JPH10251224A - New thiocarbamic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an agent for alleviating hypercholesterolemia or an agent for hyperlipemia. SOLUTION: This compound is shown by formula I [R is trifluoromethyl, phenyl, etc.; R1 is H or a lower alkyl; (1) is 0 or 1; X and Z are each carbonyl, etc.; (m) is 0 or 1; (n) is 1 or 2; Y is O, S, etc.; Q is ethylene, trimethylene, etc.; R2 is H or a lower alkyl; A is a group of formula II (R3 and R4 are each H, a halogen, etc.)] such as N-(3-thienyl)-N-methyl-3-(3-aminophenoxy) propylamine. The compound is obtained by reacting a halogenated thioformate of formula III (V is a halogen) with an amine of formula IV in an equimolar amounts or in a little excessive amount of either of the compounds in the presence or absence of a base (sodium hydroxide) in a solventless state or in a solvent (methanol) at -80 to 100 deg.C for several minutes to 24 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel thiocarbamic acid derivative having squalene epoxidase inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and a process for producing them.

[0002]

2. Description of the Related Art In recent years, it has been pointed out that arteriosclerosis and accompanying coronary and cerebral artery diseases are increasing in frequency due to aging of the population and changes in eating habits. Various factors are considered for the occurrence of this arteriosclerosis,
Elevated blood cholesterol is one of the most important risk factors, and it is said that blood cholesterol lowering agents are effective in preventing and treating arteriosclerosis. Among these blood cholesterol lowering agents, biosynthesis inhibitors of cholesterol in vivo are highly evaluated for their clear mechanism of action and strong drug efficacy.

[0003] In order to inhibit cholesterol biosynthesis in a living body, it is said that it is useful to inhibit the activity of an enzyme involved in the biosynthesis. As such cholesterol inhibitors, lovastatin, epstatin, pravastatin and the like have already been clinically used. [Proceding National Academia Science (Proc. Natl. Acad. Sci. USA), 77, 3957 (19)
80) etc.]. However, these known inhibitors include 3-hydroxymethylglutaryl-coenzyme A reductase (HM
G-CoA reductase), which is located at a relatively early stage in the cholesterol biosynthesis system. For this reason, enzyme inhibition by administration of the above-mentioned drug may also cause inhibition of the synthesis of other physiologically important metabolites such as dolichol and ubiquinone. It has been reported that triparanol, which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, accumulates desmosterol which causes cataract.

On the other hand, squalene epoxidase inhibitors which target squalene epoxidase, which is located in the middle stage of the cholesterol biosynthesis system, have a risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the living body. It is expected to provide a safer anticholesterol agent without.

[0005] Such squalene epoxidase inhibitors include (E) -N- (6,6-dimethyl-2-heptene-4-ynyl) -N-ethyl-3- [4- (3-thienyl). Arylamine-based compounds such as [-2-thienylmethyloxy] benzylamine (NB-598) (for example, JP-A-3-141275, WO 93/1206).
9, WO94 / 18191, WO95 / 03313
Etc.), dibenzylamine-based compounds (for example, WO 94 /
18167, JP-A-7-233128, etc., aryl alcohol-based compounds (for example, JP-A-6-49023)
And benzylamine compounds (WO 95/1)
8121) are known.

On the other hand, thiocarbamic acid ester derivatives are known to be useful as antifungal agents or agricultural chemicals. For example, Japanese Patent Publication No. 39-11213,
U.S. Pat. No. 3,395,230, JP-A-57-17695
No. 2 discloses a compound having antifungal activity. It is known that a thiocarbamate having antifungal activity exerts an antibacterial activity by inhibiting bacterial steroid synthesis, particularly squalene epoxidase. Further, compounds having herbicidal activity are reported in Japanese Patent Publication No. 62-54424 and the like. However, thiocarbamate derivatives having antifungal activity have been reported to show only weak activity against mammalian squalene epoxidase [Drugs of the Future]. ), 18 (1
0), 911 (1993)].

[0007]

An object of the present invention is to provide an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent which is safer and has an excellent anti-cholesterol effect as compared with existing drugs, and An object of the present invention is to provide an agent for treating and preventing arteriosclerosis.

[0008]

Means for Solving the Problems The present inventors have made intensive studies and have found that a thiocarbamate derivative having a certain substituent has a high inhibitory activity against squalene epoxidase derived from mammals. The present invention has been completed.

That is, one of the present invention is a compound represented by the general formula [1]:

[0010]

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[Wherein R represents a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, or one or more of oxygen, nitrogen or sulfur atoms or a combination of each atom. Represents a 5- or 6-membered heterocyclic ring containing two or more. Any substituent may be substituted on the heterocycle. R ₁ represents a hydrogen atom or a lower alkyl group. l represents an integer of 0 or 1. X and Z are the same or different and each represents a carbonyl group or a formula: -CHR
_9- (wherein R ₉ represents a hydrogen atom or a lower alkyl group). m represents an integer of 0 or 1. n represents an integer of 1 or 2. Y represents an oxygen atom, a sulfur atom or a group represented by the formula: —NR ₈ — (wherein R ₈ represents a hydrogen atom, a lower acyl group, or a lower alkyl group optionally substituted with a halogen atom). Represent. Q is ethylene, trimethylene or the formula [2]

[0012]

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(Wherein E represents a nitrogen atom or a CH group). R ₂ represents a hydrogen atom or a lower alkyl group. A is the formula [3]

[0014]

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(Wherein R ₃ and R ₄ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group or a dicyano group;
Lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, carbamoyl group, lower alkylcarbamoyl group,
A lower alkyl group which may be substituted with a lower acyl group, a lower acyloxy group, a halogen atom or a lower acylamino group; Or R ₃ and R ₄ are united with each other,
It may form a 5- to 6-membered ring. Or a group represented by the formula [4]

[0016]

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(Wherein F is vinylene, ethynylene or formula [5]

[0018]

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(Wherein R ₇ represents a hydrogen atom or a lower alkyl group). R ₆ represents a lower alkyl group which may be substituted with a lower alkoxy group or a cyano group. R ₅ represents a hydrogen atom or a lower alkyl group. p represents an integer of 0 or 1. ) Represents a group represented by ] The thiocarbamic acid derivative or its salt characterized by being represented by these.

Another aspect of the present invention is a compound represented by the general formula [6]:

[0021]

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(Where R, R ₁ , X, Y, Z, Q, R ₂ ,
1, m and n have the same meanings as described above. R ₁₀ represents a hydrogen atom, a lower acyl group or a lower alkoxycarbonyl group. ) Or a salt thereof.

Still another embodiment of the present invention provides a compound represented by the following general formula [7]:

[0024]

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Wherein R ₉ , Q, R ₂ , A and n have the same meanings as above, and V represents a halogen atom, or a thiocarbamate or a salt thereof. It is.

One of the production methods of the present invention is a method represented by the following general formula [8]:

[0027]

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(Where A and V have the same meanings as described above) and a general formula [6a].

[0029]

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Wherein R, R ₁ , X, Y, Z, R ₂ , Q,
wherein l, m, and n represent the same meanings as described above).

[0031]

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(Where R, R ₁ , X, Y, Z, Q, R ₂ ,
A, l, m, and n have the same meanings as described above).

Another one of the production methods of the present invention is represented by the following general formula [9] as shown in the following reaction formula.

[0034]

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(Wherein R, R ₁ , X, Y, 1, and m have the same meanings as described above) and a compound of the general formula [7]

[0036]

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Wherein V, R ₉ , Q, R ₂ , A and n have the same meanings as described above, and reacting the compound represented by the general formula [1a].

[0038]

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Wherein R, R ₁ , R ₉ , X, Y, Q,
R ₂ , A, l, m, and n represent the same meaning as described above. ).

Still another one of the production methods of the present invention is a method represented by the following general formula [10] as shown in the following reaction formula.

[0041]

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(Wherein Q, R ₂ and A have the same meanings as described above) and a compound of the general formula [11]

[0043]

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(Where R, R ₁ , X, Y, Z, V, l,
m and n have the same meaning as described above. Wherein the compound represented by the general formula [1] is reacted:

[0045]

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(Where R, R ₁ , X, Y, Z, Q, R ₂ ,
A, l, m, and n represent the same meaning as described above. ).

Still another one of the production methods of the present invention is a compound represented by the following general formula [12] A ₂ OH [12] wherein A ₂ is a compound represented by the formula [4]

[0048]

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(Wherein F, R ₅ , R ₆ and p have the same meanings as described above) and a compound of the general formula [19]

[0050]

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(Where R, R ₁ , X, Y, Z, Q, R ₂ ,
1, m and n have the same meanings as described above. R ₁₈ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group, a cyano group or a nitro group. Wherein the compound represented by the general formula [1c] is reacted:

[0052]

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(Where R, R ₁ , X, Y, Z, Q, R ₂ ,
A ₂ , l, m, and n represent the same meaning as described above. ).

The present invention also relates to a pharmaceutical composition comprising the compound of the general formula [1] or a salt thereof, and a pharmaceutically acceptable simple substance.

The present invention also provides a squalene epoxidase inhibitor and a therapeutic and / or prophylactic agent for hypercholesterolemia, hyperlipidemia or arteriosclerosis containing the compound of the above general formula [1] or a salt thereof. To provide.

Hereinafter, the present invention will be described in detail.

First, the compounds represented by the general formulas [1], [6] and [7] of the present invention will be described in detail. In the definition of the general formula of the present invention, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

Accordingly, as the lower alkyl group, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, Isopentyl group, neopentyl group, tert-pentyl group,
1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-
Methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3
-Dimethylbutyl group, 3,3-dimethylbutyl group, 1-
Ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-
2-methylpropyl group and the like, preferably methyl group, ethyl group, propyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, ter
Examples thereof include a t-pentyl group and a 1,1-dimethylbutyl group.

Examples of the lower alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 1-butenyl group,
2-butenyl group, 3-butenyl group, 1-pentenyl group,
2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methylvinyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-ethylvinyl group, 1-ethyl-1- Propenyl group, 2-methyl-1-
Propenyl group, 1,2-dimethyl-1-propenyl group,
Examples thereof include a 1,1-dimethyl-2-propenyl group and a 1,1-dimethyl-3-butenyl group, preferably a 1-methylvinyl group, a 1-methyl-1-propenyl group, and a 1,1-
Dimethyl-2-propenyl group, 1,1-dimethyl-3-
Butenyl and the like.

The lower alkyl group which may be substituted with a halogen atom includes, in addition to an unsubstituted lower alkyl group,
For example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 1,1-difluoroethyl group, a 1,2-difluoroethyl group, a 2,2-difluoroethyl group, 1,
2,2-trifluoroethyl group, 2,2,2-trifluoroethyl group, 1-fluoropropyl group, 2-fluoropropyl group, 3-fluoropropyl group, 2,2-difluoropropyl group, chloromethyl group, Dichloromethyl group, trichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 1,1-dichloroethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 1,2,2
2-trichloroethyl group, 2,2,2-trichloroethyl group, 1-chloropropyl group, 2-chloropropyl group,
3-chloropropyl group, 2,2-dichloropropyl group,
Bromomethyl group, dibromomethyl group, tribromomethyl group, 1-bromoethyl group, 2-bromoethyl group, 1,1
-Dibromoethyl group, 1,2-dibromoethyl group, 2,
2-dibromoethyl group, 1,2,2-tribromoethyl group, 2,2,2-tribromoethyl group, 1-bromopropyl group, 2-bromopropyl group, 3-bromopropyl group, 2,2- And a dibromopropyl group.

Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group,
Butoxy group, isobutoxy group, sec-butoxy group, t
ert-butoxy group, pentyloxy group, 1-methylbutyloxy group, 2-methylbutyloxy group, 3-methylbutyloxy group, 1,2-dimethylpropyloxy group,
1,1-dimethylpropyloxy group, hexyloxy group, 1-methylpentyloxy group, 1-ethylpropyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 2
-Dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1,1-dimethylbutyloxy group, 2,2-dimethylbutyloxy group, 3,3-dimethylbutyloxy group And the like, preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group,
And a 1,2-dimethylpropyloxy group.

As the lower alkylsilyl group, tert
-Butylsilyl group, sec-butylsilyl group, isobutylsilyl group, isopropylsilyl group, butylsilyl group,
Propylsilyl group, dimethylsilyl group, diethylsilyl group, ethylmethylsilyl group, methylpropylsilyl group,
Isopropylmethylsilyl group, ethylpropylsilyl group, ethylisopropylsilyl group, butylmethylsilyl group, isobutylmethylsilyl group, sec-butylmethylsilyl group, tert-butylmethylsilyl group, ethylbutylsilyl group, ethylisobutylsilyl group, sec -Butylethylsilyl group, tert-butylethylsilyl group, butylpropylsilyl group, isobutylpropylsilyl group, sec-butylpropylsilyl group, tert-butylpropylsilyl group, butylisopropylsilyl group,
Isobutylisopropylsilyl group, sec-butylisopropylsilyl group, tert-butylisopropylsilyl group, chlorodimethylsilyl group, chloroethylmethylsilyl group, chloromethylpropylsilyl group, chlorobutylmethylsilyl group, dichloromethylsilyl group, dichloroethylsilyl Group, dichloropropylsilyl group, trimethylsilyl group, dimethylethylsilyl group, diethylmethylsilyl group, triethylsilyl group, dimethylpropylsilyl group, ethylmethylpropylsilyl group, dipropylmethylsilyl group, diethylpropylsilyl group, dipropylethylsilyl Group, tripropylsilyl group, dimethylisopropylsilyl group, ethylmethylisopropylsilyl group, diisopropylmethylsilyl group, diethylisopropylsilyl group, diisopropyl Pills triethylsilyl group, triisopropylsilyl group, butyldimethylsilyl group, tert- butyldimethylsilyl group, butyl ethyl methyl silyl group,
Butylmethylpropylsilyl, butyldiethylsilyl, butylethylpropylsilyl, butyldipropylsilyl, dibutylmethylsilyl, dibutylethylsilyl, dibutylpropylsilyl, tributylsilyl, dimethylisobutylsilyl, ethylisobutylmethyl Silyl group, isobutylmethylpropylsilyl group, diethylisobutylsilyl group, ethylisobutylpropylsilyl group, isobutyldipropylsilyl group, diisobutylmethylsilyl group, diisobutylethylsilyl group, diisobutylpropylsilyl group, triisobutylsilyl group, and the like. Preferably, trimethylsilyl group, dimethylethylsilyl group, diethylmethylsilyl group, triethylsilyl group, dimethylpropylsilyl group, ethylmethylpropylsilyl group Dimethylisopropylsilyl group, butyldimethylsilyl group, a tert- butyldimethylsilyl group, and the like.

Examples of the lower acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, 1-methylpropylcarbonyl, isovaleryl, pentylcarbonyl, 1-methylbutylcarbonyl, -Methylbutylcarbonyl group, 3-methylbutylcarbonyl group, 1-ethylpropylcarbonyl group, 2-ethylpropylcarbonyl group and the like. Preferred are a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group and the like.

Examples of the lower alkylamino group include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a pentylamino group, an isopropylamino group, an isobutylamino group, a sec-butylamino group, a dimethylamino group, a methylamino group. Ethylamino group, methylpropylamino group, methylbutylamino group, diethylamino group, ethylpropylamino group, ethylbutylamino group,
Examples thereof include an ethylpentylamino group, a dipropylamino group, and a propylbutylamino group. Preferred are a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a methylethylamino group, a methylpropylamino group, a diethylamino group, an ethylpropylamino group and the like.

The lower alkylcarbamoyl group includes, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-butylcarbamoyl group, N, N-dimethylcarbamoyl group, N-ethyl-N-methyl Carbamoyl group, N-methyl-N-propylcarbamoyl group, N-ethyl-N-propylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-
And a dipropylcarbamoyl group. Preferred are an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N, N-diethylcarbamoyl group and the like.

Examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
An ec-butoxycarbonyl group, a tert-butoxycarbonyl group and the like can be mentioned. Preferred are a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and the like.

Examples of the lower acyloxy group include a formyloxy group, an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group and a valeryloxy group. Preferred are a formyloxy group, an acetoxy group, a propionyloxy group and the like.

The lower acylamino groups include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, formyl-N-methylamino, acetyl-N-
A methylamino group, a propionyl-N-methylamino group,
Formyl-N-ethylamino group, acetyl-N-ethylamino group, propionyl-N-ethylamino group, formyl-N-propylamino group, acetyl-N-propylamino group, propionyl-N-propylamino group and the like. be able to. Preferably, formylamino group, acetylamino group, propionylamino group, formyl-N-
And a methylamino group and an acetyl-N-methylamino group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Preferably, they are a fluorine atom, a chlorine atom and a bromine atom.

Examples of Y include an oxygen atom, a sulfur atom and a group represented by the formula: —NR ₈ —. Preferably, an oxygen atom or a group represented by the formula: —NR ₈ — can be mentioned. More preferably, the formula: -NR ₈
And a group represented by-.

R ₈ represents a hydrogen atom, a lower acyl group,
And a lower alkyl group which may be substituted with a halogen atom. Preferably, they are a hydrogen atom, a lower acyl group, or a lower alkyl group.

(Cyano group, lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, carbamoyl group, lower alkylcarbamoyl group, lower acyl group, lower acyloxy group, halogen atom or lower Examples of the lower alkyl group (which may be substituted with an acylamino group) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-
Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl Linear or branched lower alkyl groups such as 1,2-dimethylbutyl group and 2,2-dimethylbutyl group, methoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1-methoxypropyl Group, 2-methoxypropyl group, 1-methoxy-1-methylethyl group, 2-methoxy-1-methylethyl group, 1-methoxy-1-methylpropyl group, 2-methoxy-1-methylpropyl group, 1, 1
-Dimethyl-2-methoxyethyl group, 1,1-dimethyl-2-methoxypropyl group, 1,1-dimethyl-3-methoxypropyl group, 2-methoxy-1-methoxymethyl-1-methylethyl group, 2- A lower alkyl group substituted by a lower alkoxy group such as an ethoxy-1,1-dimethylethyl group, a 1-ethoxy-1-methylethyl group, a cyanomethyl group, a 1-cyanoethyl group, a 2-cyanoethyl group,
-Cyanopropyl group, 2-cyanopropyl group, 1-cyano-1-methylethyl group, 2-cyano-1-methylethyl group, 1-cyano-1-methylpropyl group, 2-cyano-1-methylpropyl group , 2-cyano-1,1-dimethylethyl group, 2-cyano-1,1-dimethylpropyl group, 3-cyano-1,1-dimethylpropyl group, 2-cyano-1-cyanomethyl-1-methylethyl group A lower alkyl group substituted with a cyano group, a methoxycarbonylmethyl group, a 1- (methoxycarbonyl) ethyl group,
(Methoxycarbonyl) ethyl group, 1- (methoxycarbonyl) propyl group, 1- (methoxycarbonyl) -1
-Methylethyl group, 1- (methoxycarbonyl) -1-
Methylpropyl group, 1,1-dimethyl-2- (methoxycarbonyl) ethyl group, 1,1-di (methoxycarbonyl) ethyl group, 1,1-dimethyl-2- (methoxycarbonyl) propyl group, ethoxycarbonylmethyl group , 1
-(Ethoxycarbonyl) ethyl group, 2- (ethoxycarbonyl) ethyl group, 1- (ethoxycarbonyl) propyl group, 1- (ethoxycarbonyl) -1-methylethyl group, 1- (ethoxycarbonyl) -1-methylpropyl A lower alkoxycarbonyl group such as a group, 2- (ethoxycarbonyl) -1,1-dimethylethyl group, 1,1-di (ethoxycarbonyl) ethyl group, and 1,1-dimethyl-2- (ethoxycarbonyl) propyl group. Substituted lower alkyl group, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 1-carboxypropyl group, 1-carboxy-1-methylethyl group, 1
A lower group substituted by a carboxy group such as -carboxy-1-methylpropyl group, 2-carboxy-1,1-dimethylethyl group, 1,1-dicarboxyethyl group, 2-carboxy-1,1-dimethylpropyl group; Alkyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 1-hydroxy-1-methylpropyl group, 1,1-dimethyl -2-hydroxyethyl group, 1,1-dimethyl-2-hydroxypropyl group,
A lower alkyl group substituted with a hydroxy group such as a 1,1-dimethyl-3-hydroxypropyl group, an aminomethyl group, a 1-aminoethyl group, a 1-aminopropyl group,
Amino-1-methylethyl group, 1-amino-1-methylpropyl group, 1,1-dimethyl-2-aminoethyl group,
A lower alkyl group substituted with an amino group such as a 1,1-dimethyl-2-aminopropyl group, a 1,1-dimethyl-3-aminopropyl group, an (N-methylamino) methyl group,
-(N-methylamino) ethyl group, 1- (N-methylamino) propyl group, 1- (N-methylamino) -1-methylethyl group, 1- (N-methylamino) -1-methylpropyl group 1,1-dimethyl-2- (N-methylamino) ethyl group, 1,1-dimethyl-2- (N-methylamino) propyl group, (N-ethylamino) methyl group,
-(N-ethylamino) ethyl group, 1- (N-ethylamino) propyl group, 1- (N-ethylamino) -1-methylethyl group, 1- (N-ethylamino) -1-methylpropyl group 1,1-dimethyl-2- (N-ethylamino) ethyl group, 1,1-dimethyl-2- (N-ethylamino) propyl group, 1,1-dimethyl-2- (N-propylamino) ethyl Group, 1,1-dimethyl-2- (N-
Propylamino) propyl group, 1,1-dimethyl-2-
(N-butylamino) ethyl group, 1,1-dimethyl-2
-(N-butylamino) propyl group, (N, N-dimethylamino) methyl group, 1- (N, N-dimethylamino)
Ethyl group, 1- (N, N-dimethylamino) propyl group, 1- (N, N-dimethylamino) -1-methylethyl group, 1- (N, N-dimethylamino) -1-methylpropyl group, 1,1-dimethyl-2- (N, N-dimethylamino) ethyl group, 1,1-dimethyl-2- (N, N-
Dimethylamino) propyl group, (N-ethyl-N-methylamino) methyl group, 1- (N-ethyl-N-methylamino) ethyl group, 1- (N-ethyl-N-methylamino) propyl group, 1 -(N-ethyl-N-methylamino) -1-methylethyl group, 1- (N-ethyl-N-methylamino) -1-methylpropyl group, 1,1-dimethyl-2- (N-ethyl- An N-methylamino) ethyl group,
1,1-dimethyl-2- (N-ethyl-N-methylamino) propyl group, 1,1-dimethyl-2- (N-methyl-N-propylamino) ethyl group, 1,1-dimethyl-
2- (N-methyl-N-propylamino) propyl group,
1,1-dimethyl-2- (N-butyl-N-methylamino) ethyl group, 1,1-dimethyl-2- (N-butyl-
A lower alkyl group substituted with a lower alkylamino group such as N-methylamino) propyl group, formylmethyl group, acetylmethyl group, propionylmethyl group, butyrylmethyl group, 1-formylethyl group, 2-formylethyl group, 1
-Acetylethyl group, 1-propionylethyl group, 1-
Butyrylethyl group, 1-formylpropyl group, 1-acetylpropyl group, 1-propionylpropyl group, 1-butyrylpropyl group, 1-formyl-1-methylethyl group, 1-acetyl-1-methylethyl group, 1- Methyl-
1-propionylethyl group, 1-butyryl-1-methylethyl group, 1-formyl-1-methylpropyl group, 1-
Acetyl-1-methylpropyl group, 1-methyl-1-propionylpropyl group, 1-butyryl-1-methylpropyl group, 1,1-dimethyl-2-formylethyl group, 2
-Acetyl-1,1-dimethylethyl group, 1,1-dimethyl-2-propionylethyl group, 2-butyryl-1,
1-dimethylethyl group, 1,1-dimethyl-2-formylpropyl group, 2-acetyl-1,1-dimethylpropyl group, 1,1-dimethyl-2-propionylpropyl group, 2-butyryl-1,1- Dimethylpropyl group, 1,
1-dimethyl-3-formylpropyl group, 3-acetyl-1,1-dimethylpropyl group, 1,1-dimethyl-3
An alkyl group substituted with a lower acyl group such as a propionylpropyl group, a formyloxymethyl group, an acetoxymethyl group, a propionyloxymethyl group, a butyryloxymethyl group, a 1-formyloxyethyl group, a 1-acetoxyethyl group, -Propionyloxyethyl group, 1-butyryloxyethyl group, 2-formyloxyethyl group,
2-acetoxyethyl group, 2-propionyloxyethyl group, 2-butyryloxyethyl group, 1-formyloxypropyl group, 1-acetoxypropyl group, 1-propionyloxypropyl group, 1-butyryloxypropyl group, 1 -Formyloxy-1-methylethyl group, 1-acetoxy-1-methylethyl group, 1-methyl-1-propionyloxyethyl group, 1-butyryloxy-1-methylethyl group, 1-formyloxy-1-methylpropyl Group, 1-acetoxy-1-methylpropyl group, 1-methyl-1-propionyloxypropyl group, 1-butyryloxy-1-methylpropyl group, 1,1-dimethyl-
2-formyloxyethyl group, 2-acetoxy-1,1
-Dimethylethyl group, 1,1-dimethyl-2-propionyloxyethyl group, 2-butyryloxy-1,1-dimethylethyl group, 1,1-dimethyl-2-formyloxypropyl group, 2-acetoxy-1,1 Substituted with a lower acyloxy group such as -dimethylpropyl group, 1,1-dimethyl-2-propionyloxypropyl group, 1,1-dimethyl-3-formyloxypropyl group, 3-acetoxy-1,1-dimethylpropyl group. Alkyl group, fluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl group, 1-chloroethyl group, 1-bromoethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-
Bromoethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoro-1-methylethyl group,
Substituted with a halogen atom such as a 2-fluoro-1,1-dimethylethyl group, a 2,2-difluoro-1,1-dimethylethyl group, a 1,1-dimethyl-2,2,2-trifluoromethylethyl group. Alkyl group, formylaminomethyl group, acetylaminomethyl group, propionylaminomethyl group, butyrylaminomethyl group, 1-formylaminoethyl group, 1-acetylaminoethyl group, 1-propionylaminoethyl group, 1-butyryl Aminoethyl group, 1
-Formylaminopropyl group, 1-acetylaminopropyl group, 1-propionylaminopropyl group, 1-butyrylaminopropyl group, 1-formylamino-1-methylethyl group, 1-acetylamino-1-methylethyl group, 1-methyl-1-propionylaminoethyl group, 1
-Butyrylamino-1-methylethyl group, 1-formylamino-1-methylpropyl group, 1-acetylamino-
1-methylpropyl group, 1-methyl-1-propionylaminopropyl group, 1-butyrylamino-1-methylpropyl group, 1,1-dimethyl-2-formylaminoethyl group, 2-acetylamino-1,1-dimethyl Ethyl group, 1,1-dimethyl-2-propionylaminoethyl group, 2-butyrylamino-1,1-dimethylethyl group,
1,1-dimethyl-2-formylaminopropyl group, 2
-Acetylamino-1,1-dimethylpropyl group, 1,
1-dimethyl-2-propionylaminopropyl group,
1,1-dimethyl-3-formylaminopropyl group, 3
-Acetylamino-1,1-dimethylpropyl group, 1,
1-dimethyl-3-propionylaminopropyl group, 3
-Butyrylamino-1,1-dimethylpropyl group, (formyl-N-methylamino) methyl group, (acetyl-N
-Methylamino) methyl group, (propionyl-N-methylamino) methyl group, (butyryl-N-methylamino)
Methyl group, 1- (formyl-N-methylamino) ethyl group, 1- (acetyl-N-methylamino) ethyl group, 1
-(Propionyl-N-methylamino) ethyl group, 1-
(Butyryl-N-methylamino) ethyl group, 2- (formyl-N-methylamino) ethyl group, 2- (acetyl-
N-methylamino) ethyl group, 2- (propionyl-N
-Methylamino) ethyl group, 1- (formyl-N-methylamino) propyl group, 1- (acetyl-N-methylamino) propyl group, 1- (propionyl-N-methylamino) propyl group, 1- (butyryl) —N-methylamino) propyl group, 1- (formyl-N-methylamino)
-1-methylethyl group, 1- (acetyl-N-methylamino) -1-methylethyl group, 1-methyl-1- (propionyl-N-methylamino) ethyl group, 1- (butyryl-N-methylamino) ) -1-Methylethyl group, 1-
(Formyl-N-methylamino) -1-methylpropyl group, 1- (acetyl-N-methylamino) -1-methylpropyl group, 1-methyl-1- (propionyl-N-
Methylamino) propyl group, 1- (butyryl-N-methylamino) -1-methylpropyl group, 1,1-dimethyl-2- (formyl-N-methylamino) ethyl group, 2-
(Acetyl-N-methylamino) -1,1-dimethylethyl group, 1,1-dimethyl-2- (propionyl-N-
Methylamino) ethyl group, 1,1-dimethyl-2- (formyl-N-methylamino) propyl group, 2- (acetyl-N-methylamino) -1,1-dimethylpropyl group, 1,1-dimethyl- 2- (propionyl-N-methylamino) propyl group, 1,1-dimethyl-3- (formyl-N-methylamino) propyl group, 3- (acetyl-N-methylamino) -1,1-dimethylpropyl group ,
1,1-dimethyl-3- (propionyl-N-methylamino) propyl group, (N-ethylformylamino) methyl group, (acetyl-N-ethylamino) methyl group, (N
-Ethylpropionylamino) methyl group, (butyryl-
N-ethylamino) methyl group, 1- (N-ethylformylamino) ethyl group, 1- (acetyl-N-ethylamino) ethyl group, 1- (N-ethylpropionylamino)
Ethyl group, 1- (butyryl-N-ethylamino) ethyl group, 2- (N-ethylformylamino) ethyl group, 2-
(Acetyl-N-ethylamino) ethyl group, 2- (propionyl-N-ethylamino) ethyl group, 2- (butyryl-N-ethylamino) ethyl group, 1- (N-ethylformylamino) propyl group, 1 -(Acetyl-N-ethylamino) propyl group, 1- (N-ethylpropionylamino) propyl group, 1- (butyryl-N-ethylamino) propyl group, 1- (N-ethylformylamino)
-1-methylethyl group, 1- (acetyl-N-ethylamino) -1-methylethyl group, 1-methyl-1- (N-
Ethyl propionylamino) ethyl group, 1- (butyryl-N-ethylamino) -1-methylethyl group, 1- (N
-Ethylformylamino) -1-methylpropyl group, 1
-(Acetyl-N-ethylamino) -1-methylpropyl group, 1-methyl-1- (N-ethylpropionylamino) propyl group, 1- (butyryl-N-ethylamino)
-1-methylpropyl group, 1,1-dimethyl-2- (N
-Ethylformylamino) ethyl group, 2- (acetyl-
N-ethylamino) -1,1-dimethylethyl group,
1,1-dimethyl-2- (N-ethylpropionylamino) ethyl group, 1,1-dimethyl-2- (N-ethylformylamino) propyl group, 2- (acetyl-N-ethylamino) -1,1 -Dimethylpropyl group, 1,1-dimethyl-2- (N-ethylpropionylamino) propyl group, 1,1-dimethyl-3- (N-ethylformylamino) propyl group, 3- (acetyl-N-ethylamino ) -1,1-dimethylpropyl group, (formyl-N-
Propylamino) methyl group, (acetyl-N-propylamino) methyl group, (propionyl-N-propylamino) methyl group, (butyryl-N-propylamino) methyl group, 1- (formyl-N-propylamino) ethyl A 1- (acetyl-N-propylamino) ethyl group,
1- (propionyl-N-propylamino) ethyl group,
2- (formyl-N-propylamino) ethyl group, 2-
(Acetyl-N-propylamino) ethyl group, 2- (propionyl-N-propylamino) ethyl group, 2- (butyryl-N-propylamino) ethyl group, 1- (formyl-N-propylamino) propyl group, 1- (acetyl-N-propylamino) propyl group, 1- (propionyl-N-propylamino) propyl group, 1- (butyryl-N-propylamino) propyl group, 1- (formyl-
An N-propylamino) -1-methylethyl group, a 1- (acetyl-N-propylamino) -1-methylethyl group,
1-methyl-1- (propionyl-N-propylamino) ethyl group, 1- (butyryl-N-propylamino)
-1-methylethyl group, 1- (formyl-N-propylamino) -1-methylpropyl group, 1- (acetyl-N
-Propylamino) -1-methylpropyl group, 1-methyl-1- (propionyl-N-propylamino) propyl group, 1- (butyryl-N-propylamino) -1-methylpropyl group, 1,1-dimethyl -2- (formyl-
N-propylamino) ethyl group, 2- (acetyl-N-
Propylamino) -1,1-dimethylethyl group, 1,1
-Dimethyl-2- (propionyl-N-propylamino) ethyl group, 2- (butyryl-N-propylamino)
-1,1-dimethylethyl group, 1,1-dimethyl-2-
(Formyl-N-propylamino) propyl group, 2-
A lower alkyl group substituted with a lower acylamino group such as (acetyl-N-propylamino) -1,1-dimethylpropyl group and a carbamoylmethyl group, an (N-methylcarbamoyl) methyl group, and an (N-ethylcarbamoyl) methyl group , (N-propylcarbamoyl) methyl group, 1-carbamoylethyl group, 1- (N-methylcarbamoyl)
An ethyl group, a 1- (N-ethylcarbamoyl) ethyl group,
1- (N-propylcarbamoyl) ethyl group, 1-carbamoylpropyl group, 1- (N-methylcarbamoyl)
Propyl group, 1- (N-ethylcarbamoyl) propyl group, 1- (N-propylcarbamoyl) propyl group, 1
-Carbamoyl-1-methylethyl group, 1-methyl-1
-(N-methylcarbamoyl) ethyl group, 1-methyl-
1- (N-ethylcarbamoyl) ethyl group, 1-methyl-1- (N-propylcarbamoyl) ethyl group, 1-carbamoyl-1-methylpropyl group, 1-methyl-1-
(N-methylcarbamoyl) propyl group, 1-methyl-
1- (N-ethylcarbamoyl) propyl group, 1-methyl-1- (N-propylcarbamoyl) propyl group, 2
-Carbamoyl-1,1-dimethylethyl group, 1,1-
Dimethyl-2- (N-methylcarbamoyl) ethyl group,
1,1-dimethyl-2- (N-ethylcarbamoyl) ethyl group, 1,1-dimethyl-2- (N-propylcarbamoyl) ethyl group, 2-carbamoyl-1,1-dimethylpropyl group, 1,1- Dimethyl-2- (N-methylcarbamoyl) propyl group, 1,1-dimethyl-2- (N
-Ethylcarbamoyl) propyl group, 3-carbamoyl-1,1-dimethylpropyl group, 1,1-dimethyl-3
-(N-methylcarbamoyl) propyl group, 1,1-dimethyl-3- (N-ethylcarbamoyl) propyl group,
1,1-dimethyl-3- (N-propylcarbamoyl)
Propyl group, (N, N-dimethylcarbamoyl) methyl group, (N-ethyl-N-methylcarbamoyl) methyl group, (N, N-diethylcarbamoyl) methyl group, (N
-Methyl-N-propylcarbamoyl) methyl group, 1-
(N, N-dimethylcarbamoyl) ethyl group, 1- (N
-Ethyl-N-methylcarbamoyl) ethyl group, 1-
(N, N-diethylcarbamoyl) ethyl group, 1- (N
-Methyl-N-propylcarbamoyl) ethyl group, 1-
(N, N-dimethylcarbamoyl) propyl group, 1-
(N-ethyl-N-methylcarbamoyl) propyl group,
1- (N, N-diethylcarbamoyl) propyl group, 1
-(N-methyl-N-propylcarbamoyl) propyl group, 1- (N, N-dimethylcarbamoyl) -1-methylethyl group, 1- (N-ethyl-N-methylcarbamoyl) -1-methylethyl group, 1- (N, N-diethylcarbamoyl) -1-methylethyl group, 1-methyl-1-
(N-methyl-N-propylcarbamoyl) ethyl group,
1- (N, N-dimethylcarbamoyl) -1-methylpropyl group, 1- (N-ethyl-N-methylcarbamoyl) -1-methylpropyl group, 1-methyl-1- (N,
N-diethylcarbamoyl) propyl group, 1-methyl-
1- (N-methyl-N-propylcarbamoyl) propyl group, 2- (N, N-dimethylcarbamoyl) -1,1
-Dimethylethyl group, 1,1-dimethyl-2- (N-ethyl-N-methylcarbamoyl) ethyl group, 1,1-dimethyl-2- (N, N-diethylcarbamoyl) ethyl group, 2- (N, N-dimethylcarbamoyl) -1,1-
Dimethylpropyl group, 1,1-dimethyl-2- (N-ethyl-N-methylcarbamoyl) propyl group, 2-
(N, N-diethylcarbamoyl) -1,1-dimethylpropyl group, 3- (N, N-dimethylcarbamoyl)-
1,1-dimethylpropyl group, 1,1-dimethyl-3-
Examples thereof include a carbamoyl group such as (N-ethyl-N-methylcarbamoyl) propyl group and a lower alkyl group substituted with a lower alkylcarbamoyl group.

R is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, or one or more of oxygen, nitrogen or sulfur, or a combination of each atom. A five- or six-membered heterocyclic ring containing two or more rings can be exemplified. Any substituent may be substituted on the heterocycle. Preferably, R
Is an unsubstituted or optionally substituted phenyl group, or a five- or six-membered heterocyclic ring containing one or more oxygen atoms, nitrogen atoms or sulfur atoms or a combination of two or more of each atom Rings can be mentioned. Any substituent may be substituted on the heterocycle.
More preferably, R may be a 5- or 6-membered heterocyclic ring containing one or more oxygen atoms, nitrogen atoms or sulfur atoms, or two or more of these atoms in combination. Any substituent may be substituted on the heterocycle.

[0074] As X and Z are the same or different and each carbonyl group or the formula: -CHR ₉ - group represented by may be mentioned. Preferably, X and Z are the same or different and include a group represented by the formula: —CHR ₉ —.

Q is ethylene, trimethylene or a compound of the formula [2]

[0076]

Embedded image

The following groups can be mentioned. Preferably, Q is the formula [2]

[0078]

Embedded image

Is a group represented by

R ₃ and R ₄ may be the same or different and are each a hydrogen atom, a halogen atom, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group or a (cyano group,
Lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, carbamoyl group, lower alkylcarbamoyl group,
A lower alkyl group, which may be substituted with a lower acyl group, a lower acyloxy group, a halogen atom or a lower acylamino group). Preferably, R ₃ and R ₄ are the same or different and are a hydrogen atom, a halogen atom, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group or a (cyano group, a lower alkoxycarbonyl group, a carboxy group, a hydroxy group , Amino group,
A lower alkyl group, which may be substituted with a lower alkylamino group, a lower alkoxy group, a carbamoyl group, a lower alkylcarbamoyl group, a lower acyl group, a lower acyloxy group, or a lower acylamino group.

More preferably, R ₃ and R ₄ are:
Same or different, substituted by hydrogen atom, halogen atom, lower alkylsilyl group or (cyano group, lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, lower acyloxy group A lower alkyl group.

R ₃ and R ₄ may be combined with each other to form a 5- or 6-membered ring.
(CH ₂ ) ₄ -,-(CH ₂ ) _3- , -C (Me) ₂ (C
_{H 2) 3 -, - C} (Me) 2 (CH 2) 2 -, - (CH = C
H) a ring formed by a carbon chain represented by _2- , etc.,
— (CH ₂ ) ₂ —NH—, — (CH ₂ ) ₂ —NMe—, —C
H ₂ -NMe-CH ₂ -,-(CH ₂ ) ₃ -NH-, -C
(Me) ₂ CH ₂ —NMe—, — (CH ₂ ) ₂ —O—, —C
_{H 2 -O-CH 2 -,} - (CH 2) 3 -O -, - C (Me)
_{2 CH 2 -O -, - C} (Me) 2 - (C = O) -NMe-
And the like, and a ring formed by a carbon chain via a hetero atom such as an oxygen atom or a nitrogen atom.

Preferably, R ₃ and R ₄ are taken together to form-(CH ₂ ) ₄ -,-(CH ₂ ) ₃ -,-(CH = C
H) A ring formed by a carbon chain represented by _2- may be mentioned.

Examples of the unsubstituted or optionally substituted phenyl group include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl group, 2-methylthiophenyl group, 3-methylthiophenyl group, 4-methylthiophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group , 4-fluorophenyl group, 2-nitrophenyl group,
3-nitrophenyl group, 4-nitrophenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2- Methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-mercaptophenyl group, 3-mercaptophenyl group, 4 -Mercaptophenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3-methyl-4-methoxyphenyl group, 3-methoxy-4-chlorophenyl group, 3-methylthio-4-fluorophenyl group, etc. Lower alkyl group, lower alkoxy group, halogen atom, nitro group, Anomoto, amino group, a lower alkoxycarbonyl group and / or hydroxy group is arbitrary position 1
And 3 to 3 substituted phenyl groups.
Preferable examples include a phenyl group in which one to three phenyl groups or methyl, methoxy, methylthio, mercapto, nitro, or cyano groups are substituted at any position.

The 5- or 6-membered heterocyclic ring containing one or more oxygen atoms, nitrogen atoms or sulfur atoms or two or more of these atoms in combination is a 2-furyl group or a 3-furyl group. Groups such as furyl, 2-thienyl, 3
-Thienyl group, 2-methyl-3-thienyl group, 4-methyl-3-thienyl group, 2-methoxycarbonyl-3-thienyl group, 2-chloro-3-thienyl group, 2,5-dichloro-3-thienyl Group, 2-chloro-4-methyl-3-
A thienyl group such as a thienyl group, a 5-chloro-4-methyl-3-thienyl group, a 2,5-dichloro-4-methyl-3-thienyl group, a 1-pyrrolyl group, a 2-pyrrolyl group,
A pyrrolyl group such as a pyrrolyl group, a pyrazolyl group such as a 1-pyrazolyl group, a 3-pyrazolyl group, a 4-pyrazolyl group, and a 5-pyrazolyl group; an oxazolyl group such as a 2-oxazolyl group, a 4-oxazolyl group and a 5-oxazolyl group; Isoxazolyl group such as 3-isoxazolyl group, 4-isoxazolyl group, and 5-isoxazolyl group; 2-thiazolyl group;
Thiazolyl group such as thiazolyl group and 5-thiazolyl group, 3
Isothiazolyl groups such as -isothiazolyl group, 4-isothiazolyl group and 5-isothiazolyl group; 3- (1,2,5
A 1,2,5-thiadiazolyl group, a 3- (1,2,4-thiadiazolyl) group,
A five-membered heterocyclic ring such as a 1,2,4-thiadiazolyl group such as a (1,2,4-thiadiazolyl) group, a 2-pyridyl group,
Six-membered heterocyclic rings such as pyridyl groups such as 3-pyridyl group and 4-pyridyl group can be exemplified. Further, when there is a substituent on these heterocycles, the substituent is not particularly limited, but specifically, a lower alkyl group such as a methyl group and an ethyl group, a methoxycarbonyl group, an ethoxycarbonyl group and the like. A lower alkoxycarbonyl group, a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom, a hydroxy group, an amino group, a lower alkylamino group,
Examples thereof include a nitro group. The heterocyclic ring is preferably a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 1-pyrrolyl group, a 1-pyrazolyl group, a 4-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group,
3- (1,2,5-thiadiazolyl) group, 2-methyl-
3-thienyl group, 4-methyl-3-thienyl group, 2-methoxycarbonyl-3-thienyl group, 2-chloro-3-
Thienyl group, 2,5-dichloro-3-thienyl group, 4-
Fluoro-3-thienyl group, 2-chloro-4-methyl-
5-membered heterocyclic groups such as a 3-thienyl group, a 5-chloro-4-methyl-3-thienyl group, and a 2,5-dichloro-4-methyl-3-thienyl group.

As the aromatic substituent represented by the formula [3],
Represents an unsubstituted phenyl group and 4-methoxyphenyl
Group, 4-ethoxyphenyl group, 4-propoxyphenyl
Group, 4-isopropoxyphenyl group, 4-isobutoxy
Phenyl group, 4-sec-butoxyphenyl group, 4-t
ert-butoxyphenyl group, 3-isopropoxyfe
Nyl group, 3-isobutoxyphenyl group, 3-sec-butyl
Toxiphenyl group, 3-tert-butoxyphenyl
Group, 4-methylphenyl group, 4-ethylphenyl group, 4
-Propylphenyl group, 4-isopropylphenyl group,
4-butylphenyl group, 4-isobutylphenyl group, 4
-Sec-butylphenyl group, 4-tert-butylphenyl group
Phenyl, 4-pentylphenyl, 4-isopentyl
Phenyl group, 4-neopentylphenyl group, 4-ter
t-pentylphenyl group, 4-hexylphenyl group, 4
-(1-methylpentyl) phenyl group, 4- (2-methyl
Rupentyl) phenyl group, 4- (3-methylpentyl)
A phenyl group, a 4- (4-methylpentyl) phenyl group,
4- (1,1-dimethylbutyl) phenyl group, 4-
(1,2-dimethylbutyl) phenyl group, 4- (2,2
-Dimethylbutyl) phenyl group, 3-methylphenyl
Group, 3-ethylphenyl group, 3-propylphenyl group,
3-isopropylphenyl group, 3-butylphenyl group,
3-isobutylphenyl group, 3-sec-butylphenyl
Group, 3-tert-butylphenyl group, 3-hexyl
Phenyl group, 3- (1-methylpentyl) phenyl group,
3- (2-methylpentyl) phenyl group, 3- (3-methyl
Tylpentyl) phenyl group, 3- (4-methylpentyl)
L) phenyl group, 3- (1,1-dimethylbutyl) phenyl
A nyl group, a 3- (1,2-dimethylbutyl) phenyl group,
3- (2,2-dimethylbutyl) phenyl group, 4-vinyl
Phenyl group, 4-allylphenyl group, 4- (1-pro
Phenyl) phenyl group, 4- (1-butenyl) phenyl
Group, 4- (2-butenyl) phenyl group, 4- (3-butene)
Nyl) phenyl group, 4- (1-pentenyl) phenyl
Group, 4- (2-pentenyl) phenyl group, 4- (3-pe
Pentenyl) phenyl group, 4- (4-pentenyl) phenyl
Group, 4- (1-methylvinyl) phenyl group, 4- (1
-Methyl-1-propenyl) phenyl group, 4- (1-meth
Tyl-2-propenyl) phenyl group, 4- (1-ethyl
Vinyl) phenyl group, 4- (1-ethyl-1-propeni)
Ru) phenyl group, 4- (2-methyl-1-propenyl)
Phenyl group, 4- (1,2-dimethyl-1-propeni
L) phenyl group, 4- (1,1-dimethyl-2-propane)
Nyl) phenyl group, 4- (1,1-dimethyl-3-butene)
Nyl) phenyl group, 3- (1,1-dimethyl-2-pro
Phenyl) phenyl group, 3- (1,1-dimethyl-3-bu)
(Tenyl) phenyl group, 4- (tert-butylsilyl)
Phenyl group, 4- (sec-butylsilyl) phenyl
Group, 4- (isobutylsilyl) phenyl group, 4- (iso
Propylsilyl) phenyl group, 4- (butylsilyl) phenyl
Phenyl, 4- (propylsilyl) phenyl, 4-
(Dimethylsilyl) phenyl group, 4- (diethylsilyl)
L) phenyl group, 4- (ethylmethylsilyl) phenyl
Group, 4- (methylpropylsilyl) phenyl group, 4-
(Isopropylmethyl) silylphenyl group, 4- (ethyl
Propylsilyl) phenyl group, 4- (ethylisopro
Pyrsilyl) phenyl group, 4- (butylmethylsilyl)
Phenyl group, 4- (isobutylmethylsilyl) phenyl
Group, 4- (sec-butylmethylsilyl) phenyl group,
4- (tert-butylmethylsilyl) phenyl group, 4
-(Ethylbutylsilyl) phenyl group, 4- (ethylethyl
Sobutylsilyl) phenyl group, 4- (sec-butyl
Tylsilyl) phenyl group, 4- (tert-butylethyl)
Lucyl) phenyl group, 4- (butylpropylsilyl)
Phenyl group, 4- (isobutylpropylsilyl) phenyl
Group, 4- (sec-butylpropylsilyl) phenyl
Group, 4- (tert-butylpropylsilyl) phenyl
Group, 4- (butylisopropylsilyl) phenyl group, 4
-(Isobutylisopropylsilyl) phenyl group, 4-
(Sec-butylisopropylsilyl) phenyl group, 4
-(Tert-butylisopropylsilyl) phenyl
Group, 4- (chlorodimethylsilyl) phenyl group, 4-
(Chloroethylmethylsilyl) phenyl group, 4- (chloro
Romethylpropylsilyl) phenyl group, 4- (chlorobutane)
Tylmethylsilyl) phenyl group, 4- (dichloromethyl
Silyl) phenyl group, 4- (dichloroethylsilyl) phenyl
Phenyl group, 4- (dichloropropylsilyl) phenyl
Group, 4- (trimethylsilyl) phenyl group, 4- (dim
Tylethylsilyl) phenyl group, 4- (diethylmethyl)
Silyl) phenyl group, 4- (triethylsilyl) phenyl
Group, 4- (dimethylpropylsilyl) phenyl group, 4
-(Ethylmethylpropylsilyl) phenyl group, 4-
(Dipropylmethylsilyl) phenyl group, 4- (diethyl
Propylsilyl) phenyl group, 4- (dipropylethyl)
Lucyl) phenyl group, 4- (tripropylsilyl) phenyl
Phenyl group, 4- (dimethylisopropylsilyl) phenyl
Group, 4- (ethylmethylisopropylsilyl) phenyl
Group, 4- (diisopropylmethylsilyl) phenyl
Group, 4- (diethylisopropylsilyl) phenyl group,
4- (diisopropylethylsilyl) phenyl group, 4-
(Triisopropylsilyl) phenyl group, 4- (butyl)
Dimethylsilyl) phenyl group, 4- (tert-butyl)
Dimethylsilyl) phenyl group, 4- (butylethylmethyl)
Lucyl) phenyl group, 4- (butylmethylpropyl)
Lyl) phenyl group, 4- (butyldiethylsilyl) phenyl
Nyl group, 4- (butylethylpropylsilyl) phenyl
Group, 4- (butyldipropylsilyl) phenyl group, 4-
(Dibutylmethylsilyl) phenyl group, 4- (dibutyl
Ethylsilyl) phenyl group, 4- (dibutylpropyl)
Lyl) phenyl group, 4- (tributylsilyl) phenyl
Group, 4- (dimethylisobutylsilyl) phenyl group, 4
-(Ethylisobutylmethylsilyl) phenyl group, 4-
(Isobutylmethylpropylsilyl) phenyl group, 4-
(Diethylisobutylsilyl) phenyl group, 3- (tri
Methylsilyl) phenyl group, 3- (dimethylethylsilyl)
L) phenyl group, 3- (diethylmethylsilyl) phenyl
Group, 3- (triethylsilyl) phenyl group, 3- (di
Methylpropylsilyl) phenyl group, 3- (ethylmethyi)
Propylsilyl) phenyl group, 3- (dimethylisoprop)
Ropirsilyl) phenyl group, 3- (butyldimethylsilyl)
L) phenyl group, 4-methoxymethylphenyl group, 4-
(1-methoxyethyl) phenyl group, 4- (1-methoxy)
Cypropyl) phenyl group, 4- (2-methoxypropyl)
L) phenyl group, 4- (1-methoxy-1-methylethyl)
L) phenyl group, 4- (2-methoxy-1-methylethyl)
L) phenyl group, 4- (1-methoxy-1-methylpro
Pill) phenyl group, 4- (2-methoxy-1-methyl)
Ropyl) phenyl group, 4- (1,1-dimethyl-2-me
Toxylethyl) phenyl group, 4- (1,1-dimethyl-
2-methoxypropyl) phenyl group, 4- (1,1-di
Methyl-3-methoxypropyl) phenyl group, 4- (2
-Methoxy-1-methoxymethyl-1-methylethyl)
Phenyl group, 4- (2-ethoxy-1,1-dimethyle
Tyl) phenyl group, 4- (1-ethoxy-1-methylethyl)
Tyl) phenyl group, 4-cyanomethylphenyl group, 4-
(1-cyanoethyl) phenyl group, 4- (1-cyanop)
Ropyl) phenyl group, 4- (2-cyanopropyl) phenyl
Nyl group, 4- (1-cyano-1-methylethyl) phenyl
Group, 4- (2-cyano-1-methylethyl) phenyl
Group, 4- (1-cyano-1-methylpropyl) phenyl
Group, 4- (2-cyano-1-methylpropyl) phenyl
Group, 4- (1,1-dimethyl-2-cyanoethyl) phenyl
Nyl group, 4- (1,1-dimethyl-2-cyanopropyl
L) phenyl group, 4- (1,1-dimethyl-3-cyano)
Propyl) phenyl group, 4- (2-cyano-1-cyano)
Methyl-1-methylethyl) phenyl group, 4-methoxy
Carbonylmethylphenyl group, 4- [1- (methoxy
Rubonyl) ethyl] phenyl group, 4- [1- (methoxy)
Carbonyl) propyl] phenyl group, 4- [1- (meth
Xycarbonyl) -1-methylethyl] phenyl group, 4
-[1- (methoxycarbonyl) -1-methylpropyl
L] phenyl group, 4- [1,1-dimethyl-2- (meth
(Xycarbonyl) ethyl] phenyl group, 4- [1,1-
Di (methoxycarbonyl) ethyl] phenyl group, 4-
[1,1-dimethyl-2- (methoxycarbonyl) pro]
Pyr] phenyl group, 4-ethoxycarbonylmethylphen
Nyl group, 4- [1- (ethoxycarbonyl) ethyl] f
Enyl group, 4- [1- (ethoxycarbonyl) propyl
L] phenyl group, 4- [1- (ethoxycarbonyl)-
1-methylethyl] phenyl group, 4- [1- (ethoxy)
Carbonyl) -1-methylpropyl] phenyl group, 4-
[2- (ethoxycarbonyl) -1,1-dimethylethyl
L] phenyl group, 4- [1,1-di (ethoxycarboni
L) ethyl] phenyl group, 4- [1,1-dimethyl-2
-(Ethoxycarbonyl) propyl] phenyl group, 4-
Carboxymethylphenyl group, 4- (1-carboxy
Tyl) phenyl group, 4- (1-carboxypropyl) phenyl
Phenyl group, 4- (1-carboxy-1-methylethyl)
Phenyl group, 4- (1-carboxy-1-methylpropyl
L) phenyl group, 4- (2-carboxy-1,1-dim
Tylethyl) phenyl group, 4- (1,1-dicarboxy)
Ethyl) phenyl group, 4- (2-carboxy-1,1,1-
Dimethylpropyl) phenyl group, 4- (hydroxymethyl)
L) phenyl group, 4- (1-hydroxyethyl) phenyl
Group, 4- (1-hydroxypropyl) phenyl group, 4
A-(1-hydroxy-1-methylethyl) phenyl group,
4- (1-hydroxy-1-methylpropyl) phenyl
Group, 4- (1,1-dimethyl-2-hydroxyethyl)
Phenyl group, 4- (1,1-dimethyl-2-hydroxy
Propyl) phenyl group, 4- (1,1-dimethyl-3-)
Hydroxypropyl) phenyl group, 4- (aminomethyl
L) phenyl group, 4- (1-aminoethyl) phenyl
Group, 4- (1-aminopropyl) phenyl group, 4- (1
-Amino-1-methylethyl) phenyl group, 4- (1-
Amino-1-methylpropyl) phenyl group, 4- (1,
1-dimethyl-2-aminoethyl) phenyl group, 4-
(1,1-dimethyl-2-aminopropyl) phenyl
Group, 4- (1,1-dimethyl-3-aminopropyl) phenyl
Phenyl group, 4- (N-methylaminomethyl) phenyl
Group, 4- [1- (N-methylamino) ethyl] phenyl
Group, 4- [1- (N-methylamino) propyl] phenyl
Group, 4- [1- (N-methylamino) -1-methyle
Tyl] phenyl group, 4- [1- (N-methylamino)-
1-methylpropyl] phenyl group, 4- [1,1-dimethyl
Tyl-2- (N-methylamino) ethyl] phenyl group,
4- [1,1-dimethyl-2- (N-methylamino) p
Ropyl] phenyl group, 4- (N-ethylaminomethyl)
Phenyl group, 4- [1- (N-ethylamino) ethyl]
Phenyl group, 4- [1- (N-ethylamino) propyl
L] phenyl group, 4- [1- (N-ethylamino) -1
-Methylethyl] phenyl group, 4- [1- (N-ethyl)
Amino) -1-methylpropyl] phenyl group, 4-
[1,1-dimethyl-2- (N-ethylamino) ethyl]
L] phenyl group, 4- [1,1-dimethyl-2- (N-
Ethylamino) propyl] phenyl group, 4- [1,1-
Dimethyl-2- (N-propylamino) ethyl] phenyl
Group, 4- [1,1-dimethyl-2- (N-propyl
Mino) propyl] phenyl group, 4- [1,1-dimethyl
-2- (N-butylamino) ethyl] phenyl group, 4-
[1,1-Dimethyl-2- (N-butylamino) propyl
L] phenyl group, 4- (N, N-dimethylaminomethyl
L) phenyl group, 4- [1- (N, N-dimethylamido)
No) ethyl] phenyl group, 4- [1- (N, N-dimethyl)
Ruamino) propyl] phenyl group, 4- [1- (N, N
-Dimethylamino) -1-methylethyl] phenyl group,
4- [1- (N, N-dimethylamino) -1-methylp
Ropyl] phenyl group, 4- [1,1-dimethyl-2-
(N, N-dimethylamino) ethyl] phenyl group, 4-
[1,1-dimethyl-2- (N, N-dimethylamino)
Propyl] phenyl group, 4- (N-ethyl-N-methyl
Aminomethyl) phenyl group, 4- [1- (N-ethyl-
N-methylamino) ethyl] phenyl group, 4- [1-
(N-ethyl-N-methylamino) propyl] phenyl
Group, 4- [1- (N-ethyl-N-methylamino) -1
-Methylethyl] phenyl group, 4- [1- (N-ethyl)
-N-methylamino) -1-methylpropyl] phenyl
Group, 4- [1,1-dimethyl-2- (N-ethyl-N-
Methylamino) ethyl] phenyl group, 4- [1,1-di
Methyl-2- (N-ethyl-N-methylamino) propyl
L] phenyl group, 4- [1,1-dimethyl-2- (N-
Methyl-N-propylamino) ethyl] phenyl group, 4
-[1,1-dimethyl-2- (N-methyl-N-propyl
Ruamino) propyl] phenyl group, 4- [1,1-dimension
Tyl-2- (N-butyl-N-methylamino) ethyl]
Phenyl group, 4- (formylmethyl) phenyl group, 4-
(Acetylmethyl) phenyl group, 4- (propionylme
Tyl) phenyl group, 4- (butyrylmethyl) phenyl
Group, 4- (1-formylethyl) phenyl group, 4- (1
-Acetylethyl) phenyl group, 4- (1-propioni)
Ruethyl) phenyl group, 4- (1-butyrylethyl) phenyl
Phenyl, 4- (1-formylpropyl) phenyl,
4- (1-acetylpropyl) phenyl group, 4- (1-
Propionylpropyl) phenyl group, 4- (1-butylene)
Propyl) phenyl group, 4- (1-formyl-1-me)
Tylethyl) phenyl group, 4- (1-acetyl-1-me
Tylethyl) phenyl group, 4- (1-methyl-1-pro
Pionylethyl) phenyl group, 4- (1-butyryl-1)
-Methylethyl) phenyl group, 4- (1-formyl-1)
-Methylpropyl) phenyl group, 4- (1-acetyl-
1-methylpropyl) phenyl group, 4- (1-methyl-
1-propionylpropyl) phenyl group, 4- (1-butyl
A tyryl-1-methylpropyl) phenyl group, 4- (1,
1-dimethyl-2-formylethyl) phenyl group, 4-
(2-acetyl-1,1-dimethylethyl) phenyl
Group, 4- (1,1-dimethyl-2-propionylethyl)
Phenyl) group, 4- (2-butyryl-1,1-dimethyl)
Ruethyl) phenyl group, 4- (1,1-dimethyl-2-
Formylpropyl) phenyl group, 4- (2-acetyl-
1,1-dimethylpropyl) phenyl group, 4- (1,1
-Dimethyl-2-propionylpropyl) phenyl group,
4- (2-butyryl-1,1-dimethylpropyl) fe
Nyl group, 4- (1,1-dimethyl-3-formylpropyl)
L) phenyl group, 4- (3-acetyl-1,1-dimethyl)
Propyl) phenyl group, 4- (1,1-dimethyl-3)
-Propionylpropyl) phenyl group, 4- (3-butyi)
An aryl-1,1-dimethylpropyl) phenyl group, 4-
(Formyloxymethyl) phenyl group, 4- (acetoxy)
(Methyl) phenyl group, 4- (propionyloxymethyl)
L) phenyl group, 4- (butyryloxymethyl) phenyl
Group, 4- (1-formyloxyethyl) phenyl group,
4- (1-acetoxyethyl) phenyl group, 4- (1-
Propionyloxyethyl) phenyl group, 4- (1-
Tyryloxyethyl) phenyl group, 4- (1-formyl)
Oxypropyl) phenyl group, 4- (1-acetoxyp)
Ropyl) phenyl group, 4- (1-propionyloxy)
Ropyl) phenyl group, 4- (1-butyryloxypropyl)
L) phenyl group, 4- (1-formyloxy-1-methyl)
Ruethyl) phenyl group, 4- (1-acetoxy-1-me
Tylethyl) phenyl group, 4- (1-methyl-1-pro
Pionyloxyethyl) phenyl group, 4- (1-butylene)
4- (1-methylethyl) phenyl group, 4- (1-
Formyloxy-1-methylpropyl) phenyl group, 4
-(1-acetoxy-1-methylpropyl) phenyl
Group, 4- (1-methyl-1-propionyloxypropyl)
L) phenyl group, 4- (1-butyryloxy-1-methyl)
Propyl) phenyl group, 4- (1,1-dimethyl-2)
-Formyloxyethyl) phenyl group, 4- (2-ace
Toxic-1,1-dimethylethyl) phenyl group, 4-
(1,1-dimethyl-2-propionyloxyethyl)
Phenyl group, 4- (2-butyryloxy-1,1-dimethyl)
Tylethyl) phenyl group, 4- (1,1-dimethyl-2)
-Formyloxypropyl) phenyl group, 4- (2-A
Cetoxy-1,1-dimethylpropyl) phenyl group, 4
-(1,1-dimethyl-2-propionyloxypropyl
L) phenyl group, 4- (2-butyryloxy-1,1-
Dimethylpropyl) phenyl group, 4- (1,1-dimethyl)
4-formyloxypropyl) phenyl group, 4-
(3-acetoxy-1,1-dimethylpropyl) phenyl
Group, 4-trifluoromethylphenyl group, 4- (1,
1-difluoroethyl) phenyl group, 4- (1,1-di
Methyl-2,2,2-trifluoroethyl) phenyl
Group, 4- (formylaminomethyl) phenyl group, 4-
(Acetylaminomethyl) phenyl group, 4- (propio
Nylaminomethyl) phenyl group, 4- (butyrylamino)
Methyl) phenyl group, 4- (1-formylaminoethyl
L) phenyl group, 4- (1-acetylaminoethyl) phenyl
Phenyl group, 4- (1-propionylaminoethyl) phenyl
Nyl group, 4- (1-butyrylaminoethyl) phenyl
Group, 4- (1-formylaminopropyl) phenyl group,
4- (1-acetylaminopropyl) phenyl group, 4-
(1-propionylaminopropyl) phenyl group, 4-
(1-butyrylaminopropyl) phenyl group, 4- (1
-Formylamino-1-methylethyl) phenyl group, 4
-(1-acetylamino-1-methylethyl) phenyl
Group, 4- (1-methyl-1-propionylaminoethyl)
L) phenyl group, 4- (1-butyrylamino-1-methyl)
Ruethyl) phenyl group, 4- (1-formylamino-1)
-Methylpropyl) phenyl group, 4- (1-acetyla
Mino-1-methylpropyl) phenyl group, 4- (1-meth
A tyl-1-propionylaminopropyl) phenyl group,
4- (1-butyrylamino-1-methylpropyl) fe
Nyl group, 4- (1,1-dimethyl-2-formylamino)
Ethyl) phenyl group, 4- (2-acetylamino-1,
1-dimethylethyl) phenyl group, 4- (1,1-dimethyl
Tyl-2-propionylaminoethyl) phenyl group, 4
-(1,1-dimethyl-2-formylaminopropyl)
Phenyl group, 4- (2-acetylamino-1,1-dimethyl
Tylpropyl) phenyl group, 4- (1,1-dimethyl-
2-propionylaminopropyl) phenyl group, 4-
(1,1-dimethyl-3-formylaminopropyl)
Phenyl, 4- (3-acetylamino-1,1-dimethyl)
Propyl) phenyl group, 4- (N-formyl-N-
Tyl-aminomethyl) phenyl group, 4- (N-acetyl
-N-methylaminomethyl) phenyl group, 4- (N-
Tyl-N-propionylaminomethyl) phenyl group, 4
-(N-butyryl-N-methylaminomethyl) phenyl
Group, 4- [1- (N-formyl-N-methylamino)
Tyl] phenyl group, 4- [1- (N-acetyl-N-
Tylamino) ethyl] phenyl group, 4- [1- (N-meth
Tyl-propionylamino) ethyl] phenyl group, 4-
[1- (N-butyryl-N-methylamino) ethyl] f
Enyl group, 4- [2- (N-formyl-N-methylamido)
No) ethyl] phenyl group, 4- [2- (N-acetyl-
N-methylamino) ethyl] phenyl group, 4- [2-
(N-methyl-N-propionylamino) ethyl]
Nyl group, 4- [2- (N-butyryl-N-methylamido)
No) ethyl] phenyl group, 4- [1- (N-formyl-
N-methylamino) propyl] phenyl group, 4- [1-
(N-acetyl-N-methylamino) propyl] phenyl
Group, 4- [1- (N-methyl-N-propionylamido)
No) propyl] phenyl group, 4- [1- (N-formyl)
-N-methylamino) -1-methylethyl] phenyl
Group, 4- [1- (N-acetyl-N-methylamino)-
1-methylethyl] phenyl group, 4- [1-methyl-1
-(N-methyl-N-propionylamino) ethyl] f
Enyl group, 4- [1- (N-butyryl-N-methylamido)
(No) -1-methylethyl] phenyl group, 4- [1- (N
-Formyl-N-methylamino) -1-methylpropyl
L] phenyl group, 4- [1- (N-acetyl-N-methyl)
Ruamino) -1-methylpropyl] phenyl group, 4-
[1-Methyl-1- (N-methyl-N-propionylyla
Mino) propyl] phenyl group, 4- [1,1-dimethyl
-2- (N-formyl-N-methylamino) ethyl] f
Enyl group, 4- [2- (N-acetyl-N-methylamido)
G) -1,1-dimethylethyl] phenyl group, 4-
[1,1-Dimethyl-2- (N-methyl-N-propio
Nylamino) ethyl] phenyl group, 4- [1,1-dimethyl
Tyl-2- (N-formyl-N-methylamino) prop
L] phenyl group, 4- [2- (N-acetyl-N-methyl
Ruamino) -1,1-dimethylpropyl] phenyl group,
4- [1,1-dimethyl-2- (N-methyl-N-pro
Pionylamino) propyl] phenyl group, 4- [1,1
-Dimethyl-3- (N-formyl-N-methylamino)
Propyl] phenyl group, 4- [3- (N-acetyl-N
-Methylamino) -1,1-dimethylpropyl] phenyi
Group, 4- [1,1-dimethyl-3- (N-methyl-N
-Propionylamino) propyl] phenyl group, 4-
(N-ethyl-N-formylaminomethyl) phenyl
Group, 4- (N-acetyl-N-ethylaminomethyl) phenyl
Phenyl group, 4- (N-ethyl-N-propionylamino
Methyl) phenyl group, 4- (N-ethyl-N-butyryl)
Aminomethyl) phenyl group, 4- [1- (N-ethyl-
N-formylamino) ethyl] phenyl group, 4- [1-
(N-acetyl-N-ethylamino) ethyl] phenyl
Group, 4- [1- (N-ethyl-N-propionylamido)
No) ethyl] phenyl group, 4- [1- (N-butyryl-
N-ethylamino) ethyl] phenyl group, 4- [2-
(N-ethyl-N-formylamino) ethyl] phenyl
Group, 4- [2- (N-acetyl-N-ethylamino)
Tyl] phenyl group, 4- [2- (N-ethyl-N-pro
Pionylamino) ethyl] phenyl group, 4- [1- (N
-Ethyl-N-formylamino) propyl] phenyl
Group, 4- [1- (N-acetyl-N-ethylamino)
Ropyl] phenyl group, 4- [1- (N-ethyl-N-propyl)
Lopionylamino) propyl] phenyl group, 4- [1-
(N-ethyl-N-formylamino) -1-methylethyl
L] phenyl group, 4- [1- (N-acetyl-N-ethyl
Ruamino) -1-methylethyl] phenyl group, 4- [1
-Methyl-1- (N-ethyl-N-propionylamido
No) ethyl] phenyl group, 4- [1- (N-butyryl-
N-ethylamino) -1-methylethyl] phenyl group,
4- [1- (N-ethyl-N-formylamino) -1-
Methylpropyl] phenyl group, 4- [1- (N-acetyl)
-N-ethylamino) -1-methylpropyl] phenyl
Group, 4- [1-methyl-1- (N-ethyl-N-pro
Pionylamino) propyl] phenyl group, 4- [1,1
-Dimethyl-2- (N-ethyl-N-formylamino)
Ethyl] phenyl group, 4- [2- (N-acetyl-N-
Ethylamino) -1,1-dimethylethyl] phenyl
Group, 4- [1,1-dimethyl-2- (N-ethyl-N-
Propionylamino) ethyl] phenyl group, 4- [1,
1-dimethyl-2- (N-ethyl-N-formylamido
No) propyl] phenyl group, 4- [2- (N-acetyl)
-N-ethylamino) -1,1-dimethylpropyl] F
Enyl group, 4- [1,1-dimethyl-2- (N-ethyl
—N-propionylamino) propyl] phenyl group, 4
-[2- (N-butyryl-N-ethylamino) -1,1
-Dimethylpropyl] phenyl group, 4- [1,1-dimethyl
Chill-3- (N-ethyl-N-formylamino) prop
L] phenyl group, 4- [3- (N-acetyl-N-ethyl
Ruamino) -1,1-dimethylpropyl] phenyl group,
4- (N-formyl-N-propylaminomethyl) fe
Nyl group, 4- (N-acetyl-N-propylaminomethyl
L) phenyl group, 4- (N-propionyl-N-prop
Ruaminomethyl) phenyl group, 4- (N-butyryl-N
-Propylaminomethyl) phenyl group, 4- [1- (N
-Formyl-N-propylamino) ethyl] phenyl
Group, 4- [1- (N-acetyl-N-propylamino)
Ethyl] phenyl group, 4- [2- (N-formyl-N-
Propylamino) ethyl] phenyl group, 4- [2- (N
-Acetyl-N-propylamino) ethyl] phenyl
Group, 4- [1- (N-formyl-N-propylamino)
Propyl] phenyl group, 4- [1- (N-acetyl-N
-Propylamino) propyl] phenyl group, 4- [1-
(N-formyl-N-propylamino) -1-methyl-
Tyl] phenyl group, 4- [1- (N-acetyl-N-propyl)
Ropylamino) -1-methylethyl] phenyl group, 4-
[1- (N-formyl-N-propylamino) -1-me
Tylpropyl] phenyl group, 4- [1,1-dimethyl-
2- (N-formyl-N-propylamino) ethyl] f
Enyl group, 4- [2- (N-acetyl-N-propyl
Mino) -1,1-dimethylethyl] phenyl group, 4-
[1,1-dimethyl-2- (N-formyl-N-propyl)
Ruamino) propyl] phenyl group, 4- [2- (N-A
Cetyl-N-propylamino) -1,1-dimethylpro
Pill] phenyl group, 4- [1,1-dimethyl-3- (N
-Formyl-N-propylamino) propyl] phenyl
Group, 4- (carbamoylmethyl) phenyl group, 4- (N
-Methylcarbamoylmethyl) phenyl group, 4- (N-
Ethylcarbamoylmethyl) phenyl group, 4- (N-P
Ropylcarbamoylmethyl) phenyl group, 4- (1-ca)
Rubamoylethyl) phenyl group, 4- [1- (N-methyl
Rucarbamoyl) ethyl] phenyl group, 4- [1- (N
-Ethylcarbamoyl) ethyl] phenyl group, 4- [1
-(N-propylcarbamoyl) ethyl] phenyl group,
4- (1-carbamoylpropyl) phenyl group, 4-
[1- (N-methylcarbamoyl) propyl] phenyl
Group, 4- [1- (N-ethylcarbamoyl) propyl]
Phenyl group, 4- [1- (N-propylcarbamoyl)
Propyl] phenyl group, 4- (1-carbamoyl-1-
Methylethyl) phenyl group, 4- [1-methyl-1-
(N-methylcarbamoyl) ethyl] phenyl group, 4-
[1-Methyl-1- (N-ethylcarbamoyl) ethyl
L] phenyl group, 4- [1-methyl-1- (N-propyl
Rucarbamoyl) ethyl] phenyl group, 4- (1-cal
Bamoyl-1-methylpropyl) phenyl group, 4- [1
-Methyl-1- (N-methylcarbamoyl) propyl]
Phenyl group, 4- [1-methyl-1- (N-ethylcal
Bamoyl) propyl] phenyl group, 4- [1-methyl-
1- (N-propylcarbamoyl) propyl] phenyl
Group, 4- (2-carbamoyl-1,1-dimethylethyl)
L) phenyl group, 4- [1,1-dimethyl-2- (N-
Methylcarbamoyl) ethyl] phenyl group, 4- [1,
1-dimethyl-2- (N-ethylcarbamoyl) ethyl
L] phenyl group, 4- [1,1-dimethyl-2- (N-
Propylcarbamoyl) ethyl] phenyl group, 4- (2
-Carbamoyl-1,1-dimethylpropyl) phenyl
Group, 4- [1,1-dimethyl-2- (N-methylcarba
Moyl) propyl] phenyl group, 4- [1,1-dimethyl)
2- (N-ethylcarbamoyl) propyl] phenyl
Group, 4- [1,1-dimethyl-2- (N-propylca
Rubamoyl) propyl] phenyl group, 4- (3-carba
Moyl-1,1-dimethylpropyl) phenyl group, 4-
[1,1-dimethyl-3- (N-methylcarbamoyl)
Propyl] phenyl group, [1,1-dimethyl-3- (N
-Ethylcarbamoyl) propyl] phenyl group, 4-
[1,1-dimethyl-3- (N-propylcarbamoy
Ru) propyl] phenyl group, 4- (N, N-dimethylca)
Rubamoylmethyl) phenyl group, 4- (N-ethyl-N
-Methylcarbamoylmethyl) phenyl group, 4- (N,
N-diethylcarbamoylmethyl) phenyl group, 4-
(N-methyl-N-propylcarbamoylmethyl) fe
Nyl group, 4- [1- (N, N-dimethylcarbamoyl)
Ethyl] phenyl group, 4- [1- (N-ethyl-N-
Tylcarbamoyl) ethyl] phenyl group, 4- [1-
(N, N-diethylcarbamoyl) ethyl] phenyl
Group, 4- [1- (N-methyl-N-propylcarbamoy)
L) ethyl] phenyl group, 4- [1- (N, N-dimethyl)
Rucarbamoyl) propyl] phenyl group, 4- [1-
(N-ethyl-N-methylcarbamoyl) propyl] f
Enyl group, 4- [1- (N, N-diethylcarbamoy)
L) propyl] phenyl group, 4- [1- (N-methyl-
N-propylcarbamoyl) propyl] phenyl group, 4
-[1- (N, N-dimethylcarbamoyl) -1-methyl
Ruethyl] phenyl group, 4- [1- (N-ethyl-N-
Methylcarbamoyl) -1-methylethyl] phenyl
Group, 4- [1- (N, N-diethylcarbamoyl) -1
-Methylethyl] phenyl group, 4- [1-methyl-1-
(N-methyl-N-propylcarbamoyl) ethyl] F
Phenyl group, 4- [1- (N, N-dimethylcarbamoy)
L) -1-methylpropyl] phenyl group, 4- [2-
(N, N-dimethylcarbamoyl) -1,1-dimethyl
Ethyl] phenyl group, 4- [1,1-dimethyl-2-
(N-ethyl-N-methylcarbamoyl) ethyl] Fe
Nyl group, 4- [1,1-dimethyl-2- (N, N-die
Tylcarbamoyl) ethyl] phenyl group, 4- [2-
(N, N-dimethylcarbamoyl) -1,1-dimethyl
Propyl] phenyl group, 4- [1,1-dimethyl-2-
(N-ethyl-N-methylcarbamoyl) propyl] f
Phenyl group, 4- [2- (N, N-diethylcarbamoy)
L) -1,1-dimethylpropyl] phenyl group, 4-
[1,1-dimethyl-2- (N-methyl-N-propyl
Monosubstituted phenyl such as carbamoyl) propyl] phenyl group
And 4-chloro-3-tert-pentylfe
Nyl group, 4-bromo-3-tert-pentylphenyl
Group, 4-fluoro-3-tert-pentylphenyl
A 4-iodo-3-tert-pentylphenyl group,
4-chloro-3-neopentylphenyl group, 4-bromo
-3-neopentylphenyl group, 4-fluoro-3-ne
Pentylphenyl group, 4-iodo-3-neopentyl
Phenyl group, 4-chloro-3-tert-butylphenyl
A 4-bromo-3-tert-butylphenyl group,
4-fluoro-3-tert-butylphenyl group, 4-
Iodo-3-tert-butylphenyl group, 4-chloro
-3-sec-butylphenyl group, 4-bromo-3-s
ec-butylphenyl group, 4-fluoro-3-sec-
Butylphenyl group, 4-iodo-3-sec-butylphenyl
Phenyl, 4-chloro-3-isopropylphenyl,
4-bromo-3-isopropylphenyl group, 4-fluoro
B-3-isopropylphenyl group, 4-iodo-3-i
Sopropylphenyl group, 4-chloro-3-ethylphenyi
Group, 4-bromo-3-ethylphenyl group, 4-fluoro
B-3-ethylphenyl group, 4-iodo-3-ethylphenyl
Phenyl, 4-chloro-3-methylphenyl, 4-butyl
Lomo-3-methylphenyl group, 4-fluoro-3-methyl
Ruphenyl group, 4-iodo-3-methylphenyl group, 4
-Chloro-3- (trimethylsilyl) phenyl group, 4-
Chloro-3-methoxyphenyl group, 4-bromo-3-meth
Toxiphenyl group, 4-fluoro-3-methoxyphenyi
Group, 4-chloro-3-ethoxyphenyl group, 4-bromo
Mo-3-ethoxyphenyl group, 4-fluoro-3-ethoxy
Xyphenyl group, 4-chloro-3-propoxyphenyl
Group, 4-bromo-3-propoxyphenyl group, 4-fur
Oro-3-propoxyphenyl group, 4-chloro-3-i
Sopropoxyphenyl group, 4-bromo-3-isopropo
Xyphenyl group, 4-fluoro-3-isopropoxyf
Phenyl, 4-chloro-3-butoxyphenyl, 4-
Bromo-3-butoxyphenyl group, 4-fluoro-3-
Butoxyphenyl group, 4-chloro-3-isobutoxyf
Enyl group, 4-bromo-3-isobutoxyphenyl group,
4-fluoro-3-isobutoxyphenyl group, 4-chloro
B-3-tert-butoxyphenyl group, 4-bromo-
3-tert-butoxyphenyl group, 4-fluoro-3
-Tert-butoxyphenyl group, 4-fluoro-3-
Trifluoromethylphenyl group, 4-bromo-3-tri
Fluoromethyl group, 4-methoxy-3-tert-pen
Tylphenyl group, 4-ethoxy-3-tert-pent
Ruphenyl group, 4-methoxy-3-neopentylphenyl
Group, 4-ethoxy-3-neopentylphenyl group, 4
-Methoxy-3-tert-butylphenyl group, 4-E
Toxic-3-tert-butylphenyl group, 4-methoxy
C-3-sec-butylphenyl group, 4-ethoxy-3
-Sec-butylphenyl group, 4-methoxy-3-iso
Propylphenyl group, 4-ethoxy-3-isopropyl
Phenyl group, 4-methoxy-3-ethylphenyl group, 4
-Ethoxy-3-ethylphenyl group, 4-propoxy-
3-ethylphenyl group, 4-isopropoxy-3-ethyl
Phenyl group, 4-butoxy-3-ethylphenyl group,
4-isobutoxy-3-ethylphenyl group, 4-sec
-Butoxy-3-ethylphenyl group, 4-tert-butyl
Toxic-3-ethylphenyl group, 4-methoxy-3-meth
Tylphenyl group, 4-ethoxy-3-methylphenyl
Group, 4-propoxy-3-methylphenyl group, 4-iso
Propoxy-3-methylphenyl group, 4-butoxy-3
-Methylphenyl group, 4-isobutoxy-3-methylphenyl
Phenyl group, 4-sec-butoxy-3-methylphenyl
Group, 4-tert-butoxy-3-methylphenyl group,
4-tert-butyl-3-methoxyphenyl group, 4-
(Trimethylsilyl) -3-methoxyphenyl group, 4-
(1,1-dimethyl-2-methoxyethyl) -3-meth
A disubstituted phenyl group such as a xyphenyl group;
Danyl group, 1,2,3,4-tetrahydro-6-na
Phthyl group, 2-naphthyl group, 2-oxo-1,3,3-
Trimethyl-6-indolinyl group, 1,3,3-trime
A tyl-6-indolinyl group, a 5-isoindolinyl group,
7-isochromanyl group, 4,4-dimethyl-7-isoc
A romanyl group, a 7-chromanyl group and the like.
You. Preferably, a 4-tert-butylphenyl group, 4
-Tert-pentylphenyl group, 4-chloro-3-t
tert-butylphenyl group, 4-bromo-3-tert
-Butylphenyl group, 4-fluoro-3-tert-butyl
Tylphenyl group, 4-chloro-3-isopropylphenyl
Group, 4-bromo-3-isopropylphenyl group, 4-
Chloro-3-ethylphenyl group, 4-bromo-3-ethyl
Phenyl group, 4- (1-methoxy-1-methylethyl)
L) phenyl group, 4- (1-cyano-1-methylethyl)
L) phenyl group, 4- (1,1-dimethyl-2-methoxy)
A (ethyl) phenyl group, 4- (2-cyano-1,1-di)
Methylethyl) phenyl group, 4- (1-methyl-1-me
Toxiccarbonylethyl) phenyl group, 4- (1,1-
Dimethyl-2-methoxycarbonylethyl) phenyl
Group, 4- (trimethylsilyl) phenyl group, 4- (ethyl
Dimethylsilyl) phenyl group, 5-indanyl group,
1,2,3,4-tetrahydro-6-naphthyl group, 2
-A naphthyl group or the like.

The compounds of the present invention represented by the general formula [1]
Some of [6] and [7] include an asymmetric carbon. The compound of the present invention includes a mixture of various optical isomers such as an optically active substance, a racemate, a diastereomer and the like, and an isolated form thereof.

The compounds of the present invention represented by the general formula [1]
Some of [6] and [7] have an amine residue. These amine derivatives may form an acid adduct. Examples of such salts include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid, formic acid, acetic acid, oxalic acid,
Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,
Acid adduct salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid and the like can be mentioned. Furthermore, the present compound [1]
[6] The various hydrates, solvates and polymorphic substances of [7] are also included.

The compounds of the present invention represented by the general formula [1] are shown in Tables 1 to 7.
1, but the present invention is not limited to these.

[0090]

[Table 1]

[0091]

[Table 2]

[0092]

[Table 3]

[0093]

[Table 4]

[0094]

[Table 5]

[0095]

[Table 6]

[0096]

[Table 7]

[0097]

[Table 8]

[0098]

[Table 9]

[0099]

[Table 10]

[0100]

[Table 11]

[0101]

[Table 12]

[0102]

[Table 13]

[0103]

[Table 14]

[0104]

[Table 15]

[0105]

[Table 16]

[0106]

[Table 17]

[0107]

[Table 18]

[0108]

[Table 19]

[0109]

[Table 20]

[0110]

[Table 21]

[0111]

[Table 22]

[0112]

[Table 23]

[0113]

[Table 24]

[0114]

[Table 25]

[0115]

[Table 26]

[0116]

[Table 27]

[0117]

[Table 28]

[0118]

[Table 29]

[0119]

[Table 30]

[0120]

[Table 31]

[0121]

[Table 32]

[0122]

[Table 33]

[0123]

[Table 34]

[0124]

[Table 35]

[0125]

[Table 36]

[0126]

[Table 37]

[0127]

[Table 38]

[0128]

[Table 39]

[0129]

[Table 40]

[0130]

[Table 41]

[0131]

[Table 42]

[0132]

[Table 43]

[0133]

[Table 44]

[0134]

[Table 45]

[0135]

[Table 46]

[0136]

[Table 47]

[0137]

[Table 48]

[0138]

[Table 49]

[0139]

[Table 50]

[0140]

[Table 51]

[0141]

[Table 52]

[0142]

[Table 53]

[0143]

[Table 54]

[0144]

[Table 55]

[0145]

[Table 56]

[0146]

[Table 57]

[0147]

[Table 58]

[0148]

[Table 59]

[0149]

[Table 60]

[0150]

[Table 61]

[0151]

[Table 62]

[0152]

[Table 63]

[0153]

[Table 64]

[0154]

[Table 65]

[0155]

[Table 66]

[0156]

[Table 67]

[0157]

[Table 68]

[0158]

[Table 69]

[0159]

[Table 70]

[0160]

[Table 71]

The compound represented by the formula [6] is used for the synthesis of the compound [1] as the compound [6a] when R ₁₀ is a hydrogen atom. When R ₁₀ is a lower acyl group or a lower alkoxycarbonyl group and R ₂ is a hydrogen atom, the compound represented by the formula [6] is obtained by deprotecting or reducing the lower acyl group or the lower alkoxycarbonyl group [ 6a] and used for the synthesis of compound [1].
Furthermore, when R ₁₀ is a lower acyl group or a lower alkoxycarbonyl group and R ₂ is a lower alkyl group, the compound represented by the formula [6] is obtained by deprotecting the lower acyl group or the lower alkoxycarbonyl group to obtain the compound [6a ] And used for the synthesis of compound [1]. The compound represented by the formula [6] is a novel compound, and typical examples thereof are shown in Tables 72 to 72.
Although illustrated in Table 86, the present invention is not limited to these.

[0162]

[Table 72]

[0163]

[Table 73]

[0164]

[Table 74]

[0165]

[Table 75]

[0166]

[Table 76]

[0167]

[Table 77]

[0168]

[Table 78]

[0169]

[Table 79]

[0170]

[Table 80]

[0171]

[Table 81]

[0172]

[Table 82]

[0173]

[Table 83]

[0174]

[Table 84]

[0175]

[Table 85]

[0176]

[Table 86]

The compound represented by the formula [7] is used for the synthesis of the compound [1]. The compound represented by the formula [7] is a novel compound, and typical examples thereof are shown in Tables 87 to 92, but the present invention is not limited thereto.

[0178]

[Table 87]

[0179]

[Table 88]

[0180]

[Table 89]

[0181]

[Table 90]

[0182]

[Table 91]

[0183]

[Table 92]

Production Method The compound of the present invention can be produced by various methods. The representative production methods are shown below. Production method 1 Formula 1

[0185]

Embedded image

(In these formulas, R, R ₁ , X, Y, Z,
Q, R ₂ , A, V, 1, m, and n have the same meaning as described above. The compound of the present invention [1] can be prepared by reacting a halogenated thioformate represented by the general formula [8] with an amine represented by the general formula [6a] in the presence or absence of a base, in the absence of a solvent or in a solvent. It can be produced by reacting at a temperature of 100 ° C. to 100 ° C. for several minutes to 24 hours.

As the base, for example, sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as sodium hydride and lithium hydride; alkaline earth metals such as calcium hydride; n-butyllithium and sec-butyllithium , Tert-butyllithium, organic dilithium compounds such as lithium diisopropylamide, or pyridine, collidine, lutidine, triethylamine, trimethylenediamine, 1,8-diaza-bicyclo [5.4.
0] -7-undecene (DBU). Examples of the solvent include alcoholic solvents such as methanol, ethanol, propanol, and isopropanol; acetone, ketones such as methyl ethyl ketone; esters such as ethyl acetate; ethers such as diethyl ether and tetrahydrofuran; nitriles such as acetonitrile; dimethylformamide; Solvents such as aprotic polar solvents such as dimethyl sulfoxide, carbon halides such as dichloromethane or chloroform, aliphatic hydrocarbons such as hexane, and aromatic hydrocarbons such as benzene and toluene can be used.

It is preferable that the compound [8] and the compound [6a] are subjected to the reaction in substantially equimolar amounts or one in a slight excess.

The compound represented by the general formula [6a] can be synthesized by various methods, some of which will be described below. Equation 1-1

[0190]

Embedded image

(Wherein, R, R ₁ , X, Y, Z, V, R ₂ ,
R ₁₀ , Q, l, m, and n have the same meaning as described above. The compound [6] is composed of the halogen compound [11] and the compound [1]
3] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, and at room temperature or under heating for several minutes to 24 hours.

This reaction may proceed without a solvent, but usually a solvent is used. Such solvents include water,
Examples thereof include methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, benzene, and toluene. This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary. Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and hydrogen such as sodium hydride and lithium hydride. Alkali metal hydride, alkaline earth metal hydride such as calcium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, organic lithium compound such as lithium diisopropylamide, or pyridine, lutidine, triethylamine, trimethylenediamine , 1,8-Diaza-bicyclo [5.4.0] -7
And organic bases such as undecene (DBU).

The amine compound [6a] is prepared by reacting the compound [6] (in the case where R ₁₀ is a lower acyl group or a lower alkoxycarbonyl group in the compound [6]) in the presence of a solvent and a catalyst.
It can be obtained by deprotecting a lower acyl group or a lower alkoxycarbonyl group from 0 ° C. to heating for several minutes to 24 hours.

Examples of the solvent include water, methanol, ethanol, propanol, isopropanol, ethylene glycol, acetic acid, ethyl acetate, diethyl ether, tetrahydrofuran, diglyme, chloroform, dichloromethane, nitromethane, acetonitrile, benzene and the like.

Examples of the catalyst include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, aluminum chloride, and sulfuric acid; basic catalysts such as sodium hydroxide, potassium hydroxide, and barium hydroxide; trimethylsilyl iodide, trimethylsilyl chloride, and trimethylsilyl trichloride. And silicon derivatives such as flats. Formula 1-2

[0197]

Embedded image

(Where R, R ₁ , X, Y, Z, V, Q,
1, m and n have the same meanings as described above. R ₁₉ represents a lower acyl group or a lower alkoxycarbonyl group. R ₂₀
Represents a lower alkyl group. The compound [6e] can be produced from the halogen compound [11] and the compound [13a] under the same reaction conditions as in the above formula 1-1.

The amine [6aa] can be produced by reacting the compound [6e] with a reducing agent in the presence of a solvent at 0 ° C. to under heating for several minutes to 24 hours. Solvents include water, methanol, ethanol, propanol,
Examples include isopropanol, diethyl ether, tetrahydrofuran, diglyme and the like. Examples of the reducing agent include lithium aluminum hydride and sodium borohydride.

When X and Z of compound [6e] are carbonyl groups, compound [6e] may have an amide bond. These amide bonds can be simultaneously reduced to an amino group by the above reduction. Also, by selecting appropriate reaction conditions, selective reduction can be performed. Formula 1-3

[0201]

Embedded image

(Wherein, R, R ₁ , X, Y, Z, V,
R ₁₉ , l, m, and n represent the same meaning as described above. The compound [15] can be prepared by reacting the nitro compound [14] and the halogen compound [11] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating for several minutes to 24 hours. It can be produced by reacting for hours.

This reaction may proceed without solvent, but a solvent is usually used. Such solvents include water,
Solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, benzene, toluene and the like can be mentioned.

This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and hydrogen such as sodium hydride and lithium hydride. Examples thereof include alkali metal hydrides, alkaline earth metal hydrides such as calcium hydride, and organic bases such as pyridine, triethylamine and trimethylenediamine.

The amine compound [6b] can be obtained by reducing the nitro group of the compound [15]. The amine compound [6b] is prepared by converting the compound [15] to 0 in the presence of a solvent.
It can be produced by reacting with a reducing agent for several minutes to 24 hours under a temperature of from 0 ° C. to heating. Examples of the solvent include diethyl ether, tetrahydrofuran, diglyme and the like. Examples of the reducing agent include lithium aluminum hydride and a borane-tetrahydrofuran complex. When X and Z in compound [6b] are carbonyl groups, an amide bond may be present in compound [6b]. These amide bonds can be reduced to an amino group simultaneously with the nitro group by the above reduction. Also, by selecting the reaction conditions, selective reduction is possible.

The amine [6b] can also be produced by reacting the compound [15] in the presence of a solvent in the presence of a hydrogen reduction catalyst such as platinum oxide or palladium carbon under a hydrogen atmosphere. Examples of the solvent include ethanol, ethyl acetate, water and the like. Amine compound [6
b] can be protected with a lower acyl group or a lower alkoxycarbonyl group.

The amide [6c] (in the case where R ₁₉ represents a lower acyl group in the compound [6e]) is obtained by converting an amine [6b] with an organic acid such as formic acid or acetic acid or an organic acid derivative. Several minutes to 24 hours in a solvent at room temperature or under heating
It can be produced by reacting for hours. Examples of the solvent used include methylene chloride, diethyl ether, dimethylformamide and the like. When dehydrating the amine [6b] with an organic acid such as formic acid or acetic acid, a condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide can be used. on the other hand,
In the reaction of the amine [6b] with an organic acid derivative such as acetyl chloride or acetic anhydride, pyridine, triethylamine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or the like can be used as a dehydrochlorinating agent.

The carbamate [6d] (compound [6e]
In the above, when R ₁₉ represents a lower alkoxycarbonyl group. ) Is an amine [6b], ethyl chloroformate and di-tert. Dicarbonate. -Butyl or the like in a solvent in the presence of a basic catalyst at room temperature or under heating for several minutes to 24 hours. Examples of the solvent include water, methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, and toluene. Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; and alkali metal hydrides such as sodium hydride and lithium hydride. And alkaline earth metal hydrides such as calcium hydride, and organic bases such as pyridine, triethylamine and trimethylenediamine.

From the amide [6c] or the carbamate [6d], the compound [6aa] can be obtained in the same manner as in the method shown in the above formula 1-1. Formula 1-4

[0211]

Embedded image

(Where V, Z, Q, R, R ₁ , X, Y,
1, m and n have the same meanings as described above. The compound [15] is composed of the compound [9] and the halogen compound [1]
6] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating for several minutes to 24 hours. This reaction may proceed even without solvent, but usually a solvent is used. Such solvents include water,
Solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, benzene, toluene and the like can be mentioned.

This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and hydrogen such as sodium hydride and lithium hydride. Examples thereof include alkali metal hydrides, alkaline earth metal hydrides such as calcium hydride, and organic bases such as pyridine, triethylamine and trimethylenediamine. Compound [6b] and compound [6aa] can be synthesized from compound [15] in the same manner as in formula 1-3. Formula 1-5

[0215]

Embedded image

(Where V, Z, Q, R, R ₁ , X, Y,
R ₂ , R ₁₀ , l, m, and n represent the same meaning as described above. The compound [6] is composed of the compound [9] and the halogen compound [1]
7] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating for several minutes to 24 hours.

This reaction may proceed without a solvent, but a solvent is usually used. Such solvents include water,
Solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, benzene, toluene and the like can be mentioned.

This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; hydrogens such as sodium hydride and lithium hydride. Examples thereof include alkali metal hydrides, alkaline earth metal hydrides such as calcium hydride, and organic bases such as pyridine, triethylamine and trimethylenediamine. Compound [6a] can be synthesized from compound [6] in the same manner as in formula 1-1. Formula 1-6

[0220]

Embedded image

(Wherein V, Z, Q, R ₁₉ , R, R ₁ ,
X, Y, 1, m, and n represent the same meaning as described above. ) The compound [6e] is composed of the compound [9] and the halogen compound [1].
7a] can be synthesized under the same reaction conditions as in the above reaction 1-5. From the compound [6e], the above reaction formula 1-2
In the same manner as in the above, an amine compound [6aa] can be obtained.

The halogenated thioformate represented by the general formula [8] includes a novel compound. Representative examples of these synthesis methods are shown below. The halogenated thioformate represented by the general formula [8] can be synthesized from the corresponding alcohol or phenolic compound. Formula 1-7

[0223]

Embedded image

The halogenated thioformate represented by the general formula [8] is prepared by reacting the corresponding alcohol or phenolic compound with a halogenothiocarbonylating agent such as thiophosgene in the presence of a base in the absence of a solvent or in a solvent at -10 ° C to 100 ° C. For several minutes to 24 hours.

As the base, for example, sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium carbonate,
Potassium carbonate, sodium bicarbonate, inorganic bases such as potassium bicarbonate, sodium hydride, alkali metal hydrides such as lithium hydride, alkaline earth metals such as calcium hydride, or pyridine, collidine, lutidine,
Triethylamine, trimethylenediamine, 1,8-diaza-bicyclo [5.4.0] -7-undecene (DB
And organic bases such as U).

As a solvent, water or n-hexane,
Organic solvents such as cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, dimethylformamide and the like can be mentioned. In addition, several kinds of such solvents may be used as a mixture.

The alcohol or phenolic compound and the halogenothiocarbonylating agent such as thiophosgene are preferably used in the reaction in an equimolar amount or in a slightly excessive molar amount.

Although the halogenated thioformate represented by the general formula [8] can be used after isolation,
An alcohol or phenolic compound may be reacted with a halogenothiocarbonylating agent such as thiophosgene, for example, under the above reaction conditions, and the resulting halogenated thioformate may be used as it is. In this case, the compound [1] of the present invention can be synthesized by directly reacting with the compound [6a] without isolating the halogenated thioformate formed from the alcohol or phenol derivative. Production method 2 Formula 2

[0229]

Embedded image

(Wherein, V, R ₉ , Q, R ₂ , A, R,
R ₁ , X, Y, 1, m, and n have the same meanings as described above. The compound of the present invention represented by the general formula [1a] is a compound represented by the general formula [9] and the compound represented by the general formula [7] in the absence of a solvent or in the presence of a solvent, in the presence of a phase transfer catalyst. -50 ° C to 1 in the presence or absence of a basic catalyst
It can be produced by reacting at 00 ° C. for several minutes to 24 hours.

This reaction may proceed without solvent, but usually a solvent is used. Such solvents include water,
Examples of the solvent include methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, dimethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, and toluene.

This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; and hydrogen such as sodium hydride and lithium hydride. Alkali metal hydride, alkaline earth metal hydride such as calcium hydride, or pyridine, lutidine, triethylamine, trimethylenediamine, 1,8-diaza-bicyclo [5.4.0] -7-undecene (DBU)
And other organic bases. The compounds [9] and [7] are preferably subjected to the reaction in substantially equimolar amounts or one in a slightly excessive molar amount.

The compound represented by the general formula [7] can be produced, for example, as follows. Equation 2-1

[0235]

Embedded image

(Wherein Q, R ₂ , A, V, R ₉ and n have the same meanings as described above.) The compound represented by the general formula [7] is represented by the general formula [10]. The compound represented by the general formula [18] and the compound represented by the general formula [18] are mixed for several minutes at room temperature or under heating in the absence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst,
It can be produced by reacting for 4 hours.

This reaction may proceed without solvent, but a solvent is usually used. Such solvents include water,
Solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, benzene, toluene and the like can be mentioned.

This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to.

Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; and hydrogen such as sodium hydride and lithium hydride. Examples thereof include alkali metal hydrides, alkaline earth metal hydrides such as calcium hydride, and organic bases such as pyridine, triethylamine and trimethylenediamine. Compound [18] is preferably used in an equimolar amount or an excess molar amount with respect to compound [10].

Further, by selecting appropriate reagents or reaction conditions, selective reactions can be performed. Production method 3 Formula 3

[0241]

Embedded image

(Wherein R, R ₁ , X, Y, Z, V, Q,
R ₂ , A, l, m, and n have the same meaning as described above. The compound [1] of the present invention is usually prepared by reacting the compound [10] with the halogen compound [11] in a solvent, in the presence of a base, in the presence or absence of a phase transfer catalyst, from room temperature to under heating for several minutes to 24 hours. Can be manufactured.

Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, dimethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane,
Solvents such as hexane, toluene, pyridine, lutidine, N, N-dimethylaniline and the like can be mentioned. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride and lithium hydride, and hydrogen. Examples thereof include alkaline earth metal hydrides such as calcium fluoride and organic bases such as pyridine, triethylamine, trimethylenediamine, 1,8-diaza-bicyclo [5.4.0] -7-undecene (DBU). This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary. Examples of such a phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts such as hexadecyltributylphosphonium bromide. be able to. Compound [1
[0] and [11] are preferably used in the reaction in substantially equimolar amounts or one in a slight excess. Production method 4 Formula 4

[0244]

Embedded image

(Wherein R, R ₁ , X, Y, Z, Q, R ₂ , R
₁₈ , A ₂ , l, m, and n have the same meanings as described above. The compound [1c] of the present invention can be produced usually by reacting an alcohol compound A ₂ OH [12] with a thiocarbamate compound [19] in a solvent in the presence of a base at −78 ° C. to 100 ° C. for several minutes to 24 hours. it can.

As the solvent used in the reaction, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane,
Examples of the solvent include hexane and toluene. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride and lithium hydride, and hydrogen. Examples thereof include alkaline earth metal hydrides such as calcium chloride and organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium and tert-butyllithium.
A ₂ OH [12] is preferably used in the reaction in a slight excess or a large excess over [19]. Production method 5 Equation 5

[0247]

Embedded image

(Wherein R, R ₁ , X, Z, Q, R ₂ , A,
l, m, and n have the same meaning as described above. R ₁₁ represents a lower alkyl or a lower acyl group. In the compound of the present invention [1e], when R ₁₁ represents a lower alkyl group, the compound of the present invention [1d] (in the formula, X and Z have the same meanings as described above) usually in a solvent in the presence of a base. And an alkylating agent at -78 ° C to 100 ° C for several minutes to 24 hours. As the solvent used in the reaction, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide,
Solvents such as dichloromethane, hexane, toluene, pyridine and the like can be mentioned. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metal hydrides such as sodium hydride and lithium hydride; alkaline earth metals such as calcium hydride; and lithium. Organic lithium compounds such as diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium and the like can be mentioned. Examples of the alkylating agent include alkyl halides such as methyl iodide and ethyl bromide, and sulfates such as dimethyl sulfate.
It is preferable that the alkylating agent and the compound [1d] are subjected to the reaction in substantially equimolar amounts or one of them in a slight excess.

On the other hand, the compound [1g] of the present invention [compound [1
e] wherein X and Z are the same or different and have the formula:
-CHR ₉ - (. Wherein R ₉ is represents a hydrogen atom or a lower alkyl group) represents, if R ₁₁ represents a lower acyl group. ]
Is, for example, the compound of the present invention [1f] [compound [1d], wherein X and Z are the same or different, and
_9- (wherein R ₉ represents a hydrogen atom or a lower alkyl group). ] An organic acid such as formic acid or acetic acid is dissolved in a solvent in the presence of a dehydration condensing agent at 0 ° C to under heating for several minutes to
It can be produced by reacting for hours. Examples of the solvent used include methylene chloride, diethyl ether, dimethylformamide and the like. As the dehydrating condensing agent, dicyclohexylcarbodiimide or 1-
Ethyl-3- (3'-dimethylaminopropyl) carbodiimide and the like can be mentioned. Organic acids and compounds [1
f] is preferably subjected to the reaction in a substantially equimolar or slightly excess molar amount. Production method 6 Equation 6

[0250]

Embedded image

(Wherein V, R, R ₁ , Y, R ₉ , Q, R ₂ ,
A, l, and n have the same meaning as described above. ) The compound [1h] of the present invention is obtained by converting the compound [7] to the compound [2]
0].

Compound [20] can be produced by reacting compound [7] with YH ₂ in a solvent at −78 ° C. to 100 ° C. for several minutes to 24 hours in the presence of a base.

As the solvent used for the reaction, methanol, ethanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane,
Solvents such as hexane, toluene, pyridine and the like can be mentioned. As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc .; alkali metal hydrides such as sodium hydride and lithium hydride; alkaline earth metals such as calcium hydride; pyridine Organic bases such as triethylamine and methylamine, or lithium diisopropylamide, n-
Butyl lithium, sec-butyl lithium, tert-
Organic lithium compounds such as butyllithium can be exemplified. It is preferable that YH ₂ and the compound [7] are subjected to the reaction in substantially equimolar amounts or one in a slight excess.

The compound [1h] of the present invention is usually prepared by reacting the compound [20] with an organic acid [21] in a solvent in the presence of a dehydrating condensing agent.
It can be produced by reacting at 0 ° C. or under heating for several minutes to 24 hours. In addition, a corresponding acid anhydride or acid halide can be used instead of the organic acid [21].

Examples of the solvent include methylene chloride, diethyl ether, dimethylformamide and the like.
Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. The compound [20] and the organic acid [21] are preferably subjected to the reaction in substantially equimolar amounts or one in a slight excess. Manufacturing method 7 Formula 7

[0256]

Embedded image

(Wherein R, R ₁ , X, Y, Z, Q, R ₂ ,
l, m, and n have the same meaning as described above. The compound of the present invention [1j] (wherein, R ₁₃ represents a lower alkyl group substituted with a lower alkoxy group, a lower alkylamino group, a lower acyloxy group, a lower acylamino group, or the like) is usually a base in a solvent. In the presence of the compound of the present invention [1
i] (In the formula, R ₁₂ represents a lower alkyl group substituted with a hydroxy group, an amino group or a lower acylamino group.)
And an alkylating agent or an acylating agent in the presence of a base at -7.
It can be produced by reacting at 8 ° C. to 100 ° C. for several minutes to 24 hours. Solvents used in the reaction include acetone, methyl ethyl ketone, ethyl acetate, diethyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, pentane, benzene, toluene, pyridine, lutidine, N, N-dimethylaniline and the like. Can be mentioned. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; alkali metal hydrides such as sodium hydride and lithium hydride; alkaline earth metals such as calcium hydride; and pyridine. , Lutidine, organic bases such as ethyldiisopropylamine, and organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium, and tert-butyllithium. Examples of the acylating agent include organic acid chlorides such as acetyl chloride, and organic acid anhydrides such as acetic anhydride. Examples of the alkylating agent include alkyl halides such as methyl iodide ethyl bromide, and sulfates such as dimethyl sulfate.

The alkylating agent or acylating agent and the compound [1i] are preferably subjected to the reaction in substantially equimolar amounts or in a slightly excessive molar amount. Production method 8 Formula 8

[0259]

Embedded image

(Wherein R, R ₁ , X, Y, Z, Q, R ₂ ,
l, m, and n have the same meaning as described above. The compound of the present invention [1l] (wherein R ₁₅ represents an unsubstituted amino group or a lower alkyl group substituted with an amino group in which a lower alkyl is monosubstituted) is a compound of the present invention [1k].
(Wherein R ₁₄ represents a lower alkyl group substituted by a lower acylamino group) at 0 ° C. in the presence of a solvent and a catalyst.
It can be obtained by reacting at 120 to 120 ° C. for several minutes to 24 hours to hydrolyze the lower acylamino group.

As the solvent, water, methanol, ethanol, propanol, isopropanol, ethylene glycol, diethyl ether, tetrahydrofuran, 1,4
-Dioxane, diglyme, chloroform, dichloromethane and the like.

Examples of the catalyst include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, aluminum chloride and sulfuric acid, and basic catalysts such as sodium hydroxide, potassium hydroxide and barium hydroxide.

By selecting appropriate reaction conditions,
It is possible to perform selective hydrolysis. Production method 9 Equation 9

[0264]

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(Wherein R, R ₁ , X, Y, Z, Q, R ₂ ,
l, m, and n have the same meaning as described above. The compound of the present invention [1n] wherein A ₃ is a group represented by the formula [22]

[0266]

Embedded image

(Wherein R ₁₆ and R ₁₇ are the same or different and each represent a hydrogen atom or a lower alkyl group) and / or a group represented by the formula [23]

[0268]

Embedded image

(Wherein R ₁₆ and R ₁₇ have the same meanings as described above). ] Is a compound of the present invention [1.
m] (wherein, R ₁₆ and R ₁₇ represent the same meaning as described above.)
And in the presence of a solvent in the presence of an acid catalyst at 0 ° C. to 120 ° C. for several minutes to 24 hours.

As a solvent, water, methanol, ethanol, propanol, isopropanol, ethylene glycol, diethyl ether, tetrahydrofuran, 1,4
-Dioxane, diglyme, chloroform, dichloromethane and the like. Examples of the catalyst include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, and sulfuric acid.

Since the compound of the formula [1] very selectively and strongly inhibits squalene epoxidase in vivo, it can be used as an antihypercholesterolemia agent, an antihyperlipidemic agent or an antiatherosclerotic agent. It is a useful compound that is expected to be used.

The compound [1] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, hypercholesterolemia, hyperlipidemia and arterial It can be used for treatment and prevention of sclerosis and the like.

When the compound of the present invention is used clinically, it is possible to add a pharmaceutically acceptable carrier according to the dosage form and then administer it after formulating various preparations. As the additives at that time, various additives usually used in the field of pharmaceutical preparations can be used, for example, gelatin, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, Magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate,
Sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzene alcohol, gum arabic, propylene glycol, hydroxypropyl cyclodextrin and the like can be mentioned.

Dosage forms formulated as a mixture with these additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories, and liquid preparations such as syrups, elixirs and injections. There are preparations, these are
It can be adjusted according to a usual method in the field of formulation. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use.
In particular, in the case of an injection solution, it may be dissolved or suspended in a physiological saline or glucose solution as needed, and a buffer or a preservative may be added.

The preparation of the present invention may contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 6% by weight, based on the whole drug. These formulations are:
It may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, an anti-atherosclerotic agent or an anti-hypercholesterolemia agent, the dose and frequency of administration are determined by the sex, age,
Depending on body weight, degree of symptoms, type and range of intended therapeutic effect, etc., in general, in the case of oral administration, 0.01 to 50 mg / kg per adult per day is divided into 1 to several doses and parenteral In the case of administration, it is preferable to administer 0.001 to 5 mg / kg in 1 to several divided doses.

[0277]

The compound of the present invention is a novel substance having a thiocarbamic acid skeleton which is completely different from conventionally known amine-based or allylamine-based compounds, and is highly effective against squalene epoxidase derived from mammals. Has inhibitory activity. Further, the compound of the present invention can be suitably produced by the production method of the present invention.

[0278]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. In addition, novel compounds are also included in the starting compounds of the compound of the present invention. The method for producing the starting compound of the present invention will be described with reference to Reference Examples.

Reference Example 1 Synthesis of 6- methylamino-2 (1H) -pyridone 1.0 g of 6-methoxy-2-methylaminopyridine was dissolved in 10 ml of acetic acid, 10 ml of a 48% aqueous HBr solution was added, and the mixture was heated under reflux for 5 hours. . After cooling, water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography,
g was obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.80 (s, 3 H), 5.31 (d, J = 8.3 Hz, 1 H), 5.63 (brs, 1 H) 5.75 (d, J = 8.3 Hz, 1 H ), 7.32 (t, J = 8.3Hz, 1H)

Reference Example 2 4- (acetyl) phenoxytert-butyldimethyl
Synthesis of silane To a solution of 5.0 g of 4- (acetyl) phenol and 5.5 g of imidazole in 20 ml of dimethylformamide was added te.
6.2 g of rt-butyldimethylsilyl chloride was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 200 ml of water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, silica gel column chromatography (developing solvent;
Purification with hexane: ethyl acetate = 6: 1) yielded 8.56 g of a yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 0.23 (s, 6H), 0.98 (s, 9H), 2.54 (s, 3H), 6.86 (d, J = 8.5 Hz, 2
H), 7.87 (d, J = 8.5 Hz, 2H) The following compound was synthesized in the same manner as in Reference Example 2 using the corresponding phenolic compound.

4- (Cyanomethyl) phenoxytert
- butyldimethylsilane starting compound: 4- (cyanomethyl) phenol ^{1 H-NMR (200MHz, CDCl} 3, δppm) 0.20 (s, 6H), 0.98 (s, 9H), 3.67 (s, 2H), 6.83 (d, J = 8.5Hz, 2
H), 7.18 (d, J = 8.5Hz, 2H) pale yellow crystal

4- (methoxycarbonylmethyl) pheno
Xyl tert-butyldimethylsilane raw material compound: 4- (methoxycarbonylmethyl) phenol ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 0.20 (s, 6H), 0.99 (s, 9H), 3.56 (s, 2H), 3.69 (s, 3H), 6.79
(d, J = 8.5Hz, 2H), 7.13 (d, J = 8.5Hz, 2H) pale yellow oil

Reference Example 3 4- (1-hydroxy-1-methylethyl) phenoxy
Synthesis of tert-butyldimethylsilane 4- (acetyl) phenoxy 0.81 g of an ether solution of 8 g of tert-butyldimethylsilane was added to 60 ml of an ice-cooled solution.
42 ml of an ether solution of M methylmagnesium iodide was added dropwise. After heating for 1 hour under reflux, the mixture was allowed to cool, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The collected organic layer was washed with brine and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 6: 1) to obtain 7.3 g of a pale yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 20 (s, 6H), 0.99 (s, 9H), 1.
57 (s, 6H), 1.70 (s, 1H), 6.78
(D, J = 8.7 Hz, 2H), 7.34 (d, J =
8.7 Hz, 2H) IR (neat, cm ^-1 ) 3380, 2950, 2925, 1600, 1505
1250

Reference Example 4 4- (1-cyano-1-methylethyl) phenoxyte
Synthesis of rt-butyldimethylsilane 4- (cyanomethyl) phenoxy solution of 12.6 g of tert-butyldimethylsilane in tetrahydrofuran 100
The mixture was cooled to −80 ° C., and 28 ml of a 2.0 M lithium diisopropylamide solution (a mixed solution of heptane, tetrahydrofuran, and ethylbenzene) was added dropwise. Then, 3.8 ml of methyl iodide was added, and the temperature was gradually raised to room temperature for 5 hours. Stirred. The reaction was cooled again to -80 ° C,
2.0 M lithium diisopropylamide solution (heptane, tetrahydrofuran, ethylbenzene mixed solution) 2
After dropwise addition of 8 ml, 3.8 ml of methyl iodide was added, and the mixture was stirred for 24 hours while gradually warming to room temperature. After the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil (14 g).

¹ H-NMR (500 MHz, CDC
_{l 3, δppm) 0.21 (s} , 6H), 0.99 (s, 9H), 1.70 (s, 6H), 6.83 (d, J = 8.5Hz, 2
H), 7.32 (d, J = 8.5 Hz, 2H) The following compounds were synthesized in the same manner as in Reference Example 4 using the corresponding starting compounds.

4- (1-methoxycarbonyl-1-methyl)
(Ethyl) phenoxytert-butyldimethylsilane Starting compound: 4- (methoxycarbonylmethyl ) phenoxytert -butyldimethylsilane ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.20 (s, 6H), 0.98 (s, 9H), 1.55 (s, 6H), 3.65 (s, 3H), 6.78
(d, J = 8.5Hz, 2H), 7.19 (d, J = 8.5Hz, 2H) IR (neat, cm ^-1 ) 2950,2930,1735,1610,1510,1255,1150 Orange oil

Reference Example 5 4- (2-amino-1,1-dimethylethyl) phenoxy
Tert-butyldimethylsilane and 4- (2-amido)
Synthesis of (no-1,1-dimethylethyl) phenol To a suspension of lithium aluminum hydride (414 mg) in tetrahydrofuran (20 ml) was added 4- (1-cyano-1) under ice cooling.
A solution of 3 g of (-methylethyl) phenoxytert-butyldimethylsilane in 20 ml of tetrahydrofuran was added dropwise, followed by heating under reflux for 1.5 hours. After completion of the reaction, an aqueous solution of sodium hydroxide was added dropwise, and the resulting solid was separated by filtration. Water was added to the filtrate, extracted with ethyl acetate, and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 5: 1) to give 4- (2-amino-1,1-dimethylethyl) phenoxytert-butyldimethylsilane as a pale yellow oil. 0
6 g and 260 mg of 4- (2-amino-1,1-dimethylethyl) phenol as a white solid were obtained.

4- (2-amino-1,1-dimethylethyl)
F) Phenoxytert -butyldimethylsilane ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.20 (s, 6H), 0.99 (s, 9H), 1.05-1.42 (m, 8H), 2.75 (s, 2H) 6.79 (d, J = 8.5Hz, 2H), 7.18 (d, J = 8.5Hz, 2H)

4- (2-amino-1,1-dimethylethyl)
¹ ) Phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.29 (s, 6H), 2.79 (s, 2H), 3.51 (brs, 3H), 6.72 (d, J = 8.5 Hz,
2H), 7.15 (d, J = 8.5Hz, 2H)

Reference Example 6 4- (2-formylamino-1,1-dimethylethyl)
Synthesis of phenoxy tert-butyldimethylsilane In 10 ml of a methylene chloride solution containing 331 mg of formic acid, 4 ml of a methylene chloride solution containing 1.0 g of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, and 4- (2-
Amino-1,1-dimethylethyl) phenoxy tert
-A solution of 1.0 g of butyldimethylsilane in methylene chloride 1
0 ml was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction,
The extract was washed with a saturated aqueous ammonium chloride solution and a saturated saline solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1) to obtain 890 mg of the desired pale yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.21 (s, 6H), 0.99 (s, 9H), 1.31 and 1.32 (2s, 6H), 3.24 an
d 3.46 (2s, 1H), 3.26 and 3.47 (2s, 1H), 5.19 and 5.39 (2
brs, 1H), 6.79-6.83 (m, 2H), 7.12-7.22 (m, 2H), 7.85 (d, J = 1
2.0Hz, 0.24H), 8.10 (s, 0.76H) IR (neat, cm ^-1 ) 3280,2950,1660,1505,1260

Reference Example 7 4- (2-hydroxy-1,1-dimethylethyl) fe
Synthesis of Nonoxytert-butyldimethylsilane 15 ml of a tetrahydrofuran solution of 2.2 g of 4- (1-methoxycarbonyl-1-methylethyl) phenoxytert-butyldimethylsilane was added to 15 ml of a suspension of lithium aluminum hydride in 295 mg of tetrahydrofuran under ice cooling. After dropwise addition, the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, an aqueous solution of sodium hydroxide was added dropwise, and the resulting solid was separated by filtration. Water was added to the filtrate, extracted with ethyl acetate, and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4:
Purification in 1) gave 1.43 g of the desired product as a white solid.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.19 (s, 6H), 0.98 (s, 9H), 1.21 (t, J = 4.5 Hz, 1H), 1.30 (s, 6
H), 3.55 (d, J = 4.5Hz, 2H), 6.79 (d, J = 8.5Hz, 2H) 7.22 (d, J =
8.5Hz, 2H) IR (KBr, cm ^-1 ) 3250,2960,2930,1605,1510,1250,1035

Reference Example 8 4- (2-acetoxy-1,1-dimethylethyl) fe
Synthesis of nonoxytert-butyldimethylsilane 1.43 g of 4- (2-hydroxy-1,1-dimethylethyl) phenoxytert-butyldimethylsilane and 600 mg of pyridine were dissolved in 15 ml of methylene chloride.
Under ice cooling, 15 ml of a methylene chloride solution containing 600 mg of acetyl chloride was added under ice cooling. After stirring at room temperature for 2 hours, the mixture was added to ice water and extracted with methylene chloride. 0.5% of organic layer
After washing with hydrochloric acid, it was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.59 g of the target compound as a colorless oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.20 (s, 6H), 0.98 (s, 9H), 1.33 (s, 6H), 2.01 (s, 3H), 4.07
(s, 2H), 6.78 (d, J = 8.5Hz, 2H) 7.21 (d, J = 8.5Hz, 2H) IR (neat, cm ^-1 ) 2950,1740,1605,1510,1370,1270

Reference Example 9 [4- (2-acetylamino-1,1-dimethylethyl)
(4 ) Synthesis of ( phenoxy) acetate 220 mg of 4- (2-amino-1,1-dimethylethyl) phenol was dissolved in 3 ml of pyridine, and acetic anhydride was added.
2 ml of an 8 mg pyridine solution was added under ice cooling. After stirring for 18 hours, the mixture was added to ice water and extracted with ethyl acetate. The organic layer was washed with 0.5% hydrochloric acid and then with a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 320 mg of the desired product as a pale brown oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 6H), 1.90 (s, 3H), 2.31 (s, 3H), 3.47 (2s, 2H), 5.16
(brs, 1H) 7.06 (d, J = 8.5Hz, 2H), 7.35 (d, J = 8.5Hz, 2H) IR (neat, cm ^-1 ) 3300,2960,1755,1650,1500,1365,1200

Reference Example 10 4- (2-formylamino-1,1-dimethylethyl)
Synthesis of phenol 4- (2-formylamino-1,1-dimethylethyl)
830 mg of phenoxy tert-butyldimethylsilane
Was dissolved in 10 ml of tetrahydrofuran, and 1.0 ml under ice-cooling.
4.05 ml of M tetrabutylammonium fluoride (tetrahydrofuran solution) was added. After stirring for 30 minutes, 0.5% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, silica gel column chromatography (developing solvent; chloroform: methanol =
Purification by 7: 1) gave 500 mg of the desired product as a white solid.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 6H), 3.24 and 3.48 (2s, 1H), 3.26 and 3.49 (2s,
1H), 5.28 (brs, 1H) 5.48 and 5.75 (2brs, 1H), 6.77-6.84
(m, 2H), 7.12-7.24 (m, 2H) 7.81 (d, J = 12.0Hz, 0.29H), 8.10
(s, 0.71H) IR (neat, cm ^-1 ) 3300, 2960, 1660, 1515, 1385, 1230 The following compounds were synthesized in the same manner as in Reference Example 10 using the corresponding starting compounds.

4- (1-cyano-1-methylethyl) phenyl
Enol raw material compound: 4- (1-cyano-1-methylethyl) phenoxytert-butyldimethylsilane ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.70 (s, 6H), 5.50 (s, 1H), 6.85 ( d, J = 8.5Hz, 2H), 7.32 (d, J =
8.5Hz, 2H) White solid

4- (2-acetoxy-1,1-dimethyl)
Ethyl) phenol starting compound: 4- (2-acetoxy-1,1-dimethylethyl) phenoxytert-butyldimethylsilane ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 6H), 2.02 (s, 3H) ), 4.09 (s, 2H), 5.42 (bs, 1H), 6.77-
6.82 (m, 2H), 7.20-7.24 (m, 2H) colorless oil

Reference Example 11 4- [1- (N, N-dimethylcarbamoyl) -1-me
Synthesis of tylethyl] phenol 500 mg of 4- [1-carboxy-1-methylethyl] phenol was dissolved in 5 g of thionyl chloride and stirred at room temperature for 19 hours. After distilling off excess thionyl chloride under reduced pressure,
The residue was dissolved in 20 ml of chloroform, and 5 g of a 50% aqueous dimethylamine solution was added. After stirring for 4 hours, the reaction solution was
After washing sequentially with N hydrochloric acid and water, the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from hexane-ethanol to give colorless plate-like crystals 21.
9 mg were obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.52 (s, 6H), 2.55 (brs, 3H),
2.93 (brs, 3H), 6.26 (s, 1H),
6.87 (d, J = 8.0 Hz, 2H), 7.06
(D, J = 8.0 Hz, 2H) IR (neat, cm ^-1 ) 3250, 2890, 1615, 1595, 1520,
1450, 1405, 1280, 1240

Reference Example 12 4- (1,1-dimethyl-2-methoxyethyl) pheno
To a suspension of 273 mg of 60% oily sodium hydride in dimethylformamide (10 ml) was added 1.82 g of 4- (2-hydroxy-1,1-dimethylethyl) phenoxytert-butyldimethylsilane in dimethylformamide under ice cooling. 30 ml of the suspension were added. After 10 minutes methyl iodide
After adding 0 g, the mixture was stirred at room temperature for 19 hours. After completion of the reaction, 400 ml of water was added, and the mixture was extracted with ethyl acetate (60 ml ×
3) The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 1.5 g of an oily substance was obtained. The crude product was dissolved in 15 ml of tetrahydrofuran,
Under ice-cooling, 10 ml of 1.0 M tetrabutylammonium fluoride (tetrahydrofuran solution) was added. 30
After stirring for minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) to obtain 600 mg of the desired product as a white solid.

¹ H-NMR (500 MHz, CDC
_{l 3, δppm) 1.30 (s} , 6H), 3.32 (s, 3H), 3.37 (s, 2H), 4.86 (s, 1H), 6.75
(d, J = 9.0 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H) The following compounds were synthesized in the same manner as in Reference Example 12 using the corresponding starting compounds.

4- (1-Methoxy-1-methylethyl)
Phenol raw material compound: 4- (1-hydroxy-1-methylethyl)
Phenoxytert-butyldimethylsilane ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.53 (s, 6H), 3.06 (s, 3H), 4.8
0 (brs, 1H), 6.82 (d, J = 8.9 Hz,
2H), 7.29 (d, J = 8.9 Hz, 2H) colorless crystal

Reference Example 13 Synthesis of 4,4 -dimethyl-2-pentyn-1-ol A solution of 26 g of 4,4-dimethylbutyne in 150 ml of THF
Then, 195 ml of a 1.61 M n-butyllithium solution (hexane solution) was slowly added dropwise at -80 ° C. After stirring overnight, at room temperature, 12.3 g of paraformaldehyde in TH
60 ml of the F solution was added. The mixture was heated under reflux for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with diethyl ether. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure (66 ° C./13 mmHg) to obtain 29 g of a colorless oil.

¹ H-NMR (200 MHz, CDC
_{l 3, δppm) 1.22 (s} , 9H), 4.23 (s, 2H), 4.81 (s, 1H) IR (NaCl, cm -1) 3340,2970,2240,1360,1260,1060,1000

Reference Example 14 Synthesis of 6,6-dimethyl-4-heptin-2-ol A solution of 24 g of 4,4-dimethylbutine in 100 ml of THF
200 ml of a 1.55 M n-butyllithium solution (hexane solution) was slowly added dropwise at -80 ° C. After stirring overnight, cool to -10 ° C and propylene oxide 20g
Of THF solution was added. Two hours later, 15 g of lithium perchlorate was added, and the mixture was stirred at room temperature for 60 hours. The reaction solution was poured into water and extracted with diethyl ether. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure (4
9 ° C / 7 mmHg) to obtain 14 g of a colorless oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.21 (s, 9H), 1.23 (d, J = 6.0 Hz, 3H), 1.70 (brs, 1H), 2.24-2.
38 (m, 2H), 3.85-3.95 (m, 1H) IR (neat, cm ^-1 ) 3350,2970,1460,1370,1270,1120,1090 Colorless oil

Reference Example 15 [4- (1,1-dimethyl-2-methoxyethyl) fe
Nyl ] = Synthesis of chlorothioformate 390 mg of thiophosgene in 5 ml of cyclohexane
580 mg of 4- (1,1-dimethyl-2-methoxyethyl) phenol and 140 m of sodium hydroxide at room temperature
g of an aqueous solution (10 ml) was slowly added dropwise. After stirring at room temperature for 2 hours, the mixture was extracted with cyclohexane. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, 523 mg of the desired product was obtained as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.34 (s, 6H), 3.32 (s, 3H), 3.40 (s, 2H), 7.08 (d, J = 9.0 Hz, 2
H), 7.45 (d, J = 9.0 Hz, 2H) IR (neat, cm ^-1 ) 2970, 2880, 1505, 1250, 1195, 1160, 1015 Was synthesized.

[4- (1-cyano-1-methylethyl)
Phenyl] = chlorothioformate raw material compound: 4- (1-cyano-1-methylethyl) phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.75 (s, 6H), 7.15 to 7.19 (m, 2H) , 7.53-7.58 (m, 2H) IR (neat, cm ^-1 ) 2980,2920,2230,1500,1240,1010 pale yellow solid

[4- (1-Methoxy-1-methylethyl)
Ru) phenyl] = chlorothioformate starting compound: 4- (1-methoxy-1-methylethyl)
Phenol ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.54 (s, 6H), 3.09 (s, 3H), 7.10 (d, J = 8.7 Hz, 2H), 7.15 (d, J =
8.7Hz, 2H) IR (neat, cm ^-1 ) 2980,2930,1500,1250,1160,1015 yellow solid

[4- (1-Acetyl-1-methylethyl)
Phenyl) = chlorothioformate starting compound: 4- (1-acetyl-1-methylethyl)
Phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.51 (s, 6H), 1.95 (s, 3H), 7.11-7.16 (m, 2H), 7.33-7.37 (m,
2H) pale yellow solid

[4- (1-Methoxycarbonyl-1-me)
Tyl ethyl) phenyl] = chlorothioformate raw material compound: 4- (1-methoxycarbonyl-1-methylethyl) phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.60 (s, 6H), 3.66 (s, 3H) ), 7.10 (d, J = 9.0Hz, 2H), 7.42 (d, J =
9.0Hz, 2H) IR (neat, cm ^-1 ) 2990,2920,1735,1510,1255,1195,1150 Yellow oil

[4- [1- (N, N-dimethylcarbamo)
Yl) -1-methylethyl] phenyl] = chlorothiopho
Lumate raw material compound: 4- [1- (N, N-dimethylcarbamoyl) -1-methylethyl] phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.56 (s, 6H), 2.62 (brs, 3H), 2.97 (brs, 3H), 7.10 (d, J = 8.0H
z, 2H), 7.29 (d, J = 8.0Hz, 2H) IR (neat, cm ^-1 ) 1625,1495,1395,1250 yellow oil

[4- (2-Formylamino-1,1-di)
Methylethyl) phenyl] = chlorothioformate raw material compound: 4- (2-formylamino-1,1-dimethylethyl) phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.37 and 1.38 (2s, 6H), 3.29 and 3.51 (2s, 1H), 3.31 and
3.53 (2s, 1H) 5.59 and 5.73 (2brs, 1H), 7.10-7.20 (m, 2H)
7.38-7.48 (m, 2H), 7.68- 8.11 (m, 1H) Light brown viscous substance

(4-trimethylsilylphenyl) = chloro
Rothioformate raw material compound: 4-trimethylsilylphenol ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 0.30 (s, 9H), 7.13 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H) Yellow oil

Starting material for 2-naphthyl chlorothioformate : 2-naphthol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 7.29 (dd, J = 8.6 Hz, 2.7 Hz, 1)
H), 7.55-7.57 (m, 2H), 7.60.
(D, J = 1.9 Hz, 1H), 7.83-7.96
(M, 3H) IR (neat, cm ^-1 ) 3050, 1595, 1505, 1355, 1245,
1230, 1205, 1020, 1005

[0324] 2-oxo-1,3,3-trimethyl-6
-Indolinyl chlorothioformate starting compound: 2-oxo -1,3,3- trimethyl-6
-Hydroxyindoline ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.39 (s, 6H), 3.21 (s, 3H), 6.64 (d, J = 2.5 Hz, 1H), 6.82 (dd,
J = 2.5Hz, 8.0Hz, 1H) 7.24 (d, J = 8.0Hz, 1H) IR (neat, cm ^-1 ) 2970,1720,1620,1500,1380

1,3,3-trimethyl-6-indolini
Le-chlorothioformate starting compound: 1,3,3-trimethyl-6-hydroxyindoline ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 6H), 2.76 (s, 3H), 3.17 (s , 2H), 6.17 (d, J = 2.0Hz, 1
H), 6.41 (dd, J = 2.0Hz, 8.0Hz, 1H), 6.98 (d, J = 8.0Hz, 1H) IR (neat, cm ^-1 ) 2950,1610,1490

[4- (1,1-dimethyl-2-hydroxy)
[Shiethyl) phenyl] = chlorothioformate raw material compound: 4- (2-acetoxy-1,1-dimethylethyl) phenol ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (t, J = 6.5 Hz, 1H) , 1.37 (s, 6H), 3.64 (d, J = 6.5Hz, 2H),
7.19 (d, J = 8.5Hz, 2H), 7.47 (d, J = 8.5Hz, 2H)

Reference Example 16 [4- (2-acetylamino-1,1-dimethylethyl)
Phenyl) = chlorothioformate Synthesis of [4- (2-acetylamino-1,1-dimethylethyl) phenoxy] acetate (315 mg) in methanol (1)
The mixture was dissolved in 0 ml, 4 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, methanol was distilled off under reduced pressure.
The mixture was acidified with N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain 190 mg of a white solid. 2m of an aqueous solution of the obtained white solid and 37mg of sodium hydroxide
1 with a solution of 115 mg of thiophosgene in cyclohexane 3
The mixture was slowly added dropwise to the mixture at room temperature. After stirring at room temperature for 2 hours, the mixture was extracted with cyclohexane. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 243 mg of the desired product was obtained as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 and 1.32 (2s, 6H), 1.86 (s, 3H), 3.42 and 3.44 (2s, 2
H), 5.51 and 5.52 (2brs, 1H), 7.08 and 7.16 (2d, J = 8.5H
z, 2H), 7.40 (d, J = 9.0Hz, 2H)

Reference Example 17 Synthesis of N-methyl-N-[(3-thienyl) methyl] amine
10 g of synthetic 3-thiophene carbaldehyde and 5 g of anhydrous magnesium sulfate were added to 19 g of a 40% methylamine solution (methanol solution) and stirred at room temperature for 19 hours. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, dissolved in ether (50 ml), washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.
0 g was obtained. This oily substance was dissolved in 70 ml of anhydrous methanol, and 50 ml of an anhydrous methanol solution of 1.8 g of sodium borohydride was added dropwise over 20 minutes under ice cooling. After stirring at room temperature for 3 hours, 3% hydrochloric acid (30 ml) was added, and methanol was distilled off under reduced pressure. Add 50 ml of ether to the residue and add 5%
After extraction with hydrochloric acid (100 ml × 2), the aqueous layers were combined, made alkaline, and extracted with ether. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, 6.7 g of the desired product was obtained as a brown oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.56 (bs, 1H), 2.45 (s, 3H), 3.76 (s, 2H), 7.00-7.18 (m, 2H),
7.22-7.34 (m, 1H) IR (neat, cm ^-1 ) 3320,3100,2930,2780,1440,1335,1100 bp = 75-77 ℃ / 13mmHg

N-methyl-N-[(2,5-dichloro-
4-Methyl-3-thienyl) methyl] amine starting compound: 2,5-dichloro-4-methylthiophen-3-carbaldehyde ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.23 (brs, 1 H), 2.16 ( s, 3H), 2.42 (s, 3H), 3.63 (s, 2H) IR (neat, cm ^-1 ) 3270, 2840, 1565, 1465, 1160 EIMS m / z 209 (M ⁺ , 33), 178 (100 )

The following compounds were synthesized in the same manner as in Reference Example 17 using an ethylamine solution instead of methylamine as the starting compound.

N-ethyl-N-[(3-thienyl) methyl
¹ ) Amine ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.14 (t, J = 7.0 Hz, 3 H), 1.28 (bs, 1 H), 2.70 (q, J = 7.0 Hz, 2 H),
3.82 (s, 2H), 7.00-7.16 (m, 2H), 7.22-7.29 (m, 1H) Red-brown oil

The following compounds were synthesized in the same manner as in Reference Example 17 using 2-fluoroethylamine instead of methylamine as the starting compound.

N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] amine ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.69 (s, 1H), 2.93 (dt, J = 5.0, 28.5 Hz, 2H), 3.87 (s, 2H), 4.5
6 (dt, J = 5.0,47.5Hz, 2H), 7.06 (d, J = 5.0Hz, 1H), 7.14 (d, J =
2.59,1H) 7.29 (dd, J = 2.5,5.0Hz, 1H) IR (neat, cm ^-1 ) 3310,2820,1450 yellow oil

Reference Example 18 N-methyl-N-[(3-thienyl) methyl] -2-bu
Synthesis of lomoacetamide N-methyl-N-[(3-thienyl) methyl] amine 4.4 g, triethylamine 3.5 g ether solution 5
50 ml of an ether solution of 7 g of 2-bromoacetyl bromide was added dropwise to 0 ml under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, washed with 2% hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate =
Purification by 3: 2) yielded 5.6 g of a brown oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 2.99 and 3.03 (2s, 3H), 3.90 (s, 2H), 4.58 and 4.60 (2s, 2
H), 6.92-7.03 (m, 1H) 7.05-7.18 (m, 1H), 7.21-7.40 (m, 1H) IR (neat, cm ^-1 ) 3100,2930,1660,1640,1480,1400,1285, 1080

The following compounds were synthesized in the same manner as in Reference Example 18 using the following starting amine compounds instead of N-methyl-N-[(3-thienyl) methyl] amine.

N-methyl-N-[(2-thienyl) methyl
2-bromoacetamide raw material amine compound: N-methyl-N-[(2-thienyl) methyl] amine ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 3,00 and 3.06 (2s, 3H), 3.88 and 3.93 (2s, 2H), 4.72 and
4.74 (2s, 2H), 6.92-7.01 (m, 2H), 7.21-7.30 (m, 1H) Yellow oil

N-ethyl-N-[(3-thienyl) methyl
2-bromoacetamide raw material amine compound: N-ethyl-N-[(3-thienyl) methyl] amine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.13 and 1.22 (t, J = 7.0 Hz, 3H) ), 3.37 and 3.46 (q, J = 7.0H
z, 2H), 3.85 and 3.91 (2s, 2H), 4.58 and 4.59 (2s, 2H) 6.9
8 and 7.01 (2dd, J = 1.5Hz, 5.0Hz, 1H), 7.08-7.16 (m, 1H) 7.
28 and 7.36 (2dd, J = 3.0Hz, 5.0Hz, 1H)

N-methyl-N- (3-thienyl) -2-
Bromoacetamide raw material amine compound: 3- (N-methylamino) thiophene ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 3.27 (s, 3 H), 3.73 (s, 2 H), 7.00-7.03 (m, 1 H), 7.28 (dd, J = 1.
5Hz, 3.0Hz, 1H), 7.38 (dd, J = 3.0Hz, 5.0Hz, 1H) Yellow oil

N-methyl-N- (3-methoxyphenyl
L) -2-Bromoacetamide raw material amine compound: 3-methoxy-N-methylaniline ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.29 and 3.30 (2s, 3H), 3.69 and 3.88 (2s, 2H), 3.83 and
3.84 (2s, 3H), 6.76-6.95 (m, 3H), 7.34 (t, J = 8.0Hz, 1H) White powder crystal

N-methyl-N- (2-methyl-3-thier
Nyl) -2-bromoacetamide Raw material amine compound: 2-methyl-3- (N-methylamino) thiophene ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.35 and 2.36 (2s, 3H), 3.20 and 3.21 (2s) , 3H), 3.65 and
3.67 (2s, 1.24H), 3.83 (s, 0.76H) 6.81 and 6.85 (2d, J = 5.
5Hz, 1H), 7.14 and 7.15 (2d, J = 5.5Hz, 1H) IR (neat, cm ^-1 ) 3100,2920,1670,1550,1430,1400,1360 yellow oil

N- (3-thienyl) -2-bromoaceto
Amide raw material amine compound: 3-aminothiophene ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 4.03 (s, 2H), 7.06 (dd, J = 1.5 Hz, 5.0 Hz, 1 H), 7.26 (dd, J = 3.
5.59 (dd, J = 1.5Hz, 3.5Hz, 1H), 8.41 (bs, 1H) pale yellow solid

N-methyl-N- [2- (3-thienyl)
Ethyl] -2-bromoacetamide Starting amine compound: N-methyl-N- [2- (3-thienyl) ethyl] amine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.88-3.02 (m, 5H), 3.50 and 3.83 (2s, 2H), 3.53-3.64 (m, 2
H) 6.91-7.04 (m, 2H), 7.25-7.34 (m, 1H) IR (neat, cm ^-1 ) 1640 pale yellow oil

N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] -2-bromoacetamide Starting amine compound: N- (2-fluoroethyl) -N-
[(3-thienyl) methyl] amine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.68 (tt, J = 5.0, 26.5 Hz, 2H), 3.91 and 3.98 (2s, 2H), 4.46
-4.75 (m, 4H), 6.97-7.03 (m, 1H), 7.11-7.18 (m, 1H), 7.29-
7.40 (m, 1H) IR (neat, cm ^-1 ) 2950,1640,1455 pale yellow oil

N- (2,2,2-trifluoroethyl)
-2-Bromoacetamide raw material amine compound: 2,2,2-trifluoroethylamine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.91-4.14 (m, 4H), 6.68-7.08 (m, 1H) Yellow crystals

N-methyl-N-[(2,5-dichloro-
4-methyl-3-thienyl) methyl] -2-bromoace
Toamide raw material compound: N-methyl-N-[(2,5-dichloro-4-methyl-3-thienyl) methyl] amine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.07 (s, 3H), 2.91 ( s, 3H), 3.88 (s, 2H), 4.59 (s, 2H) IR (KBr, cm- ¹ ) 1655, 1640, 1450, 1400, 1275, 1160, 1080 EIMS m / z 329 (M ⁺ , 1.4) , 296 (15), 214 (100)

Reference Example 19 Synthesis of 3- (3-bromopropyloxy) nitrobenzene
Forming 3-nitrophenol 7.37 g, potassium carbonate 8.0
90 ml of a suspension of 2 g and 21.29 g of 1,3-dibromopropane in acetonitrile was heated under reflux for 20 hours. After cooling at room temperature, insolubles were removed with a glass filter. After concentrating the filtrate, the residue was purified by silica gel column chromatography (eluent: hexane: methylene chloride = 2: 1) to obtain 7.5 g of the desired product as a pale yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.36 (quintet, J = 5.9 Hz, 2H), 3.62 (t, J = 5.9 Hz, 2H), 4.19
(t, J = 5.9Hz, 2H), 7.23 (dd, J = 2.5,8.3Hz, 1H), 7.43 (t, J = 8.
1Hz, 1H), 7.73 (t, J = 2.2Hz, 1H), 7.76-7.88 (m, 1H) IR (neat, cm ^-1 ) 3100,2940,1618,1580,1525,1345,1240,1025

Reference Example 20 N- (3-thienyl) -N-methyl-3- (3-nitro
2. Synthesis of phenoxy) propylamine 3- (3-bromopropyloxy) nitrobenzene
90 g of acetonitrile suspension of 90 g, 2.07 g of potassium carbonate and 1.50 g of 3-methylaminothiophene
Was heated to reflux for 15 hours. After cooling at room temperature, insolubles were removed with a glass filter. After concentrating the filtrate, the residue was subjected to silica gel column chromatography (developing solvent: benzene).
To give 2.49 g of the desired product as a brown oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.99-2.19 (m, 2H), 2.88 (s, 3H), 3.43 (t, J = 7.0 Hz, 2H), 4.10
(t, J = 5.9Hz, 2H), 5.90-5.98 (m, 1H), 6.78 (dd, J = 1.4,5.2H
z, 1H), 7.13-7.29 (m, 2H), 7.43 (t, J = 8.2Hz, 1H), 7.68-7.88
(m, 2H) IR (neat, cm ^-1 ) 3100,2940,2865,1545,1525,1350,1245 The following starting amine compound was used in place of 3-methylaminothiophene and the following method was used in the same manner as in Reference Example 20. Compounds were synthesized.

N-phenyl-N-methyl-3- (3-d
Trophenoxy) propylamine raw material amine compound: N-methylaniline ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.02.20 (m, 2H), 2.97 (s, 3H), 3.58 (t, J = 7.0 Hz, 2H), 4.1
0 (t, J = 5.9Hz, 2H), 6.62-6.82 (m, 3H), 7.18-7.32 (m, 3H), 7.
44 (t, J = 8.2Hz, 1H), 7.75 (t, J = 2.3Hz, 1H), 7.80-7.88 (m, 1
H) IR (neat, cm ^-1 ) 2940,2880,1600,1530,1505,1350,1240 yellow oil

Reference Example 21 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- (N-methylamino) ethoxy] fe
Nyl] thiocarbamate O- (4-tert-butylphenyl) = N-methyl-
A suspension obtained by mixing 215 mg of N- [3- (2-bromoethoxy) phenyl] thiocarbamate, 10 g of methylamine (40% methanol solution), 276 mg of anhydrous potassium carbonate, 8 mg of potassium iodide and 7 mg of tetrabutylammonium hydrogensulfate Was stirred at 50 ° C. for 2 hours. After the reaction, insolubles were removed with a glass filter, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. (50 ml × 2) The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and silica gel column chromatography (developing solvent;
Purification by chloroform: methanol = 4: 1) gave 38 mg of a pale yellow oily substance. ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 2.54 (s, 3H), 3.00-3.12 (m, 2H), 3.37 (brs, 1
H), 3.71 (s, 3H), 4.05-4.19 (m, 2H), 6.60-6.95 (m, 5H), 7.18
-7.39 (m, 3H) IR (neat, cm ^-1 ) 3310,2960,1600,1480,1380,1210

Reference Example 22 Synthesis of 2,5-dichloro-3-methylthiophene Lithium hydride was added to 30 ml of anhydrous tetrahydrofuran.
59 g and lithium aluminum hydride (3.04 g) were added and suspended, and a solution of 2,5-dichloro-3-chloromethylthiophene (16.1 g) in anhydrous tetrahydrofuran (30 m) was added.
After the dropwise addition of 1 over 35 minutes at room temperature, the mixture was heated under reflux for 60 minutes. After completion of the reaction, 200 ml of ice water and 400 ml of 1N hydrochloric acid were sequentially added, and the mixture was extracted with n-hexane (200 ml × 3). The collected organic layer was washed successively with 1N hydrochloric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica gel chromatography (developing solvent: hexane) to obtain 10.6 g of the target compound as a colorless oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.13 (s, 3 H), 6.62 (s, 1 H) IR (neat, cm ⁻¹ ) 1555, 1435, 1185, 1055, 820 EIMS m / z 168 (M ⁺ , 39), 131 (100)

Reference Example 23 2,5-Dichloro-4-methylthiophen-3-carba
Synthesis of Rudehyde 10.2 g of 2,5-dichloro-3-methylthiophene was dissolved in 40 ml of a methylene chloride solution, and tin (IV) chloride was dissolved.
After 7.5 g of the solution was added dropwise over 20 minutes under ice cooling, the solution was stirred under ice cooling for 45 minutes. Thereafter, 7.72 g of dichloromethyl methyl ether was added dropwise to the solution over 10 minutes under ice-cooling.
Stirred for 0 hours. After the reaction, 200 ml of ice water was added and 20
The mixture was stirred for 1 minute, extracted with ether (150 ml × 3), and the collected organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (developing solvent; hexane: ethyl acetate = 40: 1) to obtain 6.95 g of the desired product as an orange oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.35 (s, 3 H), 10.04 (s, 1 H) IR (neat, cm ⁻¹ ) 1685, 1540, 1445, 1380, 1
170 EIMS m / z 195 (M ⁺ )

Example 1 N- (3-thienyl) -N-methyl-3- (3-amino
Phenoxy) propylamine (Compound No. 803)
For forming tin (II) chloride dihydrate 9.23g of ethanol 50ml, N- (3- thienyl) -N- methyl-3-
A solution of 2.39 g of (3-nitrophenoxy) propylamine in 50 ml of ethanol was added. The mixture was heated to 60 ° C, 154 mg of sodium borohydride was slowly added under a nitrogen atmosphere, and the mixture was further stirred at 60 ° C for 1 hour and at room temperature for 1 hour. After completion of the reaction, the reaction mixture was put into cold water and neutralized with a 15% aqueous sodium hydroxide solution. 15% after distilling off ethanol under reduced pressure
The pH was adjusted to 9 with an aqueous sodium hydroxide solution. After adding ethyl acetate, the mixture was filtered through Celite to remove insolubles. After the filtrate was extracted with ethyl acetate, the collected organic layers were washed with saturated saline. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) to obtain 1.05 g of the desired product as a brown oil.

¹ H-NMR (500 MHz, CDC
l ₃ , δppm) 1. 94-2.10 (m, 2H), 2.87 (s, 3H), 3.41 (t, J = 7.2Hz, 2H), 3.6
5 (brs, 2H), 3.98 (t, J = 6.0Hz, 2H), 5.90-5.97 (m, 1H), 6.21-
6.37 (m, 3H), 6.76-6.83 (m, 1H), 7.06 (t, J = 7.9Hz, 1H), 7.16
-7.26 (m, 1H) IR (NaCl, cm ^-1 ) 3440,3350,2930,2860,1595,1540,1490,1185,1155 Using the corresponding starting compound, the following compound was prepared in the same manner as in Example 1. Synthesized.

N-phenyl-N-methyl-3- (3-A
Minophenoxy) propylamine (Compound No. 798) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.95-2.13 (m, 2H), 2.95 (s, 3H), 3.54 (t, J = 7.1 Hz, 2H), 3.65
(brs, 2H), 3.97 (t, J = 5.9Hz, 2H), 6.21-6.38 (m, 3H), 6.62-
6.80 (m, 3H), 7.06 (t, J = 8.0Hz, 1H), 7.17-7.29 (m, 2H) IR (neat, cm ^-1 ) 3450,3380,2940,2880,1600,1510,1465,1190 , 1160 pale yellow oil

Example 2 N- (3-thienyl) -N-methyl-3- [3- (form
Milamino) phenoxy] propylamine (compound number
804) Synthesis of N- (3-thienyl) -N-methyl-3- (3-aminophenoxy) propylamine 914 mg and formic acid 192
mg of methylene chloride in 10 ml of 1-ethyl-3-
(3′-dimethylaminopropyl) carbodiimide 79
After 20 mg of a 8 mg methylene chloride solution was added dropwise, the mixture was stirred at room temperature for 3.5 hours. After the completion of the reaction, the mixture was washed twice with water and with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 938 mg of the desired product as a brown oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.94-2.12 (m, 2H), 2.88 (s, 3H), 3.41 (t, J = 7.0 Hz, 2H), 4.02
(t, J = 5.9Hz, 2H), 5.90-5.97 (m, 1H), 6.55-7.60 (m, 7H), 8.3
4-8.74 (m, 1H) IR (neat, cm ^-1 ) 3270,2940,2870,1685,1595,1540,1490,1440,1410,1290,
1210

Example 3 O-ethyl = N- [3- [3- (N-methyl-N-fe
Nylamino) propoxy] phenyl] carbamate
Compound No. 800) 333 mg of N-phenyl-N-methyl-3- (3-aminophenoxy) propylamine and sodium carbonate 21
5 ml of a methanol solution of 217 mg of ethyl chloroformate was added to 15 ml of a 2 mg methanol-water mixed solution (1: 2), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added and the mixture was extracted with ether. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 340 mg of the desired product as a pale yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (t, J = 7.1 Hz, 3H), 1.94-2.16 (m, 2H), 2.96 (s, 3H), 3.55
(t, J = 7.0Hz, 2H), 4.00 (t, J = 5.9Hz, 2H), 4.25 (q, J = 7.1Hz, 2
H), 6.59-6.92 (m, 6H), 7.14-7.43 (m, 4H) IR (neat, cm ^-1 ) 3320,2970,2940,1710,1600,1540,1505,1445,1280,1230,
1160

Example 4 N-methyl-N-[(3-thienyl) methyl] -2-
[3- (Formylamino) phenoxy] acetamide
Synthesis of (Compound No. 821) 3-formylaminophenol 1.1 g, N-methyl-
A suspension of 2.0 g of N-[(3-thienyl) methyl] -2-bromoacetamide, 2.1 g of anhydrous potassium carbonate and 0.13 g of tetrabutylammonium hydrogen sulfate in 30 ml of a dimethylformamide suspension was stirred at 50 ° C. for 15 hours. Thereafter, 250 ml of water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 1.9 g of a pale yellow solid.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 2.89 and 2.95 and 2.99 and 3.02 (4s, 3H), 4.58 and 4.
61 (2s, 2H), 4.74 and 4.76 (2s, 2H), 6.45-8.10 (m, 8H), 8.3
2-8.74 (m, 1H) IR (neat, cm ^-1 ) 3270,3090,2930,1660,1600,1490,1280,1210 EIMS m / z 304 (M ⁺ , 3), 168 (29), 97 ( 100) The following compound was synthesized in the same manner as in Example 4 using the corresponding bromoacetic acid amide derivative and 3-formylaminophenol.

N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] -2- [3- (formylamino)
Phenoxy] acetamide (Compound No. 846) Starting compound: N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] -2-bromoacetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.60-3.77 (m, 2H), 4.47-4.84 (m, 6H), 6.52-6.80 (m, 2H), 6 .
93-7.00 (m, 1H) 7.03-7.67 (m, 5H), 8.32-8.70 (m, 1H) White solid

N-methyl-N- [2- (3-thienyl)
Ethyl] -2- [3- (formylamino) phenoxy]
Acetamide (Compound No. 845) Starting compound: N-methyl-N- [2- (3-thienyl)
Ethyl)]-2-bromoacetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.82-3.05 (m, 5H), 3.53-3.68 (m, 2H), 4.34-4.69 (m, 2H), 6.
52-6.76 (m, 2H) 6.87-7.36 (m, 5H), 7.82-8.06 (m, 1H), 8.24-
8.70 (m.1H) White solid

N-methyl-N- [2- (2-thienyl)
Ethyl] -2- [3- (formylamino) phenoxy]
Acetamide (Compound No. 844) Starting compound: N-methyl-N- [2- (2-thienyl)
Ethyl)]-2-bromoacetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.96 and 3.02 (2s, 3H), 3.05-3.16 (m, 2H), 3.60-3.68 (m, 2
H), 4.43 and 4.68 (2s, 2H), 6.55-6.99 (m, 4H), 7.10-7.31
(m, 3H), 8.31-8.35 and 8.61-8.69 (2m, 1H) IR (neat, cm ^-1 ) 3275,3145,3090,2940,1655,1605,1545,1495,1440,1295,
1260 1215,1165,1070,850,780,700

N-Ethyl-N-[(3-thienyl) methyl
] -2- [3- (formylamino) phenoxy] ace
Toamide (Compound No. 826) Starting compound : N-ethyl-N-[(3-thienyl) methyl] -2-bromoaceamide ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.08-1.26 (m, 3H), 3.32-3.53 (m, 2H), 4.60 (s, 2H), 4.72 an
d 4.76 (2s, 2H) 6.53-7.69 (m, 8H), 8.32-8.70 (m, 1H) IR (neat, cm ^-1 ) 3270,3100,2980,1650,1600,1495,1440,1210 EIMS m / z 318 (M ⁺ , 3), 182 (30), 97 (100)

N-methyl-N- (phenylmethyl) -2
-[3- (formylamino) phenoxy] acetamide
(Compound No. 816) pale yellow oil

N-methyl-N- (3-thienyl) -2-
[3- (Formylamino) phenoxy] acetamide (Compound No. 890) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.30 (s, 3H), 4.49 (s, 2H), 6.43-8.00 (m, 8H), 8.23-8.64 (m,
1H) Light brown crystal

N-methyl-N- (3-methoxyphenyl
) -2- [3- (formylamino) phenoxy] ace
Toamide (Compound No. 887) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 3.28 (s, 3H), 3.78 (s, 3H), 4.41 (s, 2H), 6.40-7.39 (m, 8H),
8.18-8.59 (m, 1H), 8.69-8.81 (m, 1H) pale yellow solid

N-methyl-N- (2-methyl-3-thier
Nyl) -2- [3- (formylamino) phenoxy] a
Cetamide (Compound No. 903) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.37 and 2.38 (2s, 2.64H), 2.89 (s, 0.36H), 2.96 and 3.2
3 (2s, 3H), 4.28-4.48 (m, 2H), 6.45-7.36 (m, 6H), 8.00-8.64
(m, 2H) IR (neat, cm ^-1 ) 3270,1695,1665,1610,1485,1205 brown solid

N- (3-thienyl) -2- [3- (phor
Milamino) phenoxy] acetamide (Compound No. 8
98) Starting compound: N- (3-thienyl) -2-bromoacetamide ¹ H-NMR (500 MHz, DMSO-d ₆ , δ ppm) 4.51-4.72 (m, 2H), 6.68-7.60 (m, 7H), 8.23 -8.83 (m, 1H), 1
0.10-10.57 (m, 2H) White powder solid

N- (2,2,2-trifluoroethyl)
-2- [3- (formylamino) phenoxy] acetoa
Mide (Compound No. 817) Starting Compound: N- (2,2,2-trifluoroethyl)
-2-Bromoacetamide ¹ H-NMR (500 MHz, DMSO-d ₆ , δ ppm) 3.84-3.98 (m, 2H), 4.34-4.61 (m, 2H), 6.40-7.40 (m, 4H), 8.
15-8.85 (m, 2H), 9.34-10.20 (m, 1H) Light brown solid

N-methyl-N-[(2,5-dichloro-
4-methyl-3-thienyl) methyl] -2- [3- (e
Lumylamino) phenoxy] acetamide (compound number
967) Starting compound: N-methyl-N-[(2,5-dichloro-4-methyl-3-thienyl) methyl] -2-bromoacetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.99 (s, 3H), 2.92 (s, 3H), 4.60 (s, 2H), 4.73 and 4.73
(2s, 2H), 6.68-6.76 (m, 2H), 7.05-7.60 (m, 3H), 8.36-
8.70 (m, 1H) IR (KBr, cm- ¹ ) 3260, 3080, 1700, 1630, 1600, 1495, 1215, 1065 EIMS m / z 386 (M ⁺ , 3.7), 214 (31), 179 (100) White powder solid

N-methyl-N-[(3-thienyl) methyl] -2-bromoacetamide and 6-methylamino-2
The following compounds were synthesized in the same manner as in Example 4 using (1H) -pyridone.

N-methyl-N- (3-thienyl) -2-
[2- (methylamino) -6-pyridyloxy] aceto
Amide (Compound No. 911) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.80 (s, 3H), 3.23 (s, 3H), 4.30 (brs, 1H), 4.66 (s, 2H), 5.88
(d, J = 8.0Hz, 1H), 6.09 (d, J = 8.0Hz, 1H), 6.87-7.40 (m, 4H)

Example 5 N- (3-thienyl) -N-methyl-3- [3- (methyl
Ruamino) phenoxy] propylamine (Compound No. 8
07) Lithium aluminum hydride (195 mg) in tetrahydrofuran suspension (5 ml) was added with N- (3-thienyl) -N under ice cooling.
-Methyl-3- [3- (formylamino) phenoxy]
880 mg of propylamine in tetrahydrofuran solution 1
After dropping 5 ml, the mixture was heated under reflux for 1.5 hours. After completion of the reaction, an aqueous solution of sodium hydroxide was added dropwise, and the resulting solid was separated by filtration. Water was added to the filtrate, extracted with ether, and the collected organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to obtain 713 mg of the desired product as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.96-2.10 (m, 2H), 2.83 (s, 3H), 2.88 (s, 3H), 3.41 (t, J = 7.0
Hz, 2H), 3.70 (brs, 1H), 3.99 (t, J = 6.0Hz, 2H), 5.93 (dd, J =
1.5,3.1Hz, 1H), 6.14-6.32 (m, 3H), 6.80 (dd, J = 1.5,5.2Hz,
1H), 7.08 (t, J = 8.1Hz, 1H), 7.20 (dd, J = 3.1,5.2Hz, 1H) IR (neat, cm ^-1 ) 3410,2940,2860,1615,1550,1510,1410, 1195,1160 Instead of the amide compound, O-ethyl = N- [3- [3-
The following compounds were synthesized in the same manner as in Example 5 using (N-methyl-N-phenylamino) propoxy] phenyl] carbamate.

N-phenyl-N-methyl-3- [3-
(Methylamino) phenoxy] propylamine (compound
No. 802) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.98-2.15 (m, 2H), 2.84 (s, 3H), 2.97 (s, 3H), 3.57 (t, J = 7.0
Hz, 2H), 3.76 (brs, 1H), 4.01 (t, J = 5.9Hz, 2H), 6.18-6.35
(m, 3H), 6.65-6.82 (m, 3H), 7.11 (t, J = 8.0Hz, 1H), 7.20-7.3
5 (m, 2H) IR (neat, cm ^-1 ) 3405,2930,2870,1600,1505,1195,1160 Brown oil

Example 6 N-methyl-N-[(3-thienyl) methyl] -2-
[3- (methylamino) phenoxy] ethylamine
Compound No. 868) was added to a suspension of lithium aluminum hydride (0.37 mg) in tetrahydrofuran (20 ml ) under ice cooling with N-methyl-N-
30 ml of a tetrahydrofuran solution of 1.5 g of [(3-thienyl) methyl] -2- [3- (formylamino) phenoxy] acetamide was added dropwise. After heating at reflux for 18 hours, an aqueous sodium hydroxide solution was added, and the generated insolubles were separated by filtration. Water was added to the filtrate, extracted with ether, and the collected organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: benzene = 5: 1).
Purification yielded 0.80 g of a yellow oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 2.36 (s, 3H), 2.73-2.90 (m, 5H), 3.19-3.90 (m, 3H), 4.08 (t,
J = 6.2Hz, 2H), 6.12-6.33 (m, 3H), 7.00-7.19 (m, 3H), 7.21-
7.34 (m, 1H) IR (neat, cm ^-1 ) 3400,3100,2930,2800,1615,1500,1200,1160 EIMS m / z 276 (M ⁺ , 4), 140 (50), 97 (100) The following compounds were synthesized in the same manner as in Example 6 using the corresponding acetic acid amide derivative.

N-methyl-N-[(2-thienyl) methyl
] -2- [3- (methylamino) phenoxy] ethyl
Amine (Compound No. 883) Starting compound: N-methyl-N-[(2-thienyl) methyl] -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.40 ( s, 3H), 2.82 (s, 3H), 2.85 (t, J = 6.0Hz, 2H), 3.70 (brs,
1H), 3.87 (s, 2H), 4.08 (t, J = 6.0Hz, 2H) 6.13-6.30 (m, 3H),
6.89-6.97 (m, 2H), 7.02-7.09 (m, 1H), 7.20-7.27 (m, 1H) Yellow oil

N-Ethyl-N-[(3-thienyl) methyl
] -2- [3- (methylamino) phenoxy] ethyl
Amine (Compound No. 866) Starting compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.21 ( t, J = 7.5Hz, 3H), 2.64 (q, J = 7.5Hz, 2H), 2.83 (s, 3H),
2.88 (t, J = 7.5Hz, 2H), 3.75 (s, 2H), 4.02 (t, J = 7.5Hz, 2H),
6.12-6.28 (m, 3H), 7.04-7.32 (m, 4H) IR (neat, cm ^-1 ) 3410,2940,1615,1500,1200,1165,1045 EIMS m / z 290 (M ⁺ , 7), 154 (75), 97 (100) yellow oil

N-methyl-N- (phenylmethyl) -2
-[3- (methylamino) phenoxy] ethylamine
(Compound No. 854) Starting compound: N-methyl-N- (phenylmethyl) -2
-[3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.34 (s, 3H), 2.82 (s, 3H), 2.83 (t, J = 6.5 Hz, 2H) , 3.63 (s, 2
H), 3.67 (brs, 1H), 4.08 (t, J = 6.5Hz, 2H), 6.12-6.33 (m, 3
H), 7.00-7.12 (m, 1H), 7.20-7.44 (m, 5H) Orange oil

N-methyl-N- (3-methoxyphenyl
Ru) -2- [3- (methylamino) phenoxy] ethyl
Amine (Compound No. 928) Starting compound: N-methyl-N- (3-methoxyphenyl) -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.82 (s, 3H), 3.06 (s, 3H), 3.57-3.85 (m, 6H), 4.13 (t, J = 6.0
Hz, 2H), 6.12-6.44 (m, 6H), 7.02-7.20 (m, 2H) IR (neat, cm ^-1 ) 3400,2940,1610,1500,1200,1165 Colorless viscous substance

N- (2,2,2-trifluoroethyl)
-2- [3- (methylamino) phenoxy] ethylami
(Compound No. 818) Starting compound: N- (2,2,2-trifluoroethyl)
-2- [3- (Formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.80 (brs, 1H), 2.81 (s, 3H), 3.09 (t, J = 5.0 Hz, 2H) , 3.25 (q,
J = 9.5Hz, 2H), 4.03 (t, J = 5.0Hz, 2H) 6.15 (t, J = 2.0Hz, 1H),
6.24 (dt, J = 2.0Hz, 8.0Hz, 2H), 7.06 (t, J = 8.0Hz, 2H) IR (neat, cm ^-1 ) 3400,2930,1610,1495,1270,1160 Yellow oil

Example 7 N-methyl-N- (3-thienyl) -2- [3- (methyl
Ruamino) phenoxy] ethylamine (Compound No. 91
Synthesis of 7) N-methyl-N- (3) was added to 80 ml of a 1.0 M borane-tetrahydrofuran complex solution in tetrahydrofuran under ice cooling.
After adding a solution of 10.3 g of -thienyl) -2- [3- (formylamino) phenoxy] acetamide in 300 ml of tetrahydrofuran, the mixture was refluxed for 14 hours. After the reaction, the mixture was ice-cooled again, 100 ml of 3N hydrochloric acid was added, and the mixture was refluxed for 30 minutes. The reaction solution was allowed to cool and then washed with diethyl ether. The aqueous layer was made alkaline with a 15% aqueous sodium hydroxide solution and extracted with diethyl ether. (200 ml × 2) The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 7.2 g of an oil were obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.84 (s, 3H), 3.00 (s, 3H), 3.64 (t, J = 6.0 Hz, 2H), 3.72 (brs,
1H), 4.12 (t, J = 6.0Hz, 2H), 5.96 (dd, J = 1.5Hz, 3.0Hz, 1H),
6.16 (t, J = 2.5Hz, 1H), 6.24-6.28 (m, 2H), 6.83 (dd, J = 2.0H
z, 5.5Hz, 1H), 7.09 (t, J = 8.0Hz, 1H), 7.24 (dd, J = 3.5Hz, 5.5
(Hz, 1H) IR (neat, cm ^-1 ) 3405, 3100, 2930, 1615, 1550, 1200, 1180 The following compounds were synthesized in the same manner as in Example 7 using the corresponding starting compounds.

N- (3-thienyl) -2- [3- (methyl
Ruamino) phenoxy] ethylamine (Compound No. 92
1) Starting compound: N- (3-thienyl) -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.83 (s, 3H), 3.47 (t, J = 5.0Hz, 2H), 3.76 (brs, 1H), 3.98-4.
25 (m, 3H), 6.04 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.20 (t, J = 2.0Hz,
1H), 6.26 (dd, J = 1.5Hz, 8.0Hz, 1H), 6.30 (dd, J = 1.5Hz, 8.0H
z, 1H) 6.67 (dd, J = 1.5Hz, 5.0Hz, 1H), 7.10 (t, J = 8.0Hz, 1H),
7.18 (dd, J = 3.0Hz, 5.0Hz, 1H) IR (neat, cm ^-1 ) 3400,2930,1615,1560,1500,1200,1165,1060 pale yellow viscous substance

N-methyl-N- (2-methyl-3-thier
Nyl) -2- [3- (methylamino) phenoxy] ethyl
Luamine (Compound No. 925) Starting compound : N-methyl-N- (2-methyl-3-thienyl) -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.36 (s, 3H), 2.79 (s, 3H), 2.81 (s, 3H), 3.26 (t, J = 6.0Hz, 2
H), 3.98 (t, J = 6.0Hz, 2H), 6.12-6.18 (m, 1H), 6.18-6.28 (m,
2H), 6.94 (d, J = 5.5Hz, 1H), 7.00 (d, J = 5.5Hz, 1H), 7.06 (t, J
= 8.5Hz, 1H) IR (neat, cm ^-1 ) 3400,2940,1615,1200,1160 brown oil

N-methyl-N- (3-thienyl) -2-
[2- (methylamino) -6-pyridyloxy] ethyl
Amine (Compound No. 934) Starting compound: N-methyl-N- (3-thienyl) -2-
[2- (Methylamino) -6-pyridyloxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.86 (s, 3H), 2.95 (s, 3H), 3.58 (t, J = 5.8 Hz, 2H ), 4.30-4.48
(m, 3H), 5.84-6.04 (m, 3H) 6.76-6.84 (m, 1H), 7.14-7.22 (m,
1H), 7.33 (t, J = 7.5Hz, 1H)

N-methyl-N- [2- (3-thienyl)
Ethyl] -2- [3- (methylamino) phenoxy] e
Tylamine (Compound No. 874) Starting compound : N-methyl-N- [2- (3-thienyl)
Ethyl] -2- [3- (formylamino) phenoxy]
Acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.42 (s, 3H), 2.73-2.92 (m, 9H), 3.70 (brs, 1H), 4.67 (t, J =
6.0Hz, 2H), 6.17-6.30 (m, 3H), 6.97 (dJ = 5.0Hz, 1H), 6.99-
7.03 (m, 1H) 7.08 (t, J = 8.0Hz, 1H), 7.23-7.28 (m, 1H) IR (neat, cm ^-1 ) 3400,2930,1610,1200 Brown oil

N-methyl-N- [2- (2-thienyl)
Ethyl] -2- [3- (methylamino) phenoxy] e
Tylamine (Compound No. 875) Starting compound : N-methyl-N- [2- (2-thienyl)
Ethyl] -2- [3- (formylamino) phenoxy]
Acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.43 (s, 3H), 2.82 (t, J = 10.2 Hz, 2H), 2.83 (s, 3H), 2.88 (t, J
= 8.2Hz, 2H), 3.07 (t, J = 10.2Hz, 2H), 3.68 (bs, 1H) 4.08 (t, J
= 8.2Hz, 2H), 6.17-6.33 (m, 3H), 6.82-7.16 (m, 4H) IR (neat, cm ^-1 ) 3420,2950,2880,2820,1620,1515,1500,1460,1345, 1305,
1200,1165,1135,1050,850,830,760,695

N-methyl-N- (3-methylthiopheny
Ru) -2- [3- (methylamino) phenoxy] ethyl
Amine (Compound No. 931) Starting compound: N-methyl-N- (3-methylthiophenyl) -2- [3- (formylamino) phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.48 (s, 3H), 2.81 (s, 3H), 3.05 (s, 3H), 3.55-3.87 (m, 3H),
4.11 (t, J = 6.0Hz, 2H), 6.15 (s, 1H), 6.25 (t, J = 9.5Hz, 2H) 6.56 (d, J = 8.5Hz, 1H), 6.64 (d, J = 8.0Hz , 1H), 6.67 (s, 1H) 7.07 (t, J = 8.0Hz, 1H), 7.16 (t, J = 8.0Hz, 1H)

N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] -2- [3- (methylamino) phenyl
Enoxy] ethylamine (Compound No. 863) Starting compound: N- (2-fluoroethyl) -N-[(3
-Thienyl) methyl] -2- [3- (formylamino)
Phenoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.81 (s, 3H), 2.87-3.02 (m, 4H), 3.72 (brs, 1H), 3.83 (s, 2H)
4.03 (t, J = 6.0Hz, 2H), 4.53 (dt, J = 5.0,47.5Hz, 2H), 6.13
(s, 1H) 6.23 (t, J = 6.0Hz, 2H), 7.03-7.17 (m, 3H), 7.24-7.30
(m, 1H) IR (neat, cm ^-1 ) 3400,2960,1620,1505,1200 Yellow oil

Example 8 O- (tert-butyl) = N- [3- [N-methyl-
N- (3-thienyl) carbamoylmethoxy] propi
Synthesis of O- (tert-butyl) = N- (3-hydroxypropyl) carbamate 8 in 5 ml of a dimethylformamide suspension of 184 mg of 60% oily sodium hydride under ice-cooling.
4 ml of a 06 mg dimethylformamide suspension were added. After 5 minutes, N-methyl-N- (3-thienyl) -2-
After adding 4 ml of a dimethylformamide suspension of 1 g of bromoacetamide, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 200 ml of water was added, and the mixture was extracted with ethyl acetate (60 ml ×
3) The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 2) to obtain a light brown oil as a target substance.
70 mg were obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.44 (s, 9H), 1.60-1.78 (m, 2H), 3.18-3.55 (m, 7H), 3.65 a
nd 3.91 (2s, 2H) 4.78 and 5.38 (2brs, 1H), 6.92 (brs, 1H),
7.13 (brs, 1H), 7.36 (brs, 1H) IR (neat, cm ^-1 ) 3350,3090,2970,1710,1690,1670,1660,1525,1265,1170 O- (tert-butyl) as a starting compound = N- (3
-Hydroxypropyl) carbamate and N-methyl-N
The following compounds were synthesized in the same manner as in Example 8 using-(3-thienylmethyl) -2-bromoacetamide.

O- (tert-butyl) = N- [2-
[N-methyl-N-[(3-thienyl) methyl] carba
Moylmethoxy] propyl] carbamate (compound number
942) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.43 (s, 9H), 1.68-1.82 (m, 2
H), 2.89 and 2.95 (2s, 3H),
3.20-3.33 (m, 2H), 3.52-3.60
(M, 2H), 4.15 and 4.19 (2s, 2
H), 4.48 and 4.55 (2s, 2H),
5.18 and 5.34 (2brs, 1H), 6.
95-7.35 (m, 3H) Yellow oil O- (tert-butyl) = N-methyl-N- (3-hydroxyethyl) carbamate and N-
The following compounds were synthesized in the same manner as in Example 8 using methyl-N-[(3-thienyl) methyl] -2-bromoacetamide.

O- (tert-butyl) = N-methyl-
N- [2- [N-methyl-N-[(3-thienyl) methyl
[Carbamoylmethoxy] ethyl] carbamate
Compound No. 957) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.43 and 1.43 (2s, 9H), 2.83-2.96 (m, 6H), 3.32-3.47 (m, 2
H), 3.58-3.69 (m, 2H), 4.17 and 4.21 (2s, 2H), 4.51 and
4.54 (2s, 2H), 6.90-7.35 (m, 3H) IR (neat, cm ^-1 ) 3340,2970,2930,1710,1660,1520,1365,1270,1250,1170 pale yellow oil

Example 9 N-methyl-N-[(3-thienyl) methyl] -2-
[2- (methylamino) ethoxy] acetamide (compound
No. 958) O- (tert-butyl) = N-methyl-N- [2-
5 ml of concentrated hydrochloric acid was added to 10 ml of a methanol solution of 500 mg of [N-methyl-N-[(3-thienyl) methyl] carbamoylmethoxy] ethyl] carbamate under ice cooling.
Stirred at room temperature for 1 hour. After the reaction, the mixture was poured into water and made alkaline with 10% sodium hydroxide. After extraction with chloroform, the collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 330 mg of a yellow oil as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.42 and 2.47 (2s, 3H), 2.51 (brs, 1H), 2.77 and 2.83 (2
t, J = 5.0Hz, 2H), 2.90 and 2.95 (2s, 3H), 3.65 and 3.84 (2
t, J = 5.0Hz, 2H), 4.20 and 4.24 (2s, 2H), 4.51 and 4.56 (2
(s, 2H), 6.92-7.36 (m, 3H)

Example 10 N-methyl-3- [2- [N-methyl-N-[(3-thio
Enyl) methyl] amino] ethoxy] propylamine
Synthesis of (Compound No. 945) O- (tert-butyl) = N- [2- [N-methyl-N-[(3-thienyl) methyl] in 10 ml of a tetrahydrofuran suspension of 234 mg of lithium aluminum hydride under ice cooling. A solution of 527 mg of carbamoylmethoxy] propyl] carbamate in 15 ml of tetrahydrofuran was added dropwise, and the mixture was refluxed for 1 hour. After completion of the reaction, an aqueous solution of sodium hydroxide was added dropwise, and the resulting solid was separated by filtration. Water was added to the filtrate, extracted with chloroform, and the collected organic layer was washed with brine and dried over anhydrous magnesium sulfate to obtain 276 mg of the desired product as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.44 (brs, 1H), 1.72-1.79 (m, 2H), 2.27 (s, 3H), 2.40 (s, 3
H), 2.58 (t, J = 6.0Hz, 2H), 2.64 (t, J = 6.5Hz, 2H), 3.49 (t, J =
6.5Hz, 2H), 3.54 (t, J = 6.0Hz, 2H), 3.58 (s, 2H), 6.98-7.33
(m, 3H) The following compounds were synthesized in the same manner as in Example 10 using the corresponding starting compounds.

N-methyl-2- [2- [N-methyl-N
-[(3-thienyl) methyl] amino] ethoxy] ethy
Luamine (Compound No. 961) Starting compound : N-methyl-N-[(3-thienyl) methyl] -2- [2- (methylamino) ethoxy] acetamide ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.27 ( s, 3H), 2.44 (s, 3H), 2.59 (t, J = 5.5Hz, 2H), 2.74 (t, J =
5.5Hz, 2H), 3.50-3.61 (m, 7H), 7.03-7.12 (m, 2H), 7.25-7.2
8 (m, 1H)

Example 11 N-methyl-3- [2- [N-methyl-N- (3-thiene
Nyl) amino] ethoxy] propylamine (compound number
954) 3.6 ml of a 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran solution was added to 10 ml of tetrahydrofuran.
O- (tert-butyl) =
After adding 10 ml of a tetrahydrofuran solution of 300 mg of N- [3- [N-methyl-N- (3-thienyl) carbamoylmethoxy] propyl] carbamate, the mixture was heated under reflux for 22 hours. After the reaction, the mixture was ice-cooled again, 20 ml of 3N hydrochloric acid was added, and the mixture was refluxed for 30 minutes. After allowing the reaction solution to cool, it was washed with methylene chloride. The aqueous layer was made alkaline with a 5% aqueous sodium hydroxide solution and extracted with methylene chloride. (40ml × 3)
The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 132 mg of a yellow oily substance as a target.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.70-1.77 (m, 2H), 2.40 (s, 3H), 2.62 (t, J = 7.0 Hz, 2H), 2.90
(s, 3H), 3.39 (t, J = 6.0Hz, 2H), 3.43 (brs, 1H) 3.48 (t, J = 6.0
Hz, 2H), 3.56 (t, J = 6.0Hz, 2H), 5.89 (dd, J = 1.5Hz, 3.0Hz, 1
H) 6.77 (dd, J = 1.5Hz, 5.0Hz, 1H), 7.19 (dd, J = 3.0Hz, 5.0Hz,
1H)

Example 12 O- (4-tert-butylphenyl) = N-methyl-
N- [3- (3-bromopropoxy) phenyl] thioca
Synthesis of Rubamate (Compound No. 972) O- (4-tert-butylphenyl) = N-methyl-
N- (3-hydroxyphenyl) thiocarbamate
0 g, potassium carbonate 0.88 g, tetrabutylammonium hydrogensulfate 27 mg and 1,3-dibromopropane 2.56 g in N, N-dimethylformamide 10
ml was heated to reflux for 18 hours. Ethyl acetate 10
The mixture was poured into 0 ml, washed twice with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 20: 1) to give the target compound as colorless crystals 0.6.
1 g was obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 2.24-2.41 (m, 2H), 3.60 (t, J = 6.4 Hz, 2H), 3.71
(brs, 3H), 4.11 (t, J = 5.8Hz, 2H), 6.80-7.04 (m, 5H), 7.24-
7.43 (m, 3H) IR (neat, cm ^-1 ) 2960,1605,1590,1480,1465,1380,1215,1165

Example 13 O- (4-tert-butylphenyl) = N-methyl-
N- [6- (3-bromopropoxy) -2-pyridyl]
Synthesis of thiocarbamate (Compound No. 1009) O- (4-tert-butylphenyl) = N-methyl-
500 ml of N- (6-hydroxy-2-pyridyl) thiocarbamate, 437 mg of potassium carbonate, 17 mg of tetrabutylammonium hydrogensulfate and 638 mg of 1,3-dibromopropane in 10 ml of a N, N-dimethylformamide suspension at 50 ° C. Stir for 15 hours. The reaction solution was poured into 100 ml of ethyl acetate, washed twice with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent;
Hexane: ethyl acetate = 7: 1) to give 250 mg of a colorless oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 2.23-2.41 (m, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.75
(s, 3H) 4.48 (t, J = 6.0Hz, 2H), 6.35 (d, J = 8.2Hz, 1H) 6.94-7.
06 (m, 3H), 7.39 (d, J = 8.5Hz, 2H), 7.62 (t, J = 7.7Hz, 1H) IR (neat, cm ^-1 ) 2960,1595,1570,1420,1370,1280, 1180,1015

Example 14 O- (4-tert-butylphenyl) = N-methyl-
N- [3- (2-bromoethoxy) phenyl] thiocar
Synthesis of Bamate (Compound No. 996) O- (4-tert-butylphenyl) = N-methyl-
N- (3-hydroxyphenyl) thiocarbamate
30 g of a dimethylformamide suspension of 30 g, 15.0 g of 1,2-dibromoethane, 11 g of anhydrous potassium carbonate, 34 mg of potassium iodide and 14 mg of tetrabutylammonium hydrogensulfate was stirred at 50 ° C. for 7 hours, and 200 ml of water was added. And extracted with ethyl acetate. (100m
1 × 2) The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 8: 1) to give a pale 1.60 g of a yellow viscous material was obtained.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 3.65 (dt, J = 1.0 Hz, 6.0 Hz, 2H), 3.72 (s, 3H), 4.
30 (t, J = 6.0Hz, 2H), 6.80-7.12 (m, 5H), 7.27-7.45 (m, 3H)

Example 15 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [3- [N-methyl-N- (3-thienyl)
Amino] propoxy] phenyl] thiocarbamate
Compound No. 35) To a solution of N- (3-thienyl) -N-methyl-3- [3- (methylamino) phenoxy] propylamine (200 mg) in acetonitrile (3 ml) at room temperature, p- (tert-butylphenyl) = 3 ml of an acetonitrile solution of 167 mg of chlorothioformate was added dropwise, followed by stirring for 1 hour. Saturated sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
6: 1) to give 329 mg of the yellow viscous target compound.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.35 (s, 9H), 1.96-2.16 (m, 2H), 2.90 (s, 3H), 3.44 (t, J = 7.
0Hz, 2H) 3.75 (brs, 3H), 4.05 (t, J = 6.1Hz, 2H), 5.96 (dd, J =
1.5,3.0Hz, 1H), 6.77-7.14 (m, 6H), 7.15-7.48 (m, 4H) IR (neat, cm ^-1 ) 2950,1590,1540,1480,1465,1370,1230,1200,1170 EIMS m / z 468 (M ⁺ ) The following compound was synthesized in the same manner as in Example 15 using the corresponding starting compound.

O- [6- (1,2,3,4-tetrahydrid
Ronaphthyl)] = N-methyl-N- [3- [3- [N-
Methyl-N- (3-thienyl) amino] propoxy] f
Phenyl] thiocarbamate (Compound No. 36) Starting amine compound: N- (3-thienyl) -N-methyl-3- [3- (methylamino) phenoxy] propylamine Starting chlorothioformate compound: 6- (1, 2,3
4-tetrahydronaphthyl) = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.74-1.90 (m, 4H), 1.96-2.18 (m, 2H), 2.68-2.85 (m, 4H), 2 .
90 (s, 3H) 3.45 (t, J = 7.0Hz, 2H), 3.75 (brs, 3H), 4.05 (t, J =
6.1Hz, 2H), 5.97 (dd, J = 1.6,3.1Hz, 1H), 6.71-7.00 (m, 6H)
7.08 (d, J = 8.0Hz, 1H), 7.21 (dd, J = 3.1,5.2Hz, 1H), 7.35 (t,
J = 7.9Hz, 1H) IR (neat, cm ^-1 ) 2920,1600,1545,1480,1375,1215,1170 EIMS m / z 466 (M ⁺ ), 126 CIMS (isobutane) m / z 467 (MH ⁺ ) Pale yellow oil

O- [4- (1-methoxy-1-methyl)
Tyl) phenyl] = N-methyl-N- [3- [3- [N
-Methyl-N- (3-thienyl) amino] propoxy]
Phenyl] thiocarbamate (Compound No. 57) Starting amine compound: N- (3-thienyl) -N-methyl-3- [3- (methylamino) phenoxy] propylamine Starting chlorothioformate compound: 4- (1- Methoxy-1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.35 (s, 6H), 1.98-2.16 (m, 2H), 2.88 (s, 3H), 3.07 ( s, 3H),
3.42 (t, J = 7.0Hz, 2H), 3.72 (brs, 3H), 4.04 (t, J = 6.1Hz, 2
H), 5.94 (dd, J = 1.5,3.0Hz, 1H), 6.75-7.11 (m, 6H), 7.17 (d
d, J = 3.2,5.1Hz, 1H), 7.24-7.48 (m, 3H) IR (neat, cm ^-1 ) 2970,2930,1600,1545,1480,1380,1230,1200,1170 EIMS m / z 484 (M ⁺ ), 126 CIMS (isobutane) m / z 485 (MH ⁺ ) yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [3- (N-methyl-N-fe
Nylamino) propoxy] phenyl] thiocarbamate
(Compound No. 1) Raw material amine compound: N-phenyl-N-methyl-3-
[3- (Methylamino) phenoxy] propylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 9H), 1.96 2.19 (m, 2H), 2.96 (s, 3H), 3.57 (t, J = 7.0
Hz, 2H), 3.74 (brs, 3H), 4.04 (t, J = 5.9Hz, 2H), 6.62-6.81
(m, 3H), 6.81-7.10 (m, 5H), 7.15-7.48 (m, 5H) IR (neat, cm ^-1 ) 2960,1600,1510,1480,1380,1235,1205,1170 pale yellow oil

O- [4- [1,1-dimethyl-2- (e
Lumylamino) ethyl] phenyl] = N-methyl-N-
[3- [2- [N-methyl-N- (3-thienyl) amido]
[No] ethoxy] phenyl] thiocarbamate (compound number
No. 408) Raw material amine compound: N-methyl-N- (3-thienyl)
-2- [3- (Methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- [1,1-dimethyl-2- (formylamino) ethyl] phenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.33 (s, 6H), 2.98 (s, 3H), 3.25and3.48 (2d, J = 5.5Hz, 2H),
3.56-3.74 (m, 5H), 4.13 (t, J = 5.5Hz, 2H), 5.25and5.38 (2b
s, 1H), 5.94 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.77-7.05 (m, 5H), 7.
08-7.43 (m, 5H) 7.81-8.12 (m, 1H) IR (neat, cm ^-1 ) 3300,2960,1680,1545,1480,1380,1210 Yellow viscous substance

O- [4- (2-acetylamino-1,1
-Dimethylethyl) phenyl] = N-methyl-N- [3
-[2- [N-methyl-N- (3-thienyl) amino]
[Ethoxy] phenyl] thiocarbamate (Compound No. 4
10) Raw material amine compound: N-methyl-N- (3-thienyl)
-2- [3- (Methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (2-acetylamino-1,1-dimethylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.31 (s, 6H), 1.87 (s, 3H), 2.98 (s, 3H), 3.43and3.44 (2s, 2
H), 3.56-3.73 (m, 5H) 4.13 (t, J = 6.0Hz, 2H), 5.14and5.22 (2
s, 1H), 5.94 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.78-7.42 (m, 10H) IR (neat, cm ^-1 ) 3300,2960,1655,1545,1480,1380,1210 Light Yellow viscous material

O- [4- (2-hydroxy-1,1-di
Methylethyl) phenyl] = N-methyl-N- [3-
[2- [N-methyl-N- (3-thienyl) amino] d
Toxy] phenyl] thiocarbamate (Compound No. 38
9) Raw material amine compound: N-methyl-N- (3-thienyl)
-2- [3- (Methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (2-hydroxy-1,1-dimethylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.19-1.27 (m, 1H), 1.32 (s, 6H), 2.98 (s, 3H), 3.54-3.60 (m,
2H), 3.64 (t, J = 6.0Hz, 2H), 3.70 (s, 3H) 4.12 (t, J = 6.0Hz, 2
H), 5.92-5.95 (m, 1H), 6.78-7.00 (m, 6H), 7.20-7.38 (m, 4H) IR (neat, cm ^-1 ) 3420,2960,1600,1545,1475,1380,1210 Pale brown oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N- (2,2,2-
Trifluoroethyl) amino] ethoxy] phenyl] thio
Carbamate (Compound No. 293) Raw material amine compound: N- (2,2,2-trifluoroethyl) -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = Chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9 H), 1.78 (bs, 1 H), 3.13 (t, J = 5.0 Hz, 2 H), 3.27 (q, J
= 9.5Hz, 2H), 3.71 (s, 3H), 4.07 (t, J = 5.0Hz, 2H), 6.81-6.99
(m, 5H), 7.26-7.42 (m, 3H) IR (neat, cm ^-1 ) 3350,2960,1600,1480,1380,1265,1210,1180 Colorless oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N- (3-thienyl)
Amino] ethoxy] phenyl] thiocarbamate (compound
Product number 435) Starting amine compound: N- (3-thienyl) -2- [3-
(Methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 3.48-3.53 (m, 2H), 3.73 (s, 3H), 4.11 (bs, 1H),
4.19 (t, J = 5.0Hz, 2H), 6.02-6.06 (m, 1H), 6.64-6.68 (m, 1
H), 6.77-7.13 (m, 5H), 7.16-7.44 (m, 4H) IR (neat, cm ^-1 ) 3380,2960,1600,1480,1380,1210 EIMS m / z 440 (M ⁺ ), 112 Yellow oil

Example 16 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N-[(3-thienyl
L) Methyl] amino] ethoxy] phenyl] thiocarba
Synthesis of mate (Compound No. 186) N-methyl-N-[(3-thienyl) methyl] -2-
[3- (methylamino) phenoxy] ethylamine
In 10 ml of a 14 g solution of tetrahydrofuran, 2.0 M
Lithium diisopropylamide solution (heptane, tetrahydrofuran, ethylbenzene mixed solution) 0.25 ml
Was added dropwise at −80 ° C., 5 ml of a tetrahydrofuran solution of 110 mg of (4-tert-butylphenyl) = chlorothioformate was added dropwise, and the mixture was stirred for 20 minutes. After the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then subjected to silica gel column chromatography.
Purification with (developing solvent; methylene chloride: ethyl acetate = 10: 1) gave 170 mg of a colorless oil.

¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 2.36 (s, 3H), 2.82 (t, J = 5.9 Hz, 2H), 3.60-3.78
(m, 5H), 4.08 (t, J = 5.9Hz, 2H), 6.79-7.19 (m, 7H), 7.22-7.4
3 (m, 4H) IR (neat, cm ^-1 ) 2960,1600,1480,1380,1210,1175 The following compounds were synthesized in the same manner as in Example 16 using the corresponding starting compounds.

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-ethyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 253) Starting amine compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-tert -Butylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.10 (t, J = 7.0 Hz, 3 H), 1.30 (s, 9 H), 2.64 (q, J = 7.0 Hz, 2 H) ,
2.88 (t, J = 6.0Hz, 2H), 3.71 (s, 3H), 3.73 (s, 2H), 4.01 (t, J =
6.0Hz, 2H), 6.77-6.98 (m, 5H), 7.07 (d, J = 5.0Hz, 1H), 7.13
(s, 1H) 7.24-7.38 (m, 4H) IR (neat, cm ^-1 ) 2960,1605,1470,1380,1210,1170 EIMS m / z 482 (M ⁺ , 15), 154 (82), 97 (100) CIMS (isobutane) m / z 483 (MH ⁺ ) pale yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 241) Starting amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-trimethylsilyl Phenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.25 (s, 9H), 2.39 (s, 3H), 2.87 (brs, 2H), 3.71 (brs, 5H), 4.
12 (brs, 2H) 6.76-7.60 (m, 11H) IR (neat, cm ^-1 ) 2960,1603,1590,1490,1385,1238,1210,1175,1125 1140,855,760 EIMS m / z 484 (M ⁺ , 7), 140 (60), 97 (100) CIMS (isobutane) m / z 485 (MH ⁺ ) pale yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-ethyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 258) Starting amine compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-trimethylsilyl Phenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.25 (s, 9 H), 1.10 (t, J = 7.0 Hz, 3 H), 2.65 (q, J = 7.0 Hz, 2 H),
2.88 (t, J = 6.0Hz, 2H), 3.72 (s, 3H), 3.74 (s, 2H), 4.02 (t, J =
6.0Hz, 2H), 6.78-6.92 (m, 3H) 6.98-7.16 (m, 4H), 7.26-7.32
(m, 2H), 7.46-7.54 (m, 2H) IR (neat, cm ^-1 ) 2960,1600,1485,1380,1210,1170 EIMS m / z 498 (M ⁺ , 3), 154 (43), 97 (100) CIMS (isobutane) m / z 499 (MH ⁺ ) yellow oil

O- [4- (1-methoxy-1-methyl)
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Ethyl-N-[(3-thienyl) methyl] amino] e
Toxy] phenyl] thiocarbamate (Compound No. 26
4) Raw material amine compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (1-methoxy-1-methyl) Ethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.11 (t, J = 7.0 Hz, 3 H), 1.52 (s, 6 H), 2.65 (q, J = 7.0 Hz, 2 H) ,
2.89 (t, J = 6.0Hz, 2H) 3.05 (s, 3H), 3.58-3.80 (m, 5H), 4.03
(t, J = 6.0Hz, 2H), 6.79-6.94 (m, 3H) 6.96-7.10 (m, 3H), 7.14
(brs, 1H), 7.26-7.46 (m, 4H) IR (neat, cm ^-1 ) 2960,1600,1480,1375,1205,1165 EIMS m / z 498 (M ⁺ , 11), 154 (75), 97 (100) CIMS (isobutane) m / z 499 (MH ⁺ ) yellow oil

O- [4- (1-cyano-1-methylethyl)
L) phenyl] = N-methyl-N- [3- [2- [N-
Ethyl-N-[(3-thienyl) methyl] amino] eth
[Xy] phenyl] thiocarbamate (Compound No. 27
0) Starting amine compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1-cyano-
1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.10 (t, J = 7.0 Hz, 3H), 1.72 (s, 6H), 2.65 (q, J = 7.0 Hz) , 2H),
2.88 (t, J = 6.0Hz, 2H) 3.72 (s, 3H), 3.74 (s, 2H), 4.02 (q, J =
6.0Hz, 2H), 6.78-6.92 (m, 3H), 7.01-7.10 (m, 3H), 7.14 (br
s, 1H), 7.25-7.34 (m, 2H), 7.42-7.54 (m, 2H) IR (neat, cm ^-1 ) 2960,2230,1600,1480,1380,1210 EIMS m / z 493 (M ⁺ , 7), 154 (58), 97 (100) CIMS (isobutane) m / z 494 (MH ⁺ ) yellow oil

O- [4- (1,1-dimethyl-2-methoate)
[Xyethyl) phenyl] = N-methyl-N- [3- [2
-[N-ethyl-N-[(3-thienyl) methyl] amido
[No] ethoxy] phenyl] thiocarbamate (compound number
No. 256) Raw material amine compound: N-ethyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (1,1-dimethyl- 2-methoxyethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.11 (t, J = 7.0 Hz, 3H), 1.32 (s, 6H), 2.65 (q, J = 7.0 Hz) , 2H),
2.89 (t, J = 6.0Hz, 2H), 3.29 (s, 3H), 3.35 (s, 2H), 3.60-3.77
(m, 5H), 4.02 (t, J = 6.0Hz, 2H), 6.78-7.00 (m, 5H), 7.06-7.1
0 (m, 1H), 7.13-7.17 (m, 1H), 7.26-7.46 (m, 4H) IR (neat, cm ^-1 ) 2955,1600,1480,1380,1210 EIMS m / z 512 (M ⁺ , 5), 154 (52), 97 (100) CIMS (isobutane) m / z 513 (MH ⁺ ) yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N- (2-fluoro
Tyl) -N-[(3-thienyl) methyl] amino] eth
[Xy] phenyl] thiocarbamate (Compound No. 26
2) Raw material amine compound: N- (2-fluoroethyl) -N-
[(3-thienyl) methyl)]-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-tert-butylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.30 (s, 9H), 2.93 (dt, J = 5.0,26.5Hz, 2H), 3.00 (t, J = 5.5H
z, 2H), 3.71 (s, 3H) 3.83 (s, 2H), 4.04 (t, J = 5.5Hz, 2H), 4.52
(dt, J = 5.0,47.5Hz, 2H), 6.76-6.98 (m, 5H), 7.07 (d, J = 5.0H
z, 1H), 7.13 (s, 1H), 7.23-7.42 (m, 4H) IR (neat, cm ^-1 ) 2950,1600,1480,1380,1210 Yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N- (2-fluoro
Tyl) -N-[(3-thienyl) methyl] amino] eth
[Xy] phenyl] thiocarbamate (Compound No. 26
3) Raw material amine compound: N- (2-fluoroethyl) -N-
[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-trimethylsilylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.24 (s, 9H), 2.88-3.06 (m, 4H), 3.71 (s, 3H), 3.83 (s, 2H),
4.04 (t, J = 5.5Hz, 2H), 4.52 (dt, J = 5.0,47.5Hz, 2H), 6.76-
6.93 (m, 3H) 7.00 (d, J = 7.0Hz, 2H), 7.07 (d, J = 5.0Hz, 1H), 7.
14 (s, 1H) 7.24-7.34 (m, 2H), 7.49 (d, J = 7.0Hz, 2H) IR (neat, cm ^-1 ) 2950,1590,1480,1380,1205, yellow oil

O- (4-trifluoromethylphenyl)
= N-methyl-N- [3- [2- [N-methyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 192) Starting amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-tri Fluoromethylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.36 (s, 3H), 2.82 (t, J = 6.0 Hz, 2H), 3.65 (s, 2H), 3.71 (s, Three
H), 4.08 (t, J = 6.0Hz, 2H), 6.83-6.89 (m, 3H), 7.06-7.13 (m,
4H) 7.26-7.34 (m, 2H), 7.60-7.61 (m, 2H) IR (neat, cm ^-1 ) 2930,1600,1480,1380,1325,1240,1210,1160 Brown oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [6- [2- [N-methyl-N- (3
-Thienyl) amino] ethoxy] -2-pyridyl] thio
Carbamate (Compound No. 470) Starting amine compound: N-methyl-N- (3-thienyl)
-2- [2- (methylamino) -6-pyridyloxy]
Ethylamine Raw material chlorothioformate compound: 4-trimethylsilylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.26 (s, 9H), 2.98 (s, 3H), 3.6
3 (t, J = 6.0 Hz, 2H), 3.73 (s, 3
H) 4.49 (t, J = 6.0 Hz, 2H), 5.96
−5.97 (m, 1H), 6.63-6.65 (m, 1
H), 6.84-6.86 (m, 1H) 7.00 (d,
J = 7.5 Hz, 1 H), 7.06 (d, J = 8.0 H)
z, 2H), 7.21-7.22 (m, 1H) 7.52.
(D, J = 8.0 Hz, 2H), 7.61 (t, J =
7.5 Hz, 1 H) IR (neat, cm ^-1 ) 2950, 1545, 1460, 1245, 1365,
1260, 1180, 1170, 850, 840 CIMS (isobutane) m / z 472 (M
H +) pale yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N- (F
Phenylmethyl) amino] ethoxy] phenyl] thiocar
Bamate (Compound No. 123) Raw material amine compound: N-methyl-N- (phenylmethyl) -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothiophore mate ^{1 H-NMR (500MHz, CDCl} 3, δppm) 1.30 (s, 9H), 2.35 (s, 3H), 2.84 (t, J = 6.0Hz, 2H), 3.62 (s, 2
H), 3.71 (s, 3H), 4.09 (t, J = 6.0Hz, 2H), 6.78-6.98 (m, 4H),
7.20-7.44 (m, 9H) IR (neat, cm ^-1 ) 2960,1605,1510,1480,1380,1215,1170 Yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[(2-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 284) Starting amine compound: N-methyl-N-[(2-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-tert -Butylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9 H), 2.41 (s, 3 H), 2.86 (t, J = 5.5 Hz, 2 H), 3.72 (s, Three
H), 3.87 (s, 2H), 4.10 (t, J = 5.5Hz, 2H), 6.78-7.00 (m, 7H),
7.18-7.70 (m, 4H) IR (neat, cm ^-1 ) 2960,1605,1480,1385,1215,1175 yellow oil

O- [4- (1-Methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N-[(3-thienyl) methyl] amino] e
Toxi] phenyl] thiocarbamate (Compound No. 21
9) Starting amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1-methoxy-1-methyl) Ethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.51 (s, 6H), 2.36 (s, 3H), 2.81 (t, J = 5.5 Hz, 2H), 3.04 ( s, 3
H), 3.58-3.78 (m, 5H) 4.07 (t, J = 5.5Hz, 2H), 6.79-7.16 (m, 7
H), 7.24-7.48 (m, 4H) IR (neat, cm ^-1 ) 2970,2930,1600,1480,1380,1200,1165 yellow viscous substance

O- [4- (1-cyano-1-methylethyl)
L) phenyl] = N-methyl-N- [3- [2- [N-
Methyl-N-[(3-thienyl) methyl] amino] eth
[Xy] phenyl] thiocarbamate (Compound No. 22
3) Raw material amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (1-cyano-
1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.71 (s, 6H), 2.36 (s, 3H), 2.81 (t, J = 5.5 Hz, 2H), 3.59 -3.74
(m, 5H) 4.07 (t, J = 5.5Hz, 2H), 6.73-7.58 (m, 11H) IR (neat, cm ^-1 ) 2980,2930,2230,1600,1480,1380 Yellow viscous substance

O- [6- (1,2,3,4-tetrahydrid
Ronaphthyl)] = N-methyl-N- [3- [2- [N-
Methyl-N-[(3-thienyl) methyl] amino] eth
[Xy] phenyl] thiocarbamate (Compound No. 18
7) Raw material amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 6- (1,2,3,6)
4-tetrahydronaphthyl) = chlorothioformate ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.63-1.90 (m, 4H), 2.37 (s, 3H), 2.62-2.84 (m, 6H), 3.59-3 .
79 (m, 5H), 4.08 (t, J = 5.9Hz, 2H) 6.61-7.19 (m, 8H), 7.21-7.
40 (m, 2H) IR (neat, cm ^-1 ) 2930,1600,1380,1220,1170 pale yellow oil

O- (5-Indanyl) = N-methyl-N
-[3- [2- [N-methyl-N-[(3-thienyl)
Methyl] amino] ethoxy] phenyl] thiocarbame
(Compound No. 188) Raw material amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 5-indanyl = chlorothio Formate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.03-2.13 (m, 2H), 2.36 (s, 3H), 2.81 (t, J = 5.5 Hz, 2H), 2.83
-2.96 (m, 4H), 3.58-3.74 (m, 5H) 4.07 (t, J = 5.5Hz, 2H), 6.70
-6.98 (m, 5H), 7.02-7.37 (m, 5H) IR (neat, cm ^-1 ) 2940,1600,1485,1380,1225,1160 pale yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [2- [2- [N-methyl-N-
[(3-thienyl) methyl] amino] ethoxy] ethy
Thiocarbamate (Compound No. 621) Starting amine compound: N-methyl-2- [2- [N-methyl-N-[(3-thienyl) methyl] amino] ethoxy] ethylamine Starting chlorothioformate compound: 4 -Tert-Butylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 9H), 2.30 and 2.31 (2s, 3H), 2.58-2.63 (m, 2H), 3.
36 and 3.47 (2s, 3H), 3.56-3.63 (m, 4H), 3.70 and 3.80 (2
t, J = 5.5Hz, 2H), 3.88 and 4.07 (2t, J = 5.5Hz, 2H) 6.95-7.1
4 (m, 4H), 7.22-7.28 (m, 1H), 7.37-7.40 (m, 2H) IR (neat, cm ^-1 ) 2960,2860,1510,1400,1215 Yellow oil

O- [4- (1-Methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [2- [2- [N
-Methyl-N-[(3-thienyl) methyl] amino] e
Toxi] ethyl] thiocarbamate (Compound No. 63
5) Raw material amine compound: N-methyl-2- [2- [N-methyl-N-[(3-thienyl) methyl] amino] ethoxy] ethylamine Raw material chlorothioformate compound: 4- (1-methoxy-1) -Methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.54 (s, 6H), 2.30 and 2.31 (2s, 3H), 2.58-2.63 (m, 2H), 3.
08 (s, 3H), 3.37 and 3.47 (2s, 3H), 3.56-3.63 (m, 4H), 3.71
and 3.81 (2t, J = 5.5Hz, 2H), 3.89 and 4.07 (2t, J = 5.5Hz,
2H), 6.95-7.28 (m, 5H), 7.37-7.40 (m, 2H) IR (neat, cm ^-1 ) 2970,2940,2860,1505,1400,1200,1120 yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [2- [N-methyl-N-[(3-thio
Enyl) methyl] carbamoylmethoxy] ethyl] thio
Carbamate (Compound No. 774) Starting amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [2- (methylamino) ethoxy]
Acetamide Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 9H), 2.91 and 2.92 (2s, 1.8H), 2.98 and 2.98 (2
s, 1.2H), 3.37 and 3.46 (2s, 1.2H) 3.40 and 3.49 (2s, 1.8
H), 3.80-4.17 (m, 4H), 4.23 and 4.26 (2s, 0.8H), 4.25 and
4.29 (2s, 1.2H) 4.50 and 4.52 (2s, 0.8H), 4.57 and 4.58
(2s, 1.2H), 6.90-7.20 (m, 4H), 7.26-7.40 (m, 3H) IR (neat, cm ^-1 ) 2960,1660,1510,1400,1210,1110 Yellow oil

O- [4- (1-Methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [2- [N-methyl
Ru-N-[(3-thienyl) methyl] carbamoylmeth
[Xy] ethyl] thiocarbamate (Compound No. 773) Starting amine compound: N-methyl-N-[(3-thienyl) methyl] -2- [2- (methylamino) ethoxy]
Acetamide Raw material chlorothioformate compound: 4- (1-methoxy-1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.54 (s, 6H), 2.91 and 2.92 (2s , 1.8H), 2.98 and 2.98 (2
s, 1.2H), 3.08 (s, 3H) 3.38 and 3.47 (2s, 1.2H), 3.42 and
3.49 (2s, 1.8H), 3.80-4.16 (m, 4H), 4.23 and 4.27 (2s, 0.8H
H), 4.25 and 4.29 (2s, 1.2H), 4.50 and 4.53 (2s, 0.8H),
4.57 and 4.58 (2s, 1.2H), 6.90-7.44 (m, 7H) IR (neat, cm ^-1 ) 2970,2930,1660,1500,1400,1210 Yellow oil

O- [4- (1-methoxy-1-methyl)
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N-[(3-thienyl) methyl] amino] e
Toxi] propyl] thiocarbamate (Compound No. 59
7) Raw material amine compound: N-methyl-3- [2- [N-methyl-N-[(3-thienyl) methyl] amino] ethoxy] propylamine Raw material chlorothioformate compound: 4- (1-methoxy- 1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.54 (s, 6H), 1.94-2.08 (m, 2H), 2.26 and 2.29 (2s, 3H), 2.
56 and 2.60 (2t, J = 5.5Hz, 2H) 3.08 (s, 3H), 3.29 and 3.42
(2s, 3H), 3.46-3.63 (m, 6H), 3.79 and 3.97 (2t, J = 7.5Hz, 2
H) 6.95-7.28 (m, 5H), 7.37-7.40 (m, 2H) IR (neat, cm ^-1 ) 2970,2930,2880,1500,1400,1200,1110 yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[(4-Methyl-3-thienyl) methyl] amino] etho
[Xy] phenyl] thiocarbamate (Compound No. 29
7) Starting amine compound: N-methyl-N-[(4-methyl-3-thienyl) methyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-trimethylsilylphenyl = chloro Thioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 0.25 (s, 9H), 2.23 (s, 3H), 2.34 (s, 3H), 2.83 (t, J = 6.0H
z, 2H), 3.52 (s, 2H), 3.72 (s, 3H), 4.07 (t, J = 6.0Hz, 2H),
6.80-7.12 (m, 7H), 7.28-7.58 (m, 3H) IR (neat, cm ^-1 ) 2950, 1600, 1585, 1485, 1380, 1205, 1170 Light yellow oil

Example 17 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N- (3-thienyl)
Amino] ethoxy] phenyl] thiocarbamate (compound
Compound No. 370) To a solution of 20 mg of N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine in 5 ml of acetonitrile, 18 mg of potassium carbonate was added.
At room temperature, 3 ml of a solution of 167 mg of p- (tert-butylphenyl) = chlorothioformate in acetonitrile was added dropwise. After stirring for 1 hour, water was added to the reaction solution, and extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent;
The residue was purified by hexane: ethyl acetate = 6: 1) to obtain 33 mg of a yellow viscous target product.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 32 (s, 9H), 3.00 (s, 3H), 3.
59-3.78 (m, 5H), 4.14 (t, J = 5.
6. Hz, 2H), 5.92-5.99 (m, 1H)
78-7.05 (m, 6H), 7.20-7.43
(M, 4H) IR (neat, cm ^-1 ) 2960, 1600, 1550, 1480, 1380,
1210, 1170 EIMS m / z 454 (M ⁺ , 5), 126 (10
0) CIMS (isobutane) m / z 455 (M
H ⁺ ) The following compounds were synthesized in the same manner as in Example 17 using the corresponding starting compounds.

O- [6- (1,2,3,4-tetrahydrid
Ronaphthyl)] = N-methyl-N- [3- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] fe
Nyl] thiocarbamate (Compound No. 371) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 6- (1,2 , 3,
4-tetrahydronaphthyl) = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.76 (bs, 4H), 2.72 (bs, 4H), 2.98 (s, 3H), 3.63 (t, J = 6.0 Hz,
2H), 3.69 (s, 3H), 4.12 (t, J = 6.0Hz, 2H), 5.92-5.96 (m, 1H),
6.62-7.10 (m, 7H), 7.19-7.32 (m, 2H) IR (neat, cm ^-1 ) 2930,1600,1550,1480,1380,1220,1170 Colorless viscous substance

O- [1,3,3-Trimethyl-6-yne
Dorinyl] = N-methyl-N- [3- [2- [N-methyl
Ru-N- (3-thienyl) amino] ethoxy] phenyl
Thiocarbamate (Compound No. 426) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 1,3,3- Trimethyl-6-indolinyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.27 (s, 6H), 2.72 (s, 3H), 2.99 (s, 3H), 3.11 (s, 2H), 3.64
(t, J = 6.5Hz, 2H) 3.70 (s, 3H), 4.13 (t, J = 6.5Hz, 2H), 5.97
(s, 1H), 6.08 (s, 1H), 6.30 (s, 1H) 6.78-6.92 (m, 5H), 7.21-
7.32 (m, 2H) IR (neat, cm ^-1 ) 2960,1610,1490,1380 Yellow oil

O- [2-oxo-1,3,3-trimethyl
Ru-6-indolinyl] = N-methyl-N- [3- [2
-[N-methyl-N- (3-thienyl) amino] ethoxy
[S] phenyl] thiocarbamate (Compound No. 422) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 2-oxo- 1,
3,3-Trimethyl-6-indolinyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.42 (s, 6H), 3.06 (s, 3H), 3.24 (s, 3H), 3.72 (t , J = 6.5Hz, 2
H), 3.78 (s, 3H) 4.21 (t, J = 6.5Hz, 2H), 6.06 (s, 1H), 6.60 (s,
1H), 6.72-6.78 (m, 1H), 6.86-7.00 (m, 4H), 7.18-7.42 (m, 3
H) IR (KBr, cm ^-1 ) 2960,2930,1715,1615,1490,1380 Yellow glassy solid

O- (4-trifluoromethylphenyl)
= N-methyl-N- [3- [2- [N-methyl-N-
(3-thienyl) amino] ethoxy] phenyl] thioca
Rubamate (Compound No. 376) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4-trifluoromethylphenyl = chlorothio Formate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.99 (s, 3H), 3.65 (t, J = 6.0 Hz, 2H), 3.71 (s, 3H), 4.14 (t, J =
6.0Hz, 2H) 5.95-5.96 (m, 1H), 6.80-6.91 (m, 4H), 7.12-7.34
(m, 4H), 7.61-7.62 (m, 2H) IR (neat, cm ^-1 ) 2930,1600,1550,1480,1380,1325,1235,1210,1170,1120,
1060 pale yellow oil

O- [4- (1-Methoxy-1-methyl)
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N- (3-thienyl) amino] ethoxy] f
Enyl] thiocarbamate (Compound No. 392) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1-methoxy) 1-Methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.53 (s, 6H), 3.00 (s, 3H), 3.06 (s, 3H), 3.59-3.78 (m , 5H),
4.14 (t, J = 5.8Hz, 2H) 5.92-5.99 (m, 1H), 6.74-7.10 (m, 6H),
7.19-7.48 (m, 4H) IR (neat, cm ^-1 ) 2980,1600,1550,1485,1380,1210 Light brown viscous substance

O- [4- (1-Cyano-1-methylethyl)
L) phenyl] = N-methyl-N- [3- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] fe
Nyl] thiocarbamate (Compound No. 396) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- (1-cyano −
1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.72 (s, 6H), 2.99 (s, 3H), 3.58-3.73 (m, 5H), 4.13 (t, J = 5.5
Hz, 2H), 5.95 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.74-7.56 (m, 10H) IR (neat, cm ^-1 ) 2980,2930,2230,1600,1550,1480,1380, 1205 EIMS m / z 465 (M ⁺ ), 126 brown viscous substance

O- [4- (1,1-dimethyl-2-methoate)
[Xyethyl) phenyl] = N-methyl-N- [3- [2
-[N-methyl-N- (3-thienyl) amino] ethoxy
[S] phenyl] thiocarbamate (Compound No. 393) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1 , 1-dimethyl-2-methoxyethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 6H), 2.98 (s, 3H), 3.28 (s, 3H), 3.35 (s, 2H), 3.64
(t, J = 6.0Hz, 2H), 3.70 (s, 3H), 4.12 (t, J = 6.0Hz, 2H), 5.93-
5.95 (m, 1H), 6.78-6.96 (m, 6H), 7.21-7.37 (m, 4H) IR (neat, cm ^-1 ) 2960,2930,2870,1600,1550,1480,1380,1210,1170, 1115 EIMS m / z 484 (M ⁺ , 3), 126 (100) CIMS (isobutane) m / z 485 (MH ⁺ ) yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N- (3
-Thienyl) amino] ethoxy] phenyl] thiocarba
Mate (Compound No. 414) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-trimethylsilylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.24 (s, 9H), 2.98 (s, 3H), 3.64 (t, J = 6.0 Hz, 2H), 3.70 (s, 3
H), 4.12 (t, J = 6.0Hz, 2H), 5.93-5.95 (m, 1H), 6.78-6.86 (m,
3H), 6.89 (d, J = 7.0Hz, 1H), 6.99 (d, J = 7.0Hz, 2H), 7.20-7.2
4 (m, 1H), 7.28-7.31 (m, 1H), 7.49 (d, J = 7.0Hz, 2H) IR (neat, cm ^-1 ) 2950,1580,1550,1480,1380,1210,1170,1120 CIMS (isobutane) m / z 471 (MH ⁺ ) colorless viscous substance

O- [4- (1-methoxycarbonyl-1
-Methylethyl) phenyl] = N-methyl-N- [3-
[2- [N-methyl-N- (3-thienyl) amino] d
Toxy] phenyl] thiocarbamate (Compound No. 39
8) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1-methoxycarbonyl-1-methylethyl) Phenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.56 (s, 6H), 2.97 (s, 3H), 3.62 (s, 3H), 3.64 (t, J = 5.5 Hz, 2
H), 3.70 (s, 3H), 4.11 (t, J = 5.5 Hz, 2H) 5.94 (dd, J = 1.5 Hz, 3.
0Hz, 1H), 6.76-7.01 (m, 6H), 7.20-7.43 (m, 4H) IR (neat, cm ^-1 ) 2980,2950,1730,1600,1545,1480,1380,1210 Light yellow viscous substance

O- [4- (1-Acetyl-1-methyl)
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N- (3-thienyl) amino] ethoxy] f
Enyl] thiocarbamate (Compound No. 404) Starting amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4- (1-acetyl) -1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.47 (s, 6H), 1.91 (s, 3H), 2.99 (s, 3H), 3.64 (t, J = 6.0Hz, 2
H), 3.69 (s, 3H), 4.13 (t, J = 6.0 Hz, 2H) 5.91-5.97 (m, 1H), 6.
75-7.02 (m, 6H), 7.16-7.34 (m, 4H) IR (neat, cm ^-1 ) 2960,1705,1595,1545,1480,1375,1205,1170,1120 pale yellow oil

O- [4- [1- (N, N-dimethylcal)
Bamoyl) -1-methylethyl] phenyl] = N-methyl
Ru-N- [3- [2- [N-methyl-N- (3-thienyl
Ru) amino] ethoxy] phenyl] thiocarbamate
(Compound No. 403) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4- [1- (N, N)
-Dimethylcarbamoyl) -1-methylethyl] phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.52 (s, 6H), 2.49 (bs, 3H), 2.91 (bs, 3H), 2.98 (s, 3H), 3.63
(t, J = 5.5Hz, 2H), 3.68 (s, 3H), 4.13 (t, J = 5.5Hz, 2H), 5.92
(dd, J = 1.5Hz, 3.0Hz, 1H), 6.75-7.0 (m, 6H), 7.10-7.36 (m, 4
H) IR (neat, cm ^-1 ) 2990,2940,1630,1555,1490,1380,1210 pale yellow viscous substance

O- (4-t-butylphenyl) = N-meth
Tyl-N- [3- [2- [N- (3-methoxyphenyl
L) -N-methylamino] ethoxy] phenyl] thioca
Rubamate (Compound No. 344) Starting amine compound: N- (3-methoxyphenyl) -N
-Methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-t-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H) ), 3.05 (s, 3H), 3.70 (s, 3H), 3.75 (t, J = 6.0Hz, 2
H), 3.80 (s, 3H), 4.14 (t, J = 6.0Hz, 2H), 6.28-6.32 (m, 2H),
6.36-6.41 (m, 1H), 6.71-6.99 (m, 5H), 7.16 (t, J = 8.5Hz, 1
H), 7.22-7.45 (m, 3H) IR (neat, cm ^-1 ) 2960,1615,1500,1490,1380,1210,1175 EIMS m / s 478 (M ⁺ ), 150 Brown oil

O- (4-t-butylphenyl) = N-meth
Cyl-N- [3- [2- [N-methyl-N- (3-meth
Tylthiophenyl) amino] ethoxy] phenyl] thio
Carbamate (Compound No. 351) Raw material amine compound: N-methyl-N- (3-methylthiophenyl) -2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-t-butylphenyl = chloro Thioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 2.48 (s, 3H), 3.05 (s, 3H), 3.55-3.85 (m, 5H),
4.14 (t, J = 4.5Hz, 2H), 6.54-6.70 (m, 3H), 6.80-6.98 (m, 5H)
7.17 (t, J = 8.5Hz, 1H), 7.24-7.42 (m, 3H) Oil

O- (4-t-butylphenyl) = N-meth
Cyl-N- [3- [2- [N-methyl-N- [2-
(3-thienyl) ethyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 208) Starting amine compound: N-methyl-N- [2- (3-thienyl) ethyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4 -t- butylphenyl = chlorothioformate ^{1 H-NMR (500MHz, CDCl} 3, δppm) 1.30 (s, 9H), 2.42 (s, 3H), 2.72-2.92 (m, 6H), 3.72 (s, 3H ),
4.08 (t, J = 5.5Hz, 2H), 6.80-7.06 (m, 7H), 7.22-7.44 (m, 4H) IR (neat, cm ^-1 ) 2950,1600,1475,1380,1210 CIMS (isobutane) m / z 483 (MH +) yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[2- (3-thienyl) ethyl] amino] ethoxy] f
Phenyl] thiocarbamate (Compound No. 209) Starting amine compound: N-methyl-N- [2- (3-thienyl) ethyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4 -Trimethylsilylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.25 (s, 9H), 2.42 (s, 3H), 2.72-2.91 (m, 6H), 3.72 (s, 3H),
4.08 (t, J = 5.5Hz, 2H), 6.78-7.06 (m, 7H), 7.21-7.36 (m, 2H)
7.44-7.58 (m, 2H) IR (neat, cm ^-1 ) 2950,1585,1480,1380,1205,1170 CIMS (isobutane) m / z 499 (MH +) pale yellow oil

O- (4-t-butylphenyl) = N-meth
Cyl-N- [3- [2- [N-methyl-N- [2-
(2-thienyl) ethyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 231) Starting amine compound: N-methyl-N- [2- (2-thienyl) ethyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4 -T-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9 H), 2.44 (s, 3 H), 2.80 (t, J = 8.2 Hz, 2 H), 2.89 ( t, J =
6.5Hz, 2H) 3.04 (t, J = 8.2Hz, 2H), 3.70 (s, 3H), 4.09 (t, J = 6.
5Hz, 2H), 6.82-7.03 (m, 7H), 7.13 (d, J = 5.4Hz, 1H), 7.28-7.
44 (m, 3H) IR (neat, cm ^-1 ) 2960,1603,1510,1478,1380,1275,1238,1210,1175,1120,
1040,838,695 pale yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[2- (2-thienyl) ethyl] amino] ethoxy] f
Phenyl] thiocarbamate (Compound No. 232) Starting amine compound: N-methyl-N- [2- (2-thienyl) ethyl] -2- [3- (methylamino) phenoxy] ethylamine Starting chlorothioformate compound: 4 -Trimethylsilylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.27 (s, 9 H), 2.43 (s, 3 H), 2.80 (t, J = 8.2 Hz, 2 H), 2.89 (t, J =
6.5Hz, 2H) 3.04 (t, J = 8.2Hz, 2H), 3.72 (s, 3H), 4.09 (t, J = 6.
5Hz, 2H), 6.82-7.08 (m, 7H), 7.13 (d, J = 5.4Hz, 1H), 7.28-7.
58 (m, 3H) IR (neat, cm ^-1 ) 2960,1605,1595,1490,1382,1238,1210,1175,1120,1043,
855,695 pale yellow oil

O- (4-t-butylphenyl) = N-meth
Tyl-N- [3- [2-[(3-thienyl) methylthio]
E] ethoxy] phenyl] thiocarbamate (compound number
No. 269) Starting amine compound: N-methyl-2-[(3-thienyl) methylthio] ethoxyaniline Starting chlorothioformate compound: 4-t-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.32 (s, 9H), 2.83 (t, J = 6.5Hz, 2H), 3.73 (s, 3H), 3.86 (s, 2
H) 4.08 (t, J = 6.5Hz, 2H), 6.79-7.46 (m, 11H) IR (neat, cm ^-1 ) 2970,1603,1590,1485,1380,1290,1235,1215,1180 1125,1110 , 1020,840,780 pale yellow oil

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2-[(3-thienyl) methyl
[Luthio] ethoxy] phenyl] thiocarbamate (compound
Article number 268) Starting amine compound: N-methyl-2-[(3-thienyl) methylthio] ethoxyaniline Starting chlorothioformate compound: 4-trimethylsilylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.24 (s, 9H), 2.81 (t, J = 6.5H)
z, 2H), 3.71 (s, 3H), 3.83 (s, 2
H) 4.06 (t, J = 6.5 Hz, 2H), 6.75
−7.58 (m, 11H) IR (neat, cm ⁻¹ ) 2950, 1600, 1585, 1480, 1445,
1380, 1230, 1205, 1170 1115, 1020, 840 Light yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N- (2
-Methyl-3-thienyl) amino] ethoxy] phenyl
Thiocarbamate (Compound No. 453) Starting amine compound: N- (2-methyl-3-thienyl)
-N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 4-t-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s) , 9H), 2.35 (s, 3H), 2.79 (s, 3H), 3.29 (t, J = 5.5Hz, 2
H), 3.72 (s, 3H), 4.02 (t, J = 5.5Hz, 2H), 6.78-7.04 (m, 7H),
7.26-7.44 (m, 3H) IR (neat, cm ^-1 ) 2960,1600,1380,1240,1210 EIMS m / z 468 (M ⁺ ), 140 Colorless viscous substance

O- [4- (1-Methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N- (2-methyl-3-thienyl) amino]
[Ethoxy] phenyl] thiocarbamate (Compound No. 4
54) Starting amine compound: N- (2-methyl-3-thienyl)-
N-methyl-2- [3- (methylamino) phenoxy]
Ethylamine Raw material chlorothioformate compound: 4- (1-methoxy-1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.53 (s, 6H), 2.34 (s, 3H) ), 2.78 (s, 3H), 3.06 (s, 3H), 3.29
(t, J = 6.0Hz, 2H), 3.72 (s, 3H), 4.02 (t, J = 5.5Hz, 2H), 6.78-
7.04 (m, 7H), 7.26-7.35 (m, 1H), 7.39 (d, J = 7.0Hz, 2H) IR (neat, cm ^-1 ) 2980,1600,1480,1380,1205,1165 Colorless viscous substance

O- (4-tert-butylphenyl) =
N-methyl-N- [6- [2- [N-methyl-N- (3
-Thienyl) amino] ethoxy] -2-pyridyl] thio
Carbamate (Compound No. 465) Starting amine compound: N-methyl-N- (3-thienyl)
-2- [2- (methylamino) -6-pyridyloxy]
Ethylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 2.97 (s, 3H), 3.62 (t, J = 6.0Hz, 2H), 3.72 (s, 3
H), 4.48 (t, J = 6.0Hz, 2H), 5.96 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.
62 (d, J = 8.0Hz, 1H), 6.84 (dd, J = 1.5Hz, 5.0Hz, 1H), 6.95-7.
02 (m, 3H), 7.19-7.22 (m, 1H), 7.37 (d, J = 9.0Hz, 2H), 7.60
(t, J = 8.5Hz, 1H) IR (neat, cm ^-1 ) 2950,1595,1545,1430,1360,1265,1180 EIMS m / z 455 (M ⁺ ), 139 CIMS (isobutane) m / z 456 (MH ⁺ ) light brown viscous material

O- [4- (1-Methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [6- [2- [N
-Methyl-N- (3-thienyl) amino] ethoxy]-
2-Pyridyl] thiocarbamate (Compound No. 468) Starting amine compound: N-methyl-N- (3-thienyl)
-2- [2- (methylamino) -6-pyridyloxy]
Ethylamine Raw material chlorothioformate compound: 4- (1-methoxy-1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.52 (s, 6H), 2.98 (s, 3H) ), 3.07 (s, 3H), 3.62 (t, J = 6.0Hz, 2
H), 3.73 (s, 3H), 4.49 (t, J = 6.0Hz, 2H), 5.95-5.98 (m, 1H),
6.64 (d, J = 8.5Hz, 1H), 6.85 (dd, J = 1.5Hz, 5.0Hz, 1H), 6.97-
7.06 (m, 3H) 7.19-7.24 (m, 1H), 7.40 (d, J = 8.5Hz, 2H), 7.61
(t, J = 7.5Hz, 1H) IR (neat, cm ^-1 ) 2970,1595,1545,1430,1370,1260,1180 EIMS m / z 471 (M ⁺ ), 139 CIMS (isobutane) m / z 472 (MH +) pale brown viscous material

O- [4- (1-Cyano-1-methylethyl)
L) phenyl] = N-methyl-N- [6- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] -2
-Pyridyl] thiocarbamate (Compound No. 469) Starting amine compound: N-methyl-N- (3-thienyl)
-2- [2- (methylamino) -6-pyridyloxy]
Ethylamine Raw material chlorothioformate compound: 4- (1-cyano-
1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.73 (s, 6H), 2.98 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 3.72 (s, 3
H), 4.49 (t, J = 6.0Hz, 2H), 5.97 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.
66 (d, J = 8.5Hz, 1H), 6.85 (dd, J = 1.5Hz, 5.0Hz, 1H), 6.99 (d,
J = 7.5Hz, 1H), 7.09 (d, J = 9.0Hz, 2H), 7.23 (dd, J = 3.5Hz, 5.0
Hz, 1H), 7.47 (d, J = 8.5Hz, 2H), 7.63 (t, J = 8.0Hz, 1H) IR (neat, cm ^-1 ) 2980,2245,1600,1555,1435,1380,1180 EIMS m / z 466 (M ⁺ ), 139 brown oil

O- (2-naphthyl) = N-methyl-N-
[3- [2- [N-methyl-N- (3-thienyl) amido]
[No] ethoxy] phenyl] thiocarbamate (compound number
No. 373) Raw material amine compound: N- (3-thienyl) -N-methyl-2- [3- (methylamino) phenoxy] ethylamine Raw material chlorothioformate compound: 2-naphthyl chlorothioformate ¹ H-NMR (500MHz, CDCl ₃ , δppm) 2.99 (s, 3H), 3.65 (t, J = 5.5Hz, 2H), 3.75 (s, 3H), 4.15 (t, J
= 5.5Hz, 2H) 5.95 (dd, J = 1.5Hz, 3.0Hz, 1H), 6.81-7.00 (m, 4
H), 7.21-7.53 (m, 6H), 7.56-7.92 (m, 3H) IR (neat, cm ^-1 ) 2880,1605,1550,1485,1380,1215 Light yellow viscous substance

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2-[(3-thienylmethyl
Ru) carbonylamino] ethoxy] phenyl] thiocar
Bamate (Compound No. 768) Starting amine compound: N- [2- [3- (methylamino)]
Phenoxy] ethyl] -2- (3-thienyl) acetamide Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 3.56-3.76 (m, 7H), 4.02 (t, J = 5.1Hz, 2H), 6.00
(brs, 1H), 6.72-7.17 (m, 7H), 7.24-7.46 (m, 4H) IR (KBr, cm ^-1 ) 3430,2970,1675,1490,1385,1215 EIMS m / z 482 (M ⁺ ), 97 CIMS (isobutane) m / z 483 (MH +) White solid

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N- (3
-Thienyl) amino] ethoxy] propyl] thiocarba
Mate (Compound No. 661) Raw material amine compound: N-methyl-3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] propylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = Chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 9H), 1.92-2.06 (m, 2H), 2.88 and 2.92 (2s, 3H), 3.24
-3.45 (m, 5H) 3.49and3.52 (2t, J = 6.0Hz, 2H), 3.58and3.61
(2t, J = 5.5Hz, 2H), 3.74and3.92 (2t, J = 7.0Hz, 2H), 5.87and
5.90 (2dd, J = 1.5Hz, 3.0Hz, 1H), 6.76and6.80 (2dd, J = 1.5H
(z, 5.5Hz, 1H), 6.95-7.01 (m, 2H), 7.15-7.23 (m, 1H), 7.37-
7.42 (m, 2H) IR (neat, cm ^-1 ) 2960,2870,1570,1505,1400,1205,1105 Yellow viscous substance

O- [4- (1-methoxy-1-methyle
Tyl) phenyl] = N-methyl-N- [3- [2- [N
-Methyl-N- (3-thienyl) amino] ethoxy] p
[Ropyl] thiocarbamate (Compound No. 669) Starting amine compound: N-methyl-3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] propylamine Starting chlorothioformate compound: 4- ( 1-methoxy-1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.54 (s, 6H), 1.92-2.06 (m, 2H), 2.88 and 2.92 (2s, 3H), 3.08
(s, 3H), 3.24-3.63 (m, 9H), 3.75and3.92 (2t, J = 7.5Hz, 2H),
5.88and5.90 (2dd, J = 2.0Hz, 3.0Hz, 1H) 6.76and6.80 (2dd, J
= 2.0Hz, 5.0Hz, 1H), 7.02 (dd, J = 3.5Hz, 8.5Hz, 2H) 7.17and
7.20 (2dd, J = 3.5Hz, 5.0Hz, 1H), 7.42 (dd, J = 1.5Hz, 8.5Hz, 2
H) IR (neat, cm ^-1 ) 2970,2930,1550,1500,1400,1200,1120 Yellow viscous substance

O- [4- (1-cyano-1-methylethyl)
L) phenyl] = N-methyl-N- [3- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] pro
Pyr] thiocarbamate (Compound No. 670) Raw amine compound: N-methyl-3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] propylamine Raw chlorothioformate compound: 4- ( 1-cyano
1-methylethyl) phenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.74 (s, 6H), 1.92-2.06 (m, 2H), 2.88 and 2.92 (2s, 3H), 3.24
-3.63 (m, 9H) 3.75and3.91 (2t, J = 7.0Hz, 2H), 5.88and5.90
(2dd, J = 2.0Hz, 3.0Hz, 1H) 6.76and6.80 (2dd, J = 1.5Hz, 5.5H
z, 1H), 7.04-7.11 (m, 2H) 7.15-7.22 (m, 1H), 7.48 (d, J = 8.5H
z, 2H) IR (neat, cm ^-1 ) 2930,2860,2230,1545,1500,1400,1200,1120 yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[(3-thienyl) methyl] amino] ethoxy] propy
Thiocarbamate (Compound No. 587) Raw material amine compound: N-methyl-3- [2- [N-methyl-N- (3-thienylmethyl) amino] ethoxy] propylamine Raw material chlorothioformate compound: 4- tert-butylphenyl chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 1.94-2.08 (m, 2H), 2.26 and 2.29 (2s, 3H), 2.
57 and 2.61 (2t, J = 6.0Hz, 2H) 3.28 and 3.42 (2s, 3H), 3.4
7-3.63 (m, 6H), 3.78 and 3.96 (2t, J = 7.5Hz, 2H) 6.95-7.14
(m, 4H), 7.22-7.28 (m, 1H), 7.37-7.40 (m, 2H) IR (neat, cm ^-1 ) 2960,2860,1510,1400,1210,1110 pale yellow oil

O- (4-tert-butylphenyl) =
N- [3- [2- [N-methyl-N- (3-thienyl)
Amino] ethoxy] propyl] thiocarbamate (compound
Article number 677) Starting amine compound: 3- [2- [N-methyl-N- (3
-Thienyl) amino] ethoxy] propylamine Raw material chlorothioformate compound: 4-tert-butylphenyl = chlorothioformate ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.33 (s, 9H), 1.86-2.00 ( m, 2H), 2.92 (s, 3H), 3.36-3.72 (m,
8H), 5.86-5.94 (m, 1H), 6.74-6.82 (m, 1H), 6.94-7.10 (m, 2
H), 7.16-7.23 (m, 1H), 7.34-7.43 (m, 2H), 7.50 (bs, 1H) IR (neat, cm ^-1 ) 3350,2960,1570,1505,1215 Yellow viscous substance

Example 18 O- (1,5,5-trimethyl-3-hexyne) = N-
Methyl-N- [3- [2- [N-methyl-N- (3-thio
Enyl) amino] ethoxy] phenyl] thiocarbame
G (Compound No. 419) in 10 ml of a methylene chloride solution of 69 mg of thiophosgene,
6,6-dimethyl-4-hexyn-2-ol 8 under ice cooling
5 ml of a methylene chloride solution of 1 mg and 56 mg of pyridine was slowly added dropwise. After stirring at room temperature for 5 hours, a solution of 122 mg of N- (3-thienyl) -N-methyl-3- [3- (methylamino) phenoxy] ethylamine in 5 ml of methylene chloride was added. After stirring at room temperature for 16 hours, 10 ml of 5% aqueous ammonia was added. The reaction mixture was extracted with methylene chloride, and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 6: 1) to obtain 64 mg of an oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.16 (s, 9H), 1.26 (bs, 3H), 2.25-2.50 (m, 2H), 2.98 (s, 3H),
3.59 (bs, 3H), 3.63 (t, J = 6.0Hz, 2H), 4.10 (t, J = 6.0Hz, 2H),
5.55 (bs, 1H), 5.93-5.94 (m, 1H), 6.70 (bs, 1H), 6.79-6.80
(m, 3H), 7.22-7.25 (m, 2H) IR (neat, cm ^-1 ) 2890,2240,1600,1550,1480,1380,1280,1240,1190,1120,
1040

Example 19 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N- (3-thienyl)
Amino] ethoxy] phenyl] thiocarbamate (compound
Synthesis of hydrochloride of compound No. 370) To 10 ml of 16% hydrogen chloride (methanol solution) was added O-
(4-tert-butylphenyl) = N-methyl-N-
205 mg of [3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] phenyl] thiocarbamate
Was dissolved and stirred for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure to obtain white crystals (205 mg). mp = 59-60 ° C ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 3.23 (s, 3H), 3.70 (s, 3H), 3.77 (s, 2H), 4.42
(s, 2H), 6.71-7.45 (m, 11H), 7.70 (bs, 1H) IR (KBr, cm- ¹ ) 2960,2450,1600,1485,1380,1210,1175 The following compounds were synthesized in the same manner as in Example 19.

O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-ethyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl
Thiocarbamate (Compound No. 258) hydrochloride starting compound: O- (4-trimethylsilylphenyl) =
N-methyl-N- [3- [2- [N-ethyl-N-
[(3-thienyl) methyl] amino] ethoxy] phenyl] thiocarbamate mp 30 ° C. or less ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 0.25 (s, 9 H), 1.50 (t, J = 7.0 Hz, 3 H), 3.09-3.25 (m, 2H), 3.36
-3.44 (m, 2H) 3.72 (s, 3H), 4.31-4.41 (m, 2H), 4.58-4.70 (m,
2H), 6.85-7.06 (m, 5H) 7.32-7.60 (m, 6H), 7.76 (bs, 1H) IR (KBr, cm ^-1 ) 2950,2460,1590,1480,1380,1210,1170

Example 20 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [3- (3-thienylamino) propoxy]
Synthesis of phenyl] thiocarbamate (Compound No. 81) O- (4-tert-butylphenyl) = N-methyl-
0.59 g of N- [3- (3-bromopropoxy) phenyl] thiocarbamate, 0.16 of 3-aminothiophene
g of potassium carbonate and 0.41 g of potassium carbonate in 60 ml of an acetonitrile suspension were heated under reflux for 18 hours. After cooling at room temperature, insolubles were removed with a glass filter. After concentrating the filtrate, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1) to obtain 0.14 g of the desired product as a brown oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 2.02-2.20 (m, 2H), 3.32 (t, J = 6.6 Hz, 2H), 3.71
(brs, 3H), 3.80 (brs, 1H), 4.11 (t, J = 6.1Hz, 2H), 5.98-6.03
(m, 1H), 6.59-6.67 (m, 1H), 6.81-7.05 (m, 5H), 7.12-7.20
(m, 1H), 7.24-7.44 (m, 3H) IR (neat, cm- ¹ ) 3360, 1600, 1560, 1480, 1375, 1230, 1205, 1170, 1115, 1105 The following compounds were synthesized in the same manner as described above.

O- (4-tert-butylphenyl) =
N-methyl-N- [6- [3- [N-methyl-N- (3
-Thienyl) amino] propoxy] -2-pyridyl] thio
Ocarbamate (Compound No. 111) Starting bromine compound: O- (4-tert-butylphenyl) = N-methyl-N- [6- (3-bromopropoxy) -2-pyridyl] thiocarbamate Starting amine compound: 3- (Methylamino) thiophene ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 1.94-2.16 (m, 2H), 2.88 (s, 3H), 3.40 (t, J = 6.6
Hz, 2H), 3.73 (s, 3H), 4.35 (t, J = 6.2Hz, 2H), 5.91-5.98 (m, 1
H), 6.66 (d, J = 8.1Hz, 1H), 6.75-6.82 (m, 1H), 6.95-7.08 (m,
3H), 7.15-7.23 (m, 1H), 7.34-7.44 (m, 2H), 7.62 (t, J = 7.7H
z, 1H) IR (neat, cm ^-1 ) 2950,1595,1550,1420,1370,1265,1180 Yellow viscous substance

Example 21 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2-[(3-thienylmethyl) amino]
Toxy] phenyl] thiocarbamate (Compound No. 25
Synthesis of 2) O- (4-tert-butylphenyl) = N-methyl-
300 ml of N- [3- (2-bromoethoxy) phenyl] thiocarbamate, 240 mg of 3- (aminomethyl) thiophene, 196 mg of anhydrous potassium carbonate, 12 mg of potassium iodide and 10 mg of tetrabutylammonium hydrogen sulfate 10 mg in dimethylformamide suspension 15 ml 50
After stirring at 15 ° C. for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 1: 1) to give 145 mg of a yellow oil. I got

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 1.83 (bs, 1H), 3.05 (t, J = 5.0 Hz, 2H), 3.72 (s, 3
H), 3.91 (s, 2H), 4.10 (t, J = 5.0Hz, 2H), 6.83-7.44 (m, 11H) IR (neat, cm ^-1 ) 3310,2960,1600,1480,1380,1210 EIMS m / z 454 (M ⁺ ), 97 The following compounds were synthesized in the same manner as in Example 21 using the corresponding starting compounds.

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2-[(2,5-dichloro-
3-thienyl) methylamino] ethoxy] phenyl] thi
Ocarbamate (Compound No. 295) Starting bromine compound: O- (4-tert-butylphenyl) = N-methyl-N- [3- (2-bromoethoxy)
Phenyl] thiocarbamate Raw material amine compound: 2,5-dichloro-3- (aminomethyl) thiophene ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 1.90 (brs, 1H), 2.96-3.02 (m, 2H), 3.71 (s, 3
H), 3.74-3.79 (m, 2H) 4.03-4.12 (m, 2H), 6.76-7.00 (m, 6H),
7.24-7.44 (m, 3H) IR (neat, cm ^-1 ) 3320,2950,1600,1480,1380,1210 CIMS (isobutane) m / z 522 (MH ⁺ ) pale yellow oil

Example 22 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N- [1- (3-thiene
Nyl) ethyl] amino] ethoxy] phenyl] thiocar
Synthesis of Bamate (Compound No. 246) O- (4-tert-butylphenyl) = N-methyl-
260 mg of N- [3- (2-bromoethoxy) phenyl] thiocarbamate, 316 mg of 3- [1- (methylamino) ethyl] thiophene and 10 mg of potassium iodide
Was stirred at 50 ° C. for 20 hours, water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and silica gel column chromatography (developing solvent; hexane: ethyl acetate 5: 2).
Purification afforded 141 mg of a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 1.39 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 2.66-2.74
(m, 1H) 2.79-2.87 (m, 1H), 3.70 (s, 3H), 3.89 (q, J = 6.8Hz, 1
H), 4.02 (t, J = 5.9Hz, 2H), 6.78-6.99 (m, 5H), 7.07-7.12 (m,
2H), 7.25-7.41 (m, 4H) IR (neat, cm ^-1 ) 2950,1600,1470,1370,1205 Yellow oil

Example 23 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N- [3- (1,2,
5-thiadiazolyl) methyl] amino] ethoxy] fe
Nyl] thiocarbamate (Compound No. 286) O- (4-tert-butylphenyl) = N-methyl-
Dimethylformamide of N- [3- (2-bromoethoxy) phenyl] thiocarbamate 162 mg, 3-[(N-methyl) aminomethyl] -1,2,5-thiadiazole 52 mg, anhydrous potassium carbonate 279 mg and potassium iodide 67 mg After stirring 5 ml of the suspension at 50 ° C. for 48 hours, water was added, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 3: 1) to obtain 102 mg of a pale yellow viscous substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.23 (s, 9H), 2.42 (s, 3H), 2.91 (t, J = 6.0 Hz, 2H), 3.72 (s, 3
H), 4.01 (s, 2H), 4.11 (t, J = 6.0Hz, 2H) 6.76-7.00 (m, 5H), 7.
19-7.41 (m, 3H), 8.60 (s, 1H) IR (neat, cm- ¹ ) 2970, 1600, 1490, 1480, 1380, 1210 Pale yellow viscous substance Same as Example 23 using the corresponding starting compound. The following compounds were synthesized by the method described above.

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N- [4
-(1,3-thiazolyl) methyl] amino] ethoxy]
Phenyl] thiocarbamate (Compound No. 285) Starting bromine compound: O- (4-tert-butylphenyl) = N-methyl-N- [3- (2-bromoethoxy)
Phenyl] thiocarbamate Starting amine compound: 4-[(N-methyl) aminomethyl] -1,3-thiazole ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 2.42 (s, 3H) , 2.91 (t, J = 6.0Hz, 2H), 3.71 (s, 3
H), 3.88 (s, 2H), 4.12 (t, J = 6.0Hz, 2H) 6.79-6.98 (m, 5H), 7.
20-7.40 (m, 4H), 8.77-8.78 (m, 1H) IR (KBr, cm ^-1 ) 2960,1600,1475,1380,1210,1175 Viscous substance

Example 24 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- (3-thienylmethoxy) ethoxy]
Phenyl] thiocarbamate (Compound No. 266)
Dimethylformamide suspension 2ml of growth of 60% oily sodium hydride 32 mg, under ice-cooling (3-thiophene) was added dimethylformamide 4ml of methanol 81 mg. After stirring at room temperature for 5 minutes, O- (4-te
rt-butylphenyl) = N-methyl-N- [3- (2
-Bromoethoxy) phenyl] thiocarbamate 300
3 ml of a solution of mg of dimethylformamide were added. After adding 5 mg of potassium iodide, the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, 150 ml of water was added, and the mixture was extracted with ethyl acetate (60 ml × 3). The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 1) to obtain 25 mg of a colorless viscous substance as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 3.70 (s, 3H), 3.82 (t, J = 4.5 Hz, 2H), 4.14 (t, J =
4.5Hz, 2H), 4.63 (s, 2H), 6.82-6.98 (m, 5H), 7.09 (d, J = 5.0H
z, 1H), 7.20-7.42 (m, 5H) IR (neat, cm ^-1 ) 2960,1600,1480,1380,1210 EIMS m / z 455 (M ⁺ ), 97

Example 25 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [N-methyl-N- (3-thienyl) carba
Moylmethoxy] phenyl] thiocarbamate (compound
No. 748) O- (4-tert-butylphenyl) = N-methyl-
N- (3-hydroxyphenyl) thiocarbamate 10
0 mg, N-methyl-N- (3-thienyl) -2-bromoacetamide (89 mg), potassium carbonate (97 mg), tetrabutylammonium hydrogensulfate (17 mg) in N, N-dimethylformamide (4 ml) were stirred at 50 ° C. for 18 hours. . 150 ml of water was added to the reaction solution, extracted with ethyl acetate (30 ml × 3), and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent;
Purification with benzene: ethyl acetate = 4: 1) gave 140 mg of the desired product as a white solid. mp = 174-176 ° C ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.31 (s, 9H), 3.29 (s, 3H), 3.69 (s, 3H), 4.50 (s, 2H) 6.67-7.
07 (m, 6H), 7.12-7.43 (m, 5H) IR (KBr, cm ^-1 ) 2960,1680,1480,1380,1230,1200 N-methyl-N- (3-thienyl) -2-bromoacetamide The following compounds were synthesized in the same manner as in Example 25 except for using the following starting compounds.

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [N-methyl-N-[(3-thio
Enyl) methyl] carbamoylmethoxy] phenyl] thio
Ocarbamate (Compound No. 730) Starting compound: N-methyl-N-[(3-thienyl) methyl] -2-bromoacetamide ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 2.97 and 3.00 (2s, 3H), 3.70 (s, 3H), 4.56 an
d 4.60 (2s, 2H), 4.74 and 4.76 (2s, 2H), 6.80-7.12 (m, 7
H), 7.22-7.44 (m, 4H) IR (KBr, cm ^-1 ) 2960,1675,1600,1485,1375,1210,1175 Colorless viscous substance

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [N-[(3-thienyl) methyl
[Carbamoylmethoxy] phenyl] thiocarbame
G (Compound No. 737) Starting compound: N-[(3-thienyl) methyl] -2-bromoacetamide mp = 158-160 ° C. ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 3.69 (s, 3H), 4.44-4.62 (m, 4H), 6.70-7.14 (m,
7H), 7.22-7.46 (m, 4H) IR (KBr, cm ^-1 ) 3410,2960,1675,1600,1530,1480,1380,1210,1175 White crystal

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [N-methyl-N- [2- (3
-Thienyl) ethyl] carbamoylmethoxy] phenyl
] Thiocarbamate (Compound No. 736) Starting compound: N-methyl-N- [2- (3-thienyl)
Ethyl] -2-bromoacetamide mp = 42-44 ° C. ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 2.82-3.03 (m, 5H), 3.51-3.79 (m, 5H), 4.38 an
d 4.66 (2s, 2H) 6.70-7.06 (m, 7H), 7.20-7.44 (m, 4H) IR (neat, cm ^-1 ) 2960,1680,1600,1480,1380,1210 CIMS (isobutane) m / z 497 (MH +) colorless solid

Example 26 O- (4,4-dimethyl-2-pentyne) = N-methyl
-N- [3- [2- [N-methyl-N- (3-thienyl
Ru) amino] ethoxy] phenyl] thiocarbamate
Synthesis of (Compound No. 416) To a 0.5 ml dimethylformamide suspension of 7 mg of 60% oily sodium hydride was added 4,4-dimethyl-2 under ice cooling.
-1 ml of a dimethylformamide solution of 20 mg of pentyn-1-ol was added. After 5 minutes, O- (4-tert-
Butylphenyl) = N-methyl-N- [3- [2- [N
After adding 2 ml of a dimethylformamide solution of 42 mg of -methyl-N- (3-thienyl) amino] ethoxy] phenyl] thiocarbamate, the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, 100 ml of water was added, and the mixture was extracted with diethyl ether (40 ml × 3).
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1) to obtain 24 mg of a colorless viscous substance as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.20 (s, 9H), 2.99 (s, 3H), 3.45-3.75 (m, 5H), 4.12 (t, J = 5.5
Hz, 2H), 5.07 (s, 2H), 5.95 (dd, J = 1.5Hz, 3.0Hz, 1H) 6.68-6.
88 (m, 4H), 7.21-7.32 (m, 2H) IR (neat, cm ^-1 ) 2960,2240,1600,1550,1470,1380,1230 EIMS m / z 416 (M ⁺ ), 126 4,4 The following compounds were synthesized in the same manner as in Example 26 using 2- (N-methyl-tert-butylcarbonylamino) ethanol in place of -dimethyl-2-pentyn-1-ol.

O- [2- (N-methyl-tert-buty)
Carbonylamino) ethyl] = N-methyl-N- [3
-[2- [N-methyl-N- (3-thienyl) amino]
[Ethoxy] phenyl] thiocarbamate (Compound No. 4
21) ¹ H-NMR (500 MHz, CDCl ₃ , δppm) 1.18 (s, 9H), 2.71 (bs, 3H), 3.00 (s, 3H), 3.42-3.68 (m, 7H),
4.11 (t, J = 5.5Hz, 2H), 4.56 (bs, 2H) 5.94-5.97 (m, 1H), 6.64
-6.86 (m, 4H), 7.22-7.32 (m, 2H) IR (neat, cm ^-1 ) 2940,1625,1480,1380,1235 EIMS m / z 463 (M ⁺ ), 126 Brown viscous substance

Example 27 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-formyl-N-[(3-thienyl
L) Methyl] amino] ethoxy] phenyl] thiocarba
Synthesis of mate (Compound No. 254) 1-Ethyl-3- (3′-dimethylaminopropyl) carbodiimide (48 mg) in methylene chloride (3 ml), formic acid (17 mg) in methylene chloride (5 ml), and O- (4-ter
t-butylphenyl) = N-methyl-N- [2-[(3
A solution of -thienylmethyl) amino] ethoxyphenyl] thiocarbamate (69 mg) in methylene chloride (5 ml) was added dropwise, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was washed with a saturated aqueous solution of ammonium chloride and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 1: 1) to obtain 48 mg of a colorless viscous substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 3.55-3.76 (m, 5H), 3.94 and 4.11 (2bs, 2H), 4.5
7and4.63 (2s, 2H), 6.74-7.47 (m, 11H), 8.27and8.31 (2s, 1
H) IR (neat, cm ^-1 ) 2960,1665,1600,1480,1380,1230,1210 EIMS m / z 482 (M ⁺ ), 97

Example 28 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-methyl-N- (2,2,2-to
Trifluoroethyl) amino] ethoxy] phenyl] thio
Synthesis of carbamate (Compound No. 292) O- (4-tert-butylphenyl) = N-methyl-N- [3- [2- [N-
4 ml of a dimethylformamide solution of 95 mg of (2,2,2-trifluoroethyl) amino] ethoxy] phenyl] thiocarbamate was added. Five minutes later, 37 mg of methyl iodide was added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, 100 ml of water was added, and the mixture was extracted with ethyl acetate (40 m
1 × 3), and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to obtain 7 mg of a colorless oil as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 2.57 (s, 3H), 3.05 (t, J = 5.5 Hz, 2H), 3.18 (q, J =
10.0Hz, 2H), 3.71 (s, 3H), 4.08 (t, J = 5.5Hz, 2H), 6.81-7.00
(m, 5H), 7.27-7.42 (m, 3H) IR (neat, cm- ¹ ) 2960, 1600, 1475, 1380, 1270, 1210 Was synthesized.

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl-N-
[(2,5-dichloro-3-thienyl) methyl] amido
[No] ethoxy] phenyl] thiocarbamate (compound number
No. 294) ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.32 (s, 9H), 2.38 (s, 3H), 2.85 (t, J = 5.0 Hz, 2H), 3.56 (s, 2
H), 3.74 (s, 3H) 4.11 (t, J = 5.0Hz, 2H), 6.83-7.02 (m, 6H), 7.
29-7.46 (m, 3H) IR (neat, cm ^-1 ) 2950,1600,1470,1375,1210,1170 CIMS (isobutane) m / z 537 (MH +) pale yellow oil

O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2- [N-methyl- (3-thio
Enylmethyl) carbonylamino] ethoxy] phenyl
Thiocarbamate (Compound No. 766) starting compound: O- (4-tert-butylphenyl) =
N-methyl-N- [3- [2-[(3-thienylmethyl) carbonylamino] ethoxy] phenyl] thiocarbamate ¹ H-NMR (200 MHz, CDCl ₃ , δ ppm) 1.31 (s, 9H), 3.04 and 3.16 (2s, 3H), 3.57-3.88 (m, 7H), 4.
00 and 4.17 (2t, J = 5.1Hz, 2H), 6.72-7.45 (m, 11H) IR (KBr, cm ^-1 ) 2960,1640,1485,1385,1210 EIMS m / z 496 (M ⁺ ), 182 CIMS (isobutane) m / z 497 (MH +)

Example 29 O- (4-tert-butylphenyl) = N-methyl-
N- [3- [2- [N-[(3-thienyl) carbonyl]
] -N-methylamino] ethoxy] phenyl] thioca
Synthesis of rubamate (Compound No. 742) 3-methyl-3- (3'-dimethylaminopropyl) carbodiimide 33 mg in methylene chloride solution 5 ml
5 mg of a methylene chloride solution of 23 mg of thiophenecarboxylic acid, 36 mg of O- (4-tert-butylphenyl) = N-methyl-N- [3- [2- (N-methylamino) ethoxy] phenyl] thiocarbamate of methylene chloride 5 ml of the solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution was added,
Extracted with methylene chloride. (50 ml × 2) The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 3: 2) to obtain 29 mg of a colorless viscous substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.30 (s, 9H), 3.24 (bs, 3H), 3.58-3.98 (m, 5H), 4.11 and 4.30
(2bs, 2H), 6.74-7.64 (m, 11H) IR (neat, cm ^-1 ) 2960,1625,1600,1480,1380,1210 EIMS m / z 482 (M ⁺ )

Example 30 O- [4- [1,1-dimethyl-2- (formyl-N-
Methylamino) ethyl] phenyl] = N-methyl-N-
[3- [2- [N-methyl-N- (3-thienyl) amido]
[No] ethoxy] phenyl] thiocarbamate (compound number
No. 409) O- [4- [1,1-dimethyl-2- (formylamino) ethyl] phenyl] = 1 ml of dimethylformamide suspension of 17 mg of 60% oily sodium hydride at room temperature.
N-methyl-N- [3- [2- [N-methyl-N- (3
A solution of 176 mg of -thienyl) amino] ethoxy] phenyl] thiocarbamate in 4 ml of dimethylformamide was added. Five minutes later, 2 ml of a dimethylformamide solution of 60 mg of methyl iodide was added, and the mixture was stirred at room temperature for 19 hours. After the completion of the reaction, 100 ml of water was added, and the mixture was extracted with ethyl acetate (60 ml × 2).
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; chloroform: ethyl acetate = 8: 1) to obtain 141 mg of a pale yellow viscous substance as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.35 (s, 6H), 2.38 and 2.51 (2s, 3H), 2.98 (s, 3H), 3.32 and 3.
49 (2s, 2H), 3.56-3.72 (m, 5H), 4.13 (t, J = 5.5Hz, 2H), 5.92-
5.95 (m, 1H), 6.78-7.44 (m, 10H), 7.81and8.00 (2s, 1H) IR (neat, cm ^-1 ) 2960,1670,1600,1550,1485,1380,1210 EIMS m / z 511 (M ⁺ ), 126

Example 31 O- [4- (2-acetoxy-1,1-dimethylethyl)
L) phenyl] = N-methyl-N- [3- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] fe
Synthesis of Nyl] thiocarbamate (Compound No. 391) O- [4- (2-hydroxy-1,1-dimethylethyl) phenyl] = N-methyl-N- [3- [2- [N-
Methyl-N- (3-thienyl) amino] ethoxy] phenyl] thiocarbamate 62 mg methylene chloride solution 1
0 ml, 5 ml of methylene chloride solution of 40 mg of pyridine
Was added. After 5 minutes, 40 mg of acetyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction, the mixture was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1),
53 mg of a pale yellow oil was obtained as the desired product.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.34 (s, 6H), 1.99 (s, 3H), 2.98 (s, 3H), 3.64 (t, J = 6.0 Hz, 2
H), 3.69 (s, 3H), 4.08 (s, 2H), 4.12 (t, J = 6.0Hz, 2H), 5.93-
5.95 (m, 1H), 6.78-6.96 (m, 6H), 7.20-7.36 (m, 4H) IR (neat, cm ^-1 ) 2960,1735,1600,1545,1480,1380

Example 32 : O- [4- [1,1-dimethyl-2- (N-methylamido)
No) ethyl] phenyl] = N-methyl-N- [3- [2
-[N-methyl-N- (3-thienyl) amino] ethoxy
[S] phenyl] thiocarbamate (Compound No. 412)
Synthesis of O- [4- [1,1-dimethyl-2- (formyl-N-
Methylamino) ethyl] phenyl] = N-methyl-N-
104 mg of [3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] phenyl] thiocarbamate
Was dissolved in 4 ml of 1,4-dioxane, and 4 ml of concentrated hydrochloric acid was added. After stirring at 100 ° C. for 2 hours, water was added, and the mixture was made alkaline with 15% sodium hydroxide. After extraction with methylene chloride, the collected organic layers were washed with saturated saline. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; chloroform: ethyl acetate = 8: 1) to obtain 31 mg of a brown viscous substance as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.38 (s, 6H), 2.37 (s, 3H), 2.74 (s, 2H), 2.88 (bs, 1H), 2.98
(s, 3H), 3.56-3.73 (m, 5H), 4.12 (t, J = 6.0Hz, 2H), 5.94 (dd,
J = 1.5Hz, 3.5Hz, 1H), 6.74-7.15 (m, 6H), 7.19-7.43 (m, 4H) IR (neat, cm ^-1 ) 3305,2955,1600,1550,1480,1380,1210

Example 33 O- [4- (1-Hydroxy-1-methylethyl) fe
Nyl] = N-methyl-N- [3- [2- [N-methyl-
N- (3-thienyl) amino] ethoxy] phenyl] thio
Synthesis of Ocarbamate (Compound No. 388) O- [4- (1-Methoxy-1-methylethyl) phenyl] = N- [3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy ] Propyl] thiocarbamate was added to 2 ml of a tetrahydrofuran solution of 96 mg under ice cooling.
4 ml of N hydrochloric acid were added. After stirring at room temperature for 4.5 hours,
A saturated aqueous sodium hydrogen carbonate solution was added again under ice cooling to make the mixture alkaline. The mixture was extracted with diethyl ether, and the collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to obtain 46 mg of a yellow oil as a target substance.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 1.57 (s, 6H), 1.77 (bs, 1H), 2.
99 (s, 3H), 3.65 (t, J = 5.5 Hz, 2
H), 3.71 (s, 3H), 4.13 (t, J = 5.
5 Hz, 2H), 5.95 (dd, J = 1.5 Hz,
3.0 Hz, 1 H), 6.78-7.02 (m, 6
H), 7.23 (dd, J = 3.5 Hz, 5.0 Hz,
1H), 7.27-7.35 (m, 1H), 7.47.
(D, J = 7.5 Hz, 2H) IR (neat, cm ^-1 ) 3400, 2970, 1600, 1550, 1380

Example 34 O- [4- (1-Methylvinyl) phenyl] = N-methyl
Ru-N- [3- [2- [N-methyl-N- (3-thienyl
Ru) amino] ethoxy] propyl] thiocarbamate
Synthesis of (Compound No. 385 ) To 5 ml of 16% hydrogen chloride (methanol solution) was added O- [4-
(1-Methoxy-1-methylethyl) phenyl] = N-
50 mg of methyl-N- [3- [2- [N-methyl-N- (3-thienyl) amino] ethoxy] phenyl] thiocarbamate was dissolved and stirred for 30 minutes. After the reaction, the solvent was distilled off under reduced pressure, and a 1N sodium hydroxide solution was added to the residue.
Extracted with ether. The collected organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent;
Purification with hexane: ethyl acetate = 4: 1) afforded 24 mg of an oil as the desired product.

¹ H-NMR (500 MHz, CDC
_{l 3, δppm) 2.13 (s} , 3H), 2.99 (s, 3H), 3.64 (t, J = 5.5Hz, 2H), 3.70 (s, 3
H), 4.13 (t, J = 5.5Hz, 2H), 5.06 (s, 1H) 5.33 (s, 1H), 5.93-5.
95 (m, 1H), 6.76-6.98 (m, 6H), 7.15-7.47 (m, 4H) IR (neat, cm ^-1 ) 3080,2960,2940,1630,1600,1550,1480,1410,1380, 1210,
1165

Example 35 O-methyl = N-methyl-N- [3- [2-[(3-thio
Enyl) methylthio] ethoxy] phenyl] carbame
Preparative Synthesis O- ethyl = S (Compound 880) - [(3-thienyl) methyl] = dithiocarbonato 500mg and O- methyl = N- methyl -
A solution of 660 mg of N- [3- (2-bromoethyl) phenyl] carbamate in 1 ml of ethylenediamine was added at room temperature to 2 ml.
Stir for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography.
(Developing solvent; hexane: ethyl acetate = 3: 1) to obtain 500 mg of the target product as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.81 (t, J = 6.5 Hz, 2H), 3.28 (s, 3H), 3.72 (s, 3H), 3.85 (s, 2
H), 4.07 (t, J = 6.5Hz, 2H) 6.68-6.88 (m, 3H), 7.04-7.16 (m, 2
H), 7.19-7.34 (m, 2H) IR (neat, cm ^-1 ) 2950,1705,1595,1485,1445,1360,1215,1195,1155,1025,
765,695 EIMS m / z 337 (M ⁺ )

Example 36 N-methyl-3- [2-[(3-thienyl) methylthio]
Synthesis of o] ethoxy] aniline (Compound No. 879) 151 mg of O-methyl = N-methyl-N- [3- [2-[(3-thienyl) methylthio] ethoxy] phenyl] carbamate and 450 mg of potassium hydroxide in methanol Water-tetrahydrofuran mixed solvent (6: 1: 1)
The mixture was heated under reflux for 10 hours. After allowing the reaction solution to cool, water was added,
Extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent;
Purification with hexane: ethyl acetate = 3: 1) gave 66 mg of the desired product as a yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.80 (t, J = 7.0 Hz, 2H), 2.83
(S, 3H), 3.73 (brs, 1H), 3.86
(S, 2H) 4.07 (t, J = 7.0 Hz, 2H),
6.14 (s, 1H), 6.22-6.27 (m, 2
H) 7.05-7.16 (m, 3H), 7.30 (t,
J = 4.0 Hz, 1 H) IR (neat, cm ⁻¹ ) 3400, 2910, 1610, 1500, 1490,
1335, 1300, 1260, 1195, 1160,
1020,820 EIMS m / z 279 (M ⁺ )

Example 37 N-methyl-N-[(2,5-dichloro-4-methyl-
3-thienyl) methyl] -2- [3- (methylamino)
Phenoxy] ethylamine (Compound No. 970), N
-Methyl-N-[(2-chloro-4-methyl-3-thier
Nyl) methyl] -2- [3- (methylamino) phenoxy
[E] ethylamine (Compound No. 969), N-methyl-
N-[(2-chloro-3-methyl-4-thienyl) methyl
] -2- [3- (methylamino) phenoxy] ethyl
Synthesis of amine (Compound No. 968) Lithium aluminum hydride (690 mg) was added to and suspended in anhydrous tetrahydrofuran (20 ml ) , and N-methyl-N-
2.35 g of [(2,5-dichloro-4-methyl-3-thienyl) methyl] -2- [3- (formylamino) phenoxy] acetamide in anhydrous tetrahydrafuran 6
After 0 ml was added dropwise over 25 minutes under ice cooling, the mixture was stirred for 60 minutes.
After the completion of the reaction, 0.69 ml of water, 0.69 ml of a 15% aqueous solution of potassium hydroxide, and 2.07 ml of water were sequentially added, and the insoluble matter was filtered with a glass filter. The filtrate was concentrated under reduced pressure, separated and purified by silica gel chromatography (developing solvent; chloroform: methanol = 20: 1) to obtain the desired three compounds (compound No. 970: 419 mg, compound No. 96).
9: 145 mg, Compound No. 968: 340 mg).

N-methyl-N-[(2,5-dichloro-
4-methyl-3-thienyl) methyl] -2- [3- (meth
Tylamino) phenoxy] ethylamine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.19 (s, 3H), 2.29 (s, 3H), 2.78-2.84 (m, 5H), 3.47 (s, 2
H), 3.71 (brs, 1H), 4.05 (t, J = 6.0Hz, 2H), 6.15 (t, J = 2.5
Hz, 1H), 6.21-6.27 (m, 2H), 7.07 (t, J = 8.0Hz, 1H) IR (neat, cm ^-1 ) 3410, 2800, 1615, 1510, 1200, 1160 EIMS m / z 358 ( M ⁺ , 6.2), 222 (34), 179 (100) pale yellow oil

N-methyl-N-[(2-chloro-4-meth
Tyl-3-thienyl) methyl] -2- [3- (methyla
Mino) phenoxy] ethylamine ¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.24 (s, 3H), 2.29 (s, 3H), 2.80-2.84 (m, 5H), 3.50 (s, 2
H), 3.71 (brs, 1H), 4.06 (t, J = 6.0Hz, 2H), 6.14-6.28 (m,
3H), 6.69, (s, 1H), 7.07 (t, J = 8.0Hz, 1H) EIMS m / z 324 (M ⁺ , 0.9), 188 (47), 145 (100) pale yellow oil

N-methyl-N-[(2-chloro-3-meth
Tyl-4-thienyl) methyl] -2- [3- (methyla
Mino) phenoxy] ethylamine ¹ H-NMR (500 MHz, CDCl ₃ 3, δ ppm) 2.16 (s, 3H), 2.31 (s, 3H), 2.79-2.83 (m, 5H), 3.47 (s, 2
H), 3.70 (brs, 1H), 4.06 (t, J = 6.0Hz, 2H), 6.14-6.27 (m,
3H), 6.91, (s, 1H), 7.07 (t J = 7.5Hz, 1H) EIMS m / z 324 (M ⁺ , 6.3), 188 (35), 145 (100) pale yellow oil

Example 38 N-methyl-N-[(4-methyl-3-thienyl) methyl
] -2- [3- (methylamino) phenoxy] ethyl
Synthesis of amine (Compound No. 971) N-methyl-N-[(2,5-dichloro-4-methyl-
3-thienyl) methyl] -2- [3- (methylamino)
[Phenoxy] ethylamine (362 mg) was added to a methanol solution (15 ml), hydrazine monohydrate (3 ml) and 10% palladium carbon (260 mg) were added, and the mixture was stirred at room temperature for 24 hours.
After completion of the reaction, palladium carbon was filtered, the filtrate was concentrated under reduced pressure, 100 ml of ether was added, and the mixture was washed with saturated saline and dried over potassium carbonate. After the solution was concentrated under reduced pressure, silica gel chromatography (developing solvent; hexane: ethyl acetate = 3:
Purification in 2) gave 209 mg of the desired product as a pale yellow oil.

¹ H-NMR (500 MHz, CDCl ₃ , δ ppm) 2.24 (s, 3H), 2.33 (s, 3H), 2.80-2.85 (m, 5H), 3.52 (s, 2
H), 4.06 (t, J = 6.0Hz, 2H), 6.14-6.28 (m, 3H), 6.88-6.92
(m, 1H), 7.04-7.13 (m, 2H) IR (neat, cm ^-1 ) 3410, 2940, 2800, 1615, 1510, 1495, 1200, 1165 EIMS m / z 290 (M ⁺ , 9.4), 154 (43), 111 (100)

[0536]

[Efficacy test] The squalene / epoxidase inhibitory activity and cholesterol biosynthesis inhibitory activity of the present invention were confirmed by the following methods.

(1) Preparation of rat squalene epoxidase Rat squalene epoxidase was obtained from Journal
Journal of Lipid Researc
h), Volume 31, p. 2095 (1990). After the male SD rat is exsanguinated to death, the liver is refluxed with 0.1 M Tris-HCl (pH 7.5, 4 ° C.). The liver is removed and 3% w / v 0.1 M
Homogenize with Tris-HCl (pH 7.5, 4 ° C) and add 1
Centrifuged at 500 × g for 15 minutes. Add one more supernatant
After centrifugation at 05000 × g for 30 minutes, the obtained microsomes were suspended in 0.1 M Tris-hydrochloric acid (pH 7.5, 4 ° C.), quantified for the amount of protein, and stored at −80 ° C.

(2) Squalene Epoxidase Activity Measurement Method The squalene epoxidase activity was measured by the Journal of Lipid Research (Journal of Lipid Research).
rch), vol. 31, p. 2095 (1990). The squalene / epoxidase fraction (protein mass: 1.0 mg / ml) prepared in (1), 0.0
67M Tris-HCl (pH 7.5), 0.1% Triton X
-100, 0.3 mM AMO-1618, 0.1 mM
FAD, 1.0 mM EDTA, 1.0 mM NAD
A solution of a test drug in dimethyl sulfoxide is added to a solution consisting of a suspension of PH, 4 μM 3H-squalene-Tween 80 to make a total volume of 0.3 ml, and the mixture is reacted at 37 ° C. for 60 minutes. 10% potassium hydroxide / methanol solution 0.3
The reaction was stopped by adding ml, and reacted at 37 ° C. for 30 minutes. After the saponified substance is extracted with petroleum ether, it is concentrated to dryness. The obtained residue was dissolved in a small amount of ethyl ether, and spotted on silica gel thin-layer chromatography.
Develop with ethyl acetate (99.5: 0.5). A portion of the generated 3H-squalene-2,3-epoxide was cut out and measured with a liquid scintillation counter. Thus, the inhibition rate of the compound of the present invention with respect to squalene epoxidase was determined.

(3) Test results From this, the concentration of the compound of the present invention that inhibits squalene epoxidase by 50% (IC ₅₀ value) was determined, and the results are shown in the following table.

[0540]

[Table 93]

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/41 A61K 31/41 31/42 31/42 31/425 31/425 31/44 ADN 31/44 ADN 31/505 31 / 505 31/695 31/695 C07C 333/08 C07C 333/08 C07D 209/08 C07D 209/08 209/34 209/34 209/44 209/44 209/46 209/46 213/74 213/74 239 / 26 239/26 277/28 277/28 277/42 277/42 285/08 285/08 285/10 285/10 333/16 333/16 333/20 333/20 333/28 333/28 333/32 333 / 32 333/36 333/36 333/38 333/38 409/12 209 409/12 209 213 213 307 307 311 311 417/12 213 417/1213 (72) Inventor Hiroyuki Ito Tachibanadai, Aoba-ku, Yokohama, Kanagawa Prefecture 2-chome No. 3 Tosoh Aobadai Dormitory (72) Inventor Takashi Yamamoto 5-33, No. 33, Rokkakubashi, Kanagawa-ku, Yokohama-shi, Kanagawa 4 No. 01 (72) Inventor Kimio Katsuura 2-23-3 Nishi-Ochiai, Shinjuku-ku, Tokyo (72) Inventor Naomichi Ishida 2-25-1, Shodai Otani, Hirakata City, Osaka Inside Midori Cross Research Institute, Ltd. Inventor Maki Goda 2- 25-1, Shodai Otani, Hirakata City, Osaka Prefecture, Japan Inside the Midori Cross Central Research Institute, Inc. (72) Inventor Sumio Matsuno 2-25-1, Sumida Otani, Hirakata City, Osaka Prefecture Research on Midori Cross Central, Ltd. In-house (72) Inventor Yoshihisa Inoue 2- 25-1, Invitation Otani, Hirakata City, Osaka Pref. Inside the Midori Cross Research Laboratory (72) Inventor Kenji Yamauchi 2- 25-1, Invitation Otani, Hirakata City, Osaka Pref. Green Cross Research Institute

Claims (13)

[Claims] 1. A compound of the general formula [1] [Wherein R represents a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, or one or more oxygen, nitrogen, or sulfur atoms or a combination of two or more atoms. Represents a 5- or 6-membered heterocyclic ring. Any substituent may be substituted on the heterocycle. R ₁ represents a hydrogen atom or a lower alkyl group. l
Represents an integer of 0 or 1. X and Z are the same or different, a carbonyl group, or the formula: -CHR ₉ - (wherein R ₉
Represents a hydrogen atom or a lower alkyl group. ) Represents a group represented by m represents an integer of 0 or 1. n represents an integer of 1 or 2. Y is an oxygen atom, a sulfur atom or a formula:
NR ₈ - (wherein R ₈ represents a hydrogen atom, a lower acyl group or substituted with a halogen atom represent also a lower alkyl group,.) Represents a group represented by. Q is ethylene, trimethylene or a compound of the formula [2] (Wherein E represents a nitrogen atom or a CH group). R ₂ represents a hydrogen atom or a lower alkyl group. A is represented by the formula [3] (Wherein R ₃ and R ₄ are the same or different and each represents a hydrogen atom,
Halogen atom, lower alkenyl group, lower alkoxy group,
Lower alkylsilyl group, or dicyano group, lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, carbamoyl group, lower alkylcarbamoyl group, lower acyl group, lower acyloxy group, halogen Represents a lower alkyl group which may be substituted with an atom or a lower acylamino group. Alternatively, R ₃ and R ₄ may be combined to form a 5- to 6-membered ring. Or a group represented by the formula [4]: (Wherein F is vinylene, ethynylene or the formula [5] (In the formula, R ₇ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by R ₆ represents a lower alkyl group which may be substituted with a lower alkoxy group or a cyano group. R ₅ represents a hydrogen atom or a lower alkyl group. p represents an integer of 0 or 1. ) Represents a group represented by ] The thiocarbamic acid derivative or its salt characterized by being represented by these. 2. A compound of the general formula [6] (In the formula, R, R ₁ , X, Y, Z, Q, R ₂ , l, m, and n have the same meanings as described above. R ₁₀ represents a hydrogen atom, a lower acyl group, or a lower alkoxycarbonyl group. Or a salt thereof. 3. A compound of the general formula [7] (Wherein R ₉ , Q, R ₂ , A, and n have the same meanings as described above, and V represents a halogen atom), or a thiocarbamic acid ester or a salt thereof. 4. A compound of the general formula [8] (Where A and V have the same meanings as described above) and a halogenated thioformate represented by the general formula [6a]: Wherein R, R ₁ , X, Y, Z, R ₂ , Q, l, m, and n have the same meanings as described above, and a compound represented by the general formula [ 1] (Where R, R ₁ , X, Y, Z, Q, R ₂ , A, l, m, n
Represents the same meaning as described above). 5. A compound of the general formula [9] (Wherein R, R ₁ , X, Y, l, and m have the same meanings as described above) and a compound represented by the general formula [7]: (Wherein V, R ₉ , Q, R ₂ , A and n have the same meanings as described above), characterized by reacting a compound represented by the general formula [1a]: (Wherein, R, R ₁ , R ₉ , X, Y, Q, R ₂ , A, l,
m and n have the same meaning as described above. )). 6. A compound of the general formula [10] (Wherein Q, R ₂ and A have the same meanings as described above) and a compound represented by the general formula [11]: (Wherein, V, R, R ₁ , X, Y, Z, V, 1, m, and n represent the same meanings as described above). ] (Where R, R ₁ , X, Y, Z, Q, R ₂ , A, l, m,
n represents the same meaning as described above. )). 7. A general formula [12] A ₂ OH [12] wherein A ₂ is a formula [4] [Wherein F is vinylene, ethynylene or the formula [5] (In the formula, R ₇ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by R ₆ represents a lower alkyl group which may be substituted with a lower alkoxy group or a cyano group. R ₅ represents a hydrogen atom or a lower alkyl group. p represents an integer of 0 or 1. ] Represents the group represented by these. And a compound represented by the general formula [19]: (Wherein, R, R ₁ , X, Y, Z, Q, R ₂ , l, m, and n represent the same meaning as described above. R ₁₈ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl Or a lower alkoxy group, a lower alkylsilyl group, a cyano group or a nitro group). (Where R, R ₁ , X, Y, Z, Q, R ₂ , A ₂ , l,
m and n have the same meaning as described above. )). 8. The compound of the general formula [1], [6] or [7], which is an optically active compound, a racemic product, or a mixture or an isolated product of optical isomers such as diastereomers. 4. The compound according to 2, 3 or 4. 9. The compound according to claim 1, 2 or 3, wherein the compound of the general formula [1], [6] or [7] contains an acid adduct thereof. 10. The compound according to claim 1, 2 or 3, wherein the compound of the general formula [1], [6] or [7] is a hydrate, a solvate or a polymorph thereof. . 11. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier. 12. A squalene epoxidase inhibitor comprising the compound of claim 1 or a salt thereof. 13. A therapeutic and / or prophylactic agent for hypercholesterolemia, hyperlipidemia or arteriosclerosis, comprising the compound of claim 1 or a salt thereof.