [XVI["] by reacting compound [XXI] with compound [XXII] or reacting compound [XX[Il] with compound [] is the step of producing compound [XVI["] Compound [XIX] is reacted with compound [XI[] to form compound [X
X] can be carried out in the same manner as the process for manufacturing.

The step of producing compound [XV]Ib] by reducing compound [X°] is carried out by reducing l~ This can be done by contacting for 10 hours.

The step of converting compound [X°] into compound [X°] is to convert the compound [X°] as it is or after protecting it with an appropriate protecting group into an organic solvent such as methylene chloride, chloroform or ethyl ether. , for 0.5 to 3 hours at 0 to 60 °C, the resulting reaction solution is concentrated to dryness, and then reacted with methanol, for example, in the presence of a base such as sodium hydroxide or potassium hydroxide. 1-1 at the boiling point of the solvent in an alcohol solution such as ethanol or isopropanol
This can be done by treating for 0 hours.

The step of converting the compound [XVI[''] into the compound [■°] and the step of converting the compound [XVI['] into the compound [■6] are the steps of converting the compound [X■] into the compound [■°], respectively.
] can be carried out in the same manner as the step of converting into

Production: ``Nim Q The step of producing compound [VT] by reacting compound [XVI'l with compound ['] is to react the compound [XVI] with compound [X■] to form compound [■ °] can be carried out in the same manner as the process for manufacturing.

In addition, the compound [V"l used in this case is, for example, compound [I The compound [XXIV] can be produced by reacting with phthalimide to produce the compound [XXIV], which is then reacted with hydrazine in, for example, ethanol or dimethylformamide to produce the compound ['], such as the so-called Gabriel method. can.

Hairband Kaminigoko Frog Compound [X! The step of producing the compound [XX■] by reacting the compound [X■] with the compound [XVI
] with compound [X■] to produce compound [■8], or reduce compound [XIV''] to produce compound [XXV], which is then converted into compound [XXVI]
In the step of converting into compound [XVI], compound [X
■The process of converting into [°]] can be carried out in the same way.

Alternatively, compound [XXVI] can be reacted with compound [V], or compound [XX■] can be reacted with compound [I]1 to produce compound [XX■1], which can then be deprotected if necessary. The step of obtaining compound [IX] is the above-mentioned production method A.
Alternatively, it can be carried out using the same method as method B.

In addition, in the raw material compound of this production route (e), the protecting group represented by B in the formula is one of various types commonly used in the field of synthetic organic chemistry as a protecting group for a hydroxyl group, a mercapto group, or an amino group. can be a protecting group, specifically, for example, a methoxymethyl group, a tetrahydropyranyl group,
Examples include trityl group, tert-butoxycarbonyl group, and dimethyl (tert-butyl)silyl group.

The process of reducing compound [XXIX] to produce compound [XXX] is a partial reduction that takes advantage of the difference in the reactivity of coexisting carbonyl groups to reduction, for example, at -20°C to room temperature. , in a solvent such as ethanol or tetrahydrofuran,
For example, compound [XXIX] is reduced with 1 to 2 equivalents of a reducing agent such as sodium borohydride or diisobutylaluminum hydride for 1 to 5 hours, or catalytically reduced in the presence of a catalyst such as palladium-carbon for 1 to 5 hours. This can be done by doing. Compound [XXX] is converted into compound [XXX
The step of converting the compound [Xxv] into the compound [XXVI] and then reacting it with the compound [V] to produce the compound [XXXI[] is to convert the compound [Xxv] into the compound [XXVI], and then react it with the compound [V]. ] can be carried out in the same manner as the step of producing compound [XX■].

Compound [XXXI] is converted to compound [XXXIII]
The process of manufacturing is such that T is the formula "CHR"- (where R
1 has the above-mentioned meaning) by reduction in the case of an alcohol product [XXX[], and by hydrolysis in the case of a carboxylic acid product [XXE[] in which r represents a carbonyl group. can be done. Compound [XX
)I] to produce the corresponding alcohol [XXXIII
] The step of producing compound [XVI] is a step of producing compound [X■] or compound [X
It can be carried out in the same manner as the step of producing compound [X°] by reducing . The step of producing the corresponding carboxylic acid compound [XXE[] by hydrolyzing the compound [XXXff1] is, for example, a step of hydrolyzing the compound [XXXff1] in the presence of an equimolar or excess molar amount of a base such as sodium hydroxide, for example, in aqueous ethanol or This is carried out by dissolving the solution in a solvent such as hydrous tetrahydrofuran and heating the solution at room temperature to 100°C for 1 to 10 hours.

The step of converting compound [XXEI] to produce compound [XXE] is carried out, for example, in the absence of a solvent or in a solvent such as chloroform or methylene chloride with a halogenating reagent such as thionyl chloride or phosphorus tribromide at 0°C. This can be carried out by treating at room temperature for 1 to 5 hours.

The products obtained in each of the above steps can be purified or isolated by performing known purification methods such as chromatography, recrystallization, solvent extraction, precipitation, distillation, etc. alone or in appropriate combinations, if necessary. can do.

Compounds that serve as starting materials for these raw material intermediates can be purchased as commercial products or described in literature [Journal of Medicinal Chemistry (J, Med,
Chem, Volume 27, Page 1539, (1984); Journal of Medicinal Chemistry (
J, Med, Chem,) Volume 29, Page 112 (
1986); JP-A-56-32440, JP-A No. 57-1
No. 23177, No. 58-208252, No. 61-45
No. 62-201850, No. 63-5059, etc.] or by using known synthesis methods in organic synthetic chemistry.

The compound of the present invention represented by the general formula [I] inhibits squalene epoxidase in mammals extremely selectively and strongly, and can be used as an antihyperlipidemic agent and an antiarteriosclerotic agent. This is a promising and useful compound.

In order to prove this, pharmacological test examples and acute toxicity test examples will be given and explained below.

Pharmacological test example 1 Squalene epoxidase (1) Preparation of squalene epoxidase
Epoxidase is published in the Journal of Biological Sciences.
Chemistry (J, Biol.

Chem,) Volume 245, Page 1670 (197
250, p. 1572 (1975).

That is, SD female rats are killed by exsanguination and then their livers are removed. The liver is homogenized in 2 volumes of O, 1M Tris-HCI buffer (pH 7.5) and centrifuged at 9750Xg for 10 minutes. The obtained supernatant was further diluted with 1105
Centrifuge for 1 hour at 000X and then transfer the pellet to 0.1M
After washing with Tris-HCI buffer (pH 7,5),
Centrifuge at 1105000X for 1 hour. The obtained microsomes were heated with O, so that the protein ff was 140 mg/m/m.
Suspend in 1M Tris-HCI buffer (pH 7,5) and solubilize by stirring in the presence of 2% Triton X-100 while cooling with water. After this solubilization treatment, 1mM EDTA and 1
Triton X-100 concentration was reduced to 0 with mM dithiothreitol.
．． Dilute to 5% and centrifuge at 1105000X for 1 hour. The obtained supernatant is used as a squalene epoxidase fraction in the test described below.

(2) Method for measuring squalene epoxidase activity Measurement of squalene epoxidase activity is described in the Journal of Biological Chemistry (J.

Biol, Chem,) Volume 245, Page 1670 (
(1970).

That is, 0.2 m7 of the squalene epoxidase fraction prepared in (1) [0.4 mg protein fi, 0.5% Triton X-100, 20 μM Tris-HCI buffer (pH 7,5)], 100 μM FADSlmM
To a solution consisting of a suspension of ADPH, 1mM EDTA, and 8μM H-squalene-Tweeter 80, 311! of a dimethyl sulfoxide solution of the test drug was added, and the total volume was reduced to 0.
The volume was adjusted to 3 ml, and the mixture was shaken and reacted at 37°C for 30 minutes. 10%
The reaction is stopped by adding 0.3 ml of potassium hydroxide-methanol solution and left at room temperature for 1 hour. Next, unsaponifiable substances are extracted with petroleum ether, and then concentrated to dryness under a nitrogen stream. The resulting residue was dissolved in a small amount of ethyl ether and spotted on Pre-coated silicagel TLC, and benzene-ethyl acetate (99,5:0.
Expand in 5). Furthermore, the generated 3H-squalene-2,
The position of 3-epoxide in TLC was confirmed using ergosterol acetate as a marker, and the 3H-
Cut out the squalene-2,3-epoxide part. The T
The LC piece is immersed in a toluene scintillator and measured using a liquid scintillation counter. As a result, the 50% inhibitory concentration (IC, value) of the compound of the present invention against squalene epoxidase was determined, and the results are shown in Table 1.

Table 1 Squalene epoxidase inhibitory effect Pharmacological test example 2 Cholesterol Huma
10 n Hepatoma (Hep-G2) cells
After culturing until a monolayer formed in a cm" Petri dish, 1 ml of the culture solution was replaced, 1 μCi of +4C-sodium acetate and 11 liters of a dimethyl sulfoxide solution of the test drug were added, and the cells were incubated at 37°C in air mixed with 5% carbon dioxide for 6 hours. Cultivate.

After culturing, the medium was removed by suction and cooled on ice, followed by Dul
Wash with becco's buffered saline. The obtained cells are scraped off with a rubber policeman and collected by centrifugation. The collected cells were mixed with 0.3N sodium hydroxide 40
After dissolving at 0 J, 200μ of the sample was used for extraction, and the rest was used as a sample for protein quantification.

Add 15% potassium hydroxide-ethanol to 200 Iil of the extracted sample, add 1 ml of water saponified at 75°C for 1 hour, and extract unsaponified substances twice with 2 ml of petroleum ether. The obtained petroleum ether extract was washed with 1 mi' of water and concentrated to dryness under a nitrogen stream. The residue was purified with Pre-coated Silicagel using a small amount of chloroform.
Spot on TLC, develop with hexane-ethyl ether-acetic acid (85:15:4), detect cholesterol and squalene moieties on TLC with iodine, and cut out the corresponding TLC moieties. The TLC piece is immersed in a toluene-based scintillator, and radioactivity is measured using a liquid scintillation counter. The results are published in the Journal of
Biological Chemistry (J.

Biol, Chem, Volume 193, Page 265 (1)
Corrected using the protein amount measured by the method described in 1999). Thereby, the 50% inhibitory concentration (IC, value) of the compound of the present invention against cholesterol biosynthesis in cultured Hep-G2 cells was determined and the results are shown in Table 2.

Table 2 Cholesterol biosynthesis inhibition effect in cultured cells Pharmacological test example 3 The in vivo test of cholesterol in cultured cells uses female SD rats of 5 weeks of age.

b) In an environment where the lighting is reversed from day to night (6 a.m. to 6 p.m.)
The animals were kept for 9 days (dark and dark) and allowed access to solid food and water ad libitum. The test drug shows the maximum amount of cholesterol synthesis,
Administer orally 2 hours before dark/6 o'clock. The compounds are dissolved in water containing 5% dimethyl sulfoxide and 2% Tween 80, and 3 mg/kg each is administered orally in a volume of 1 ml/100 g body weight. In addition, for the control group, the same volume of the used solvent (Ve
hicle). One hour after administering the test drug, rats were given 14c-sodium acetate (56 mCi/m
mole) is administered intraperitoneally at 20 μCi/100 g body weight. Blood samples are obtained from the abdominal artery under ether anesthesia at 6 o'clock in the dark, and plasma is separated by centrifugation.

Plasma is saponified by adding 2 m7 of 15% potassium hydroxide-methanol solution per m7 and heating at 75°C for 3 hours. The sample is 2ml with 2ml of petroleum ether.
Extract twice and then wash with 2 ml of distilled water.

Finally, the extract is dried under a nitrogen stream.

The resulting residue was dissolved in a small amount of ethyl ether and pre
- Spot the entire amount on coated silicagel TLC. The plate is developed with a solvent system of hexane/ethyl ether/acetic acid (85:15:4). Coloring is done by iodine, and cholesterol site 1
The radioactivity in the tube is measured using a liquid scintillation counter.

The results (Table 3) show that the generated 14C- present in 1 mJ of plasma
Expressed in dpm value of cholesterol. In addition, the inhibition of cholesterol biosynthesis is calculated by comparing the amount of 14C-cholesterol biosynthesis between the test group and the control group.

Table 3 Cholesterol biosynthesis inhibition test in rats (n = 5) Acute toxicity test example Each test drug (compound of Example 3.9.19.20.25.51; all free bases) was mixed with medium chain fatty acid glycerin ester. (MCT) and orally administered to mice (ddy male mice, weight 28±2 g, 2 mice in 11 groups), and acute toxicity was examined from the mortality rate one week after administration.

The toxicity of each test drug was extremely low, and no deaths were observed even at a high dose of 1000 mg/kg.

As is clear from the above results, the compound of the present invention strongly inhibits squalene epoxidase and inhibits cholesterol biosynthesis. ,
It is effective in treating and preventing diseases such as hyperlipidemia and arteriosclerosis. Further, the squalene epoxidase inhibitory effect of the compound of the present invention is not observed in fungi and the like and is specific to mammals, and furthermore, the toxicity is low, so the present invention is extremely useful in the pharmaceutical field.

The compound of formula [I] of the present invention can be administered orally or parenterally, and by formulating it into a form suitable for such administration, it can be used to treat hypercholesterolemia, hyperlipidemia and arteriosclerosis. It can be used for the treatment and improvement of diseases, etc. When using the compound of the present invention clinically, it is also possible to prepare various formulations by adding pharmaceutically acceptable additives according to the dosage form, and then administer the compound. As additives in this case, various additives commonly used in the pharmaceutical field can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and corn starch. , microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinyl Examples include pyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrin.

Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories, or liquid preparations such as syrups, elixirs or injections. These can be prepared according to conventional methods in the pharmaceutical field.

In addition, in the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the same time. Moreover, especially in the case of an injection, it may be dissolved or suspended in physiological saline or glucose solution, and a buffer or a preservative may be added as necessary.

These formulations contain the compounds of this invention at a total dosage of 1.0 to 10
It can be contained in a proportion of 0% by weight, preferably 1.0 to 60% by weight. These formulations may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, antiarteriosclerotic agent, or antihypercholesterolemic agent, the dosage and frequency of administration should be determined depending on the patient's sex, age, weight, severity of symptoms, and purpose. Although it varies depending on the type and scope of the therapeutic effect, in general, in the case of oral administration, the dose per day for adults is 0.01~
It is preferable to administer 20 mg/kg in one to several doses, and in the case of parenteral administration, administer o, ooi to 2 mg 7 kg in one to several doses.

The present invention will be described in more detail below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

Example 1 (E)-N-(6,6-dimethyl-2-heptene-4-
190 mg of (inyl)-N-methyl-3-hydroxybenzylamine was dissolved in 3 ml of anhydrous tetrahydrofuran,
Add 31 mg of 60% oily sodium hydride while stirring under water cooling, and stir for 10 minutes. Add 3 prepared in advance to this solution.
-(2-furyl)benzyl chloride ether solution [3
-(2-furyl)benzyl alcohol (160 mg) and thionyl chloride (73 Atl) were reacted in 3 ml of anhydrous ethyl ether under ice-cooling and stirring for 3 hours, and this liquid was then washed with saturated brine and 5% aqueous sodium bicarbonate] and dimethyl Add 1 ml of formamide and stir at room temperature overnight. 30 ml of water and 30 ml of ethyl ether are added to the reaction mixture to separate the layers, and the organic layer is separated, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off. The residue was subjected to medium pressure liquid chromatography [column: Lobar
column, 5ize B, Lichropre
Purification using pSi 60F (manufactured by Merck) and elution solvent: hexane/ethyl acetate = 10/1 → 8/1 yields 63 mg (yield: 21%) of the free base of the title compound as a colorless oil. . Treatment of the above free base with a solution of hydrogen chloride and methanol, followed by recrystallization from a mixture of ethyl acetate/ethyl ether, yields the title hydrochloride salt, m, p,
115-116° C1 is obtained.

rRv"4cm-': 2968.2488.160
5.1497.1461°1266,789 NMR (CDC/,) δ: 1.25 (9H, s),
2.60 (3H, s).

3.50-3.64 (2H, m), 4.00-4.1
3 (2H.

m), 5.20 (2H, s), 5.78-5.84
(IH, m).

6.18-6.32 (IH, m), 6.47 (LH
, dd, J=3.5Hz, 2.0Hz), 6.70 (
LH, d, J = 3.5Hz).

7.05-7.11 (2H, m), 7.30-7.
47 (5H.

m), 7.62 (LH, d, J = 7.1Hz),
7.78 (IH,s) Example 2 (E)-N-(6,6-dimethyl-2-heptene-4-
Inyl)-N-ethyl-3-hydroxybenzylamine loomg was dissolved in 1 m4 of anhydrous tetrahydrofuran,
Add 20 mg of 60% oily sodium hydride while stirring under water cooling, and stir for 10 minutes. To this solution was added 1 m4 of a solution of 100 mg of 3-(1-pyrrolyl)benzyl methanesulfonate in dimethylformamide, and the mixture was stirred overnight at room temperature.
m1 and 30 m7 of ethyl ether for extraction. The organic layer is separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was subjected to silica gel column chromatography [Wakogel C-200° 20g, elution solvent: hexane/ethyl acetate = 10/1 → 5/1]
110 mg of the title compound as a colorless oil (
A yield of near 0%) is obtained.

IR: cm-': 296B, 1596.150
6.1488.1455゜1341, 1263.107
1.786.726NMR(CD(J'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.
6Hz), 3.49 (2H.

s), 5.06 (2H, s), 5.59 (LH, d
t, J = 15.9Hz, 1.6Hz), 6.01
(IH, dt, J = 15.9Hz.

6.4Hz), 6.30 (2H, t, J = 2.1
Hz), 6.80 (IH, ddd, J = 8.3Hz
, 2.6Hz, 0.8Hz).

6.88 (IH, d, J = 7.6Hz), 6.9
6-6.98 (IH.

rn), 7.06 (2H,t,J = 2.1Hz)
, 7.17 (IH.

t, J = 7.8Hz), 7.25-7.32 (2
H, m), 7.39 (lH, t, J = 7.8Hz)
, 7.44-7.45 (IH,m) Example 3 1'(E)-N-ethyl-N-(6-medoxy6-methyl-2-hepten-4-ynyl)-3-hydroxy of benzylmine 57.5 mg of benzylamine and 0.5 mg of anhydrous tetrahydrofuran
mj, 8.1 mg of 60% oily sodium hydride was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. To this liquid was added 1 m4 of a solution of 53.7 mg of 3.(3-thienyl)benzyl methanesulfonate in dimethylformamide, and after stirring overnight at room temperature, the solvent was distilled off under reduced pressure. Methylene chloride and water were added to the residue, and after treatment by a conventional method, medium pressure liquid chromatography [column: Lobar colu
mn.

5ize A, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
Purification by 6/l→1/1F gives 81.6 mg (yield: 89%) of the free base of the title compound as a colorless oil. Treatment of the above free base with a hydrogen chloride-methanol solution followed by recrystallization from a mixture of ethyl acetate/ethyl ether yields the title hydrochloride salt, m, p, 153-155°C.
, is obtained.

IR: cm-': 3340, 2986, 2932
,1605,1455°1266, 11?3. 10
71.777NMR (CDC/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 (IH, d
, J = 15.9Hz), 6.36 (IH, dt,
J-15,9Hz, 7.9Hz).

7.00-7.20 (2H, m), 7.33 (IH
, t, J = 7.9Hz), 7.40-7.70 (
7H,m), 7.73 (LH,s) Example 4 5-(3-methylphenyl)isoxazole 106m
g.

119 mg of N-bromosuccinimide and 2 mg of benzoyl peroxide are dissolved in 10 mA' of carbon tetrachloride and refluxed for 3 hours with stirring. After cooling, the precipitate was filtered off and concentrated under reduced pressure to obtain 5-(3-bromomethylphenyl)isoxazole as a pale yellow oil.

The bromomethyl compound obtained above was dissolved in 5 ml of dimethylformamide, and this solution was preliminarily mixed with (E)-N-(6°6
-Simethyl-2-hebuten-4-ynyl)-N-methyl-3-hydroxybenzylamine (171 mg) and 30 mg of 60% oily sodium hydride were added to a solution of phenolate in tetrahydrofuran (10 mi') under water cooling. Stir for 1 hour. The reaction solution is diluted with water and ethyl ether, and the organic layer is separated and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar
column, 5tze A, Lichropr
epSi 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 10/1 → 5/l] and preparative thin layer chromatography [thin layer plate: Kieselgel 6
0F2B4, Art.

5744 (manufactured by Merck & Co., Ltd.), developing solvent: hexane/ethyl acetate = 3/1] to obtain 19 mg (yield: 11%) of the title compound as a colorless oil.

IRv":::cm-': 2974.27B8.1
584.1491.1470°1266, 786 NMR (CDC4,) δ: 1.24 (9H, s),
2.19 (3H, s).

3.04 (2H, dd, J = 6.5Hz, 1.4
Hz), 3.47 (2H,s), 5.13 (2H,s
), 5.65 (IH, dt, J = 15.8Hz, 1
．． 4Hz), 8.08 (2H, dt, J = 15.8
Hz, 6.5Hz), 6.55 (IH, d, J =
1.9Hz).

6.88 (IH, ddd, J = 8, IHz, 2.
6Hz, 0.9Hz).

6.70-6.75 (IH, m), 7.00-7.0
3 (IH.

m), 7.24 (IH, t, J = 8.1Hz),
7.50-7.55 (2H, m), 7.77 (IH,
dt, J = 6.7HzSl; 9Hz).

7.88-7.91 (IH, m), 8.30 (I
H, d, J = 1.9 Hz) Example 5 l-(3-hydroxymethylphenyl)imidazole 9
Dissolve 0 mg in 10 mj of chloroform and add 100 IJJ! of thionyl chloride! and stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl ether and water, and after separating the organic layer, a 5% aqueous sodium bicarbonate solution,
Then, it is washed with water successively and dried with anhydrous magnesium sulfate. After filtering off the desiccant, ethyl ether was distilled off to obtain 1-
(3-chloromethylphenyl)imidazole is obtained as a pale yellow oil.

The chloromethyl compound obtained above was dissolved in 1.5 m/dimethylformamide, and (E)-N-(6,6-dimethyl-2-hebuten-4-ynyl)-N-methyl-3-hydroxybenzylamine Examples 1-
By carrying out the same reaction as in 4, 110 mg (yield: 57%) of the title compound is obtained as a colorless oil.

IRv":::cm': 1599.1506.1
491.1455.1311゜1263, 1056.1
026.786NMR (CDC1's) δ: 1.24
(9H,s), 2.18 (3H,s).

3.36 (2H, dd, J = 6.5Hz, 1.4
Hz), 3.47 (2H,s), 5.13 (2H,s
), 5.65 (LH, dtj = 15.8Hz, 1.
4Hz), 6.07 (IH, dt, J = 15.8H
z, 6.5Hz), 6.87 (LH, ddd, J =
8.3Hz, 2.7Hz, 1.0Hz), 6.92
(IH, d, J = 8.3Hz), 6.99-7.1
0 (LH, m), 7.22 (IH, t.

J = 1.4T(z), 7.24 (IH,t,J
= 7.7Hz) 7.31 (IH, t, J = 1.
4)(z), 7.34-7.45 (2H.

m), 7.50 (IH, t, J=7.7Hz), 7.
51 (IH.

s), 7.88 (IH, t, J = 1.4 Hz) In place of the various raw material compounds of Examples 1 to 5 above, the corresponding 3
-Hydroxybenzylamine derivatives and 3-heterocyclic-substituted benzyl halogen derivatives or methanesulfonyl derivatives, or the raw materials thereof, and the same reactions as in Examples 1 to 5 were carried out to obtain the compounds of Examples 6 to 44. Obtained.

Example 6 Luamine IRv'::cm': 2968,1458,126
3,1161,10591038.1020,873,
777 NMR (CDC4) 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 (IH, dt, J
= 15.9Hz, 1.5Hz), 6.07 (IH,
dt, J = 15.9Hz, 6.4Hz).

6.71 (IH, dd, J = 1.8Hz, 0.9
Hz), 6.87 (LH, dd, J = 7.8Hz,
2.0Hz), 6.92 (IH.

d, J = 7.6 Hz), 7.02 (LH, br,
s), 7.22 (IH, t, J=7.8Hz), 7.3
4 (LH, dt, J=7.4Hz, 1.7Hz), 7
．． 39 (IH, t, J = 7.1 Hz).

7.45 (IH, dt, J = 7.4Hz, 1.7
Hz), 7.48 (IH, t, J = 1.7Hz),
7.57 (IH,,br,s).

7.75 (IH, t, J = 1.4Hz) Example 7 IRv':::cm-': 2968,1599,1
491,1455,1365゜1266.1152,1
026,786,696NMR (CD(J3) δ:
1.24 (9H, s), 2.18 (3H, s).

3.04 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.47 (2H,s), 5.10 (2H,s
), 5.65 (LH, dt, J = 15.8Hz, 1
．． 5Hz), 6.08 (IH, dt, J = 15.8
Hz, 8.6Hz), 6.86-6.93 (2H, m
).

7.00 (IH, br, s), 7.23 (LH, t
, J = 7.8Hz).

7.29 (LH, dd, J = 5.1Hz, 1.I
Hz), 7.33 (I H, dd, J = 3.6Hz
, 1, 1 Hz), 7.36-7.39 (LH,
m), 7.40 (IH, t, J = 7.6Hz),
7.57 (I H, dt, J = 7.6Hz, 1.
8Hz), 7.68-7.71 (IH, m) Example 8 IRv cm-': 2968, 1599, 1491
, 1455, 1365° 1263.1026.774 NMR (CDCJ,) δ0.24 (9H, s), 2.
18 (3H, s).

3.03 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.47 (2H,s), 5.10 (2H,s
), 5.64 (IH, dt, J = 15.8Hz, 1
．． 5Hz), 6.08 (IH, dt, J=15.8H
z, 6.6Hz), 6.86-6.92 (2H, m)
.

7.00 (LH, br, s), 7.23 (LH, t
, J = 8.0Hz).

7.36 (IH, dt, J = 7.6Hz, 1.6
Hz), 7.39-7.40 (2H, m), 7.41
(IH, t, J=7.6Hz).

7.46-7.48 (IH, m), 7.55 (IH
, dt, J=7.6Hz, 1.7Hz), 7.67 (
LH, br, s) Example 9 E -N-66-dityl-2-hen-4-nyl-N-m, p: 168-169°C IRI, I: cm-': 2974,2500, 160
2,1461. ．． 1266°1173.777.759
,747 NMR (CD(JJ) δ: 1.25 (9)(,
5), 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 (IH, d, J
= 15.7Hz).

6.22 (IH, dt, J = 15.7Hz, 7.
5Hz), 7.06 (LH, ddd, J=8.3Hz,
2.5Hz, 0.8Hz).

7.09 (lH, d, J = 8.3Hz), 7.3
3 (LH, t.

J = 8.1Hz), 7.37-7.43 (4H, m
), 7.51 (l H, dd, J = 2.8 Hz,
1.5Hz), 7.53-7.58 (2H, m), 7.
73 (LH, br, s) Example 10 Zylamine m, p,: 164-166°C IRv:, cm-': 296B, 1605,145
8,1266.777NMR (CDCfl) 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. C19 (2H.

br, s), 5.23 (2H, s), 5.78 (I
H, d, J15.6Hz), 6.21 (IH, dt,
J = 15.6Hz, 7.8Hz), 7.04-7.
09 (2H, m), 7.33 (LH, tJ = 8
．． 1Hz), 7.35-7.43 (4H, m), 7.
50 (I H, dd, J = 2.5Hz, 1.5H
z), 7.53-7.57 (2H, m), 7.74
(LH,s) Example 11 Zylamine IRv'::, cm-': 1596.1506.1
488.1458.1341゜1266.1029,7
86,726 NMR (CDC7,) δ: 1.24 (9H, s)
2.18 (3H, s).

3.03 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.47 (2H,s), 5.11 (2H,s
), 5.64 (IH, dt, J = 15.8Hz, 1
．． 5Hz), 6.07 (LH, dt, J=15.8H
z 6.6Hz), 6.35 (2H,t, J = 2
．． 2Hz).

6.86 (LH, ddd, J = 10.8Hz, 2
．． 3Hz, 0.8Hz), 6.91 (IH, d, J
= 7.8Hz), 6.98-6.99 (LH, m),
7.10 (2H, t, J = 2.2H, z), 7.
22 (IH, t, J = 7.8Hz), 7.25-7
．． 50 (4H, m) Example 12 IRv: cm-': 2968, 1596, 1506,
1488, 1455° 1341.1263, 1071.
723NMR (CDC4) δ: 0.85 (3H,t
, J = 7.4Hz), 1.24 (9H,s), 1.
47 (2H, 5ext, J = 7.4Hz) 2.3
6 (2H, t, J = 7.4Hz), 3.06 (
2H, dd.

J = 6.4Hz, 1.6Hz), 3.53 (2H
, s), 5.11 (2H, s), 5.63 (IH, d
t, J = 15.9Hz, 1.6Hz), 6.05
(IH, dt, J = 15.9Hz, 6.4Hz).

6.35 (2H, t, J = 2.2Hz), 6.8
5 (IH, ddd.

J = 8.2Hz, 2.6Hz, 0.9Hz), 6.
92 (LH.

d, J = 7.6Hz), 7.00-7.03 (
IH,m), 7.11(2H,t,J = 2.2
Hz), 7.21 (LH, t, J = 7.8Hz)
, 7.28-7.37 (2H, m), 7.44 (I
H,t.

J = 7.8Hz), 7.49 (IH, t, J =
1.5Hz) Example 13 IRv'::cm' :2968,1587,1464
,1365,1263°1152.1026.768 NMR (CD(J,) δ: 1.24 (9H,s
), 2.18 (3H,s).

3.03 (IH, dd, J = 6.5Hz, 1.5
Hz), 3.47 (2H,s), 5.15 (2H,s
), 5.64 (LH, dt, J = 15.9Hz, 1
．． 5Hz), 6.08 (IH, dt, J = 15.9
Hz, 6.5Hz), 6.86-6.92 (2H, m
).

7.00 (IH, br, s), 7.22-7.27
(3H, m).

7.49-7.51 (2H, m), 7.75-7.7
7 (2H.

m), 7.93-7.96 (IH, m), 8.08
(IH, br.

s), 8.70 (IH, dt, J = 4.8Hz,
1.5Hz) Example 14 E -N-66-cymethyl-2-hebun-4-nyl-
N-IRshi::cm-': 2968.1599,1
491,1458,1365゜1263.1152,1
023.783NMRCCDC1,) δ: 1.2
4 (9H, s), 2.18 (3H, s).

3.03 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.47 (2H,s), 5.62 (2H,s
)5.64 (LH, dt, J= 15.9Hz, 1.
5Hz), 6.07 (IH, dt, J = 15.9H
z, 6.6Hz), 6.87-6.93 (2H, m)
.

7.01 (IH, br, s), 7.23 (IH, t
, J = 7.9Hz).

7.37 (IH, ddd, J = 6.8Hz, 5.
0Hz, 0.9Hz).

7.48-7.57 (3H, m), 7.67 (LH
,br,s).

7.87-7.91 (IH, m), 8.60 (IH
, dd, J=4.8Hz, 1.7Hz), 8.86 (
LH, dd, J = 2.4Hz.

0.9Hz) Example 15 2A: Length 2 IRv'::cm' + 2968.1596.145
8,1263.786NMR(CD(J',) δ:
], 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 (IH, dd, J = 15.9Hz, 1
．． 4Hz), 6.06 (LH, dt, J= 15.9
hz, 6.3Hz) 6.87 (IH, dd, J =
8.0Hz, 2.7Hz), 6.92 (IH, d, J
= 7.6Hz), 7.03 (LH, br, s).

7.22 (IH, t, J=7.8Hz), 7.36
(LH, dddJ = 7.6Hz, 4.9Hz, 1.2
Hz), 7.48-7.57 (3H, m), 7.66
(IH, d, J = 1.2Hz), 7.877.91
(IH, m), 8.60 (IH, dd, J=5.1H
z.

1.8Hz), 8.85 (IH, dd, J = 2.
7 Hz, 1.2 Hz) Example 16 21 Kuni Length 2 IRv':::cm-': 2972.1596,1
490,1458.13641266.1152,10
26.786NMR (CD(J,) δ: 1.24
(9H,s), 2.18 (3H,s).

3.04 (IH, dd, J = 6.5Hz, 1.5
Hz), 3.47 (2H,s), 5.14 (2H,s
), 5.64 (LH, dt, J = 15.8Hz, 1
．． 5Hz); 6.08 (IH, dt, J = 15.9
Hz, 1.5Hz), 6.87-6.93 (,2H,
m).

7.00 (IH, br, s), 7.24 (IH, t
, J = 8.0Hz).

7.51-7.54 (4H, m), 7.59-7.6
2 (LH2m), 7.72-7.74 (IH, m)
, 8.67 (2H, dd.

J = 4.5Hz, 1.7Hz) Example 17 IRv'::, cm-': 2974,1590,1
491,1458,1365゜1266.1152,1
026,798,729NMR (CDC/1) δ:
1.24 (9H, s), 2.18 (3H, s).

3.30 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.46 (2H,s), 5.12 (2H,s
)5.63 (LH, dd.

J = 15.8Hz, 1.5Hz), 6.08 (I
H, dt, J = 15.8 Hz, 6.6 Hz), 6.8
5-6.92 (2H, m).

6.99-7.15 (LH, m), 7.22 (IH
, tj = 7.7Hz), 7.24 (IH, d, J =
1.1Hz), 7.48 (LH.

t, J = 7.7Hz), 7.54 (1'H, d,
J = 7.9Hz).

7.72 (IH, d, J = 1.1Hz), 8.0
1 (LH, dt.

J = 7.9Hz, 1.2Hz), 8.13-8.1
6 (IH, m) Example 18 Benzylamine IR Shifu cm-': 2968.1596.1458
．． 1263.1152°1026, 954.789.6
93 NMR (CDC4) δ: 1.24 (9H, s), 2
．． 19 (3H, s).

3.04 (2H, dd, J = 6.5Hz, 1.4
Hz), 3.47 (2H, s), 5.11 (2H,
s), 5.65 (IH, dt, J = 15.9Hz,
1.4Hz), 6.08 (LH, dt, J15.9H
z, 6.5Hz), 6.86-6.93 (2H, m)
.

7.00-7.02 (LH, m), 7.23 (IH
, t, J = 7.9Hz), 7.38 (IH, s)
, 7.42-7.43 (IH, m).

7.45 (LH, t, J = 7.6Hz), 7.6
0-7.64 (IH.

m), 7.74-7.76 (IH, m), 7.93
(IH,s) Example 19 IRv'::cm-' :2968,1491,145
8.1263,1107954.789 NMR (CD(J3)δ: 1.03 (3H, t, J
= 7.1Hz), 1.24 (9H, s), 2.50
(2H, q, J = 7.1Hz), 3.09 (2H
, ddj=6.4Hz, 1.5Hz), 3.54 (2
H.

s), 5.11 (2H, s), 5.64 (IH, d
t, J = 15.8Hz, 1.5Hz), 6.07
(IH, dt, J = 15.8Hz.

6.4Hz>, 6.84-6.89 (LH, m), 6
．． 93 (IH.

d, J = 7.7Hz), 7.03 (IH, br, s
), 7.23 (IH, t, J = 7.7Hz), 7.
39 (LH, s), 7.40-7.49 (2H, m
), 7.62 (IH, dt, J=6.6Hz.

2.1Hz), 7.75 (IH, br, s), 7.9
3 (IH,s) The free base obtained above was converted into hydrogen chloride-
When treated with methanol in a conventional manner, hydrochloride, m, p,
160°C (dec,) is obtained.

Example 20 E -N-66-dimethyl-2-hebuten-4-ynyl-N-IRv'::cm-' :2968,1596,
1491.1455,1263゜1107.954,7
89 NMR (CDC/,)δ: 0.85 (3H,t,J
= 7.4Hz), 1.47 (2H, 5ext, J=
7.4Hz), 2.37 (2H,t,,1=7.4
Hz), 3.07 (2H, dd, J = 6.4Hz
, 1.5Hz), 3.53 (2H,s), 5.10
(2H, s), 5.63 (IH, dt, J = 15.
9Hz, 1.5Hz), 6.06 (IH.

dt, J = 15.9Hz, 6.4Hz), 6.84
-6.89 (IH.

m), 6.92 (LH, d, J = 7.8Hz),
7.02 (IH.

br, s), 7.22 (IH, t, J = 7.8H
z), 7.38 (IH.

s), 7.40-7.49 (2H, m), 7.62
(LH, dt.

J = 6.6Hz, 2.1Hz), 7.75 (H(
, br, s) 7.93 (IH, s) Example 21 Benzylamine IRv'::cm':2974,1602,1494.
145B, 1266°NMR (CD CI+)
δ: 1.24 (9H, s), 2.19 (3H, s
).

3.04 (2H, dd, J -6,5Hz, 1.4H
z), 3.48 (2H, s), 5.10 (2H, s)
, 5.65 (LH, dt, J= 15.9Hz, 1.
4Hz), 6.08 (IH, dt, J=15.9Hz
, 6.5Hz), 6.85-6.95 (2H, m).

7.01 (IH, br, s), 7.24 (IH, t
, J = 8.0Hz).

7.38-7.49 (3H, m), 7.57 (IH
,br,s).

8.58 (IH, s), 8.70 (IH, s) Example 22 No. 1" and Beggar's IRv";::cm-' :2972,15B8,14
90,1456,1364°1266 1148.10
22,788,692 NMR (CDC13) δ: 1.
19 (9H, s) 2.14 (3H, s).

2.99 (2H, dd, J = 6.6Hz, 1.4
Hz), 3.42 (2H,s), 5.08 (2H,s
), 5.60 (IH, dt, J = 15.8Hz, 1
．． 4Hz), 6.04 (IH, dt, J=15.8H
z, 6.6Hz), 6.83 (IH, dd, J =
8.1Hz, 1.5Hz), 6.87 (IH, d, J
=8.1Hz).

6.95 (IH, d, J = 1.5Hz), 7.1
8 (IH, t.

J = 7.8Hz), 7.30 (LH, d, J =
3.3Hz).

7.42 (LH, t, J = 8.1Hz), 7.4
7. (4H, d.

J = 7.6Hz), 7.83 (IH, d, J =
3.3Hz).

7.87 (IH, d, J = 7.3Hz), 8.0
1 (IH, s) Example 23 Sa2 Yuhi r = 2 IRv drift cm-': 2968, 1590, 1491
,1458,13651263, 1152,1026
．． 78ON M R (CD CI = ) 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 (LH, dt, J = 15.9Hz,
1.5Hz), 6.07 (IH, dt, J=15.9
Hz, 6.5Hz), 6.85-6.94 (2H, m
).

7.01 (IH, t, J=2.1Hz), 7.23
(IH, t.

J = 7.9Hz), 7.40-7.50 (2H,
m), 7.55 (LH, dt, J=6.9Hz, 1.9
Hz), 8.73 (IH.

s), 8.79 (IH, s) Example 24 IRv':::cm-': 2968,1590,1
491,1458,1419゜1368,1266,1
152.7js, 756NMR (CD(J,) δ
: 1.24 (9H, s), 2.19 (3H, s)
.

3.04 (2H, dd, J = 6.2Hz, 1.5
Hz), 3.48 (2H, s), 5.11 (2H,
s), 5.65 (LH, dt, J = 15.6Hz,
1.5Hz), 6.08 (IH, dt, J = 15.
6Hz, 6.2Hz), 6.88 (IH, ddd, J
= 8.2Hz, 2.8Hz, 1.0Hz), 6.8
9-6.90 (2H, m).

7.00-7.03 (IH, m), 7.23 (IH
, t, J = 7.8Hz), 7.43 (IH, d,
J = 2.1Hz), 7.45-7.50 (2H, m
), 7.54-7.59 (IH, m), 7.68-7
．． 71 (IH, m), 8.48 (LH, d, J =
2.1Hz) Example 25 E-N-66-dityl-2-hebun-4-nyl-
N-ethyl-3-3-1-imidazolyl benzyloxybenzylamine IRv':::cm-': 2968.1506.1
491.1458.1308°1263, 1056.7
89 NMR (CD(J3)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, 1.5Hz), 3.54
(2H.

s), 5.13 (2H, s), 5.64 (LH, d
t, J = 15.9Hz, 1.5Hz), 6.06
(LH, dt, J = 15.9Hz.

6.4Hz), 6.85 (IH, ddd, J = 8
．． 0Hz, 2.0Hz, 0.9Hz), 6.93 (I
H, d, J = 7.5Hz).

7.00-7.05 (IH, m), 7.21 (IH
, t, J = 1.4Hz), 7.23 (IH, t,
J=8.0Hz), 7.31 (IH.

t, J = 1.4Hz), 7.33-7.53 (4
H, m), 7.88 (IH, t, J = 1.4 Hz) Example 26 Penzylamine IRv only cm': 2968, 1599, 1506
．． 1488.14551308.1263,1152,
1056,786N M R (CD Cla) δ
: 0.85 (3H, t, J = 7.4Hz), 1
．． 24 (9H, s), 1.47 (2H, 5ext, J
=7.4Hz).

2.37 (2H, t, J = 7.4Hz), 3.0
6 (2H, dd.

J = 6.3Hz, 1.5Hz), 3.53 (2H
,,s), 5.13 (2H,s), 5.63 (IH,
dt, J = 15.6Hz, 1.5Hz), 6.05
(IH, dt, J=15.6Hz, 6.3Hz).

6.84 (IH, ddd, J = 8.2Hz, 3.
4Hz, 0.8Hz).

6.93 (IH, d, J = 7.6Hz), 7.01
(IH, br.

s), 7.21 (IH, t, J = 1.4Hz),
7.22 (IH.

tj=8.2Hz), 7.31 (IH,t,J=1
．． 4Hz).

7.33-7.53 (4H, m), 7.88 (IH
, t, J = 1.4Hz) Example 27 No. 2''24 length 2 IRv'::cm-': 2974,1584,14
55,1419,1266°786.756 NMR (CDC/3) δ: 1.24 (9H, s
), 2.19 (3H,s).

3.04 (2H, d, J = 6.2Hz), 3.4
7 (2H, s).

5.15 (2H, s), 5.64 (IH, d, J
= 15.9Hz).

6.07 (IH, dt, J = 15.9Hz, 6.
2Hz), 6.82-6.93 (2H, m), 7.0
2 (IH, br, s), 7.23 (LH, t, J =
7.5Hz), 7.54-7.55 (3H, m).

7.67 (IH, s), 8.96 (2H, s), 9
．． 22 (IH.

S) Example 28 IRv'::cm-1: 2974.1599.151
2.145B, 1266°1215.1146.75
9 NMR (CD(J,)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 (LH, dt
J = 15.9Hz, 1.5Hz), 6.06 (IH
, dt, J=15.9Hz, 6.6Hz), 6.85
(IH, ddd, J = 7.9Hz, 2.7Hz, 0
．． 5Hz), 6.92 (IH, d, J = 7.9H
z), 6.98-7.05 (IH, m), 7.23
(IH, tJ = 7.9Hz), 7.45-7.49
(IH, m), 7.53 (LH, t, J = 7.8
Hz), 7.64 (IH, dt, J = 7.8Hz,
1.8Hz), 7.80 (IH, br, s), 8.1
1 (LH, s), 8.58 (LH, s) Example 29 IRv:, cm-': 1605, 1506, 1341
,1170,1149°1074.960,789,7
23,696NMR (CD(J3)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, 1.5Hz
), 3.35 (3H.

s), 3.61 (2H,s), 5.12 (2H,s
), 5.73 (IH.

dt, J = 15.9Hz, 1.5Hz), 6.20
(IH, dt.

J = 15.9Hz, 6.5Hz), 6.37 (2
H, t, J = 2.1 Hz), 6.86 (IH, dd
, J = 7.8Hz, 1.6Hz) 6.93 (IH
, d, J = 7.8Hz), 6.99-7.05 (
IH.

m), 7.10 (2H, t, J=2.1Hz), 7.
23 (IH.

t, J = 7.5Hz), 7.29-7.46 (3
H, m), 7.48-7.50 (IH, m) Example 30 IRv drift cm-': 2968, 2788, 1584
,1491,1455゜1365.1263,1152
, 1023,783NMR (CD(J,) δ: 1
．． 24 (9H,s), 2.18 (3H9s).

3.03 (2H, dd, J = 6.6Hz, 1.4
Hz), 3.11-3.19 (2H, m), 3.35
-3.43 (2H, m), 3.46 (2H, s), 5
．． 04 (2H, s), 5.64 (LH, dt, J=
15.9Hz, 1.4Hz), 6.08 (IH, d
t, J = 15.9Hz, 6.6Hz), 6.59 (
IH, t, J = 2.1 Hz).

6.83-6.93 (2H, m), 6.97-7.0
0 (LH.

m), 7.19-7.33 (4H, m), 7.39-
7.42 (IH.

m) Example 31 ruoxybenzylmine IRv':::cm-' :2968,2926,15
87,1491,1455゜1365.1263,11
49.777NMR(CDCf,) 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, 1.5H
z), 3.15 (2H.

dtj=8.4Hz, 1.8Hz), 3.38 (2H
, t, J=8.4Hz), 3.53 (2H,s), 5
．． 04 (2H, s).

5.64 (IH, dt, J -15,8Hz, 1.5
Hz), 6.07 (IH, dt, J = 15.8Hz
, 6.4Hz), 6.59 (IHt, J = 1.8
Hz), 6.82-6.87 (IH, m), 6.89
-6.94 (IH, m), 6.98-7.02 (I
H, m), 7.21 (IH, t, J = 7.8Hz)
, 7.23-7.35 (3H, m).

7.39-7.42 (IH, m) Example 32 IRv:cm-': 1452, 1380, 1365
,1254,1173゜1149.1077.819,
777.693 NMR (CD(J,) 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 (IH, dt, J = 15.7Hz, 1.
8Hz), 6.16 (IH, dt, J = 15.7H
z, 6.6Hz), 6.59 (IH.

t, J = 1.6Hz), 6.83-6.89 (I
H, m), 6.90-6.95 (LH, m), 6.9
8-7.04 (IH, m), 7.21 (IH, t, J
= 7.5Hz), 7.25-7.35 (3H, m
).

7.39-7.40 (IH, m) Example 33 IRv cm-': 2968, 2920, 1587,
1491,1455゜1365.1263,1152.
777NMR (CDCf3) 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, 1.5Hz), 3.5
3 (2H.

s), 3.91-3.96 (2H, m), 4.11-
4.15 (2Hm), 5.06 (2H,s), 5.
64 (IH, dt, J = 15.8Hz, 1.5H
z), 6.05 (IH, dt, J-15, 8Hz.

6.4Hz), 6.26 (IH, quint, J=2
．． 0Hz).

6.82-6.87 (IH, m), 6.89-6.9
4 (IHm), 6.99-7.01 (IH,m)
, 7.21 (IH, t.

J = 8.0Hz), 7.34-7.37 (3H,
m); 7.47-7.49 (IH, m) Example 34 22-2 1: Length 2 IRv'::cm-': 2968, 1608, 158
4,1506,1491°1458.136B, 1
266, 1152,768N M R (CD Cls
) δ: 1.24 (9H, s), 1.97-2.0
2 (4H.

m), 2.18 (3H, s), 3.03 (2H, d
d, J = 6.6Hz, 1.5Hz), 3.29-3
．． 31 (4H, m), 3.46 (2H, s), 5.
01 (2H, s), 5.64 (IH, dt, J=
15.9Hz, 1.5Hz), 6.08 (LH, d
t, J = 15.9Hz, 6.5Hz), 6.51
(IH, ddj = 8.3Hz, 2.4Hz), 6.
62-6.64 (IH, m), 6.72 (IH, d,
J=7.4Hz), 6.85-6.90 (2H, m)
.

6.98 (IH, t, J = 2.1Hz), 7.2
0-7.22 (2Hm) Example 35 IR reservoir cm-': 2968, 2926, 1596,
1446,1377゜1260, 1017.852,
801,771NMR (CD(J',) δ: 1.
04 (3H, t, J = 7.0Hz), 1.24 (
9H, s), 2.50 (2H, q, J = 7.0H
z), 3.10 (IH, dd, J=6.3Hz, 1.4
Hz), 3.54 (2) (s), 5.18 (2H,
s), 5.64 (LH, dt, J = 15.9Hz
, 1.4Hz), 6.08 (LH, dt, J-15,
9Hz.

6.3Hz), 8.86 (IH, dd, J = 8.
0Hz, 2.7Hz).

6.93 (LH, d, J = 7.6Hz), 7.0
0-7.04 (2H.

m), 7.07 (H(, d, J = 3.6Hz),
7.22 (IH.

t, J = 8.0Hz), 7.29 (IH, dd
, J = 5.2Hz.

1.2Hz), 7.33 (IH, dd, J = 5.
2Hz, 4.5Hz).

7.36 (LH, dd, J = 4.5Hz, 1.
2Hz) Example 36 E -N-66-di-thyl-2-hebun-4-ynyl-N-IRv'::cm-' :2968,1620,
1491, 1455, 1365゜1266.1113,
957,831,762NMR (CD(J,) δ:
1.24 (9H, s), 2. I9 (3H, s).

3.05 (2H, dd, J = 6.5Hz, 1.5
Hz), 3.48 (2H,s), 5.14 (2H,s
), 5.65 (IH, dt, J = 15.9Hz, 1
．． 5Hz), 6.09 (LH, dt, J = 15.9
Hz, 6.5Hz), 6.86 (IH, ddd, J
= 7.9Hz, 2.7Hz, 0.9Hz>, 6.94
(IH, d, J -7,9Hz), 7.00-7.0
1 (IH, m), 7.25 (IH, t.

J = 7.9Hz), 7.32 (IH, dtj =
5.0Hz.

0.8Hz), 7.73 (IH,s), 7.76-7
．． 77 (IHm), 7.99 (IH,s), 8.6
4 (IH, dd, J = 5.0Hz, 0.8Hz) Example 37 Oxybenzylamine IRv: cm': 2968.161? , 1584
, 1494, 1455° 1263, 1155. 11
13.957NMR (CDC/3) δ: 1.24
(9H,s), 2.19 (3H,s).

3.04 (2H, d, J = 6.5Hz), 3.4
8 (2H, s).

5.24 (2H, s), 5.64 (IH, dt, J
=, 15.9Hz.

1.7Hz), 6.08 (LHldt, J = 15
．． 9Hz, 6.5Hz), 6.88-6.95 (2H
, m), 7.04-7.05 (IH.

m), 7.19-7.27 (IH, m), 7.46
(IH, dd.

J = 5.4Hz, 1.5Hz), 7.59 (IH
, s), 7.79 (IH, m), 8.00 (IH, s
), 8.65 (IH, d, J = 6.2 Hz) Example 38 IRv';::cm-': 2968,2926,1
458. '1263,1107゜1020.963,
789 NMR (CDCJ,) 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 (IH, dt, J= 15.9Hz, 1
．． 5Hz), 6.09 (IH, dt, J = 15.9
Hz, 6.5Hz), 6.53 (IH, d, J =
3.4Hz).

6.64 (IH, d, J = 3.4Hz), 6.8
7 (IH, ddd.

J = 8.1Hz, 2.7Hz, 0.8Hz), 6.
93 (lH.

d, J = 8.1Hz), 7.00 (1)1. m)
, 7.24 (LH.

t, J=8.1Hz), 7.30 (LH,s), 7.
86 (IH.

S) Example 39 IRv"::, cm-': 2968,1584,1
461,1269,1152゜1098.1041,1
032,891,831NMR (CDCJ,) δ:
1.24 (9H, s), 2.20 (3H, s).

3.05 (2H, dd, J = 6.5Hz, 1.4
Hz), 3.48 (2H,s), 4.97 (2H,s
), 5.66 (IH, dt, J = 15.8Hz, 1
．． 4Hz), 6.09 (IH, J = 15.8Hz
, 6.5Hz), 6.75 (IH, d, J = 0.
8Hz).

6.82-6.88 (IH, m), 6.92 (
IH, d, J = 7.8 Hz), 6.98 (IH, b
r, s), 7.23 (IH, t.

J = 7.8Hz), 7.28 (IH,s), 7.
54d, J = 0.8Hz), 7.86 (IH, 5
) (IHl Example 40 IRv丑cm': 2968, 1596, 1491, 14
55,1263°115B, 1104,1059,10
17,966.894NMR (CDC1,) δ: 1.
19 (9H, s), 2.14 (3H, s).

3.00 (2H, dd, J = 6.6Hz, 1.4
Hz), 3.43 (2H, S), 5.22 (2)1.
d, J = 1.0Hz), 5.60 (IH, dt, J
-15,8Hz, 1.4Hz), 6.03 (IH.

dt, J = 15.8Hz, 6.6Hz), 6.83
(LH, ddd.

J = 7.6Hz, 2.6Hz, 0.8Hz), 6.
89 (IH.

d J = 7.6Hz), 6.97 (LH, m),
7.19 (IH.

t, J = 7.6Hz), 7.37 (IH, t, J
= 1.0Hz).

7.63 (IH, s), 7.92 (IH, s) Example 41 E -N-66-dimethyl-2-hebun-4-ynyl-N-thyl-3-6-5-ox ・1-2-pytomi DylmethylocybenzylminIRv'::cm-': 2968.1596.14
52.1365.1260゜1158.1107,80
4,786 NMR (CDCj,) δ: 1.24 (9H, s),
2.18 (3H, s).

3.03 (2H, dd, J = 6.5Hz, 1.4
H, z), 3.46 (2H, s), 5.25 (2H,
s), 5.64 (LH, dt, J = 15.8Hz,
1.4Hz), 6.07 (LH, dt, J = 15.
8Hz, 6.5Hz), 6.86-6.91 (IH,
m).

6.91-6.95 (LH, m), 7.01-7.0
4 (LH.

m), 7.23 (18,t, J = 8.0Hz),
7.51 (IH.

dd, J = 7.8Hz, 0.9Hz), 7.59
(IH, dd.

J = 7.8Hz, 0.9Hz), 7.72 (IH
, s), 7.80 (IH, t, J = 7.8Hz),
7.99 (LH,s) Example 42 IRv'::cm-': 2968.1590.14
91.1455.1266゜1152.1107,10
26,963,759NMR (CD(J3)δ: 1.
24 (9H, s), 2.19 (3H, s).

3.05 (2H, dd, J = 6.6Hz, 1.4
Hz), 3.48 (2H,s), 5.13 (2H,s
), 5.65 (IH, dt, J = 15.9Hz, 1
．． 4Hz), 6.09 (IH, dt, J=15.9H
z, 6.6Hz), 6.88 (IH, dd, J =
7.8Hz, 2.6Hz), 6.94 (LH, d, J
= 7.8Hz).

7.01-7.04 (IH, m), 7.25 (IH
,t, J = 7.8Hz), 7.49 (IH,s)
, 8.00 (IH, s), 8.05 (IH, t, J
= 2.0Hz), 8.65 (IH, d, J = 2
．． 0Hz), 8.90 (IH, d, J = 2.0H
z) Example 43 m, p,: 137-139°C IRvcm': 2968, 2500, 1599, 1
497,1458°1332.1263,1038.7
23NMR (CDCI, ) δ: 1.25 (9H
,s), 2.18 (3H,s)2.65 (3H,s
), 3.48-3.61 (LH, m), 3.65-3
．． 78 (IH, m), 3.95-4.08 (IH,
m), 4.16-4.29 (IH, m), 5.21
(2H,s), 5.85 (IH.

dj=15.6Hz), 6.20-6.36 (IH
, m), 6.32 (2H,t, J -2,1Hz), 6
．． 79 (2H, t, J = 2.1Hz), 7.04
-7.11 (IH, m), 7.24-7.30 (2
H.

m), 7.35 (IH, t, J=7.9Hz), 7.
51 (IH.

t, J = 4.5Hz), 7.63 (LH,br,
s) Example 44 IR code: cm': 296B, 1590, 1518,
1488, 1455° 1341.1266.1026.
723NMR (CDCI,) δ: 1.24 (9
H,s), 2.19 (3H,s).

2.39 (3H, s), 3.04 (2H, dd, J
= 6.5H2゜1.5Hz), 3.48 (2H,
s), 5.06 (2H, s), 5.65 (IH, dt
, J = 15.9Hz, 1.5Hz), 6.08 (I
H.

dt, J = 15.9Hz, 6.5Hz), 6.33
(2H, t.

J = 2.2Hz), 6.86-6.95 (28,
m), 6.99-7.02 (IH, m), 7.07
(2H, t, J = 2.2Hz) 7.21-7.27
(3H, m), 7.50 (IH, br, s) Example 45 E -N-66-dimethyl-2-hebuten-4-ynyl-N-2-chloro-4-(3-tolyl)thiazole 60
N-bromosuccinimide 5 was dissolved in a mixture of 8 ml of carbon tetrachloride and 2 ml of 1,2-dichloroethane.
11 mg and 3 mg of benzoyl peroxide were added, and the mixture was stirred and refluxed for 3 hours.

After cooling, the precipitate was filtered from the reaction solution, washed with an aqueous sodium bicarbonate solution, and the solvent was distilled off under reduced pressure to obtain 4-(3-bromomethylphenyl)-2-chlorothiazole as a pale yellow oil.

The bromomethyl compound obtained above was dissolved in 2 ml of dimethylformamide, and 388 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxybenzylamine and 60% The phenolate prepared from 68 mg of oily sodium hydride is added to a tetrahydrofuran solution (8 m4) and stirred for 1 hour under water cooling and then for 2 hours at room temperature. Water and ethyl ether are added to the reaction mixture to separate the layers, and the organic layer is separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [Wakogel C-200, 80 g, elution solvent: hexane/ethyl acetate = 6/l → 4/l] to obtain (E).
-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2-chloro-4-thiazolyl)benzyloxy]benzylamine 396 mg (
Yield: 57%) is obtained as a pale yellow oil.

92 mg of the ether obtained above was mixed with 0.8 mg of acetic acid.
40 mg of zinc powder was added at once while stirring and heating to 57-60°C, and the mixture was stirred for 30 minutes. Pour the reaction solution into ice water and add sodium carbonate to adjust the pH to 9.0.
After adjusting to , extract with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar col
umn.

5ize B, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
6/l→3/l] to obtain 52 mg (yield: 60%) of the title compound as a colorless oil.

IR::cm-': 296B, 1587.14
91.1455.1365゜1266.1026.78
9 NMR (CDC1s) δ: 1.24 (9H,s
), 2.18 (3H,s).

3.03 (2H, dd, J = 6.5Hz, 1.5
Hz), 3.47 (2H,s), 5.13 (2H,s
), 5.64 (LH, dtj = 15.8Hz, 1.
5Hz), 6.08 (IH, dt, J = 15.8H
z, 6.5Hz), 6.86-6.92 (,2H, m
).

7.00 (LH, br, s), 7.22 (LH, t
, J = 7.8Hz).

7.44-7.45 (IH, m), 7.57 (LH
, d, J=2.0Hz), 7.64 (IH, t, J
= 7.7Hz), 7.87-7.91 (IH, m
), 8.02 (LH, br, s), 8.84 (IH,
d, J = 2.0 Hz) Instead of the raw material 4-(3-bromomethylphenyl)-2-chlorothiazole, 5-(3-bromomethylphenyl)-2 obtained from 5-(3-tolyl)thiazole -bromothiazole [J, Org, Chem, 51
3375 (1986): Org, React, (
2381; see Ann, 628 (1981)]
After condensing this with the corresponding 3-hydroxybenzylamine derivative, the same dehalogenation reaction as in Example 45 was performed to obtain the compounds of Examples 46 to 48.

Example 46 E-N-66-di-2-hepun-4-ynyl-N-IRv"::', cm-': 2974.159
0,1458,1266.873゜789.693 NMRCCDC13) δ: 1.24 (9H,s
), 2.19 (3H,s).

3.04 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.47 (2H,s), 5.10 (2H,s
), 5.64 (IH, dt, J = 15.8Hz, 1
．． 5Hz), 6.08 (IH, dtj = 15.8H
z, 6.6Hz), 6.88 (IH, dd, J =
8.1Hz, 1.8Hz), 6.92 (IH, d, J
= 7.8Hz).

7.00 (IH, t, J = 1.8Hz), 7.2
3 (LH, t.

J = 7.8Hz), 7.42-7.44 (2H,
m), 7.53-7.56 (IH, m), 7.65-
7.66 (IH, m), 8.10 (IH, d, J =
0.6Hz), 8.76 (IH, d, J = 0.
6Hz) Example 47 22'' and L2 IRv drift cm': 2972, 1588, 1490,
1456,1364゜1264,1152,1046,
874,788NMR (CDC/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 (IH
, d, J = 15.8 Hz), 6.02 (LH, dt
, J = 15.8Hz, 6.0Hz), 6.82 (I
H.

dd, J = 8.1Hz, 2.1Hz), 6.89
(IH, d, J=8.0Hz), 6.98 (IH, b
r, s), 7.18 (IH.

t, J=8.0Hz), 7.38-7.41 (2H,
m), 7.48-7.52 (LH, m), 7.62
(IH,s), 8.05 (IH.

d, J = 0.6Hz), 8.71 (IH, d,
J = 0.6Hz) Example 48 IRv"::cm': 2968, 1490, 145
8,1364,1264゜1152.872,788,
694 NMR(CDCls) δ: 0.85 (
3H,t,J = 7.4Hz), 1.24(9H,s
), 1.46-151 (2H, m), 2.37 (2
H.

t, J=7.1Hz), 3.07 (2H, ddj=6
．． 4Hz.

1.3Hz), 3.53 (2H,s), 5.10 (
2H, s), 5.63 (LH, ddj= 15.9Hz
, 1.3Hz), 6.04 (LH.

dt, J = 15.9Hz, 6.4Hz), 6.86
(IH, dd.

J = 7.8Hz, 1.8Hz), 6.92 (IH
,d,,J = 7.4Hz), 7.20(IH,s
), 7.22 (LH, t, J=7.8Hz), 7.4
3-7.44 (2H, m), 7.53-7.55 (
IH.

m), 7.66 (IH, br, s), 8.10 (I
H,s), 8.78 (IH,s) Example 49 Isocyanoacetic acid methyl ester 280All and 1.8-
Diazabicyclo[5,4,0]undec-7-ene (D
BU) 400111 was added to 20 mA' of tetrahydrofuran, and (E)-N-(6
, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-formylbenzyloxy)benzylamine in a solution of 500 mg in tetrahydrofuran (5 m/
) and stirred at the same temperature for 5 hours. After the reaction solution is left to cool, it is neutralized by adding neutralizing acid, the solvent is distilled off under reduced pressure, and the residue is extracted with ethyl acetate and water. After separating the organic layer, it was dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200, 30 g, elution solvent: hexane/ethyl acetate = 5/ 1], (E)-N-(6
,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[3-(2゜4-dimethoxycarbonyl-3
-pyrrolyl)benzyloxy]benzylamine 140m
g (yield: 20%) is obtained as a pale yellow oil.

32 mg of the pyrrolyl derivative obtained above is added to a mixed solution of 2 g of potassium hydroxide and 6 ml of water, and heated under reflux for 6 hours while stirring. After cooling, ethyl ether is added to the reaction mixture for extraction, the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was subjected to silica gel column chromatography [
Wakogel C-200, 30g1 Elution solvent: hexane/
Ethyl acetate=ICL/1→2/l] to obtain 12.4 mg (yield: 50%) of the title compound as a pale yellow oil.

IRv'::cm-' :3440,2972,292
8,2872,1610°1490.1454,136
4,1266.1034°NMR (CDC/S) δ
: 1.24 (9H, s), 2.18 (3H, s)
.

3.03 (2H, dd, J = 6.6Hz, 1.5
H, z), 3.47 (2H, s), 5.08 (2H,
s), 5.64 (IH, dt, J = 15.8Hz,
1.5Hz), 6.09 (IH, dt, J = 15.
8Hz, 6.6Hz), 6.54-6.57 (IH,
m).

6.82-6.92 (3H, m), 6.99-7.0
1 (LH.

m), 7.10-7.13 (IH, m), 7.22
(IH, t.

J = 7.6Hz), 7.23-7.28 (IH,
m), 7.35 (IH, t, J = 7.4Hz), 7.
49 (LH, dt, J = 7.4Hz, 1.7Hz)
, 7.59-7.61 (IH, m), 8.20-8.
40 (IH,br) Example 50 (E)-N-(6,6-dimethyl-2-heptene-4-
Inyl)-N-methyl-3-(3-methoxylponylbenzyloxy)benzylamine (1731 ng) was dissolved in ethanol (3rr+4) and 98% hydrazine hydrate (100 ml) was added.
mg and heated under reflux for 3 hours. After evaporating the reaction solution under reduced pressure, ethyl acetate and water are added to the residue for extraction, and the organic layer is separated and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off, and the residual acid hydrazide was added to 4 ml of methyl orthoformate and heated under reflux for 8 hours. After distilling off excess orthoformic acid methyl ester under reduced pressure, the residue is extracted with a mixture of ethyl acetate and water, and the organic layer is separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [Wakogel C-
200.30g.

Elution solvent: hexane/ethyl acetate = 271] and medium pressure liquid chromatography [column: Lobar col
umn.

5ize A, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
3/1→2/1] to obtain 18 mg (yield: 10%) of the title compound as a colorless oil.

IRv':', cm-': 2974.1590.1
491.1455.1388°1266, 1152.9
60.726 to separate the organic layer and dry it with anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200
, 15 g, elution solvent: hexane-hexane/ethyl acetate = 10/11 to give 88 mg (yield: 67%) of the free base of the title compound as a colorless oil.

The free base obtained above is treated with a hydrogen chloride-methanol solution and then recrystallized from a chloroform-hexane mixture to give the title hydrochloride, m, p, 132-133°C1.

IRv':! :, cm-' : 3430,2968,
2482,1464,966°777.699 NMR (CDC4) δ: 1.25 (9H, s)
, 2.61 (3H,s) 3.56-3.61 (2
H, m), 4.05-4.10 (2H.

m), 5.84 (IH, d, J = 15.9Hz),
6.27 (LH.

dtj=15.9Hz, 7.3Hz), 7.12-7
．． 29 (2H.

m), 7.37-7.53 (8H, m), 7.58
(LH, dt.

J=7.4Hz, 1.9Hz), 7.74 (IH,b
r, s).

7.79 (IH, br, s) NMR (CD (J,) δ: 1.24 (9H, s)
, 2.19 (3H,s).

3.04 (IH, dd, J = 6.5Hz, 1.5
Hz), 3.47 (2H,s), 5.15 (2H,s
), 5.65 (IH, dt, J = 15.8Hz, 1
．． 5Hz), 6.08 (LH, dt, J=15.8H
z, 6.5Hz), 6.85-6.90 (, IH, m
).

6.90-6.94 (IH, m), 7.00 (IH
,br,s).

7.24 (lH, t, J=7.8Hz), 7.55
(IH, t.

J = 7.6Hz), 7.63-7.87 (IH,
m), 8.05 (IH, dt, J = f3.3Hz,
1.5Hz), 8.18 (IH.

br, s), 8.49 (l H, s) Example 51 (E)-3-[2-[3-(3-thienyl)phenyl]
(E)-N-methyl-6,6-
Dimethyl-2-hepten-4-ynylamine hydrochloride 58
mg and 126 mg of potassium carbonate were added, and the mixture was stirred overnight at room temperature. The reaction solution was distilled off under reduced pressure, and ethyl ether and water were added to the residue to add (E)-3-[2-[3-(3-
thienyl)phenyl]ethynyl]benzyl chloride and (
E) -N-methyl-6,6-dimethyl-2-heptene-
In place of 4-ynylamine hydrochloride, the corresponding benzyl chloride, the same promide, or the same methanesulfonate derivative and the hydrochloride of various 2-hebuten-4-ynylamines were used, and the other reaction was carried out in the same manner as in Example 51. hand,
Compounds of Examples 52 to 66 were obtained.

Example 52 m, p: 174-176°C IRvcm-': 3436,2968,966.
777.699NMR (CD(J,)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
(IH, d.

J = 15.6Hz), 6.25 (IH, dt, J
= 15.6Hz.

7.3Hz), 7.12-7.25 (2H, m), 7
．． 30-7.53 (9H, m), 7.56 (IH, d
, J = 7.5Hz), 7.74-7.75 (LH, m), 7.86 (IH, br, s) Example 53 IRv drift cm-': 2968, 2806, 1605
,963,774°NMR (CDC) 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 (IH, d, J
= 15.8Hz).

6.11 (IH, dt, J -15,8Hz, 6.4
Hz), 7.16 (2H, s), 7.22-7.26
(IH, m), 7.30 (LH.

t, J=7.2Hz), 7.36-7.51 (8H,
m), 7.73-7.74 (IH, m) Example 54 IRv'::cm': 2980°2932°2818°1605°1251°1170.1149,1074,774,699NMR
(CD(J,) 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, 1.2Hz), 3.36
(3H.

s), 3.59 (2H, s), 5.71 (IH, d
t, J = 15.9Hz, 1.2Hz), 6.20
(IH, dt, J = 15.9Hz.

6.4Hz), 7.16 (2H,s), 7.20-7
．． 25 (2H.

m), 7.31 (IH, t, J = 7.5Hz),
7.35-7.55 (7H, m), 7.74 (LH,
t, J=2.3Hz) Example 55 IRv':::, cm-': 2968.1605,
1506,1341,1071゜963.756,72
3,696 NMR (CDC1,) δ: 1.24 (9H,s
), 2.22 (3H,s).

3.08 (2H, ddj=6.6Hz, 1.5Hz)
, 3.51 (2H, s), 5.67 (LH, dt, J
= 15.9Hz, 1.5Hz), 6.12 (LH
, dt, J-15, 9Hz, 6.6Hz).

6.37 (2H, t, J = 2.1Hz), 7.1
3 (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 IRv'::cm-' :2968,2926,160
8,1587,1506°1341.1071,963
,723 NMR (CDC7,) δ: 1.07 (3H,t
j = 6.8Hz), 1.24 (9H, s), 2.5
4 (2H, q, J = 6.8Hz), 3.14 (2
H, ddJ=6.5Hz, 1.5Hz), 3.60 (
2H.

s), 5.67 (LH, dt, J = 15.9Hz
, 1.5Hz) 6.10 (IH, 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), 7.2
5-7.34 (3H.

m), 7.38-7.44 (3H, m), 7.50
(LH,s).

7.52-7.54 (IH, m) Example 57 EE-N-ethyl-N-6-mexy-6-methyl-2
-hen-4-nyl-3-2-3-1-pyrrol
FeIRv=cm-': 1605, 1506, 13
41,1170.1149゜1074.960,789
,723,696NMR(CDCls)δ:
1.09 (3H, t, J = 6.9Hz), 1.
46 (6H, s), 2.56 (2H, q, J = 6
．． 9Hz), 3.15 (2H, dd, J = 6.5H
z, 1.5Hz), 3.35 (3H.

s), 3.61 (2H, s), 5.73 (LH, d
t, J = 15.9Hz, 1.5Hz), 6.20
(IH, dt, J = 15.9Hz.

6.5Hz), 8.37 (2H,t,J = 2.7
Hz), 7.127.16 (4H, m), 7.25-
7.35 (3H, m), 7.38-7.45 (3H
, m), 7.50-7.54 (2H, m) Example 58 IRv'::cm-' :3016,2974,160
5,1473,1365°1266.1215,963
,759,711NMR (CD(J,) δ: 1.
07 (3H, t, J = 7.1Hz), 1.24 (
9H, s), 2.55 (2H, q, J = 7.1H
z), 3.13 (LH, dd, J=6.7Hz, 1.5
Hz), 3.60 (2H.

s), 5.70 (IH, dt, J = 15.9Hz
, 1.5Hz).

6.10 (IH, dt, J = 15.9Hz, 6.
7Hz), 7.19 (2H, s), 7.23-7.59
(8H, m), 7.71 (LH.

br, s), 7.89-7.94 (IH, m), 8.
61 (IH.

dd, J = 4.8Hz, 1.6Hz), 8.89
<IH, d, J = 1.6 Hz) Example 59 IRv'::cm-': 2968, 2926, 12
63,1107,960°798.756,696 NMR (CDC4) δ: 1.07 (3H,t,
J = 7.0Hz), 1.24 (9H, s), 2.5
1-2.58 (2H, m), 3.12-3.14 (2
H, m), 3.58-3.62 (2H, m), 5.6
8 (IH.

d, J = 15.7Hz), 6.10 (IH, dt
, J = 15.7Hz, 6.1Hz), 7.15-7
．． 57 (IOH, m), 7.81 (IH, t, J =
1.5Hz), 7.94 (LH,s) Example 60 EE-N-Eru N-6-xy-6-ru 2-IRv
':? cm-': 3128, 2984, 2936,
2820,1604°1582.1506.968 NMR (CDC/,) δ: 1.08 C3H,t,J
= 7.0Hz), 1.46 (6H, s), 2.56
(2H, q, J = 7.0Hz), 3.15 (2H
, d, J = fi, 3Hz), 3.36' (3H, s
), 3.60 (2H, s), 5.71 (IH, dt
, J = 15.8Hz, 1.5Hz), 5.21 (I
H, dt, J = 15.8Hz, 6.3Hz).

7.13 (IH, d, J = 16.1Hz), 7.
14 (IH.

d, J = 16.1 Hz), 7.32 (LH, t,
J = 7.5Hz).

7.41 (IH,s), 7.42-7.45 (2H
, m), 7.49-7.50 (2H, m), 7.51
-7.52 (IH, m), 7.55 (IH, dt, J
=7.5Hz, 1.6Hz), 7.81 (IH.

t, J = 1.6Hz), 7.94 (LH,s)
Example 61 -Nyl benzylmine IR compression cm-': 2968,1608,1506
,1341,1071゜960.723,696 NMR (CDCIs) δ: 0.89 (3H,t
, J = 7.3Hz), 1.24 (9H, s) 1.4
8-1.60 (2H, m) 2.42 (2H.

t, J = 7.3Hz), 3.12 (2H, d, J
= 6.2Hz).

3.58 (2H, s), 5.66 (LH, d, J
= 15.8Hz).

6.10 (IH, dt, J = 15.8Hz, 6.
2Hz), 6.37 (2H, t, J = 2.2H2)
,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 (IH.

m), 7.52-7.54 (LH, m) Example 62 IRv'::cm': 2972, 2B64, 160
8,1588,1504°1308, 1060.96
2 NMR (CD(J3)δ: 1.10 (3H,t,J
= 7.2Hz), 1.25 (9H, s), 2.57
(2H, q, J = 7.2Hz), 3.18(2
H, dd, J=6.3Hz, 1.5Hz), 3.61
(2Hs), 5.64 (IH, dt, J = 15.
9Hz, 1.5Hz).

6.06 (IH, dt, J = 15.9Hz, 6.
3Hz), 7.14 (IH, d, J = 16.0Hz
), 7.19 (IH, d, J = 16.0 Hz), 7
．． 21-7.58 (9H, m), 7.67-7.74
(IH, m), 7.91 (IH, br, s) Example 63 IRv';::cm-': 1602,1479,1
458,1365,12631203.975,852
,774 NMR (CD(J,) δ: 1.24 (9H,s
), 2.34 (3H,s).

3.10 (2H, dd, J = 7.0Hz, 1.6
Hz), 3.52 (2H, s), 5.68 (LH, d
t, J = 15.8Hz, 1.6Hz), 6.10
(IH, dt, J = 15.8Hz, 7.0Hz).

7.14 (IH, d, J = 5.6Hz), 7.2
3 (IH, dJ = 16.4Hz), 7.41-7
．． 48 (4H, m), 7.49-7.55 (3H,
m), 7.68 (LH, d, J = 16.4Hz)
.

7.81 (IH, t, J = 1.8Hz), 8.5
4 (IH, d, J = 4.7Hz) Example 64 IRv'::cm-' :2968,1458,136
5,963,774°NMR (CD(J,)δ: 1.
24 (9H, s), 2.16 (3H, s).

2.95 (4H, s), 3.02 (2H, dd, J
= 6.6Hz.

J = k, 5Hz), 3.45 (2H, s), 5.
63 (LH.

dt, J=15.9Hz4.5Hz), 6.08 (I
H, dt.

J = 15.9Hz, 6.6Hz), 7.07-7.
25 (5H.

m), 7.27-7.52 (6H, m) Example 65 NRv':', cm' 2 2968. 2928
．． 2864. 2796. 1610°1594.1
506.726 NMR (CDCi'3) δ: 1.03 (3H,t,
J = 7.1Hz), 1.24 (9H, s), 2.4
8 (2H, q, J = 7.1Hz), 2.95 (4
H, s), 3.06 (2H, dd, J = 6.2
Hz, 2.3Hz).

3.53 (2H, s), 5.62 (LH, dt, J
= 15.8Hz.

2.3Hz), 6.06 (IH, dtj= 15.8
Hz, 6.2Hz), 6.33 (2H, t, J =
2.2Hz), 7.04 (2H.

t, J = 2.2Hz), 7.04-7.08 (2
H, rn); 7.13-7.17 (3H, m), 7.
19-7.23 (2H, m), 7.31 (LH, t,
J = 7.8Hz) Example 66 2 IRv';::cm-': 2968, 2932, 2
866.1473,1458°1365.789,70
5 NMR (CDC/,) δ: 1.02 (3H,t,
J = 7.3Hz), 1.24 (9H, s), 2.5
0 (2H, qj = 7.3Hz), 2.96-2.
99 (4H, m), 3.01 (2H, d, J=6.
4Hz) 3.54 (2H, s), 5.63 (IH,
d, J = 16.2Hz).

6.08 (IH, dt, J = 16.2Hz, 6.
4Hz), 7.06-7.11 (LH, m), 7.1
5-7.27 (4H, m), 7.32-7.42 (
4)1. m), 7.83 (IH, dt, J=8.4H
z.

1.8Hz), 8.60 (IH, br, s), 8.8
0 (IH,br,s)Example 67 (E)-N-(6,6-dimethyl-2-heptene-4-
18 mg of (inyl)-N-ethyl-5-formylfurfurylamine and 3-(3-thienyl)benzylphosphonic acid
Dimethyl ester [synthesized by condensation of 3-(3-thienyl)benzyl bromide and trimethyl phosphite 119 mg
was dissolved in 1 ml of dimethylformamide, 2.6 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution under reduced pressure, the residue was subjected to preparative thin layer chromatography [thin layer plate: Kieselgel 60F2, 1.
Art, 5715 (manufactured by Merck & Co., Ltd.), developing solvent: hexane/ethyl acetate = 3/1] to obtain 15 mg (yield: 55%) of the title compound as a pale yellow solid.

IRv';::cm': 2968.1602.1
458.1365.1266°1020, 960.77
4 NMR (CD(J,)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 (IH.

d, J = 15.9Hz), 6.13 (IH, dt
, J = 15.9Hz, 6.8Hz), 6.25-6
．． 35 (2H, m), 6.90 (IH, d, J =
16.4Hz), 7.04 (IH, d, J = 16.
4H2), 7.32-7.52 (6H, m), 7.6
7 (lH.

br, s) Instead of the raw material (E)-N-(6,6-dimethyl-2-heptene, 4-ynyl)-N-ethyl-5-formylfurfurylamine, the corresponding formyl derivatives were used, and the others were Example 6 was obtained by carrying out the same reaction as in Example 67.
8 and Example 69 were obtained.

Example 68 IR drift cm-': 2968°2868°1602°1450°1266°966°NMR (CDC/,) δ: 1.24 (9H,s
), 2.35 (3H,s).

3.20-3.27 (2H, m), 3.74-3.7
9 (2H.

m), 5,72 (IH, d, J -15,7Hz),
6.18 (IH.

dt, J = 15.7Hz, 6.6Hz), 7.19
(IH, d.

J -16,4Hz), 7.19-7.63 (9H,
m), 7.75-7.77 (IH, m), 8.52
(IH, d, J = 5.3Hz) Example 69 IRν: cm→: 2968.2926.1440.13
65.963°852.774 NMR (CD(J,)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 (LH, s), 5.71 (IH,
d, J=15.9Hz), 6.08 (IH, dt, J
=15.9Hz.

6.5Hz), 6.40-6.48 (IH, m), 7
．． 15-7.25 (2H, m), 7.38-7.53
(5H, m), 7.56 (IH.

dt, J = 7.1Hz, 2.1Hz), 7.73
(LH,s) Example 70 E -N-66-dimethyl-2-othen-4-ynyl-N-ethyl-3-3-3-thienyl benzyl xy ben 2 ni 1≦≦N-ethyl per meter 50 mg of -3-[3-(3-thienyl)benzyloxy]benzylamine hydrochloride was dissolved in 1.5 ml of dimethylformamide, and 1-bromo-6,6-dimethyl-2-octen-4-yne (E-form and 2 about 4:
1) and 65 mg of sodium carbonate were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl ether, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column:
Lobar column, 5ize A, Li
chloroprepSt 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 771] to obtain 39 mg (yield: 63%) of the title compound as a colorless oil.

IRv'::cm': 2968.2926.28
00.1584.1491°1458, 1260.77
4 N M R (CD C1s ) δ: 0.97 (3H
, t, J = 7.3Hz), 1.00-1.10
(3H, m), 1.18 (68, s), 1.44
(2H.

q, J = 7.3Hz), 2.45-2.60 (2
H, m), 3.05-3.15 (2H, m), 3.5
0-3.60 (2H, m), 5.11 (2H, s),
5.65 (IH, d, J = 15.9Hz), 6.
07 (IH, dt, J = 15.9Hz, 6.4Hz
), 6.85-6.90 (IH, m), 6.90-6.
95 (IH, m), 7.01-7.06 (IH, m)
, 7.22 (IH, t, J=8.0Hz), 7.35
-7.45 (4H, m), 7.47 (IH, dd,
J = 2.3Hz.

1.8Hz), 7.55 (IH, dt, J = 7.
0Hz, 1.8Hz).

7.66-7.69 (LH,m) Example 71 (E)-N-(6,6-dimethyl-2-heptene-4-
3-(3-thienyl)-N-methyl-3-hydroxy-4-methoxymethyloxybenzylamine (3-(3-thienyl) ) Add a solution (1 m4) of 32 mg of benzyl bromide in dimethylformamide and stir at room temperature for 2 hours. Ethyl ether was added to the reaction solution, insoluble inorganic salts were filtered off, and concentrated under reduced pressure. The residue was dissolved in 1 ml of 10% hydrogen chloride-methanol.
1 ml of tetrahydrofuran and left at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was extracted with a 5% aqueous sodium hydrogen carbonate solution and ethyl ether.
The organic layer is separated and dried over anhydrous magnesium sulfate.

After filtering off the drying agent, the solvent was distilled off, and the residue was purified by silica gel column chromatography [Wakogel C-200, 5 g, elution solvent: hexane/ethyl acetate = 371] to give 31 mg of the free base of the title compound (yield :56%)
is obtained as a colorless oil. Treatment of the above free base with a hydrogen chloride-methanol solution and recrystallization from an ethyl ether/isopropyl ether mixture yields the title hydrochloride salt.
m.

p, 88-90°C is obtained.

IRvshicm-': 2968.1521.1464
．． 1446.1281°NMR (CDC/3) δ: 1
．． 25 (9H, s), 2.57 (3H, s) 3.3
9-3.54 (IH, m), 3.59-3.74 (
LH.

m), 3.83-4.00 (IH, m), 4.01-
4.20 (IH.

m), 5.31 (2H, s), 5.81 (lH, d
, J = 15.6Hz), 5.91 (IH,br,
s), 6.21 (IH, dt, J = 15.6Hz,
7.7Hz), 6.80 (IH, d, J=7.8Hz
), 6.91 (IH, d, J = 7.8Hz), 7
．． 38-7.48 (4H, m), 7.50-7.55
(IH, m), 7.56-7.62 (IH, m), 7.
75 (IH,s), 7.82 (IH,s) Starting compound (E) -N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxy-4-methoxy Methyloxybenzylamine and/or 3-(3
-thienyl)benzyl bromide, the corresponding methoxymethyloxybenzylamine derivative and/or 3-
Example 7 The same reaction as in Example 71 was carried out except for using (5-oxacylyl)benzyl methanesulfonate.
Compounds 2 and 73 were obtained.

Example 72 IRv"::cm': 2968,1476.136
5,1245,1107゜1035.954,789,
750,693NMR (CD(J3) 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 (I
H, d, J = 15.7 Hz), 6.08 (IH, d
t, J = 15.7Hz, 7.0Hz), 6.59-
6.64 (IH, m), 6.67 (LH, t, J=8
．． 0Hz), 6.84 (IH, dd, J=8.0Hz,
1.8Hz), 7.37 (IH.

s), 7.38-7.50 (2H, m), 7.60
(LH, dt.

J = 7.0Hz, 1.8Hz), 7.77 (IH
, s), 7.91 (IH, s) Example 73 IRv':::cm-': 2968,1518,1
461,1365,1275゜1200.1119,7
95,759 MR (CDCJJ 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 (IH, d
, J = 16.1 Hz), 6.08 (IH, dt, J
= 16.1Hz, 6.7Hz), 6.80 (LH.

dt, J = 8.0Hz, 1.7Hz), 6.89
(IH, d, J=8.0Hz), 7.02 (IH, b
r, s), 7.39 (LH.

s), 7.39-7.42 (IH, m), 7.48
(IH, t, J = 7.6Hz), 7.65 (IH,
dt, J = 7.6Hz, 1.6Hz), 7.73
(lH,s), 7.93 (IH,s) Example 74 (E)-N-(6,6-dimethyl-2-heptene-4-
(inyl)-N-ethyl-3-aminobenzylamine 90
m g and 3-(3-thienyl)benzaldehyde 6
3 mg is dissolved in 2.5 m/m of absolute methanol and stirred overnight at room temperature in the presence of molecular sieves 3A. After filtering the molecular sieves from the reaction solution, 12.5 mg of sodium borohydride was added, and the solution was further heated for 30 min at room temperature.
Stir for a minute.

After distilling off the solvent under reduced pressure, the residue is dissolved in a mixture of methylene chloride and water, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200, 5g
, Elution solvent: hexane/ethyl acetate = 10/1 → 5/l
] to give 80 mg of the title compound as a pale yellow oil.
(Yield: 55%) is obtained.

IRv'::cm-': 2968.2926.16
08.1491.774NMR(CD(Jl)δ: 1
．． 01 (3H, tj = 7.1Hz), 1.24 (
9H, s), 2.49 (2H, q, J = 7.IH
, z), 3.08 (2H, dd, J = 6.4Hz,
1.5Hz), 3.48 (2H.

s), 4.37 (2H, s), 5.63 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.06
(IH, dt, J = 15.9Hz.

6.4) 1z), 6.51-6.56 (IH, m),
6.66-6.69 (II, m), 7.11 (IH,
t, J = 8.0 Hz), 7.31 (I H, dt,
J = 7.8Hz, 1.7Hz), 7.35-7
．． 40 (3H, m), 7.45 (IH, t, J =
2.2Hz), 7.51 (IH, dt, J=7.8)1
z, 1.7Hz), 7.61 (LH.

br, s) To the raw material compound (E)-N-(6,6-dimethyl-2-hebuten-4-ynyl)-N-ethyl-3-aminobenzylamine and/or 3-(3-thienyl)benzaldehyde Instead, the corresponding 3-aminobenzylamine derivatives and/or 3-substituted benzaldehyde derivatives were used, but the same reaction as in Example 74- was carried out to obtain compounds of Examples 75 to 80.

Example 75 2 table length 2 IRv';::cm-': 2968,1608,1
491, 1458, 1365°NMR (CDC11)
δ: 1.24 (9H, s), 2. I8 (3H,
s).

3.02 (2H, dd, J = 6.5Hz, 1.4
Hz), 3.42 (2H,s), 4.37 (2H,s
), 5.63 (LH, dt, J = 15.8Hz, 1
．． 4Hz), 6.07 (LH, dt, J ~15.8
Hz, 6.5Hz), 6.52-6.56 (LH,
m).

6.65-6.68 (2H, m), 7.11 (IH
, t, J=7.9Hz), 7.30 (IH, dt, J
= 7.5Hz, 1.4Hz) 7.35-7.40
(3H, m), 7.45 (IH, t, J = 2.1
Hz), 7.51 (LH, dt, J = 7.5Hz
, 1.7Hz).

7.61 (IH, br, s) Example 76 E -N-66-di-2-hebuten-4-ynyl-N-ethyl-3-3-1-pyrrol benzyl mino
Ben 2 side 2 IRv”:::cm-': 2968.1608.1
506.1338.1071゜783.726 NMR (CDC7,) 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, 1.5Hz), 3.48
(2H.

s), 4.39 (2H, s), 5.62 (IH, d
t, J = 15.8Hz, 1.5Hz), 6.05
(IH, dt, J = 15.8Hz.

6.5Hz), 6.33 (2H,t, J = 2.2
Hz), 6.49-6.53 (IH, m), 6.66
-6.69 (2H, m), 7.08 (2H, t, J
= 2.2Hz), 7.10 (IH, t, J = 8
．． 1Hz), 7.24-7.32 (2H, m),
7.36-7.42 (2H, m) Example 77 IRv':::cm-': 2974.1611.1
506.1494.1458゜1107.954.69
6 NMR (CD (Jri δ: 1.20 (9H, s), 2
．． 14 (3H, s).

3.05 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.42 (2H, s), 4.38 (2H, S
), 5.59 (IH, dt, J = 15.9Hz, 1
．． 5Hz), 6.03 (LH, dt, J ~15.9
Hz, 6.6Hz), 6.52 (IH, dt, J =
8.0Hz, 1.0Hz), 6.67-6.69 (
2H, m), 7.11 (IH, t, J = 8.0Hz
), 7.35-7.42 <3H, m).

7.57 (LH, dt, J = 7.4Hz, 1.6
Hz), 7.68 (IH, br, s), 7.91 (
IH, s) Example 78 IR: cm-': 2968, 2926, 1611,
1506,1494゜1476.1266.1107,
954,789,759NMR (CDC1',) δ:
1.00 (3H, t, J = 7.1Hz), 1.2
4 (9H, s), 2.48 (2H, q, J = 7.
1Hz), 3.07 (2H, dd, J=6.4Hz, 1
．． 5Hz), 3.48 (2H.

s), 4.38 (2H, s), 5.62 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.05
(IH, dt, J = 15.9Hz.

6.4Hz), 6.50-6.54 (IH, m), 6
．． 67-6.69 (2H, m), 7.11 (LH,
t, J = 7.9Hz), 7.38(IH,s),
7.37-7.44 (2H, m), 7.57 (LH
.

dt, J = 7.2Hz, 1.7Hz), 7.68
(IH, br.

s), 7.91 (IH, s) Example 79 Benzylamine IRv:・cm': 3412.3100.29
80.2932.2818゜1608.1491,14
73.1365NMR (CDC1,) 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 (
IH, d, J = 16.2Hz), 6.16 (LH,
dt, J = 16.2Hz, 6.0Hz), 6.52
-6.57 (IH, m), 6.66-6.72 (2H
, m), 7.12 (LH.

t, J = 7.8Hz), 7.29-7.40 (4
H, m), 7.45 (IH, t, J = 2.2Hz)
, 7.51 (LH, dt, J = 7.5 Hz, 2.
1Hz), 7.61 (IH, br, s) Example 80 E -N-66-dimethyl-2-hepten-4-ynyl-NIRv::cm': 2968,1611,1
569,1515,1464゜1368, 1269.
774 NMR (CD(J,) δ: 0.81 (3H,t
, J = 7.3Hz), 1.24 (9H,s), 1.
40 (2H, 5ext, J=7.3Hz).

2.32 (2H, t, J = 7.3Hz), 3.0
3 (2H, dd.

J = 6.4Hz, 1.4Hz), 3.42 (2H
, s), 4.53 (2H, s), 5.59 (IH, d
t, J = 15.9Hz, 1.4Hz), 5.99
(IH, dt, J = 15.9Hz, 6.4Hz)6
．． 48 (IH, d, J = 1.6Hz), 6.58
(IH, dd.

J = 5.4Hz, 1.6Hz), 7.27-7.3
1 (IH, m).

7.34-7.40 (3H, m), 7.45 (IH
, t, J -1,8Hz), 7.50 (IH, dt,
J = 7.6Hz, 1.7Hz).

7.59 (IH, br, s), 7.96 (IH, d
t, J = 7.6Hz, 1.7Hz) Example 81 E -N-66-dimethyl-2-hebuten-4-nyl-
N-ethyl-3-N-thyl-3-3-thienyl benzylamino (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N- obtained in Example 74 of benzylamine Ethyl-3-[3
-(3-thienyl)benzylaminocobenzylamine 1
00 mg was dissolved in 3 ml of acetonitrile, 0.1 ml of a 35% aqueous formaldehyde solution and 22.7 mg of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 30 minutes. After evaporating the reaction solution 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. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200
, 5g, elution solvent: hexane/ethyl acetate = 10/1→
6/1] to give 55 mg of the title compound (
Yield: 53%) as pale yellow crystalline solid, m, p, 51 5
Obtained as 2°C1.

IRv"4cm-': 2974.2926.160
5.1500.136B.

1218,762 NMR (CD(J,)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 (IH, dd, J = 6.3Hz
, 1.4Hz).

3.51 (2H,s), 4.56 (2H,s), 5
．． 61 (IH.

dt, J = 15.8Hz, 1.4Hz), 6.05
(18, dt.

J = 15.8Hz, 6.3Hz), 6.63-6.
71 (2H.

m), 6.78-6.79 (IH, m), 7.12-
7.19 (2Hm), 7.31-7.38 (3H,
m), 7.41 (IH, dd.

J = 2.7Hz, 1.5Hz), 7.46-7.
49 (2H,m) Example 82 (E)-N-(6,6-dimethyl-2-heptene-4-
ynyl) N-ethylglycyl hydrazide [(E)-N-
Synthesized by condensing ethyl-6゜6-dimethyl-2-hebuten-4-ynylamine and bromoacetic acid methyl ester in the presence of sodium hydrogen carbonate, and then allowing hydrazine to act on this] 57 mg and sodium hydrogen carbonate 20 mg
was added to 1 ml of dioxane, and 3-(3-
thienyl)cinnamic acid [3-(3-thienyl)cinnamic acid chloride prepared from synthetic 150 mg and 0.3 ml of thionyl chloride by heating condensation of 3-(3-thienyl)benzaldehyde and malonic acid in the presence of piperidine/pyridine. Add dioxane solution (1 mi') and stir at room temperature for 30 minutes.

After filtering off the inorganic salts and distilling off the solvent under reduced pressure, the residue was dissolved in 0.8 m4 of phosphorus oxychloride and heated and stirred at 65°C for 16 hours. Pour the reaction solution into ice water, neutralize by adding sodium bicarbonate, and extract by adding ethyl acetate.

After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography [10 g of Wakogel C-200, elution solvent: hexane/ethyl acetate = 3/11 to yield 37 mg of the title compound as a colorless oil. (Yield: 36%) is obtained.

IRv":::cm-': 2972.1648.1
364.1266, 964°854.778 NMR (CDCj,) 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, 1.5Hz), 3.95
(2H.

s), 5.73 (IH, dt, J = 15.9Hz
, 1.5Hz).

6.07 (LH, dt, J = 15.9Hz, 6.
8Hz), 7.09 (LH, d, J-16, 3Hz),
7.39-7.50 (4H.

m), 7.51 (IH, dd, J=3.1Hz, 1
．． 7Hz).

7.60 (IH, d, J = 16.3Hz), 7.6
2 (IH.

dt, J = 7.4Hz, 1.8Hz), 7.76
(IH, t, J = 1.8 Hz) Example 83 (E) -N-(6,6-dimethyl-2-heptene-4
-ynyl)-N-ethyl-3-aminobenzylamine 8
3 mg and 100 mg of 3-(l-pyrrolyl)benzoic acid were dissolved in a mixture of 1 ml of methylene chloride and 2 ml of tetrahydrofuran, and N,N'-dicyclohexylcarbodiimide (D
Add 92 mg of CC) and stir at room temperature for 3 hours. After evaporating the reaction solution under reduced pressure, the residue was dissolved in methylene chloride, and after filtering off insoluble materials, the mixture was washed successively with a 5% aqueous sodium bicarbonate solution, 5% hydrochloric acid, and saturated brine. After drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography [Wakogel C-200, 20 g, elution solvent: hexane/ethyl acetate ===10/1→3/l] to give a pale 98 mg (yield: 61%) of the title compound as a yellow oil are obtained.

IRv'::cm-': 2968.1653.15
93.1554.1503゜1443, 1341.72
3NMR(CDCls)δ: 1.05 (3H
,t, J = 7.1Hz), 1.23(9H,s),
2.52 (2H, q, J = 7.1Hz), 3.1
0 (2H, dd, J = 6.7Hz, 1.6Hz),
3.56 (2H.

s), 5.65 (LH, dt, J = 15.8Hz
, 1.6Hz).

6.08 (LH, dt, J = 15.8Hz, 6.
7Hz), 6.37 (2H,t,J = 2.5Hz)
, 7.11-7.15 (3H, m).

7.31 (IH, t, J = 7.8Hz), 7.4
8-7.58 (3H.

m), 7.62-7.70 (2H, m), 7.91-
7.94 (2Hm) Example 84 3-(1,3,4-)lyazol-1-yl)benzoic acid ethyl ester [J, Med, Chem,, 'g
, 38B (1962) according to the manufacturing method described]
430 mg was dissolved in a mixture of 20 m4 of tetrahydrofuran and 20 m4 of dioxane, 100 mg of lithium aluminum hydride was added thereto, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was partitioned between ethyl acetate and water, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was purified by silica gel column chromatography [Wakogel C-200, 20 g, elution solvent: chloroform/methanol = 20/1].
240 mg (yield: 69%) of (3-hydroxymethylphenyl)-1,3,4-triazole is obtained.

220mg of the above alcohol and 20ml of chloroform
Add 2 ml of thionyl chloride and stir at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was partitioned between chloroform and water, and the organic layer was separated and washed with a 5% aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 143 mg of -(3-chloromethylphenyl)-1,3,4-triazole.
(Yield: 59%) is obtained.

38 mg of the above chloromethyl compound was dissolved in 2 ml of dimethylformamide, and (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-
The phenolate is added to a tetrahydrofuran solution (2 ml) prepared from 60 mg of hydroxybenzylamine and 14 mg of 60% oily sodium hydride and stirred at room temperature for 5 hours. Add ethyl ether and water to the reaction solution to separate the layers,
After separating the organic layer, it was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the residue was evaporated into a medium-pressure liquid column.

5ize A, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
1/1→115] to obtain 48 mg (yield: 59%) of the title compound as a pale yellow oil.

IRve, cm-': 296B, 1599, 151
8,1491,1452゜1368.1269,115
2,1092,1032°786.762 NMR (CD(J,) δ: 1.24 (9H,s
), 2.19 (3H,s).

3.03 (2H, dd, J=6.8Hz, 1.5Hz
), 3.48 (2H, s), 5.15 (2H, s),
5.64 (LH, dt, J= 15.3Hz, 1.5
Hz), 6.05 (IH, dt, J=15.3Hz,
6.6Hz), 6.87 (IH, ddd, J = 7
．． 8Hz, 2.7Hz, 1.2Hz), 6.93 (I
H, d, J = 7.8Hz), 6.99-7.02
(IH, m), 7.24 (IH, t.

J = 7.8Hz), 7.35 (IH, dt, J
= 6.9Hz.

2.4Hz), 7.50-7.59 (3H, m), 8
．． 50 (2H,s) Example 85 10 mg of 3-[3-(3-thienyl)benzylthio]benzaldehyde is dissolved in 1 m/ml of ethanol, 1.8 mg of sodium borohydride is added, and the mixture is stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, ethyl ether and water are added to the residue for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent is distilled off, the residue is dissolved in 1 m4 of ethyl acetate, 4.4 mg of methanesulfonyl chloride and 5.9 mg of triethylamine are added, and the mixture is stirred at room temperature for 10 minutes. After filtering off the precipitated triethylamine hydrochloride, the solvent was distilled off, and the residue was dissolved in 1 ml of dimethylformamide. , 5
mg and 10 mg of potassium carbonate were added, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethyl ether, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to preparative thin layer chromatography [thin layer plate: Kieselg
el 60Fzsa, Art, 5744 (manufactured by Merck & Co., Ltd., developing solvent: hexane/ethyl acetate = 5/1) to obtain 7.5 mg (yield: 51%) of the title compound as a colorless oil.

IRv:cm-': 1478.1363.1265
．． 844.777N M R (CD C/)) δ: 1
．． 00 (3H, t, J = 7.1Hz), 1.24
(9H, s), 2.44 (2H, q, J = 7.1
Hz), 3.03 (2H, d, J = 6.5Hz),
3.49 (2H, s), 4.15 (2H, s), 5.
62 (IH, d, J = 15.9Hz), 6.04
(IH, dt, J = 15.9Hz, 6.5Hz),
7.13-7.42 (8H, m), 7.45 (IH,
t, J = 1.7Hz), 7.46-7.51 (2
(E)-3-[ 2-[3-(5-thiazolyl)phenyl]ethynyl]benzoic acid methyl ester [3-methoxycarbonylbenzylphosphonic acid dimethyl ester and 3-
(E) obtained by condensation of bromobenzaldehyde
Synthesis by condensing -3-[2-(3-bromophenyl)ethynyl]benzoic acid methyl ester with 5-trimethylstannylthiazole; 5ynthesis, 757 (1
986)] 116 mg and 3 ml of tetrahydrofuran
14 m of lithium aluminum hydride dissolved in water and cooled with water.
g and stir for 30 minutes. The reaction mixture is poured into water, extracted with ethyl ether, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent is distilled off, and the residue is dissolved in a mixture of 3 ml of ethyl acetate and 3 ml of methylene chloride. 31 p of methanesulfonyl chloride and 70 II of triethylamine are added, and the mixture is stirred at room temperature for 30 minutes. Triethylamine hydrochloride was filtered off and then distilled off under reduced pressure. The residue was dissolved in 3 ml of dimethylformamide, and (E)-N-ethyl-
81 mg of 6,6-dimethyl-2-heptene-4-ynylamine hydrochloride and 42 mg of sodium carbonate are added, and the mixture is stirred at room temperature for 3 hours. After evaporating the reaction solution under reduced pressure, the residue was separated by adding ethyl ether and water, and the organic layer was separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off and the residue was subjected to medium pressure liquid chromatography.
Lobar column.

5ize A, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
8/l→6/l] to obtain 63 mg (yield: 36%) of the title compound as a colorless oil.

IRv'::cm-': 2968.2872.16
05.1458.1392゜1365, 1266, 96
3.876, 795NMR (CDC/3) δ: 1.0
7 (3H, t, J = 7.1Hz), 1.24 (9
H, s), 2.54 (2H, q, J = 7.1Hz
), 3.11 (IH, d, J = 6.7Hz), 3.
59 (2H, s), 5.67 (IH, d, J = 1
5.9Hz), 6.11 (IH, dt, J = 15.
9Hz, 6.7Hz), 7.15 (2H,s), 7.
297.57 (7H, m), 7.69 (LH9dd
, J = 3.6Hz1.7Hz), 8.12 (IH
, s), 8.77 (IH, s) Example 87 E -N-66-dimethyl-2-hepten-4-ynyl-N-thyl-3-3-3-te-hyrochenyl benzyl 3-(3-tetrahydrothienyl ) Dissolve 25 mg of benzyl alcohol in 5 ml of ethyl ether and dissolve 1511 of methanesulfonyl chloride! and triethylamine 3
Add 0AtI and stir for 1 hour under water cooling. After filtering off the precipitated triethylamine hydrochloride, the solvent was distilled off, and the residue was dissolved in 1 ml of dimethylformamide.
E) -N-(6,6-dimethyl-2-hebuten-4-ynyl)-N-methyl-3-hydroxybenzylamine 1
00 mg of phenolate and 30 mg of 60% oily sodium hydride (10 ml) and stirred at room temperature for 3 hours. The reaction solution is diluted with water and ethyl ether, and the organic layer is separated and dried over magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar column, 5ize A,
LichroprepSi 60F (manufactured by Merck & Co.),
Elution solvent: hexane/ethyl acetate = 20/1 → 10/1
] to give 42 mg of the title compound as a colorless oil (
A yield of near 5%) is obtained.

IRv"::cm-': 1446, 1365, 12
72,1152,1026°885.786,693 NMR (CD(J,) δ: 1.24 (9H, s)
, 2.07 (IH, dat.

J = 12.2Hz, 10.6Hz, 8.5Hz), 2
．． 19 (3H.

s), 2.42 (IH, dq, J = L2.2Hz
, 4.6Hz).

2.88-3.01 (3H, m), 3.04 (2H
, dd, J=6.6Hz, 1.5Hz), 3.17 (
LH, dd, J = 10.2Hz, 6.7Hz), 3
．． 29-3.41 (IH, m), 3.47 (2H,
s), 5.04 (2H, s), 5.64 (IH, d
t, J = 15.8Hz, 1.5Hz), 6.07 (
IH, dt, J15.8Hz, 6.6Hz), 6.86
(IH, dddj=8.2Hz, 2.6Hz, 1.4
Hz), 6.91 (IH, d, J=7.5Hz), 6
．． 99 (LH, br, s), 7.19-7.35 (
4H.

m), 7;37 (IH, br, s) 3-(3
-tetrahydrothienyl)benzyl alcohol and (E
)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-hydroxybenzylamine, the corresponding benzyl alcohol derivative and (E)-
N-(6,6-cymethyl-2-hebuten-4-ynyl)
-N-ethyl-3-hydroxybenzylamine,
Other reactions were conducted in the same manner as in Example 87 to obtain compounds of Example 88 and Example 89.

Example 88 IRv"::cm':2968,2926,2866
．． 1599,1491°1455 1263.777 NMR (CDC/3) δ: 1.03 (3H,t,
J = 7.1Hz), 124 (9H, s), 2.14
-2.23 (IH, m), 2.50 (2H.

q, J = 7.1Hz), 2.46-2.58 (2
H, m), 2.88-2.93 (2H, m), 3.0
9 (2H, d, J = 6.5Hz).

3.54 (2H, s), 5.04 (2H, s), 5
．． 64 (IH.

dt, J = 15.9Hz, 1.5Hz), 6.06
(IH, dt.

J = 15.9Hz, 6.5Hz), 6.45 (L
H, s), 6.85 (IH, dd, J=8.4Hz, 2
．． 0Hz), 6.92 (LH.

d, J = 7.2Hz), 7.00 (IH, br,
s), 7.19-7.36 (4H, m), 7.39
(IH, br, s) Example 89 E -N-66-dityl-2-hethen-4-nyl-
N-IRv'::cm-' :3034,2968,2
926.1?40,1602゜1491.1458.1
263 NMR (CD(J3)δ: 1.04 (3H,t,J
= 7.1Hz), 1.24 (9H, s), 2.45
-2.59 (4H, m), 2.77 (2H.

t, J = 5.7H2), 3.09 (2H, d, J
= 6.5Hz).

3.50 (2H, dd, J = 3.9Hz, 2.1
Hz), 3.55 (2H, br, s), 5.05 (2
H, s) 5.65 (IH, d.

J= 15.9Hz), 6.07 (IH, dt, J=
15.9Hz.

6.5Hz), 6.11-6.17 (IH, m), 6
．． 83-6.89 (IH, m), 6.92 (IH, d
, J=7.5Hz), 7.01 (IH, br, s), 7
．． 19-7.36 (4H, m), 7.40 (LH, b
r, s) Example 90 104 mg of 3-(3-(3-thienyl)phenoxymethyl]benzyl alcohol was dissolved in 1 m4 of ethyl acetate,
While cooling with water and stirring, 45 d of methanesulfonyl chloride and 88 ui of triethylamine are added and stirred for 1 hour.

The precipitate was separated by filtration, and the organic layer was separated and washed with saturated saline.
Dry with anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off to obtain 3-[3-(3-thienyl)phenoxymethyl]benzyl methanesulfonate as a pale yellow oil.

The sulfonate obtained above was dissolved in 2 ml of dimethylformamide, 71 mg of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 37 mg of potassium carbonate were added, and the mixture was stirred overnight. . After extraction by adding water and ethyl acetate to the reaction solution, the organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar colu
mn, 5ize A, Lichroprep 5
i60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 20/l] to obtain 61 mg (yield: 40%) of the free base of the title compound as a colorless oil. After treatment of the above free base with a hydrogen chloride-methanol solution, recrystallization from ethyl ether yields the title hydrochloride salt, m
, p, 125-127°C.

IRv":, cm': 2974.1605.14
55.1278.1218°1185,777 NMR (CD(J,)δ: 1.24 (9H,s),
1.25 (3H.

s), 2.76-2.77 (2H, m), 3.33-
3.37 (2H.

m), 3.37-3.89 (2H, m), 5.14
(2H, s).

5.72 (IH, d, J = 15.8Hz), 6.
12-6.22 (IH, rn), 6.85-6.93
(LH, m), 7.18-7.25 (3H, m), 7.
31 (IH, t, J = 7.9Hz), 7.367
．． 39 (3H, m), 7.41-7.47 (3H,
m) Raw material compounds 3-[3-(3-thienyl)phenoxymethylcobenzyl alcohol and (E)-N-ethyl-
In place of 6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, the corresponding benzyl alcohol derivatives and various 2-hebuten-4-ynylamine hydrochlorides were used, and the other reaction was the same as in Example 90. The compounds of Examples 91-104 were obtained.

Example 91 E -N-66-dityl-2-hepten-4-nyl-
N-IRv: cm': 2974, 2872, 16
05,1584,1365゜1218.771 N MR (CD Cls) δ: 1.24 (9
H,s), 2.19 (3H,s).

3.05 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.51 (2H,s), 5.10 (2H,s
), 5.64 (IH, dt, J = 15.9Hz, 1
．． 5Hz), 6.08 (IH, dt, J = 15.9
Hz, 6.6Hz), 6.91 (LH, add, J=
8.2Hz, 2.6Hz, 1.2Hz), 7.18-7
．． 22 (2H, m) 7.27-7.38 (6H, m
), 7.40-7.42 (IHm), 7.43-7.
45 (IH, m) Example 92 m, p,: 160 165°C IRve, cm-': 2974, 1605° 158
4゜1455゜1287゜1182.774 NMR (CDCl2) δ: 0.92 (3H, t, J
= 7.4Hz), 1.25 (9H, s), 1.88
-1.92 (2H, m), 2.80-2.84 (2H
, m), 3.45-3.75 (2H, m), 4.12
-4.15 (2H, m), 5.77 (IH, d, J
= 15.8Hz), 6.23(IH, dt, J =
15.8Hz, 7.5Hz), 6.89 (IH.

ddd, J = 7.9Hz, 2.5Hz, 1.2H
z), 7.19-7.22 (2H, m), 7.28
-7.40 (3H, m), 7.457.56 (3H
, m), 7.68 (IH, d, J = 6.5Hz)
.

7.71-7.73 (IH, m) Example 93 IRv';::cm-': 2980.2938.1
605.1584.1365゜1251.1173,1
074.771N M R (CD C1s ) δ: 1
．． 04 (3H, t, J = 7.1Hz), 1.46
(6H, s), 2.52 (2H, q, J = 7.1
Hz), 3.11 (2H, dd, J = 6.3Hz,
1.4Hz), 3.35 (3H.

s), 3.60 (2H,s), 5.11 (2H,s
), 5.68 (IH.

dt, J = 15.9Hz, 1.4Hz), 6.15
(LH, dt.

J = 15.9Hz, 6.3Hz), 6.92 (IH
, ddd, J= 8.0Hz, 2.3Hz, 0.9Hz
), 7.18-7.22 (2H.

m), 7.26-7.31 (2H, m), 7.32-
7.35 (2H.

m), 7.36-7.38 (2H, m), 7.40
-7.45 (2H, m) Example 94 IRv"4cm-': 2974.2926.260
8.2500.1593゜1458.1431.777 NMR(CD C1s)δ: 1.25 (9H
, s), 1.29-1.41 (3H.

m), 2.73-2.98 (2H, m), 3.30-
3.60 (2H.

m), 3.90-4.15 (2H, m), 4.17
(2H, s).

5.73 (IH, d, J = 16.1Hz), 6.
12-6.26 (IH, m), 7.20-7.49 (
IOH, m), 7.55-7.64 (IH, m) Example 95 Benzylmine IRv':::cm-': 2980.2938.2
818.1593.1380゜1251.1206.1
173 NMR (CDC7,) δ: 1.00 (3H, t, J
= 7.1Hz), 1.46 (6H, s), 2.46
(2H, q, J = 7.1Hz), 3.05 (2H
, dd, J = 6.4Hz, 1.4Hz), 3.36
(3H.

s), 3.51 (2H, s), 4. L4 (2H,s
), 5.65 (IH.

dt, J = 15.8Hz, 1.4Hz), 6.13
(IH, dt.

J = 15.8Hz, 6.4Hz), 7.18-7.
28 (6H.

m), 7.30 (IH, dd, J = 4.5Hz,
1.5Hz).

7.357.42 (3H, m), 7.47-7.50
(IH, m) Example 96 IRv: cm-': 2974.2872.2806
．． 1503.1458°1107.948 NMR(CDCl5)δ: 1.00 (3H,
t, J = 7.1Hz), 1.24 (9H, s), 2
．． 45 (2H, q, J = 7.1Hz), 3.03
(2H, dd, J=6.6Hz, 1.5Hz), 3.5
1 (2H.

s), 4.15 (2H, s), 5.61 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.03
(LH, dt, J = 15.9Hz.

6.6Hz), 7.13-7.35 (7H, m), 7
．． 45 (LH.

dt, J = 7.0Hz, 1.7Hz), 7.55-
7.57 (IH.

m), 7.90 (IH, s) Example 97 IRv":::cm': 2938.1596.1
455.1380.1257゜1149.1074.7
74 NMR (CD(J,)δ: 0.86 (3H,t,J
= 7.4Hz), 1.46 (6H, s), 1.49
-1.52 (2H, m), 2.37 (2H.

t, J = 7.4Hz), 3.10 (2H, dd,
J = 6.4Hz.

1.8Hz), 3.35 (3H,s), 3.53 (
2H, s), 5.10 (2H, s), 5.65 (IH
, dt, J = 15.9Hz, 1.8Hz), 6.1
5 (LH, dt, J = 15.9Hz, 6.4Hz
)6.86 (IH, dd, J = 7.6Hz, 2.
7Hz), 6.90 (IH, d, J = 7.6Hz)
, 7.22 (IH, t, J = 7.6Hz), 7.
36-7.44 (4H, m), 7.47 (IH, d
d.

J = 2.8Hz, 1.7Hz), 7.55 (IH
, dt, J = 7.3Hz, 1.7Hz) 7.66-7
．． 68 (IH, m) Example 98 IRv'::cm-' : 2986, 2938, 28
18,1380.13651251.1149.101
0 74N (CDC4j) δ: 1.00 (3H, t,
J = 7.1Hz), 1.46 (6H, s), 2.4
5 (2H, q, J = 7.1Hz), 3.04 (2
H, dd, J = 6.4Hz, 1.8Hz), 3.3
5 (3H.

s), 3.48 (2H,s), 4.14 (2H,s
), 5.65 (IH.

dt, J = 15.9Hz, 1.8Hz), 6.11
(IH, dt.

J = 15.9Hz, 6.4Hz), 7.13-7.
17 (IH.

m), 7.19-7.24 (3H, m), 7.28-
7.34 (4M.

m), 7.38 (IH, dd, J=3.0Hz, 1.
5Hz).

7.44-7.80 (2H, m) Example 99 Animal 1-L2 IR;, cm-': 2968,1596,150
6,1341,1071°NMR (CDC4) δ:
0.99 (3H, t, J = 7.1Hz), 1.2
4 (9H, s), 2.45 (2H, q, J = 7.
1Hz), 3.03 (2H, dd, J=6.4Hz, 1
．． 5Hz), 3.48 (2Hs), 4.06 (2H,
s), 5.61 (IH, dt, J = 15.9Hz
, 1.5Hz), 6.02 (LH, dt, J= 15
．． 9Hz.

6.4Hz), 6.32 (2H,t, J = 2.2
Hz), 7.02 (2H, t, J = 2.2Hz),
7.12-7.22 (4H, m) 7.23-7.37
(4H, m) Example 100 Zylamine IR; cm-': 2974, 2932, 2872,
2806,1476°1107.957,693,64
6 NMR (CDC4) δ: 0.99 (3H,t,J
= 7.1Hz), i, 24 (9H, s), 2.44
(2H, q, J = 7.1Hz), 3.03 (2H,
dd, J = 6.3Hz, 1.4Hz), 3.47
(2H.

s), 4.13 (2H, s), 5.61 (LH, d
t, J = 15.9Hz, 1.4Hz), 6.02
(LH, dt, J = 15.9Hz.

6.3Hz), 7.11-7.21 (3H, m), 7
．． 24-7.30 (2H, m), 7.31 (IH, s
), 7.33-7.36 (IH.

m), 7.52 (IH, dt, J=7.9Hz, 1.
4Hz).

7.54-7.56 (IH, m), 7.90 (IH
, s) Example 101 ≦2j L2 IRv = cm-1; 2974. 2932. 1
476, 1458. 1365°1203.1179
．． 783 NMR (CDC/,) δ: 0.99 (3H,t,
J = 7.5Hz), 1.24 (9H, s), 2.4
5 (2H, q, J = 7.5Hz), 3.03 (2
H, dd, J = 6.3Hz, 1.4Hz), 3.4
9 (2H.

s), 4.30 (2H, s), 5.60 (LH, d
t, J = 15.9Hz, 1.4Hz), 6.03
(LH, dt, J = 15.9Hz.

6.3Hz), 7.07-7.09 (IH, m), 7
．． 14-7.19 (IH, m), 7.20 (IH, d
, J = 1.2Hz), 7.21-7.25 (2H
, m), 7.24 (IH, dd, J=6.0Hz.

1.5Hz), 7.27 (IH, dd, J = 3.
0Hz, 1.5Hz).

7.31 (LH, dd, J = 6.0Hz, 3.0Hz),
7.32-7.35 (IH, m) Example 102 IRv'::cm-' :29B0,2938,281
8,1473,1362゜1248.1206,117
3,1149,783NMR (CD(J,)δ: 1.
QO (3H, t, J = 7.1Hz), 1.46 (6
H,s), 2.46 (2H,q, J -7,1Hz)
, 3.05 (2H, dd, J = 6.4Hz, 1.8
Hz), 3.35 (3H.

s), 3.50 (2H,s), 4.30 (2H,s
), 5.65 (LH.

dt, J = 15.9Hz, 1.8Hz), 6.12
(IH, dt.

J = 15.9Hz, 6.4Hz), 7.07-7.
09 (IH.

m), 7.15-7.34 (8H, m) Example 103 IR+, ":cm-': 2974, 2932, 14
13,1029.777NMR (CDC4) δ:
1.05 (3H, t, J = 7.1Hz), 1.2
4 (9H, s), 2.25 (2H, q, J = 7.1H
z), 3.15 (2H, dd, J=6.3Hz, 1.5
Hz), 3.73 (2H.

s), 4.43 (2H, s), 5.65 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.07
(IH, dt, J = 15.9Hz.

6.3Hz), 7.00 (LH,s), 7.26-7
．． 40 (4H.

m), 7.44 (IH, dd, J=2.6Hz, 1.
5Hz).

7.49 (LH, dt, J=7.4Hz4.7Hz)
, 7.59 (IH, t, J = 1.7 Hz) Example 104 IRv'::cm-': 2980, 2938, 14
58,1365,1251°1149, 1077.7
74 NMR (CD(J,) δ: 1.03 (3H,t,J
= 7.1Hz), 1.46 (6H, s), 2.45
(2H, q, J = 7.1Hz), 2.95 (4H,
s), 3.08 (2H, dd, J = 6.3Hz
, 1.4Hz).

3.35 (3H,s), 3.53 (2H,s), 5
．． 66 (IH.

dt, J = 15.8Hz, 1.4Hz), 6.15
(IH, dt.

J = 15.8Hz, 6.3Hz), 7.05-7.
17 (4H.

m), 7.23 (IH, t, J = 7.3Hz),
7.30 (IH.

t J = 7.3Hz), 7.37-7.39 (2
H, m), 7.397.41 (IH, m), 7.4
1-7.43 (LH,m) Example 105 34 mg of 3-[4-(3-thienyl)-2-thienylthiomethyl]benzaldehyde was dissolved in 1 ml of ethanol, and 1 m4 of 43% ethylamine-tetrahydrofuran solution was added. After stirring for 2 hours, 6 mg of sodium borohydride was added and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent and extracting with water and ethyl ether, separate the organic layer.
After washing with saturated saline, drying with anhydrous magnesium sulfate. After removing the desiccant by filtration, the solvent was distilled off, and the residue was dissolved in 1 m/dimethylformamide, (E)-1-bromo-6,
Add 5 mg of 6-dimethyl-2-hebuten-4-yne and 5 mg of potassium carbonate, and stir at room temperature overnight.

After distilling off the solvent and adding water and ethyl acetate for extraction, the organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar col
umn, 5ize A, LichroprepSi
60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 1071] to obtain 3 mg (yield: 6%) of the colorless, curved title compound.

IRv7::cm-': 2968.2926.11
88.963.783NMR (CD(J,)δ: 0.
98 (3H, t, J = 7.1Hz), 1.24 (
9H, s), 2.43 (2H, q, J = 7.1H
z), 3.01 (2H, dd, J = 6.5Hz,
1.5Hz), 3.48 (2H.

s), 3.98 (2H, s), 5.60 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.03
(IH, dt, J = 15.9Hz.

6.5Hz), 7.08-7.13 (3H, m), 7
．． 18-7.29 (4H, m), 7.20-7.25
(2H,m) Example 106 (E)-N-ethyl-N-(6-medoxy6-methyl-2-hepten-4-ynyl)-3-aminobenzylamine 65 mg and 3-(3-thienyl) 43 mg of benzaldehyde is dissolved in 2 ml of methanol and stirred overnight at room temperature. While stirring under water cooling, 12.9 mg of sodium borohydride is added, and the mixture is further stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in a mixture of ethyl acetate and water,
The organic layer is separated and dried over anhydrous magnesium sulfate.

After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C ~ 200.5 g.

Elution solvent: methylene chloride/methanol = 60/1] to give 87 mg of the title compound as a pale yellow oil.
(Yield: 84%) is obtained.

IRv cm': 3400, 2980, 1611
, 1206, 1074°MR (CDC1,) δ: 1.02 (3H, t, J =
7.0Hz), 1.46 (6H,s), 2.49 (2
H, q, J = 7.0Hz), 3.09 (2H, dd
, J-6,4Hz, 1.8Hz), 3.35 (3H.

s), 3.49 (2H, s), 4.05 (LH, b
r, s), 4.37 (2H, s), 5.67 (IH,
dt, J = 15.8Hz, 1.8Hz), 6.15
(IH, dt, J = 15.8Hz, 6.4Hz).

6.54 (IH, ddd, J = 7.9Hz, 2.
7Hz, 1.0Hz).

6.65-6.70 (2H, m), 7.11 (IH
, t, J = 7.9Hz), 7.30 (IH, dt
, J = 7.8Hz, 2.3Hz).

7.37 (IH, t, J = 7.8Hz), 7.3
8 (2H, d.

J = 2.2Hz), 7.45 (IH,t, J =
2.2Hz).

7.51 (IH, dt, J=7.8Hz, 2.3Hz
), 7.60-7.62 (IH, m) Example 107 5-(3-thienyl)-3-thienylmethanol 118
mg was dissolved in 3 ml of chloroform, 58 ml of thionyl chloride was added under water cooling, and the mixture was stirred for 40 minutes. A 5% aqueous sodium bicarbonate solution and chloroform are added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the remaining 5-(3-thienyl)-
3-Thienylmethyl chloride in dimethylformamide 2
After dissolving in ml of (E)-N-(6,6-cymethyl-2-
The phenolate obtained from 163 mg of (hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine and 28 mg of 60% oily sodium hydride is added to a tetrahydrofuran solution (5 ml) and stirred overnight at room temperature. Water and ethyl acetate are added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobar column, 5izeB, Li
chloroprep Si 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 12/l] to give 109 mg of the title compound as a colorless oil (yield: 4
0%) is obtained.

IRv cm': 2974.1590.1458.1
218.756NMR (CD(J,)δ: 1.03
(3H, t, J = 7.0Hz), 1.24 (9H,
s), 2.50 (2H, q, J = 7.0Hz),
3.09 (IH, dd, J = 6.3Hz, 1.5H
z), 3.54 (2H.

s), 5.03 (2H, s), 5.64 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.07
(IH, dt, J = 15.9Hz.

6.3Hz), 6.85 (IH, dd, J = 7.
5Hz, 2.5Hz).

6.92 (IH, d, J = 7.5Hz), 6.9
9-7.01 (LH.

m), 7.18-7.24 (3H, m), 7.30
(LH, dd.

J = 4.8Hz4.5Hz), 7.34 (IH, d
d, J=4.8Hz, 3.0Hz), 7.38 (IH
, dd, J = 3.0Hz.

1.5Hz) In place of the raw material compound 5-(3-thienyl)-3-thienylmethanol, various alcohol derivatives were used, and the other reactions were carried out in the same manner as in Example 107 to obtain Examples 108 to 1.
12 compounds were obtained.

Example 108 IR::cm-': 2974,1599,145
5,1263,783 NMR (CDC4,) δ: 1.
03 (3H, t, J = 7.0Hz), 1.23 (
9H, s), 2.50 (2H, q, J = 7.0H
z), 3.09 (LH, dd, J=6.3Hz, 1.5
Hz), 3.55 (2H.

s), 5.13 (2H, s), 5.67 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.07
(LH, dt, J = 15.9Hz.

6.3Hz), 6.87 (I H, dd, J =
7.8Hz, 2.8Hz).

6.95 (IH, d, J = 7.8Hz), 7.0
2-7.04 (IH.

m), 7.23 (IH, t, J=7.8Hz), 7.
42 (IH.

dd, J = 4.8Hz, 1.2Hz), 7.45
(IH, dd.

J = 4.8Hz, 2.9Hz), 7.56 (I
H, dd, J = 2.9Hz, 1.2Hz), 7.97
(IH, t, J = 2.0Hz).

8.60 (IH, d, J = 2.0Hz), 8.83 (
IH, d.

J = 2.0Hz) Example 109 IRv"::cm-': 2968, 2926, 158
4,1491,1455.1368.1152,102
0.693NMR (CDC43) δ: 1.04 (3
H,t,J = 7.1Hz), 1.23(9H,s)
, 2.51 (2H,q, J = 7.1Hz), 3.
10 (2H, dd, J=6.3Hz, 1.4Hz), 3
．． 54 (2H.

s), 5.03 (2H, s), 5.65 (IH, d
t, J = 15.9Hz, 1.4Hz), 6.07
(IH, dt, J = 15.9Hz.

6.3Hz), 6.44 (IH, d, J = 3.5
Hz), 6.47 (IH, d, J -3,5Hz), 6
．． 87 (IH, dd, J = 8.0Hz, 2.7Hz
), 6.93 (IH, d, J = 7.6Hz)7.
02-7.04 (IH, m), 7.22 (IH, t
, J = 8.1Hz), 7.32 (2H,d,J
= 2.5Hz), 7.49 (IH.

dd, J = 2.0Hz, 1.5Hz) Example 110 IRv'::cm-' :2974,1458.136
5,1263.1155°NMR (CDC13) δ:
1.03 (3H, t, J = 7.5Hz), 1.2
4 (9H, s), 2.50 (2H, q, J = 7.
5Hz), 3.09 (2H, dd, J = 6.3Hz
, 1.9Hz), 3.54 (2H.

s), 5.24 (2H, s), 5.63 (IH, d
t, J = 15.9Hz, 1.9Hz), 6.07
(LH, dt, J = 15.9Hz.

6.3Hz), 6.70 (IH, dd, J = 7.
9Hz, 2.8Hz).

6.93 (LH, d, J = 8.1Hz), 7.0
3-7.05 (IH.

m), 7.22 (LH, t, J = 7.9Hz),
7.25-7.26 (IH, m), 7.38 (IH,
dd, J = 5.2Hz, 2.8Hz).

7.56 (IH, dd, J = 5.2Hz, 1.6
Hz), 7.86 (IH, dd, J= 2.8Hz, f
, 9Hz) Example 111 E-N-66-di-2-h-cy-4-ynyl-NIRv'::cm-': 2974,1590,
1491,1449,1365゜1263.789 NMR (CD(J,) δ: 1.03 (3H,t,
J = 7.5Hz), 1.24 (9H, s), 2.5
0 (2H, q, J = 7.5Hz), 3.09 (I
H, dd, J=6.8Hz, 1.9Hz), 3.54
(2H.

s), 5.34 (2H, s), 5.62 (IH, d
t, J = 15.9Hz, 1.9Hz), 6.06
(LH, dt, J = 15.9Hz.

6.8Hz), 6.85 (If(, dd, J = 7
．． 5Hz, 2.4Hz).

6.95 (IH, d, J = 7.5Hz), 7.0
1-7.03 (IH.

m), 7.23 (LH, t, J=7.5Hz), 7.
37 (LH.

dd, J = 5.4Hz, 3.0Hz), 7.45 (
IH, t, J = 1.2Hz), 7.61 (IH, d
d, J = 5.4Hz, 1.2Hz), 7.76 (
IH, dd, J=3.0Hz, 1.2Hz) Example 11
2 oxybenzylmine IRv=cm-': 2974, 1590, 1491,
1455,1365°1260.963 NMR (CDCJ,) δ: 1.03 (3H,t
, J = 7.2Hz), 1.24 (9H,s), 2.
50 (2H, q, J = 7.2Hz), 3.09 (
2H, dd, J -6, 3Hz, 1.5Hz), 3.5
4 (2H.

s), 5.64 (IH, dt, J = 15.9Hz
, 1.5H2).

6.07 (IH, dt, J = 15.9Hz, 6.
3Hz), 6.85 (IH, ddd, J=8.0Hz,
2, IHz, 1.0Hz).

6.94 (LH, d, J = 8.0Hz), 7.0
0-7.02 (IH.

m), 7.19 (IH, s), 7.22 (IH, t
, J = 8.0Hz).

7.30-7.33 (IH, m), 7.52 (IH
, d, J = 1.5 Hz), 7.85 (LH, s) Example 113 64 mg of 3-(3-tetrahydrothiopyranyl)benzyl alcohol was dissolved in 1 m of ethyl acetate, and 85 Iil of triethylamine and methanesulfonyl Chloride 3
Add 14 and stir for 30 minutes. The precipitate is separated by filtration, and the organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the remaining 3-(3-tetrahydrothiopyranyl)benzyl methanesulfonate was dissolved in 1 ml of dimethylformamide.
(E) -N-(6,6-dimedel-2-hebutene-4
-ynyl)-N-ethyl-3-hydroxybenzylamine loOmg and phenolate obtained from 18mg 60% oily sodium hydride in tetrahydrofuran (1
m7) and stirred at room temperature for 2 hours. Extract by adding water and ethyl acetate, separate the organic layer and wash with saturated saline,
Dry with anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography (Lobar column).

5ize A, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
20/l→10/1] to obtain 60 mg (yield: 85%) of the title compound as a colorless oil.

IRν::cm″″’:2968.2926.1600
．． 1460.70ONMR (CD(J,)δ: 1.0
3 C3H,t, J = 7.1Hz), 1.24 (9
H, s), 1.51-1.67 (IH, m), 1.7
8-2.23 (3H, m), 2.50 (2H, q, J
=7.1Hz), 2.52-3.10 (5M, m),
3.08 (2H, d, J=6.5Hz).

3.54 (2H, s), 5.03 (2H, s), 5
．． 64 (IH.

d, J = 15.9Hz), 6.06 (IH, dt,
J = 15.9Hz, 6.5Hz), 6.83-6.8
9 (IH, m), 6.92 (IH, d, J = 7.2H
z), 6.99-7.01 (LH, m).

7.15 (IH, dt, J = 6.9Hz, 1.8
Hz), 7.22 (IH, t, J=7.2Hz), 7.
26-7.36 (3H,m) 3-(3-
3-(5,6-sihydro2H-thiopyran-4-
The compound of Example 114 was obtained by carrying out the same reaction as in Example 113 except for using yl)benzyl alcohol.

Example 114 IRv':::cm-': 2974,1584,1
491,1365,1200゜1044.960,78
3,696 NMR (CDC/3) δ: 1.03 (3H, t, J = 7.1Hz),
1.24 (9H, s), 2.50 (2H, q, J =
7.1Hz), 2.67-2.74 (2H, m),
2.89 (2H, t, J=5.7Hz).

3.08 (2H, dd, J = 6.4Hz, 1.2
Hz), 3.34 (2H, dt, J=4.4Hz, 2.
2Hz), 3.53 (2H.

s), 5.05 (2H, s), 5.64 (LH, /
dt, J = 15.9Hz, 1.2Hz), 6.06
(IH, dt, J = 15.9Hz.

6.4Hz), 6.19 (LH, tt, J = 4.
4Hz, 2.2Hz).

6.85 (LH, dd, J = 8.3Hz, 2.0
Hz), 6.91 (IH, d, J=7.6Hz), 6.
99-7.01 (IH, m).

7.21 (IH, t, J=7.6Hz), 7.27-
7.36 (3Hm), 7.40-7.42 (IH
, m) Example 115 (E)-3-[2-[3-(2,a-dihydro-4-thienyl)phenyl]ethynyl]benzyl alcohol 40
m g was dissolved in 2 ml of methylene chloride and stirred under water cooling.
Add triethylamine 60111 and methanesulfonyl chloride 20111 and stir at room temperature for 1 hour. Water is added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off and the residue (E
)-3-[2-[3-(2,3-dihydro-4-thienyl)phenyl]ethynyl]benzyl methanesulfonate was dissolved in 1 mj of dimethylformamide, (E)-N-
27 mg of ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 94 mg of potassium carbonate are added and stirred overnight at room temperature. The solvent is distilled off, condensed water and ethyl acetate are added for extraction, and the organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was purified by silica gel column chromatography [Wakogel C-200, 5 g, elution solvent: benzene/ethyl acetate = 40/1 → 15/11] to give a colorless oil with the title title Compound 15mg (yield: 25%)
is obtained.

IRv=cm-': 2972.1600,1466
．． 1264.758NMR (CDCjs) δ: 1.
06 (3H, t, J = 7.1Hz), 1.24 (
9H, s), 2.54 (2H, q, J = 7.1H
z), 3.12 (2H, dd, J = 6.3Hz, 1
．． 3Hz), 3.15-3.22 (2H, m), 3.3
8-3.44 (2H, m), 3.58 (2H.

s), 5.66 (IH, dt, J -15,9Hz,
1.6Hz).

6.10 (IH, dt, J = 15.9Hz, 6.
3Hz), 6.62 (IH, t, J-2, 1Hz)7.
10 (2H, s), 7.21-7.41 (6H,
m), 7.45-7.48 (2H, m) The raw material compound (E)-3-[2-[3-(2,3-dihydro-4-thienyl)phenyl]ethenyl cobenzyl alcohol and (
E) -N-ethyl-6,6-dimethyl-2-hebutene-
In place of 4-ynylamine hydrochloride, the corresponding alcohol derivatives and hydrochlorides of various 2-hebuten-4-ynylamines were used, and the same reaction as in Example 115 was carried out, except for the reaction of Examples 116 to 119. The compound was obtained.

Example 116 IRv"::, cm-': 2974,2932,1
365,954,795°NMR (CDC4) δ:
1.08 (3H, t, J = 7.1Hz), 1.
25 (9H, s), 2.57 (2H, q, J = 7
．． 1Hz), 3.16 (2H, dd, J=6.7Hz,
1.5Hz), 3.76 (2H.

s), 5.69 (IH, dt, J = 15.9Hz
, 1.5Hz).

6.09 (IH, dt, J = 15.9Hz, 6.
7Hz), 6.78 (IH, d, J = 3.8Hz)
, 8.89 (IH, d, J = 16.1 Hz), 6
．． 90 (IH, d, J = 3.6Hz), 7.22
(LH.

d, J = 16.1Hz), 7.35-7.50 (
6H,m), 7.64-7.66 (IH,m) Example 117 IRv::cm-':2974,1458,1365
,1266.960°876.795 NMR (CDCZ,) δ: 1.24 (9H,s
), 2.22 (3H,s).

3.08 (IH, dd, J = 6.5Hz, 1.5
Hz), 3.52 (2H, s), 5.67 (IH, d
t, J = 15.9Hz, 1.5Hz), 6.11 (
IH, dt, J = 15.9Hz, 6.5Hz).

7.16 (2H, s), 7.23 (LH, d, J
= 7.6Hz).

7.32 (IH, t, J = 7.6Hz), 7.4
0-7.52 (5H.

m), 7.69 (IH, t, J = 1.8Hz), 8
．． 13 (IH.

s), 8.77 (IH, s) Example 118 IRv ox cm-': 2974, 1365, 1266
．． 963,876°NMR (CDCj'3) δ: 0
．． 89 (3H, t, J = 7.3Hz), 1.24
(9H, s), 1.48-1.80 (2H, m), 2
．． 41 (3Ht, J = 7.3Hz), 3.12
(IH, dd, J = 6.3Hz.

1.5Hz), 3.58 (2H,s), 5.64 (
IH, dt, J = 15.8Hz, 1.5Hz), 6.
10 (LH, dt, J=15.8Hz, 6.3Hz)
, 7.15 (2H,d, J = 2.2Hz).

7.26-7.27 (LH, m), 7.31 (IH
, t, J = 7.6Hz), 7.40-7.53 (
5H, m), 7.70 (IH, t.

J = 1.8Hz), 8.13 (IH,s), 8.
78 (IH,s) Example 119 Nyl-2-thenylmelamine IRv'::cm-': 2974,2932,13
65,960,849°NMR (CDCjs) δ: 1
．． 11 (3H, t, J = 7.1Hz), 1.25 (
9H, s), 2.57 (2H, q, J = 7.1H
z), 3.17 (2H, dd, J = 6.3Hz, 1
．． 5Hz), 3.78 (2H.

s), 5.69 (IH, dt, J = 15.9Hz
, 1.5Hz).

6.09 (IH, dt, J = 15.9Hz, 6.
3Hz), 6.93 (LH, d, J = 16.4Hz
), 7.09 (IH, d, J = 16.4 Hz), 7
．． 15-7.18 (2H, m), 7.36-7.43
(4H, m), 7.45-7.50 (2H, m), 7
．． 66-7.68 (IH, m) Example 120 40 mg of (E)-3-[2-[4-(3-thienyl)-2-thienyl]ethynyl]benzyl chloride was dissolved in 1 m7 of dimethylformamide, Add 31 mg of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride and 52 mg of potassium carbonate, and stir overnight. The solvent is distilled off, water and ethyl acetate are added for extraction, and the organic layer is separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lo
bar column, 5ize A, Lichr
op, rep 5i60F (manufactured by Merck & Co., Ltd.), elution solvent:
Hexane/ethyl acetate=30/1→15/1] to give 44 mg (yield near 6%) of the title compound as a white crystalline powder, m, p.

10G -102°C is obtained.

IRv:cm' :3466.2974,1104,9
57,741NMR (CDC13) δ: 1.06 (
3H,t,J = 7.1Hz), 1.24(9H,s
), 2.53 (2H, q, J = 7.1Hz), 3
．． 12 (2H, dd, J = 6.3Hz, 1.5Hz
), 3.57 (2H.

s), 5.66 (IH, dt, J = 15.9Hz
, 1.5Hz).

6.10 (LH, dt, J = 15.9Hz, 6.
3Hz), 6.95 (LH, d, J = 16.1Hz
), 7.19-7.38 (9H.

m), 7.42-7.45 (IH, m) Instead of the starting compound (E)-N-ethyl-6,6-dimethyl-2-hebuten-4-ynylamine hydrochloride, the corresponding amine derivative was used. Compounds of Examples 121 to 123 were obtained by carrying out the same reaction as in Example 120 except for using the following methods.

Example 121 1R: cm-': 3442, 2974, 1458
,1365,954825.744 NMR (CD(J,) δ: 1.24 (9H,s
), 2.21 (3H,s).

3.08 (2H, dd, J = 6.6Hz, 1.5
Hz), 3.50 (2H, s), 5.67 (IH, d
tj=15.9Hz, 1.5Hz), 6.11 (I
H, dt, J = 15.9Hz, 6.6Hz).

6.95 (IH, d, J = 16.0Hz), 7.
18-7.38 (9H, m), 7.42-7.46 (
IH, m) Example 122 IRv'::cm-': 2968,1458,13
65,1203,954°N M R (CD CI3) δ: 0.88 (3H, t, J = 7.4Hz),
1.24 (9H, s), 1.47-1.54 (2H,
m), 2.39 (2H.

q, J = 7.4Hz), 3.11 (2H, dd,
J = 6.3Hz.

1.1Hz), 3.56 (2H,s), 5.65 (
IH, dt, J = 15.9Hz, 1.1Hz), 6.
10 (IH, dt, J = 15.9Hz, 6.3Hz
), 7.95 (IH, d, J = 16.6Hz),
7.19-7.38 (9H, m), 7.43-7.4
5 (IH, m) Example 123 IRv';::cm' :2938,1605,136
5,1251,11491074.963,774 NMR (CD(J,) δ: 0.90 (3H,t
, J = 7.3Hz), 1.46 (6H,s), 1.
48-1.60 (2H, m), 2.41 (2H.

t, J = 7.3Hz), 3.14 (2H, dd,
J = 6.3Hz.

1.4Hz), 3.35 (3H,s), 3.59 (
2H, s), 5.70 (IH, dt, J = 15.8H
z, 1.4Hz), 6.20 (LH.

dt, J = 15.8Hz, 6.3Hz), 7.15
(2H, s).

7.20-7.23 (IH, m), 7.31 (IH
, t, J=7.6Hz), 7.36-7.50 (8H
, m), 7.73 (LH, t.

J = 1.4 Hz) Example 124 228 mg of 2.4-thiophene dirubaldehyde 2-ethylene acetal is dissolved in 3 ml of ethanol, 57 mg of sodium borohydride is added, and the mixture is stirred at room temperature for 30 minutes. The solvent is distilled off, water and ethyl ether are added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200, I
130 mg of 4-hydroxymethyl-2-thiophenecarbaldehyde ethylene acecool as a colorless oil.

127 mg of the above alcohol is dissolved in 4 ml of chloroform, 121 mg of thionyl chloride is added, and the mixture is stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution is added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off, and the residue was dissolved in 2 ml of dimethylformamide, followed by (E)-N-ethyl-6,6-
Cymethyl-2-hepten-4-ynylamine hydrochloride 14
0 mg and 144 mg of potassium carbonate are added and stirred at room temperature overnight. The solvent was distilled off and after treatment by a conventional method, medium pressure liquid chromatography [column: Lobar col
umn, 5ize B, LichroprepSi
(E)-N-(6,
6-dimethyl-2-hepten-4-ynyl)-N-ethyl-2-formyl-4-thienylmethylamine 108
mg as a colorless pellet.

46 mg of the above formyl compound and 3-(3-thienyl)
43 mg of benzylethylphosphonate) was dissolved in 1.5 m4 of dimethylformamide, 6 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl ether are added for extraction, and the organic layer is separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent is distilled off,
The residue was subjected to medium pressure liquid chromatography [column: Lob
ar column, 5ize B, Lichro
PrepSf 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 8/1] to obtain 51 mg (yield near 7%) of the title compound as a colorless oil.

IRv':gcm-': 2974.2932.13
65.954.852°NMR (CDC4,) δ: 1
．． 06 (3H, t, J = 7.1Hz), 1.24
(9H, s), 2.52 (2H, q, J = 7.1
Hz), 3.11 (2H, ddJ = 6.5Hz, 1
．． 4Hz), 3.54 (2H.

s), 5.66 (IH, dt, J = 15.9Hz
, 1.4Hz).

6.08 (LH, dt, J -15,9Hz, 6.5
Hz), 6.94 (IH, d, J -16,1Hz),
6.96 (IH,s), 7.04-7.05 (IH
, m), 7.23 (IH, d, J = 16.1Hz
).

7.35-7.43 (4H, m), 7.45-7.5
0 (2H.

m), 7.66 (IH, br, s) Example 125 (E)-N-(6,6-dimethyl-2-heptene-4-
ynyl)-N-methylglycyl hydrazide [(E)-N
-Methyl-6゜Synthesized by condensing 6-dimethyl-2-hepten-4-ynylamine and methyl bromoacetate in the presence of sodium hydrogen carbonate, and then reacting hydrazine with this] 2.56 g and 16.6 g of sodium hydrogen carbonate
g to 25 ml of dioxane, and 3-(
1.0 g of 3-thienyl) cinnamic acid and 6 ml of thionyl chloride
A dioxane solution (20mj) of 3-(3-thienyl)cinnamic acid chloride prepared from above was added, and the mixture was stirred at room temperature for 30 minutes. After filtering off the inorganic salts, the solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of phosphorus oxychloride and heated and stirred at 60° C. for 12 hours. The reaction solution is poured into ice water, neutralized by adding sodium bicarbonate, and extracted by adding ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off and the residue was subjected to medium pressure liquid chromatography [column: Lobar c
olumn, 5ize C, Lichroprep S
i 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 271] to obtain 3.7 g (yield: 81%) of the free base of the title compound as a colorless oil.

Treatment of the above free base with a hydrogen chloride-methanol solution followed by recrystallization from ethyl acetate gave the title hydrochloride salt, m.

p, 144-145°C is obtained.

IRv":pcm': 2974.2872.24
58.1644.1533゜1464.1365,12
66.966.777NMR (CD(J,)δ: 1.
24 (9H, s), 2.91 (3H, s).

3.87 (2H, d, J = 7.5Hz), 4.5
2 (2H, s).

5.97 (LH, d, J = 15.6Hz), 6.
30 (IH.

dt, J = 15.6Hz, 7.5Hz), 7.10
(IH, d.

J = 16.5Hz), 7.40-7.54 (5H
, m), 7.65 (IH, dt, J = 6.9Hz,
1.8Hz), 7.72 (IH.

d, J = 16.5Hz), 7.77-7.79 (
IH, m) In place of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylglycyl hydrazide of the starting compound, (E)-N-(6,6-cymethyl-2
-Hepten-4-ynyl)-N-propylglycyl hydrazide, and the same reaction as in Example 125 was carried out, except that the compound of Example 126 was obtained.

Example 126 Ruamine m, p,: 50.5-52°C IRv": cm-': 2968.2872.282
4.1647.1536°1458, 1365.126
6,966,852.777NMR(CD(J3)δ:
0.91 (3H, t, J = 7.3Hz), 1.
24 (9H, s), 1.50-1.57 (2H, m)
, 2.49-2.54 (2H, m), 3.25 (2H
, dd, J = 6.6Hz, 1.4Hz).

3.94 (2H, s) 5.73 (IH, dt, J
= 15.9Hz.

1.4Hz), 6.06 (IH, dt, J = 15
．． 9Hz, 6.6Hz), 7.08 (IH, d, J
= 16.3Hz), 7.26-7.51 (5H, m
), 7.59 (IH, d, J = 16.3 Hz).

7.60-7.63 (IH, m), 7.75-7.7
6 (IH, m) Example 1 127 100 mg of 2-hydroxymethyl-4-(3-thienyl)thiophene was suspended in 5 ml of chloroform, and dimethylformamide 24 and thionyl chloride 804 were mixed under water cooling and stirring.
Add and stir for 30 minutes. Neutralize with excess saturated aqueous sodium bicarbonate solution under water cooling, separate the organic layer, wash with saline, and dry over anhydrous magnesium sulfate. After the drying agent is filtered off, chloroform is distilled off to obtain 2-chloromethyl-4-(3-thienyl)thiophene as a pale yellow powder.

Add 3 ml of the dimethylformamide solution of the chloromethyl compound obtained above to (E)-N-(6,6-dimethyl-2.
Hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine (165 mj) was dissolved in anhydrous tetrahydrofuran (3 mj).
ml, add 26 mg of 60% oily sodium hydride under stirring under water cooling, stir for 10 minutes, and add to the prepared phenolate solution. After stirring at room temperature for 3 hours, extract by adding 20 m4 of water and 30 m7 of ethyl acetate. After the organic layer was separated, it was washed with Japanese saline, dried over anhydrous magnesium sulfate,
The solvent is distilled off. The residue was subjected to medium pressure liquid chromatography [
Column: Lobar column, sizeB,
Lichroprep Si 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 20/1 → 10
/1] and recrystallized with methanol,
179 mg of the free base of the title compound (yield near 8%, m
, p.

68-69°C) as white needles. Treatment of the above free base with a hydrogen chloride-methanol solution followed by recrystallization from ethyl acetate yields the title hydrochloride salt, m, p, 128-1.
29°C is obtained.

IRX:, cm-': 2974.2926.260
8.1602.1458°1266, 1179.786 NMR (CDC/A) 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 (IH, dt, J = 15.9Hz, 2.
1Hz), 6.18 (I H, dt, J = 15.9
Hz, 8.9Hz), 7.00-7.10 (2H, m)
, 7.15-7.40 (5H, m), 7.49-7.
65 (2H, m ) Example 128 E -N-66-dityl-2-hepun-4-nyl-
N-ethyl-3-4-3-dynyl-2-enyl (E)-N-(6,6-dimethyl-2-hepten-4-ynyl) obtained in Example 127 above -N-ethyl-3
- Dissolve 100 mg of -[4-(3-thienyl)-2-thienylmethyloxy]benzylamine in L ml of methylene chloride, and prepare a solution of 26 mg of maleic acid in 1 ml of methylene chloride.
1, the solvent was distilled off, and recrystallization from ethyl ether yielded 115 mg of the title maleate salt (yield: 90%).
), m, p.

100-102°C1 is obtained.

IRv'::cm': 3466, 2974.15
84.1497.13891371, 1266, 118
5.786NMR (CD(J,)δ; 1.26 (9
H,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 (2Hs), 5.82 (IH, d, J
= 15.6Hz), 5.95 (LH.

dt, J = 15.6Hz, 7.3Hz), 6.99
(IH, d.

J -7.5Hz), 7.25 (IH, dd, J =
7.5Hz.

2.1Hz), 7.12-7.16 (IH, m), 7
．． 29-7.39 (6H, m) Instead of the raw material compound (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine, the corresponding various 3 Compounds of Examples 129 to 133 were obtained by carrying out the same reaction as in Example 127 except using the -hydroxybenzylamine derivative.

Example 129 IRv"::cm-': 2974,2788,15
84,1488,1455°1269.1026.78
3 NMR (CDC/,) δ: 1.24 (9H,s
), 1.60 (3H,s).

3.04 (2H, dd, J = 8.6Hz, 1.5
Hz), 3.47 (2H,s), 5.22 (2H,s
), 5.65 (IH, dt, J = 15.9Hz, 1
．． 5Hz), 6.01 (IH, dt, J = 15.
9Hz, 6.6Hz), 6.85-6.94 (2H,
m).

6.99-7.01 (IH, m), 7.23 (IH
, t, J = 7.8Hz), 7.29-7.36 (
5H, m) Example 130 E -N-66-di-2-hepten-4-nyl-
N-Ethyl-3-4-3-thienyl-2-dinylmethylocybenzylmine IRv: cm-': 2968.2872.1584
．． 1455.1263°1029,783 NMR (CD(J,) δ: 0.86 (3H,t,
J = 7.3Hz), 1.24 (9H, s) 1.4
6-1.52 (2H, m), 2.36-2.40 (2
H, m), 3.07 (2H, dd, J = 6.3H
z, 1.4Hz).

3.53 (2H,s), 5.21 (2H,s), 5
．． 63 (IH.

dt, J = 15.9Hz, 1.4Hz), 6.06
(LH, dt.

J = 15.9Hz, 6.3Hz), 6.86 (I
H, ddd, J = 7.8Hz, 2.6Hz, 0.9Hz
), 6.93 (IH, d.

J = 7.8Hz), 7.01-7.03 (LH,
m), 7.21 (IH, t, J=7.8Hz), 7.2
8-7.35 (5H, m) Example 131 1Rν::cm″″’: 2986, 1455, 1365
,1251,1170゜1152.1074,1023
．． 783NMR (CDCIs) δ: 1.46 (
6H,s), 2.20 (3H,s).

3.08 (2H, dd, J = 7.8Hz, 1.5H
z), 3.35 (3H, s), 3.48 (2H, s)
, 5.22 (2H, s), 5.69 (IH, dt, J
= 15.8Hz, 1.5Hz), 6.18 (IH.

dt, J = 15.8Hz, 7.8Hz), 6.87
-6.94 (2H.

m), 6.99-7.01 (IH, m), 7.21-
7.36 (6H, m) Example 132 IRv'::, cm-': 1455, 1377.1
365,1254,1173゜1149, l<)74,
1032,837,783 copies MR (CD (J3) 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,
1.4Hz), 3.35 (3H.

s), 3.54 (2H,s), 5.22 (2H,s
), 5.69 (LH.

dt, J = 15.8Hz, 1.4Hz), 6.16
(IH, dt.

J = 15.8Hz, 6.4Hz), 6.86 (IH
, ddd, J = 7.9Hz, 2.7Hz, 1.0Hz
), 6.93 (IH, dJ = 7.9Hz), 7.
00-7.10 (IH, m), 7.23 (IH, t,
J = 7.9Hz), 7.29 (IH, dd, J
=4.6Hz, 1.3Hz), 7.33-7.39 (
4H, m) Example 133 IRv cm': 1455, 1365, 1254,
1173.115210?7,1032.783 NMR(CDCls) δ: 0.87 (3
H, 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 (LH, dt
, J = 15.9Hz, 1.4Hz), 6.16 (I
H.

dt, J = 15.9Hz, 6.4Hz), 6.87
(LH, dd.

J = 7.9Hz, 2.9Hz), 6.93 (IH
, d, J = 7.9Hz), 7.00-7.03 (
IH, m), 7.22 (IH, t.

J = 7.9Hz), 7.30 (IH, dd, J
= 4.5Hz.

1.4Hz), 7.32-7.36 (4H, m) Example 134 25 parts of the compound (hydrochloride) of Example 19 of 19 was dissolved in a mixture consisting of 500 parts each of ethanol and chloroform, Add -3075 parts to polyvinylpyrrolidone and dry under reduced pressure by a conventional method. After crushing the solid residue into fine particles, lactose 250
145 parts of corn starch and 5 parts of magnesium stearate were added and mixed uniformly to give 500 mg.
It is made into a powder containing 25 mg of the active ingredient.

Example 135 25 parts of the compound (hydrochloride) of Example 19 of 19 Aru Cell was dissolved in a mixture consisting of 500 parts each of ethanol and chloroform, and 3072.5 parts of -3072.5 parts and 602.5 parts of Tween were added to polyvinylpyrrolidone. and dry under reduced pressure using a conventional method. After pulverizing the residual solid matter into fine particles, 50 parts of lactose, 45 parts of corn starch and 5 parts of magnesium stearate were added and mixed uniformly, and 200 mg of each was filled into hard gelatin capsules to form 1 capsule. Inside, Lord! Capsules containing 25 mg.

Example 136 Example 1 of chamber 19 capsule
Suspend 25 parts of compound 9 (hydrochloride) in 1000 parts of water,
After adding 150 parts of β-cyclodextrin and stirring at room temperature for 12 hours, 1000 parts of water was added and the mixture was further stirred at room temperature for 3 hours. After freeze-drying in a conventional manner, the flocculent solids obtained are lightly ground and 70 mg of each is filled into hard gelatin capsules to form capsules containing 10 mg of the crude drug per capsule. .

Reference examples will be described below, and a one-boat fishing synthesis method for the raw material compounds used in the above examples will be explained.

Reference Example 1 10.0 g of 3-hydroxybenzaldehyde and 9.55 g of 40% methylamine-methanol solution were mixed, and then the solvent was distilled off. The resulting Schiff base was mixed with 50 ml of ethanol.
Sodium borohydride was dissolved in 10% of sodium borohydride under water-cooled stirring.
．． After adding 0 g, stir overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and saturated brine.

After separating the organic layer, it was dried over anhydrous sodium sulfate, and then the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-100, 100 g, elution solvent:
methylene chloride/methanol = 10/1 → 5/l] to give 8.88 g (yield near 9%) of N-methyl-3-hydroxybenzylamine as pale yellow crystals, m, p,
Obtained as 138-140°C1.

N-methylamine compound obtained above 8.88. 13. Dissolve g and 18.0 g of potassium carbonate in 30 ml of dimethylformamide, and stir at room temperature to prepare l-bromo-6,6-dimethyl-2-hepten-4-yne (approximately 3:1 mixture of 8 and 2 compounds). 0g dimethylformamide solution (10m/
) and stir overnight at room temperature. After the reaction is completed, the solvent is distilled off, and the residue is extracted with a system of ethyl acetate and saturated brine.

After separating the organic layer, it was dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200, 300].
g, elution solvent: hexane/ethyl acetate = 10/1] to give 7.94 g of the title compound as pale yellow crystals.
(Total yield: 39%), m, p, 76-77°C1 are obtained.

A methanol solution of ethylamine or propylamine is used in place of the raw material methylamine-methanol solution, and if necessary, l-proso-6,6-dimethyl-2-hepten-4-yne is replaced with When the same reaction as in Reference Example 1 above was carried out using 6-medoxy-6-methyl-2-hepten-4-yne, (E)-N-(6,6-
dimethyl-2-hepten-4-ynyl)-N-ethyl-
3-Hydroxybenzylamine, (E)-N-(6,6
-Simethyl-2-hepten-4-ynyl)-N-propyl-3-hydroxybenzylamine or (E)-N-ethyl-N-(6-medoxy6-methyl-2-hepten-4-ynyl)-3-hydroxy 3 used in Examples 1-48 and Examples 127-133 such as benzylamine
-Hydroxybenzylamine derivative is obtained.

Reference Example 2 3-(2-furyl)benzoic acid ethyl ester of 3-2-furyl benzyl chloride [J, Chem.

Soc, (B), 197 U, 2305] was dissolved in 5 m7 of anhydrous ethyl ether, and while stirring while cooling with water, 23 mg of lithium aluminum hydride was added and stirred for 40 minutes. After the reaction is complete, add water and ethyl ether for extraction,
After post-treatment by a conventional method, 170 mg (yield: 83%) of 3-(2-furyl)benzyl alcohol is obtained.

Reference example 3 m- of 3-1-pyromyl benzyl menthul-
Add 1.6 g of aminobenzoic acid ethyl ester to 10 liters of glacial acetic acid.
The mixture was dissolved in r+4, added with 1.3 g of 2.5-dimethoxytetrahydrofuran, and heated under reflux for 2 hours. The solvent is distilled off, the residue is dissolved in a mixture of ethyl acetate and water, the organic layer is worked up by the preparative method, and finally purified by recrystallization from hexane to obtain 3-(l-pyrrolyl). 1.7 g (yield: 82%) of benzoic acid ethyl ester as colorless needle-like crystals, m
, p, 64-65°C1.

1.1 g of the above pyrrolyl compound was dissolved in 30 ml of ethyl ether, and 0.0 g of lithium aluminum hydride was dissolved under water cooling and stirring.
Add 2g and stir for 1 hour. After adding water and ethyl ether to the reaction solution and extracting it, and performing post-treatment using a conventional method,
If recrystallized from a mixture of ethyl acetate and hexane, 3
-(1-pyrrolyl)benzyl alcohol 0.80g (
Yield: 91%) as colorless needles, m, p.

66-68°C.

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

Reference Example 4 790 m of magnesium in 1 ml of anhydrous tetrahydrofuran of 3-3-enylbenzylmensulfo-
After adding a small amount of 1,2-dibromoethane and confirming foaming, a solution of 5 g of 3-bromobenzaldehyde dimethyl acecool in tetrahydrofuran (12 m4) was added dropwise over 1.5 hours while stirring at room temperature. do. 45-55
After stirring for 30 min at °C, bis(diphenylphosphino)
80 mg of ethane nickel (If) chloride and a solution of 3-bromothiophene in tetrahydrofuran (6 mj) are added, and the mixture is stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and after filtering off insoluble koji, ethyl acetate is added to extract an oil. After treating the extract in a conventional manner, it was subjected to silica gel column chromatography [Wakogel C-100, 70g
, Elution solvent: hexane/ethyl acetate = 50/1 → 10/
1] to obtain 1.35 g of 3-(3-thienyl)benzaldehyde dimethylacecool (yield: 27%).
), m, p, 45-46°C.

1.35 g of the above thienyl compound was dissolved in a mixture of 4 ml of 1N hydrochloric acid and 8 ml of tetrahydrofuran, stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. The residue was extracted with an ethyl acetate-water system and post-treated in a conventional manner to obtain 1.05 g of 3-(3-thienyl)benzaldehyde (yield: 96%).
, m, p, 44-45°C are obtained.

1.05 g of the above aldehyde is dissolved in 15 m/ml of ethanol, 250 mg of sodium borohydride is added, and the mixture is stirred at room temperature for 30 minutes. After evaporating the reaction solution under reduced pressure, the residue was extracted with an ethyl acetate-water system, and after post-treatment using a conventional method,
Silica gel column chromatography [Wako gel C-
100.20g, elution solvent: hexane/ethyl acetate = 5
71] to give 960 mg of 3-(3-thienyl)benzyl alcohol (yield: 86%), m, p, 8
9-90°C.

Add 300 mg of the above alcohol to 7 ml of ethyl acetate.
Dissolved in 320 m of triethylamine under water cooling and stirring.
A solution (1 m4) of 270 mg of methanesulfonyl chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 30 minutes.

After filtering off the precipitated salt, the reaction mixture is washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain the title compound as a pale yellow powder.

When the reaction was carried out in the same manner as in Reference Example 4 except that the corresponding bromo-substituted heterocyclic derivative was used in place of the starting material 3-bromothiophene, 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 are obtained.

Reference Example 5 1.56 g of 3-ethynyltoluene from 5-3-melphenyl solution was dissolved in 20 ml of ethyl ether, cooled to -70°C, stirred, and mixed with 8.5 ml of 1.5 M n-butyllithium-hexane solution. / and ethyl formate 1.2m
1 and stirred at the same temperature for 20 minutes. The reaction solution was poured into ice water, the organic layer was separated, and the solvent was distilled off, yielding 900 m of 3-(3-methylphenyl)-2-propanaldehyde.
g (yield: 47%) is obtained as a colorless oil.

130 mg of the above aldehyde was dissolved in 20 m/g of ethanol, and an aqueous solution of 70 m/g of hydroxylamine hydrochloride (
After adding 5 mj), the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography [column: Lobarcolu
mn, 5ize A, Lichroprep Si
60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 10/1], 3-(3-
Methylphenyl〉-2-propynaldehyde oxime 1
22 mg (yield: 85%) are obtained as a pale yellow oil.

122 mg of the above oxime is dissolved in 20 ml of ethanol, 1 dip of 1N aqueous sodium hydroxide solution is added and the mixture is allowed to stand for 3 minutes, and then 3 drops of 1N hydrochloric acid are added to terminate the reaction.

After distilling off the solvent under reduced pressure, the residue is extracted with a mixture of water and ethyl ether, the organic layer is separated, and the solvent is distilled off to obtain 106 mg (yield: 87%) of the title compound as a pale yellow oil.

Reference Example 6 Loading amount of 1-3-hydroxycarbonylphenyl 1-(3-ethoxycarbonylphenyl)imidazole [J, Am, Chem, Soc, 79.49
22 (1957)] Dissolve 230 mg in 10 m4 of ethyl ether and add 50 m of lithium aluminum hydride.
mg and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, the organic layer was separated and dried over anhydrous magnesium sulfate, the desiccant was filtered off, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wako Gel C-20].
0°20g, elution solvent: chloroform/methanol = 2
0/1] to give the title compound 16 as a colorless oil.
0 mg (yield: 92%) is obtained.

Reference Example 7 3-2-osasylbenzyl derivative ゛2-(3
-methylphenyl)oxazole [Ang, Chem,
.

75, 165 (1963)] 200 mg was dissolved in 5 ml of carbon tetrachloride, 231 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added, and the mixture was stirred under reflux for 2 hours. After the reaction is complete, insoluble matter is filtered off and the solvent is distilled off under reduced pressure to obtain the title compound.

3-(2-thiazolyl)benzyl bromide can be synthesized by a similar method.

Reference Example 8 3-(hydroxymethyl)benzaldehyde of 3-5-ol benzyl alcohol [produced by reducing isophthalaldehyde with an equivalent amount of sodium borohydride]
400 mg 574 mg of p-toluenesulfonylmethyl isocyanide and 406 mg of potassium carbonate are added to 10 m4 of methanol, and the mixture is heated under reflux for 1 hour while stirring. After evaporating the reaction solution under reduced pressure, the residue was extracted with an ethyl acetate-water system, and after post-treatment using a conventional method, it was subjected to silica gel column chromatography [Wakogel C-200° 50g 1 elution solvent: hexane/ethyl acetate = 1/l] Purification by 375 mg (near 3% yield) of the title compound as a white powder is obtained.

If the above alcohol is mesylated in the same manner as in Reference Example 3, colorless oily 3-(5-oxacylyl)benzyl methanesulfonate is obtained.

Reference Example 9 4- of 3-4-isoosyl bromine
(3-methylphenyl)isoxazole [J, He
terocyclicChem,, 11.51 (1
974), J, Chem, Soc.

See Perkin II, 1121 (1977)]
185 mg was dissolved in 8 ml of carbon tetrachloride, 206 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added, and the mixture was stirred under reflux for 3 hours. After filtering off the insoluble materials, the solvent was distilled off, and the residue was purified by silica gel column chromatography [Wakogel C-200, 30 g, elution solvent: hexane/ethyl acetate = lo/B] to give 210 mg of the title compound as a colorless powder ( A yield of near 6%) is obtained.

Instead of the raw material 4-(3-methylphenyl)isoxazole, 4-(3-methylphenyl)isothiazole [J, prakt, Chem, 318
．． 507 (1976)], 5-(3-methylphenyl)isothiazole [Jprakt, Chem.
318.507 (1976)], 5-(3-methylphenyl)pyrimidine [J, Heterocyc
licChem,, 11. 55 (1974)
; Heterocycles.

1080 (1982)] or 1-(3-methylphenyl)-1,2,4-triazole [J, O
rg, Chem,.

Rainbow, 1037 (1956), JP-A-51-4173
3-(4-isothiazolyl)benzyl bromide,
3-(5-inchazolyl)benzyl bromide, 3-(
5-pyrimidyl)benzyl bromide or 3-(1,2,
4-) Riazol-1-yl)benzyl bromide is obtained.

Reference example 10 3-bromobenzaldehyde dimethyl acetal 2,3
In a tetrahydrofuran solution (15 mj) of Grignard reagent prepared from 1 g and 0.36 g of metallic magnesium,
While cooling with water and stirring, a solution of tetrahydrofuran-3-one in tetrahydrofuran (10 m4) was added dropwise, and after the dropwise addition, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, ethyl ether was added to extract the product, and the product was post-treated using a conventional method.
-(3-Hydroxytetrahydro-3-thienyl)benzaldehyde dimethyl acetal crude 1.20g
(yield: 47%).

Add 1.20g of the above alcohol to 22g of tetrahydrofuran.
Dissolve in a mixture of 0 ml and 3 ml of 10% hydrochloric acid, leave to stand at room temperature for 2 hours, dilute with ethyl ether and water, and separate the organic layer. After evaporating the solvent under reduced pressure, the residue was dissolved in 20 m4 of methylene chloride, 1.0 m/m of methanesulfonyl chloride and 2.0 m7 of triethylamine were added, and the mixture was stirred for 30 minutes under water cooling. The reaction solution is poured into ice water, the organic layer is separated and dried under reduced pressure, the residue is dissolved in ethanol lom7, 0.2 g of sodium borohydride is added, and the mixture is stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, the residue was extracted with ethyl ether and water, and after post-treatment by a conventional method, the product was subjected to medium pressure liquid chromatography [column: Lobar column,
5ize B, LichroprepSi 60F
(manufactured by Merck & Co., Ltd.), elution solvent: hexane → hexane/ethyl acetate = 10/11 to purify and separate the title 3-(2,3-dihydro-4-thienyl)benzyl alcohol 0.45 g (yield: 50 %) and 3-(2,5-
dihydro-3-thienyl)benzyl alcohol 0.20
g (yield: 22%) is obtained.

Reference example 11 3-1-pyrrolidinyl benzyl alcohol N-(3
-ethoxycarbonylphenyl)succinimide [m-
Synthesis by heating and condensing aminobenzoic acid ethyl ester and succinic anhydride in acetic acid] 0.25 g was dissolved in 5 ml of anhydrous tetrahydrofuran, and while stirring under water cooling, 0.17 g of lithium aluminum hydride was added and the mixture was heated at room temperature for 30 minutes. Heat under reflux for 4 hours.

After completion of the reaction, ethyl acetate and water were added to branch, and the organic layer was post-treated by the preparative method and subjected to medium pressure liquid chromatography [column: Lobar column, 5ize].
B, Lichroprep Si 60F (manufactured by Merck & Co.), elution solvent: hexane/ethyl acetate = 10
Purification by /11 yields the title compound as a colorless oil, 84m
g (yield 47%) is obtained.

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

Reference Example 12 5 g of 3-bromothiophene in 5-3-thienyl-2-thienylmethanol was dissolved in 35 ml of anhydrous ethyl ether, cooled to -70 to -65°C and stirred to prepare 19 ml of 15% n-butyllithium-hexane solution. & 10.5 g of tributyltin chloride are added and stirred at the same temperature for 1 hour, then at room temperature for 1 hour.The reaction solution is washed with a saturated aqueous sodium bicarbonate solution, the solvent is distilled off, and the residue is purified by distillation under reduced pressure. Tributyl(3-thienyl)stannane 8.5g (
Yield near 4%), b, p, 150-158°C/2
m m Hg is obtained.

1.19 g of the above tin compound and 5-bromothiophene-
0.56 g of 2-carbaldehyde is dissolved in 3 ml of toluene, 20 mg of tetrakis(triphenylphosphine)palladium is added, and the mixture is heated and stirred under reflux for 7 hours. The reaction solution was washed with 10% potassium fluoride aqueous solution and 5% potassium carbonate aqueous solution, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [Wakogel C-200° 50g, elution solvent: hexane/ethyl acetate = 10/l ] to obtain 0.36 g (yield: 63%) of 5-(3-thienyl)thiophene-2-carbaldehyde.

144 mg of the above aldehyde was added to tetrahydrofuran A.
ml by adding 15.6 mg of lithium aluminum hydride for reduction and post-treatment by a conventional method to obtain 134 mg (yield: 92%) of the title compound as a colorless oil.

By carrying out the same reaction as in Reference Example 12 except using 4-promothiophene-2-carbaldehyde in place of the starting compound 5-bromothiophene-2-carbaldehyde, 4-(
3-thienyl)-2-thienylmethanol is obtained.

Reference Example 13 Pyridine-2,4-dicarboxylic acid dimethyl ester of 2-5-oxymil-4-bi-1-dinetanol 1.07
Dissolve g in 20ml of toluene, cool to -80 to -70'C while stirring, add 6.04mf of 1M diisobutylaluminum hydride toluene solution dropwise over 2.5 hours, and stir at the same temperature for 1 hour. . Pour the reaction solution into ice water, add ethyl ether to separate the organic layer, and after post-treatment using a conventional method,
Medium pressure liquid chromatography [Column: Lobar
column, 5ize B, Lichropre
2-
Formylisonicotinic acid methyl ester 0.27g (
Yield: 30%) is obtained as a colorless crystalline powder.

203 mg of the above formyl compound was dissolved in 8 m4 of methanol, and p-toluenesulfonylmethylisocyanide 2
Add 40 mg of potassium carbonate and 170 mg of potassium carbonate, and heat under reflux for 10 minutes. The reaction solution was dried to dryness under reduced pressure, the residue was extracted with a methylene chloride-water system, and post-processed using a conventional method.
224 mg (yield: 91%) of 2-(5-oxacylyl)isonicotinic acid methyl ester are obtained as a pale yellow powder.

102 mg of the above oxacylyl compound was dissolved in 2 ml of anhydrous tetrahydrofuran, and 14 mg of lithium aluminum hydride was added while stirring under water cooling, and the mixture was stirred at the same temperature for 30 minutes.

The reaction solution was poured into ice water, extracted with methylene chloride, and then post-treated in a conventional manner, followed by silica gel column chromatography [Wakogel C-200° 5.5 g, elution solvent: methylene chloride/methanol = 50/l → 20/ 1] to give 49.5 mg of the title compound as a pale yellow crystalline powder.
(Yield: 56%) is obtained.

Reference Example 14 Pyridine-3,5-dicarboxylic acid dimethyl ester of 1-3-pyridinemethanol 1.6
7 g was dissolved in 30 ml of anhydrous tetrahydrofuran, 162 mg of lithium aluminum hydride was added thereto under stirring under water cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water, extracted with ethyl ether, and then worked up by a conventional method.
Crude 5-hydroxymethylnicotinic acid methyl ester is obtained. This crude product was dissolved in 20 m/m of methylene chloride,
Add 2.2 g of pyridinium chlorochromate and stir at room temperature overnight. The reaction solution was poured into ice water, the organic layer was separated and worked up by a conventional method, and purified by silica gel column chromatography [Wakogel C-200, 80 g, eluent dichloroform/methanol = 20/l] to obtain 5- Formylnicotinic acid methyl ester 0.37g (yield:
26%), m, p96-97°C.

Reference Example 13 using 110 mg of the above formyl compound as a raw material
When the same oxacylylation and reduction reactions are carried out, 77 mg (yield: 64%) of the title compound is obtained as a colorless oil.

When the same reaction as in Reference Example 14 was carried out using pyridine-2,6-dicarboxylic acid dimethyl ester instead of the starting compound pyridine-3,5-dicarboxylic acid dimethyl ester, 6-(5-oxacylyl) -2-pyridinemethanol is obtained.

Reference example 15 5-formylfurfuryl alcohol
4758 publication reference 1300mg methanol 10m4
502 mg of p-)luenesulfonylmethylisocyanide and 329 mg of potassium carbonate were added, and the mixture was heated under reflux for 1 hour. The reaction solution was distilled off under reduced pressure, the residue was dissolved in water and ethyl acetate shin fluid, and the organic layer was separated and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [Wakogel C-200, 45 g 1 elution solvent: hexane/ethyl acetate = 3/2 → 1/l] to obtain 260 mg of the title compound. (Yield: 66%) is obtained as a pale yellow crystalline powder.

Reference Example 16 Thiazole-2,4-dicarboxylic acid diethyl ester 1
．． Suspend 5g in 15m4 of ethanol, and add 0.16g of sodium borohydride and 0.5g of calcium chloride at -10℃.
After adding 3 ml of 8 g of ethanol solution, the mixture was stirred at the same temperature for 2 hours. After decomposing the excess reducing agent by adding acetone, the solvent is distilled off under reduced pressure, dilute sulfuric acid is added to the residue, and insoluble calcium sulfate is filtered off. The filtrate was purified with an aqueous potassium carbonate solution.
After adjusting to H10, chloroform is added for extraction. The chloroform layer was dried over anhydrous magnesium sulfate and then dried under reduced pressure, and the residue was treated with isopropyl ether.
0.78 g (yield: 64%) of 2-hydroxymethylthiazole-4-carboxylic acid ethyl ester is obtained as a colorless crystalline powder.

0.78 g of the above hydroxymethyl compound was added to chloroform 4
0ml, add 25g of activated manganese dioxide, and stir at room temperature for 5 days. After filtering off the precipitate, the filtrate was dried under reduced pressure to obtain 0.67 g (yield: 87%) of 2-formylthiazole-4-carboxylic acid ethyl ester as colorless needle crystals.

80 mg of the formyl compound obtained above, 91 mg of p-toluenesulfonylmethyl isocyanide and 6 potassium carbonate.
2-(5-oxacylyl)thiazole- obtained by carrying out the same reaction as in Reference Example 13 above using 0 mg
60 mg of 4-carboxylic acid ethyl ester was added to 3 mL of ethanol.
ml, and in this solution add 6 sodium borohydride,
6 mg of calcium chloride and 24 mg of calcium chloride were added and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, 10% sulfuric acid is added to the residue, the resulting precipitate is filtered off, and potassium carbonate is added to the filtrate to adjust the pH to 1o. The product was extracted by adding chloroform, the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to preparative thin layer chromatography [
Laminate: Kieselgel 60Fm.

Art, 5744 (manufactured by Merck & Co., Ltd.), 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 Furan-3,5-dicarboxylic acid dimethyl ester [J.

Chem, Soc, Perkin I, 113
(1973)] was dissolved in 4 ml of anhydrous tetrahydrofuran, and 5 ml of lithium aluminum hydride was dissolved in 4 ml of anhydrous tetrahydrofuran.
Add 9rrrg and stir overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and then post-treated in a conventional manner and subjected to silica gel column chromatography [Wako Gel C
-200, 20g, elution solvent: hexane/ethyl acetate=
2/1] to give 44 m of 5-hydroxymethylfuran-3-carboxylic acid methyl ester as a colorless oil.
g (yield: 13%).

Add 44 mg of the above alcohol to 2 ml of chloroform.
60 mg of pyridinium chlorochromate was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water, the organic layer was separated and post-treated by a conventional method, and subjected to silica gel column chromatography [Wakogel C-200, 2g, elution solvent:
Hexane/ethyl acetate 3/1] to obtain 28 mg of formyl compound. Dissolve this in 2 ml of methanol and add 35 mL of p-toluenesulfonylmethylisocyanide.
After adding 25 mg of potassium carbonate and refluxing for 30 minutes, post-treatment was carried out using a conventional method to obtain 30 mg of 5-(5-oxacylyl)furan-3-carboxylic acid methyl ester.
get. Next, this was dissolved in 2 ml of tetrahydrofuran, 6 mg of lithium aluminum hydride was added under water cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution is poured into ice water, extracted with ethyl ether, and then worked up by a conventional method to obtain 22 mg (yield: 48%) of the title compound as a pale yellow oil.

Reference Example 18 Preparation of 6-methyl-3-1-pyrobenzyl alcohol 3-amino-6-methylbenzoic acid methyl ester 158
mg was dissolved in 3 ml of acetic acid, 139 mg of 2,5-dimethoxytetrahydrofuran was added, and the mixture was heated under reflux for 1 hour.

After drying the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography [Wakogel C-200510g, elution solvent: hexane/ethyl acetate = 10/1] to obtain 3-(1-pyrrolyl)-6-methylbenzoic acid. Methyl ester 185 mg (yield: 87%), m, p, 56-5
Obtain 7°C1.

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

When the same reaction as in Reference Example 18 was carried out except that 3-amino-2-methylbenzoic acid methyl ester was used in place of the starting compound 3-amino-6-methylbenzoic acid methyl ester, 2-methyl-3 -(l-pyrrolyl)benzyl alcohol is obtained.

Reference Example 19 Eyonige γ Mokuto (E) -N-(6,6-cymethyl-2-heptene-4
- 150 mg of N-methyl-3-hydroxybenzylamine (inyl).

A solution of 90 mg of 3-chloromethylbenzaldehyde in dimethylformamide (1.5 m/) is added to a phenolate solution prepared from 23.2 mg of 60% oily sodium hydride and 1 m7 of tetrahydrofuran and stirred overnight at room temperature. After evaporating the solvent under reduced pressure, the residue was extracted with an ethyl acetate-water system, and after post-treatment by a conventional method, it was subjected to silica gel column chromatography [Wakogel C-200゜15
g1 elution solvent: hexane/ethyl acetate = 10/1 → 5
/1] to give the title compound as a colorless oil, 85m
g (yield: 39%) is obtained.

Using 3-bromomethylbenzoic acid methyl ester instead of the raw material compound 3-chloromethylbenzaldehyde,
Otherwise, when the same reaction as in Reference Example 19 was carried out, (E)-N-
(6,6-dimethyl-2-hebuten-4-ynyl)-N
-Methyl-3-(3-methoxycarbonylbenzyloxy)benzylamine is obtained.

Reference Example 20 E -3-2-3-34-enyl phenyl ethenylbenzyl 1' of 1' 2.40 g of 3-(3-thienyl)benzyl chloride was dissolved in 40 ml of toluene, and triphenylphosphine 3.
Add 62 g and heat under reflux for 50 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration to obtain 3.60 g of 3-(3-thienyl)benzyltriphenylphosphonium chloride (
Yield: 66%).

1.21 g of the above phosphonium salt was added to 45 ml of ethanol.
0.35 g of 3-formylbenzyl alcohol dissolved in
and 0.27 g of sodium ethoxide and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned in an ethyl acetate-water system, followed by post-treatment in a conventional manner and subjected to silica gel column chromatography [Wakogel C-3005 100g
, Elution solvent: hexane/ethyl acetate = 10/l → 5/1
], the E of 3-[2-[3-(3-thienyl)phenyl]ethynyl]benzyl alcohol is 0
．． 34 g (yield: 46%) and 0.34 g of Z monolith were obtained.

Dissolve 0.20 g of monolithic alcohol (E) obtained above in 6 ml of chloroform, add 0.15 m4 of thionyl chloride and 1 drop of dimethylformamide, and stir at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the residue was distributed in an ethyl ether-water system, and after post-treatment by a conventional method, silica gel column chromatography [Wakogel C-100, 20 g, elution solvent: hexane/ethyl acetate = 20/1 ] to give 0.19 g (yield: 87%) of the title compound as a colorless crystalline powder, m, p, 79-81 °C1.

In place of the starting compound 3-(3-thienyl)benzyl chloride, the corresponding 3-substituted penzyl chloride or the same bromide was used, and the other reaction was carried out in the same manner as in Reference Example 20.
(E)-3-[2-[3-(5-oxacylyl)phenyl]ethynyl]benzyl chloride, (E)-3-[2-
[3-(5-thiazolyl)phenyl]ethenylcopenzyl chloride and (E)-3-[2-[3-(1-imidazolyl)phenyl]ethynyl]benzyl chloride are obtained.

Reference Example 21 E -3-2-3-1-pyrrol phenyl ethynylbenzyl alcohol 1 3-(dimethoxymethyl)benzyltriphenylphosphonium bromide [After bromination of 3-hydroxymethylbenzaldehyde with phosphorus tribromide, Synthesized by acetalization in anhydrous methanol in the presence of p-toluenesulfonic acid, followed by reaction with triphenylphosphine] 560 mg
and 3-(l-pyrrolyl)benzaldehyde [3-(1-
Synthesized by oxidizing benzyl (pyrrolyl) alcohol with pyridinium chlorochromate in chloroform] 180
mg was dissolved in 20 mj of methanol, 110 mg of sodium methoxide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was distilled off under reduced pressure, and the residue was extracted with ethyl acetate-water.
After treatment by a conventional method, the mixture was subjected to medium pressure liquid chromatography [column: Lobar column.

5ize B, Lichroprep Si 60F
(manufactured by Merck), elution solvent: hexane/ethyl acetate =
Purified by 10/11 to give 3-[2-[3-(1-
pyrrolyl)phenyl]ethynyl]benzaldehyde dimethyl acecool (E) 135mg (yield: 42%)
and Z together gives 127mg.

135 mg of the above monolithic acetal (E) was dissolved in a mixture of 5 ml of tetrahydrofuran and 5 m4 of 2N hydrochloric acid, and after stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. After the residue is worked up by a conventional method, the obtained formyl compound is dissolved in 10 m7 of ethanol, 40 mg of sodium borohydride is added, and the mixture is stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, the residue was distributed in an ethyl acetate-water system, and after post-treatment by a conventional method, silica gel column chromatography [Wako Gel C-1
00.20g, elution solvent: hexane/ethyl acetate = 5
/l] to give the title compound 78 mg (yield;
67%) is colorless crystalline powder, m, p, 108-110'
It is obtained as c.

When 3-(3-pyridyl)benzaldehyde was used in place of 3-(1-pyrrolyl)benzaldehyde as the starting compound and the same reaction as in Reference Example 21 was carried out, (E)-3
-[2-[3-(3-pyridyl)phenyl]ethynyl]
Benzyl alcohol is obtained.

Reference Example 22 81 mg of (Z)-3-[2-[3-(3-thienyl)phenyl] ethenyl]benzyl alcohol was dissolved in 3 ml of ethanol, and the solution was dissolved at room temperature and pressure in the presence of 15 mg of 10% palladium-carbon. Catalytic reduction for 15 hours. After filtering off the catalyst, the solvent is distilled off to obtain the title compound as a colorless oil in quantitative yield.

In place of the raw material compound (Z)-3-[2-[3-(3-thienyl)phenyl]ethynyl]benzyl alcohol,
(Z)3-[2-[3-(1-pyrrolyl)phenyl]ethynyl]benzyl alcohol or (Z)-3-[2-[
When reduction was carried out in the same manner as in Reference Example 22 using 3-(3-pyridyl)phenyl]ethynyl]benzyl alcohol, 3-[2-[3-(1-pyrrolyl)phenyl]ethyl]benzyl alcohol and 3 - [2-[3-(3-
Pyridyl)phenyl]ethyl]benzyl alcohol is obtained.

Reference Example 23 5-Hydroxymethylfurfural Loom/ is dissolved in 2 ml of anhydrous ethyl ether, and while stirring under water cooling, an ethyl ether solution (1 m/) of phosphorus tribromide 307d is added and stirred at the same temperature for 10 minutes. After washing the reaction solution with a saturated aqueous sodium bicarbonate solution, 183 m of (E)-N-ethyl-6゜6-dimethyl-2-hepten-4-ynylamine hydrochloride was added.
g.

136 mg of potassium carbonate and 3 m of dimethylformamide
1 and stirred at room temperature overnight. After distilling off the reaction solution under reduced pressure,
The residue was partitioned in an ethyl ether-water system, worked up by a conventional method, and purified by silica gel column chromatography to give 132 mg of the title compound as a pale yellow oil (yield:
53%) is obtained.

Reference Example 24 (E) -N-(6,6-dimethyl-2-heptene-4
-ynyl)-N-methyl-4-ethoxycarbonyl-2
-pyridylmethylamine [4-ethoxycarbonyl-2
- After tosylating pyridine methanol with p4 luenesulfonyl chloride and triethylamine, it was condensed with (E)-N-methyl-6゜6-dimethyl-2-hepten-4-ynylamine, and 160 mg of the synthesized product was dissolved in 2 ml of toluene, - 1M diisobutylaluminum hydride-toluene solution 0.56 mA under stirring while cooling to 75 to -70°C
' and stirred at the same temperature for 40 minutes. The reaction solution was poured into ice water, ethyl ether was added to separate the layers, and the organic layer was post-treated using a conventional method and subjected to medium pressure liquid chromatography [column:
Lobar column, 5ize A, Lic
Purification using hroprep 5t60F (manufactured by Merck & Co., Ltd., elution solvent: hexane/ethyl acetate = 4/1) gives 15 mg (yield: 1%) of the title compound as a pale yellow oil.

(E) -N-(6,6-cymethyl-2-
(E) in place of (hebuten-4-ynyl)-N-methyl-4-ethoxycarbonyl-2-pyridylmethylamine
-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-ethoxycarbonyl-5-isoxacylmethylamine[5methylisoxazole-
After bromination of 3-carboxylic acid ethyl ester with N-bromosuccinimide, (E)-N-ethyl-6,6-
Synthesis by condensation with 2-hebuten-4-ynylamine] was carried out in the same manner as in Reference Example 24.
4-ynyl)-N-ethyl-3-formyl-5-isoxacylylamine is obtained.

Reference Example 25 3 g of 3.4-dihydroxybenzaldehyde and 0.87 g of 60% oily sodium hydride were added to 1 part of tetrahydrofuran.
A solution of 3.3 ml of methoxymethyl chloride in dimethytriformnamide (10 m/) was added, and the mixture was stirred at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the residue was partitioned in an ethyl acetate-water system, and the organic layer was worked up by a conventional method.
Silica gel column chromatography [Wako gel C-
200,150g, elution solvent: hexane/ethyl acetate=
471] to give 1.78 g of 3-hydroxy-4-methoxymethyloxybenzaldehyde (yield: 4
5%).

40% of 360 mg of the above methoxymethyloxy compound
Dissolve in 6 ml of methylamine-methanol solution, add 151 mg of sodium borohydride, and stir at room temperature for 1 hour. After evaporating the reaction solution under reduced pressure, the residue was partitioned in an ethyl acetate-water system, the organic layer was separated, and the solvent was evaporated. The residue was dissolved in 10 m7 of dimethylformamide, l-bromo-6,
6-dimethyl-2-hepten-4-yne (2 bodies: 2 bodies-
93:1 mixture) 361 mg and potassium carbonate 276 m
g and stirred at room temperature overnight. After concentrating the reaction solution under reduced pressure,
The residue was partitioned in an ethyl ether-water system, and the organic layer was separated and post-treated in a conventional manner, followed by silica gel column chromatography [Wako Gel C-200, 30 g].

Elution solvent: hexane/ethyl acetate = 371] to give 140 mg of the title compound as a pale yellow oil (yield: 2
2%) is obtained.

Using 2,3-dihydroxybenzaldehyde instead of the raw material 3,4-dihydroxybenzaldehyde, this was selectively alkylated with methoxymethyl chloride and triethylamine in chloroform to produce 3-hydroxy-2-methoxymethyloxybenzaldehyde. Synthesis and then a reaction similar to Reference Example 25 results in (E)-
N-(6,6-cymethyl-2-hepten-4-ynyl)
-N-methyl-3-hydroxy-2-methoxymethyloxybenzylamine is obtained.

Reference example 26 E-N-66-dityl-2-hepten-4-nyl-
N-N-(3-bromomethylphenyl)phthalimide (
N-(m-)lyl)phthalimide in carbon tetrachloride
Synthesized by bromination with bromosuccinimide]6. O
Dissolve g in 100 ml of dimethylformamide, (E)
-N-Ethyl-6,6dimethyl-2-hepten-4-ynylamine hydrochloride 3.82g and potassium carbonate 7.87g
and stir overnight at room temperature. After distilling off the reaction solution under reduced pressure, the residue was extracted with an ethyl acetate-water system, the organic layer was separated, the solvent was distilled off, and the residue was washed with a small amount of ethyl ether.
E) -N-(6,6-dimethyl-2-hebutene-4-
5.5 g (yield near 2%), m, p, 96-98°
Obtain C1.

150 mg of the above benzylamine compound in 5 ml of ethanol
Add 23 mg of hydrazine to the
Stir for a minute. After filtering off the precipitate, the solvent was distilled off, and the residue was partitioned in a methylene chloride-water system, and the organic layer was post-treated in a conventional manner and subjected to silica gel column chromatography [Wakogel C-100, 5 g, elution solvent: hexane/ Ethyl acetate=
10/1 → 3/l] to give the title compound 95
mg (yield: 95%) pale yellow crystalline powder, m, p, 6
Obtained as 5-66°C1.

1. Instead of the starting compound (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride. (
E) -N-ethyl-6-medoxy 6-methyl-2-hepten-4-ynylamine hydrochloride was used, and the others were Reference Example 2.
If a reaction similar to 6 is carried out, (E)-N-ethyl-N.
(6-Medoxy6-methyl-2-hebuten-4-ynyl)-3-aminobenzylamine is obtained.

Reference Example 27 3-bromobenzaldehyde dimethyl acetal 1. O
0.3 g of sulfur in a tetrahydrofuran solution (20 m/) of Grignard reagent prepared from
After stirring 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 solution is poured into ice water, made acidic by adding hydrochloric acid, and then extracted by adding ethyl ether. After the extract is post-treated in a conventional manner, the solvent is distilled off to obtain 0.36 g (yield: 60%) of 3-mercaptobenzaldehyde.

60 mg of the above mercapto compound was dissolved in 5 ml of dimethylformamide, 50 mg of 3-(3-thienyl)benzylbromide and 30 ml of 60% oily sodium hydride.
g and stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and after post-treatment by a conventional method, it was subjected to medium pressure liquid chromatography [
Column: Lobar column, 5ize A
, LichroprepSt 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 30/1 → 10
/l] to give the title compound as a colorless oil, 2.3
mg (yield: 4%) is obtained.

Reference Example 28 30 mg of 3-(2,5-dihydro-3-thienyl)benzyl alcohol obtained in Reference Example IO was dissolved in 250 ml of ethanol, and 50 m of 10% palladium-carbon was dissolved in 250 ml of ethanol.
g was added thereto, and catalytic reduction was carried out under a hydrogen pressure of 3.5 kg/cm2 for 8 hours.

After filtering off the catalyst, the solvent is distilled off under pressure. colorless oily 25 mg (yield: 82%) of the title compound is obtained.

Reference Example 29 Using 3-bromobenzaldehyde dimethyl acetal and tetrahydrothiopyran-3-one as raw materials, Reference Example 1
534 mg of 3-(tetrahydro-3-hydroxy-3-thiopyranyl)benzaldehyde dimethyl acecool obtained by the same reaction as in Example 0 was added to 5 m of ethyl acetate.
Methanesulfonyl chloride 187
Add d and 553μ of triethylamine and stir for 30 minutes. After filtering off triethylamine hydrochloride, the solvent was distilled off,
After dissolving the residue in 20 ml of benzene, add 90% potassium t.
Add 373 mg of ert-butoxide and stir at room temperature for 15 minutes.
Stir for an hour. Ethyl ether and water were added to the reaction solution, and after post-treatment using a conventional method, the obtained dimethyl acecolyte of 3-dihydrothiopyranylbenzaldehyde was dissolved in a mixture of 3 ml of 1N hydrochloric acid and 6 ml of tetrahydrofuran, and the solution was stirred at room temperature for 3 hours. Stir. After evaporating the reaction solution under reduced pressure, the residue was partitioned between ethyl ether and water, and after post-treatment by a conventional method, the obtained formyl compound was dissolved in 20 ml of tetrahydrofuran, and 380 mg of lithium aluminum hydride was added. Stir for 1 hour while cooling with water. The reaction solution was poured into ice water, and after post-treatment by a conventional method, it was purified by silica gel column chromatography [Wakogel C-200, 20 g, elution solvent: hexane/ethyl acetate = 2/1] to obtain the title 3-(3,4 -dihydro-2H-thiopyran-5-yl)benzyl alcohol 7 mg (yield: 2%) and 3-(5
, 6-dihydro-2-thiopyran-3-yl)benzyl alcohol (4 mg (yield: 1%)).

By using tetrahydrothiopyran-4-one in place of the starting compound tetrahydrothiopyran-3-one and carrying out the same reaction as in Reference Example 29, 3-(5,6-sihydro-2H-thiopyran-4 -yl)benzyl alcohol is obtained.

Reference Example 30 3-3-3-thienyl phenol 1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and 3 to bromophenol 1
．． A solution of phenolate prepared from 5 g and 0.36 g of 60% oily sodium hydride in tetrahydrofuran (5 m4
) and stir at room temperature for 2 hours. The solvent is distilled off, water and ethyl acetate are added, and the mixture is extracted and then worked up by a conventional method to obtain crude 3-(3-bromophenoxymethyl)benzaldehyde.

By carrying out the same reaction as in Reference Example 12 using 440 mg of the above aldehyde, 747 mg of tributyl(3-thienyl)stannane, and 10 mg of tetrakis(triphenylphosphine)palladium, 3-[3-(3-thienyl)phenoxy methyl]benzaldehyde 341 m
g (yield near 7%) is obtained.

341 mg of the above thienyl compound was suspended in 5 ml of ethanol, 44 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 30 minutes. After evaporation of the solvent, extraction with water and ethyl ether, and post-treatment in a conventional manner, 288 mg (yield: 83%) of the title compound as white powder crystals, m, p
, 62-63°C.

3-(3-(3-thienyl)phenylthiomethyl]benzyl alcohol is obtained by performing the same reaction as in Reference Example 30, except using 3-bromothiophenol instead of 3-bromophenol as the starting compound. .

Reference Example 31 200 mg of 3-mercaptobenzaldehyde was dissolved in 6 ml of dimethylformamide, and 291 mg of 3-hydroxymethylbenzyl bromide and 402 mg of potassium carbonate were dissolved.
mg and stirred at room temperature for 3 hours. The solvent was distilled off, extracted with water and ethyl ether, and after post-treatment by a conventional method, purified by silica gel column chromatography [Wakogel C-200, Log, elution solvent: hexane/ethyl acetate = 2/11, Pale yellow oily 3-[3-(
190 mg (yield: 51%) of human"roxymethyl)benzylthio]benzaldehyde is obtained.

172 mg of the above aldehyde, 130 mg of p-)luenesulfonylmethylisocyanide, and 9 potassium carbonate.
By carrying out the same reaction as in Reference Example 8 using 2 mg, 167 mg (yield: 84%) of the title compound is obtained.

Reference Example 32 47 mg of 3-(l-pyrrolyl)benzyl methanesulfonate obtained in Reference Example 3 was added to 1 g of dimethylformamide.
3-mercaptobenzaldehyde dissolved in 36 ml
mg and 36 mg of potassium carbonate are added and stirred overnight at room temperature. The solvent was distilled off, and after treatment by a conventional method, silica gel column chromatography [Wakogel C-20
34 mg (yield: 58%) of 3-[3-(1-pyrrolyl)benzylthio]benzaldehyde is obtained.

The above aldehyde is reduced by a conventional method using sodium borohydride to obtain the title compound as a colorless oil.

In place of the starting compound 3-(1-pyrrolyl)benzyl methanesulfonate and/or 3-mercaptobenzaldehyde, the corresponding methanesulfonate derivative and/or 3-hydroxybenzaldehyde were used, and the other conditions were the same as in Reference Example 32. If the reaction is carried out, 3-[3-(3
-thienyl)benzyloxy]benzyl alcohol, 3
-[4-(3-thienyl)-2-thienylmethylthio]
Benzyl alcohol, 3-[3-(5-oxacylyl)
benzylthio]benzyl alcohol and 3-[3-(l
-pyrrolyl)benzyloxy]benzyl alcohol is obtained.

Reference Example 33 3-(3-thienyl)benzyl bromide [3-(3-
(thienyl) benzaldehyde reduced with sodium borohydride followed by phosphorus tribromide] and 4-carboethoxy-2-mercaptothiazole [J, Org.

Chem., 25 1337 (1960)], the same reaction as in Reference Example 32 is carried out, and the obtained ester is reduced with lithium aluminum hydride to obtain the title compound.

Reference Example 34 5-bromo-3-thiophenecarboxylic acid ethyl ester of 5-3-thienyl-3-dinyl [J, A
m, Chem, Soc, 26.2446. (1
If the same reaction as in Reference Example 12 is carried out using 730 mg of butyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 5-(3-thienyl)- 3-thiophenecarboxylic acid ethyl ester 172m
g (yield: 51%) is obtained.

172 mg of the above thienylthiophene derivative is dissolved in 3 ml of anhydrous tetrahydrofuran, and under water cooling, 28 mg of lithium aluminum hydride is added and stirred for 20 minutes.

Extraction with water and ethyl ether followed by conventional work-up gives the title compound in quantitative yield.

5-bromo-3-pyridinecarboxylic acid methyl ester or 5-bromo-2-furancarboxylic acid methyl ester [J, Org, Chem,
21517 (1956)], and in the same manner as in Reference Example 34, 5-(3-thienyl)-3-pyridylmethanol and 5-(3-thienyl)-2-furylmethanol are obtained.

Reference Example 35 J, Het using 3-thiocarbamoylthiophene of 2-3-unyl-5-thiol as a starting material
erocyclic Chem,, 23.577
(1986).

Reference example 36 3-3-thienyl-5-iso゛tlumenol 3
- J using carbamoylthiophene as starting material.

Chem, Soc, Perkin I, 234
2 (1987).

Reference Example 37 700 m, g of 3-(tetrahydro-3-hydroxy-3-thiopyranyl)benzaldehyde dimethylacecool obtained in Reference Example 29, 0.72 m of triethylamine
1 and methanesulfonyl chloride 0,24 m / were reacted in 7 ml of ethyl acetate, the obtained crude methanesulfonate was dissolved in ethyl ether 1 /,
495 m of lithium aluminum hydride under water cooling and stirring
g and stirred at room temperature for 3 hours. After post-treatment in a conventional manner, the solvent is distilled off, the residue is dissolved in 10 ml of tetrahydrofuran, 8 ml of 2N hydrochloric acid is added, and the mixture is stirred at room temperature for 1 hour. Extract with ethyl ether and work up in a conventional manner to obtain 3-tetrahydrothiopyranylbenzaldehyde.

When the obtained aldehyde is reduced by a conventional method using lithium aluminum hydride, the title compound 7 is obtained as a colorless oil.
5 mg (yield: 14%) is obtained.

Reference Example 38 3-(2,3- obtained as an intermediate in Reference Example 10)
dihydro-4-thienyl)benzaldehyde 100 m
g and 3-carboethoxybenzylethylphosphonate [Autralian J, Chem, 18.1
63. (1965)] Dissolve 157 mg in 1 m/m of dimethylformamide, add 31 mg of 60% oily sodium hydride, and stir at room temperature for 3 hours. The solvent was distilled off, water and ethyl acetate were added, and the mixture was extracted. After post-treatment by a conventional method, medium-pressure liquid chromatography [column: Lobar
column.

5ize A, Lichroprep Si 60F
(manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 30/1 → 20/1], and (E)-3-
[2-[3-(2,3-dihydro-4-thienyl)funinyl]ethynyl]benzoic acid ethyl ester 70 mg (
Yield: 41%).

The above ester was reduced in the same manner as in Reference Example 34, and subjected to silica gel column chromatography [Wakogel C-200
, Ig, elution solvent: hexane/ethyl acetate = 10/1→
2/l] to obtain 41 mg (yield: 63%) of the title compound.

Reference example 39 2-thiophenecarbaldehyde dimethyl acecool 12
．． 5 g of anhydrous ethyl ether was dissolved in 80 m/m of anhydrous ethyl ether, 19.7 mj of a 15% n-butyllithium hexane solution was added at -10°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. A solution of 2.46 ml of dimethylformamide in 30 ml of ethyl ether was added to the reaction mixture at -4.0° C. under stirring, and the mixture was stirred at room temperature for 2 hours. After extraction with ethyl ether, after-treatment by conventional methods and purification by vacuum distillation, 3.3 g (yield: 59%) of 2,5-thiophene diurbaldehyde monodimethyl acetal as a pale yellow oil is obtained.

Using 100 mg of the above aldehyde, 168 mg of 3-(3-thienyl)benzylethylphosphonate, and 22 mg of 60% oily sodium hydride as raw materials, a reaction similar to that in Reference Example 38 was carried out, followed by a 50% aqueous trifluoroacetic acid solution. and stirred at room temperature for 1 hour. After neutralization by adding a saturated aqueous sodium hydrogen carbonate solution, post-treatment was carried out by a conventional method, and the column was subjected to medium pressure liquid chromatography [column: Lobar
column, 5ize B, Lichropr
If purified using epSi 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/ethyl acetate = 5/I], (E)-
5-[2[3-(3-thienyl)phenyl]ethynyl]
-2-thiophenecarbaldehyde 11 mg (yield: 6
9%) is obtained as a yellow oil.

The title alcohol is obtained by reducing the above aldehyde using sodium borohydride in a conventional manner.

4-Bromo-2-thiophenecarbaldehyde ethylene acetal [J, Org, Che
m.

Su,, 1320. (1976)] and carrying out the same reaction as in Reference Example 39, (E)-4-[2-
[3-(3-thienyl)phenyl]ethynyl]-2-thienylmethanol is obtained.

Reference Example 40 2.
4-(5-
The title compound is obtained by deacetalizing and reducing dimethylacecool (oxacylyl)-2-thiophenecarbaldehyde in the same manner as in Reference Example 39.

Reference Example 41 4-(3-thienyl)-2-thiophenecarbaldehyde loomg and 3-chloromethylbenzyltriphenylphosphonium chloride [produced by heating and refluxing α,α°-dichloro-m-xylene and triphenylphosphine in xylene ] 250 mg was suspended in 1 m7 of tetrahydrofuran, and 31 m of 60% oily sodium hydride was added under water cooling.
g and stirred at room temperature for 1.5 hours. The solvent was distilled off, the mixture was neutralized with 1N hydrochloric acid, and then extracted with ethyl acetate.

After post-treatment, it is purified by silica gel column chromatography [Wako Gel C-300, 5 g 1 elution solvent: hexane/ethyl acetate = 1071] and recrystallized from chloroform-hexane to give 80 mg of the title compound as a pale yellow crystalline powder ( Yield: 49%), m, p, l 3
7-138°C2 is obtained.

Reference example 42 E-3-2-3-5-yl phenyl etheny3
- Using 1.0 g of bromobenzaldehyde and 2.7 g of 3-carbomethoxypenzyltriphenylphosphine bromide [manufactured by heating and refluxing 3-bromomethylbenzoic acid methyl ester and triphenylphosphine in xylene] as raw materials, Reference Example 41 and If a similar reaction is performed, 3-[2
1.3 g of a mixture of the (E) and (Z) forms of -(3-bromophenyl)ethynyl]benzoic acid methyl ester is obtained.

1.3 g of the above geometric isomer mixture was dissolved in 6 ml of toluene, 70 mg of iodine was added, and the mixture was heated under reflux overnight.

After washing the reaction solution with an aqueous sodium dithionite solution, post-treatment using a conventional method and recrystallization from ethyl acetate-hexane yields (E)-3-[2-(3-bromophenyl)ethynyl]benzoic acid methyl ester. 817 mg (yield: 47
%), m, p, 79-84°C, is obtained as a pale yellow crystalline powder.

3-[2-[3-(5-thiazolyl)phenyl]ethynyl]benzoic acid methyl ester obtained by reacting the above bromo compound and tributyl (5-thiazolyl) stannane under the same conditions as in Reference Example 12, Reduction using lithium aluminum hydride in a conventional manner yields the title compound.

Reference Example 43 4-Bromo-2-thiophenethiol [Chem, A
bst,.

3-(4-bromothienylthiomethyl)benzaldehyde and tributyl(3-thienyl )
If the same reaction as in Reference Example 12 is carried out using stannane and tetrakis(triphenylphosphine)palladium,
The title compound is obtained as a colorless oil.

By inhibiting mammalian squalene epoxidase, the compound of the present invention inhibits cholesterol biosynthesis and lowers blood cholesterol levels. Therefore, it can be expected to be effective as a therapeutic and preventive agent for diseases caused by excess cholesterol, such as obesity, hyperlipidemia, arteriosclerosis, and associated heart and brain diseases.

Claims (16)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, A^1 and A^2 are the same or different and represent a methine group, nitrogen atom, oxygen atom, or sulfur atom; Q^ 1 and Q^2 may be the same or different and may contain one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and adjacent carbon atoms and A^
Represents a group that forms a 5- or 6-membered aromatic ring with 1 or A^2; X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, and the formula: -CHR^
A group or formula represented by a- (where R^a represents a hydrogen atom or a lower alkyl group): -NR^b- (here, R
^b represents a hydrogen atom or a lower alkyl group), or both X and Y together represent a vinylene group or an ethynylene group; R^1 represents a nitrogen atom, an oxygen atom, or One selected from the group consisting of sulfur atoms ~
Represents a 5- or 6-membered heterocyclic group containing 4 heteroatoms; R^2 represents a lower alkyl group, allyl group, propargyl group, or cyclopropyl group; R^3 and R^4 are the same or different represents a lower alkyl group, or represents a group where both combine to form a cycloalkane with adjacent carbon atoms; R^5 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; R^6 and R ^7 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. However, either X or Y is an oxygen atom, a sulfur atom, or a formula: -N
When a group represented by R^b- (where R^b has the above meaning), the other is a carbonyl group or a group of the formula: -C
A substituted allylamine derivative represented by HR^a- (herein, R^a has the above-mentioned meaning) and a non-toxic salt thereof. (2) R^1 is a pyrrolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group,
Tetrazolyl group, furazanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolyl group Dinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1,2-dithiolanyl group, 1,3-dithiolanyl group, 1,2-dithiolyl group, 1,3-dithiolyl group, dihydrothiopyrani 1,4-dithianyl group, 1,4-dithienyl group, 1,4-oxathiinyl group, or thiomorpholinyl group; Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or formula: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼The 5-membered or 6-membered aromatic rings represented by ▼ are the same or different and may be benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, iso The substituted allylamine according to claim 1, which is a thiazole ring, an imidazole ring, a 1,3,4-oxadiazole ring, a 1,3,4-thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring or a triazine ring. Derivatives and non-toxic salts thereof. The substituted allylamine derivative and non-toxic salt thereof according to claim 2, wherein the 5- or 6-membered aromatic ring represented by formula (3): ▲ includes numerical formula, chemical formula, table, etc. ▼ is a benzene ring or a thiophene ring. (4) R^1 is a thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyridyl group, or dihydrothienyl group; Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The 5- or 6-membered aromatic ring represented by ▼ is a benzene ring or thiophene ring; Formula: ▲ Numerical formula, chemical formula, table, etc. The 5- or 6-membered aromatic ring represented by ▼ is a benzene ring or pyrrole ring , furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, 1,3,4-oxadiazole ring, 1,3,4-thiadiazole ring, pyridine ring, pyridazine ring, The substituted allylamine derivative according to claim 1, which is a pyrimidine ring, pyrazine ring or triazine ring, and a non-toxic salt thereof. (5) R^1 is 3-thienyl group, 1-pyrrolyl group, 5-
Oxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 4-thiazolyl group, 5-thiazolyl group,
3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-
The substituted allylamine derivative according to claim 4, which is a 4-thienyl group or a 2,5-dihydro-3-thienyl group, and a non-toxic salt thereof. (6) Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. The 5- or 6-membered aromatic ring represented by ▼ is a benzene ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring , 1,3,4-oxadiazole ring, 1,
The substituted allylamine derivative according to claim 4 or 5, which is a 3,4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring, and its non-toxic salt. (7) X is a methylene group; Y is a methylene group, an oxygen atom, a sulfur atom, or an imino group; or Y is a methylene group; X is a methylene group, an oxygen atom, a sulfur atom, or an imino group. or 4th, 5th or 6th, wherein both X and Y together are (E)-vinylene group.
Substituted allylamine derivatives and non-toxic salts thereof according to the claims. (8) The seventh aspect, wherein R^2 is a methyl group, ethyl group, or propyl group; R^3 and R^4 are methyl groups; and R^5 is a methyl group, ethyl group, or methoxy group. Substituted allylamine derivatives and non-toxic salts thereof. (9) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, A^1, A^2, Q^1, Q^2, X, Y, R
^1, R^2, R^6 and R^7 are as defined in the first claim] or an appropriately protected compound thereof; etc. ▼ [III] [In the formula, Z represents a leaving group; R^3, R^4 and R^5
is as defined in the first claim], and then, if necessary, the protecting group is removed, or the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [IV] [Formula Medium, A^1, A^2, Q^1, Q^2, X, Y, R
^1, R^6, R^7 and Z have the above meanings] Compounds represented by the formula or appropriately protected derivatives thereof include the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [V] [Formula wherein R^2, R^3, R^4 and R^5 have the above-mentioned meanings],
The substituted allylamine derivative represented by the general formula [I] according to claim 1 and its non-toxic salt, which is characterized in that the protecting group is then removed if necessary, and then converted into a non-toxic salt if necessary. manufacturing method. (10) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [VI] [In the formula, A^1, A^2, Q^1, Q^2, X, Y, R
^1, R^3, R^4, R^5, R^6 and R^7 are as defined in the first claim] or an appropriate substituted allylamine derivative thereof. The protected compound has the general formula Z-R^2 [VII], where R^2 is as defined in the first claim;
Z represents a leaving group], and then, if necessary, the protecting group is removed, and then, if necessary, it is converted into a non-toxic salt. A method for producing a substituted allylamine derivative represented by the general formula [I] and a nontoxic salt thereof. (11) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [VIII] [In the formula, X^a is a carbonyl group or formula: -CHR^a-
(Here, R^a represents a hydrogen atom or a lower alkyl group); Z represents a leaving group; A^1, Q
^1, R^1 and R^6 are as defined in the first claim] or its suitably protected derivatives have the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ [IX ] [In the formula, Y^a is an oxygen atom, a sulfur atom, or the formula: -NR^
Represents a group represented by b- (where R^b represents a hydrogen atom or a lower alkyl group); also A^2, Q^2, R^
2, R^3, R^4, R^6 and R^7 are as defined in the first claim] or a suitably protected compound thereof, and then as required. There are general formulas▲mathematical formulas, chemical formulas, tables, etc.▼[ I ^a] [where A^1, A^ 2, Q^1, Q^2, X^a, Y
^a, R^1, R^2, R^3, R^4, R^5, R^
6 and R^7 have the above-mentioned meanings] A method for producing a substituted allylamine derivative and a non-toxic salt thereof. (12) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [X] [In the formula, X^b is an oxygen atom, a sulfur atom, or the formula: -NR^
represents a group represented by b- (where R^b represents a hydrogen atom or a lower alkyl group); A^1, Q^1, R^1 and R^6 are defined in the first claim; ] Compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [X I ] [wherein, Y^b is a carbonyl group or the formula: -CHR^ a-
(Here, R^a represents a hydrogen atom or a lower alkyl group); Z represents a leaving group; A^2, Q
^2, R^2, R^3, R^4, R^5 and R^7 are as defined in the first claim] or an appropriately protected compound thereof. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [I ^b] [wherein, A ^1, A^2, Q^1, Q^2, X^b, Y
^b, R^1, R^2, R^3, R^4, R^5, R^
6 and R^7 have the above-mentioned meanings] A method for producing a substituted allylamine derivative and a non-toxic salt thereof. (13) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [XII] [In the formula, A^1, Q^1, R^1 and R^6 are as defined in the first claim] Compounds represented include general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [XIII] [In the formula, A^2, Q^2, R^2, R^3, R^4, R
^5 and R^7 are as defined in the first claim]
There are general formulas ▲mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting a compound represented by and then reducing ▼[ I ^C] [In the formula, A^1, A^2, Q^1 , Q^2, R^1, R
^2, R^3, R^4, R^5, R^6 and R^7 have the above-mentioned meanings] A method for producing a substituted allylamine derivative or a non-toxic salt thereof. (14) A hypercholesterolemia treatment agent containing the substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1. (15) A hyperlipidemia treatment agent containing a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to the first claim. (16) An agent for treating arteriosclerosis, comprising a substituted allylamine derivative represented by the general formula [I] or a non-toxic salt thereof according to claim 1.