JPH08301826A - Squalene epoxidase inhibitory active substance - Google Patents

Abstract

(57) [Summary] [Structure] General formula [I] [Wherein Q, V, W are the same or different from each other by an oxygen atom, a sulfur ^{atom, N-R 3, N-} R 4 (R 3, R 4 represents a hydrogen atom or a lower alkyl group) or an CH ₂ , L and n represent 0 or 1. R ¹ represents a lower alkyl group, a lower alkylene group, a lower alkoxy group, or a phenyl group which may be substituted with an aralkyloxy group. R
² is the formula [III] (In the formula, Z represents CH or a nitrogen atom, R ⁵ is a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group,
It represents a hydroxy lower alkyl group, a formyl group and the like. )]
And a salt thereof. EFFECTS OF THE INVENTION The present invention can provide a compound useful in the field of medicine, particularly in the fields of treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis. INDUSTRIAL APPLICABILITY The compound of the present invention is a novel substance having a completely different skeleton from the conventionally known amine-based or allylamine-based compounds, and has a high inhibitory activity against squalene epoxidase derived from mammals.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel compound, and more particularly to a compound useful in the field of medicine, particularly in the fields of treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis. .

[0002]

2. Description of the Related Art In recent years, it has been pointed out that the incidence of arteriosclerosis and various coronary and cerebral arterial diseases associated with it increases with the aging of the population and changes in eating habits.

Although various factors have been considered for the occurrence of this arteriosclerosis, in particular, an increase in blood cholesterol is one of the most important risk factors, and therefore, it is used in the prevention and treatment of arteriosclerosis. It is said that blood cholesterol lowering agents are effective. Among these blood cholesterol lowering agents, cholesterol biosynthesis inhibitors in vivo are highly evaluated due to their clear mechanism of action and strong drug efficacy.

In order to inhibit cholesterol biosynthesis in the living body, it is said that it is useful to inhibit the oxygen activity involved in the biosynthesis. Lovastatin, epstatin, pravastatin and the like have already been clinically used as such cholesterol inhibitors. [Proceeding National Academy Science (Proc. Natl. Acad. Sci.), 77, 3957 (1980), etc.].

However, these known inhibitors include 3-hydroxymethylglutaryl-coenzyme A reductase (H
MG-CoA reductase) as a target enzyme, and this enzyme is located at a relatively early stage in the cholesterol biosynthesis system. Therefore, the enzyme inhibition by the administration of the above drug may cause the inhibition of the synthesis of other physiologically important metabolites such as dolichol and ubiquinone. Further, it has been reported that triparanol, which is known as an inhibitor of an enzyme located in the latter stage of the cholesterol biosynthesis system, accumulates desmosterol which causes cataract.

On the other hand, the squalene epoxidase inhibitor whose target enzyme is squalene epoxidase, which is located in the middle stage of the cholesterol biosynthesis system, has no risk of inhibiting the synthesis of metabolites such as dolichol and ubiquinone described above.
Further, it can be a safer anticholesterol agent without the risk of accumulation of harmful substances in the body.

Such squalene epoxidase inhibitors include (E) -N- (6,6-dimethyl-2-heptene-4-ynyl) -N-ethyl-3- [4- (3-thienyl). Allylamine compounds such as 2-thienylmethyloxy] benzylamine (NB-598) (for example, JP-A-3-141275, WO 93/12069).
Etc.), dibenzylamine compounds (for example, WO 94 /
18167) and allyl alcohol compounds (for example, JP-A-6-49023).

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
Compounds having antifungal activity are reported in Japanese Patent Publication No. 2 and the like. It is known that thiocarbamic acid ester having antifungal activity exhibits antibacterial activity by inhibiting steroid synthesis of bacteria, particularly squalene epoxidase. In addition, compounds having herbicidal activity have been reported in Japanese Examined Patent Publication No. 62-54424.

However, it has been reported that a thiocarbamate derivative having antifungal activity shows only weak activity against squalene epoxidase in mammals [Drugs of the Future (Drugs of the Future)]. t
he future), 18 (10), 911 (1993)]. Further, it is known that urea compounds such as benzoylureas are useful as insecticides, and arylureas and sulfonylureas are useful as herbicides in the agricultural field.

[0010]

An object of the present invention is to provide an antihypercholesterolemic agent, an antihyperlipidemic agent and an antihyperlipidemic agent which are more safe and have an excellent anticholesterol action than existing agents. It is an object of the present invention to provide a novel substance that can be used as a therapeutic and preventive agent for arteriosclerosis.

[0011]

As a result of intensive studies, the present inventors have found that a certain compound has a high inhibitory activity against squalene epoxidase derived from mammals, and completed the present invention. .

That is, according to the present invention, the general formula [I] [Wherein Q, V, W are the same or different from each other by an oxygen atom, a sulfur ^{atom, N-R 3, N-} R 4 (R 3, R 4 represents a hydrogen atom or a lower alkyl group) or an CH ₂ , L and n represent 0 or 1. R ¹ is a lower alkyl group, a lower alkylene group, a lower alkoxy group or a phenyl group which may be substituted with an aralkyloxy group, or a compound of the formula [II] (In the formula, m represents 0 or 1). R ² is the formula [II
I] (In the formula, Z represents CH or a nitrogen atom, R ⁵ is a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group,
Hydroxy lower alkyl group, formyl group or A ₁ -A
_2- R ⁶ (A ₁ represents an oxygen atom, CH ₂ or CH ₂ O, A ₂ represents CH ₂ , a nitrogen atom substituted with a lower alkyl group, a phenylene group or a 5- or 6-membered heterocyclic group,
R ⁶ is a lower alkyl group, a phenyl group which may be optionally substituted with a halogen atom or a lower alkoxy group, or 5 to
Represents a 6-membered heterocyclic group or middle of carbon chain of the double bonds and / or C ₆ may have a triple bond -C ₂₀ substituent. )). However, W and Q are the same or different and represent an oxygen atom or a sulfur atom, and V is N—R ³
When n is 0, R ¹ is a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group or a lower alkylene group and R ³ is a lower alkyl group, R ⁵ in the formula [III] is Excluding those which are C ₁ -C ₄ alkyl groups, halogen atoms and lower alkoxy groups. ] The present invention provides a compound and a salt thereof.

The compound represented by the general formula [I] will be described in detail. [Wherein Z, A ₁ , A ₂ , R ³ and R ⁶ are the same as defined above, Q ₁ and W ₁ are different from each other and represent an oxygen atom or a sulfur atom, and R ⁷ and R ⁸ are the same or different. And a hydrogen atom, a lower alkyl group or R ⁷ and R ⁸ together represent a lower alkylene group. However, R ⁷ and R ⁸ are not hydrogen atoms at the same time. ] Or a compound of the general formula [V] [Wherein Z, R ³ , R ⁵ , R ⁷ and R ⁸ are the same as defined above], or a general formula [VI] [Wherein m, n, Z, R ³ and R ⁵ are the same as defined above], or a general formula [VII] [In the formula, n ¹ represents 0 or 1, and W ₂ represents an oxygen atom or a sulfur atom. R ³ and R ⁴ are the same or different from each other and represent a hydrogen atom or a lower alkyl group, and R ⁹ is a lower alkyl group, a lower alkoxy group, an aralkyloxy group or halogen. ] The compound characterized by being represented by these, or the compound characterized by being O-pt-butylphenyl Nm-methylphenyl thiocarbamate, or O-pt-butylphenyl N-methyl A compound characterized by being -Nm-hydroxyphenyl thiocarbamate can be mentioned. Hereinafter, the present invention will be described in more 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. Therefore, as the lower alkyl group, specifically, for example, a methyl group, an 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 group, 2-methylpentyl group,
3-methylpentyl group, 1,1-dimethylbutyl group,
2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 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 is preferred, and methyl group, ethyl group, propyl group, isopropyl group and the like are preferable.

Examples of the lower alkylene include methylene, ethylene, propylene and butylene.

As the lower alkoxy group, a methoxy group,
Ethoxy group, n-propoxy group, i-propoxy group, n
-Butoxy group, sec-butoxy group, t-butoxy group, i
-Butoxy group and the like can be mentioned.

Examples of the aralkyloxy group include a benzyloxy group, an o-tolylmethoxy group, an m-tolylmethoxy group, a p-tolylmethoxy group, an o-chlorophenylmethoxy group, an m-chlorophenylmethoxy group, a p-chlorophenylmethoxy group and an o. -Methoxyphenylmethoxy group, m
Examples thereof include -methoxyphenylmethoxy group and p-methoxyphenylmethoxy group.

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

In the present invention, the unsubstituted or substituted phenyl group includes phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group,
2-, 3-, or 4-propylphenyl group, 2-, 3
-, Or 4-butylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4
Examples thereof include a lower alkyl group such as a chlorophenyl group, a lower alkoxy group, and a phenyl group substituted with a halogen atom. Two or more of these substituents may be simultaneously substituted on the phenyl group. Preferable examples include a phenyl group or a phenyl group in which a methyl group, a propyl group, a butyl group, or a methoxy group is substituted at any position.

In A ₂ or R ⁶ , the 5- or 6-membered heterocyclic group contains one or more oxygen atoms, nitrogen atoms, or sulfur atoms, or a combination of two or more atoms. 6-membered heterocyclic ring, specifically, a 5-membered heterocyclic ring such as furyl group, thienyl group, pyrrolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, etc. And a 6-membered heterocyclic ring. Preferred is a 5-membered heterocyclic ring such as a furyl group, a thienyl group, a pyrrolyl group or a pyrazolyl group. Examples of the substituent having a C _{6 to} C ₂₀ carbon chain which may have a double bond and / or a triple bond in the middle include, for example, a 4,4-dimethyl-2-pentynyl group,
6,6-Dimethylheptene-2-en-4-ynyl group and the like can be mentioned. In addition, in this substituent, when a double bond is included in the middle, geometric isomers represented by E and Z exist, but the present invention includes any geometric isomer.

In the general formula [IV], Q ₁ is preferably an oxygen atom, and W ₁ is preferably a sulfur atom. R ³
As the above, a hydrogen atom, a methyl group, an ethyl group or an n-propyl group is preferable. As R ⁷ and R ⁸ , R ⁷ represents a hydrogen atom and R ⁸ represents an i-propyl group or a t-butyl group,
Alternatively, it is preferable that R ⁷ and R ⁸ together represent a propylene group or a butylene group.

That is, as the compound represented by the general formula [IV], thiocarbamate is preferable, and especially as the O-substituent, pt-butylphenyl, pi-propylphenyl, 1,2,3. , 4-Tetrahydro-6-naphthyl, 5-indanyl, p-chlorophenyl, m-t-butyl-p-chlorophenyl and the like are preferable.

Examples of the substituent represented by A ₁ -A ₂ -R ⁶ include benzyloxy group, o-xylyloxy group, m-xylyloxy group, p-xylyloxy group, o-chlorophenylmethoxy group, m-chlorophenylmethoxy group. , P
-Chlorophenylmethoxy group, o-methoxyphenylmethoxy group, m-methoxyphenylmethoxy group, p-methoxyphenylmethoxy group, 4- (3-thienyl) -2-
A thienylmethoxy group, a 3- (3-thienyl) phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group,
3- (1-pyrazolyl) phenylmethoxy group, 6- (3
-Thienyl) -2-pyridylmethoxy group, 6- (1-pyrrolyl) -2-pyridylmethoxy group, 6- (1-pyrazolyl) -2-pyridylmethoxy group, Z- [N- (6,6
-Dimethyl-2-heptene-4-ynyl) -N-ethylaminomethyl group, E- [N- (6,6-dimethyl-2-
Examples thereof include a heptene-4-ynyl) -N-ethylaminomethyl group.

Preferably, benzyloxy group, o-xylyloxy group, m-xylyloxy group, o-chlorophenylmethoxy group, m-chlorophenylmethoxy group, o-
Methoxyphenylmethoxy group, m-methoxyphenylmethoxy group, 4- (3-thienyl) -2-thienylmethoxy group, 3- (3-thienyl) phenylmethoxy group, 3-
(1-Pyrrolyl) phenylmethoxy group, 3- (1-pyrazolyl) phenylmethoxy group, Z- [N- (6,6-dimethyl-2-heptene-4-ynyl) -N-ethylaminomethyl group, E- [N- (6,6-dimethyl-2-heptene-4-ynyl) -N-ethylaminomethyl group. The substitution position of A ₁ -A ₂ -R ⁶ is m when the aromatic substituent on the nitrogen atom is a benzene ring (ie, Z = CH).
In the case of a pyridine ring (Z = N), the 6-position is preferred.

As the substituent of the compound represented by the general formula [V], R ³ is preferably a hydrogen atom, a methyl group, an ethyl group or an n-propyl group. R ⁷ and R ⁸ are those in which R ⁷ is a hydrogen atom and R ⁸ represents an i-propyl group or a t-butyl group, or R ⁷ and R ⁸ together represent a propylene group or a butylene group. preferable.

That is, as the O-substituent of the thiocarbamate represented by the general formula [V], pt-butylphenyl, p-i-propylphenyl, 1,2,3,4-tetrahydro-6- Naphthyl, 5-indanyl and the like are preferable. R ⁵ is a methyl group, ethyl group, n-propyl group, methoxy group, ethoxy group, n-propoxy group, chlorine atom, bromine atom, benzyloxy group, o-xylyloxy group, m-xylyloxy group, o-chlorophenylmethoxy group. A group, m-chlorophenylmethoxy group, o-methoxyphenylmethoxy group, m-methoxyphenylmethoxy group, 4- (3-thienyl) -2-thienylmethoxy group and the like are preferable. The substitution position is preferably the m-position when the aromatic substituent on the nitrogen atom is a benzene ring (that is, Z = CH) and the 6-position when the aromatic substituent on the nitrogen atom is a pyridine ring (Z = N).

As the substituent of the compound represented by the general formula [VI], R ³ is preferably a hydrogen atom, a methyl group, an ethyl group or an n-propyl group. R ⁵ is a methyl group, ethyl group, n-propyl group, methoxy group, ethoxy group, n-propoxy group, chlorine atom, bromine atom, benzyloxy group, o-xylyloxy group, m-xylyloxy group, o-chlorophenylmethoxy group. Group, m-chlorophenylmethoxy group, o-methoxyphenylmethoxy group, m-
Methoxyphenylmethoxy group, 4- (3-thienyl)-
A 2-thienylmethoxy group and the like are preferable. The substitution position is such that the aromatic substituent on the nitrogen atom is a benzene ring (ie Z = CH).
In the case of, the m-position is preferred, and in the case of a pyridine ring (Z = N), the 6-position is preferred.

Representative examples of carbamate compounds are shown in Table 1.

[0029]

[Table 1]

The symbols A _{1 to} A ₆ and B _{1 to} B ₅ in the table are as follows.

As the substituent of the compound represented by the general formula [VII], R ³ and R ⁴ are the same or different from each other, and a hydrogen atom, a methyl group and an ethyl group are preferable. R ⁹ is a methyl group, an ethyl group, an n-propyl group, a methoxy group, an ethoxy group, an n-propoxy group, a chlorine atom, a bromine atom, a benzyloxy group, an o-xylyloxy group, an m-xylyloxy group, an o-chlorophenylmethoxy group. , M-chlorophenylmethoxy group, o-methoxyphenylmethoxy group, m-
Methoxyphenylmethoxy group, 4- (3-thienyl)-
A 2-thienylmethoxy group and the like are preferable.

Table 2 shows typical examples of ureas. Further, the compounds of the present invention are shown in Table 3.

[0033]

[Table 2]

[0034]

[Table 3]

The compounds of the present invention [I], [IV] to [VI]
[I] may include an asymmetric carbon. Therefore, 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 isolated thereof. The compounds [I] and [IV] to [VII] of the present invention have an amine residue, and thus may form an acid adduct. Examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, Examples thereof include acid adduct salts with organic acids such as citric acid and methanesulfonic acid. Further, various hydrates, solvates and crystalline polymorphic substances of the compounds [I] and [IV] to [VII] of the present invention are also included.

The compound of the present invention can be produced by combining various methods. Typical examples are shown below.

Manufacturing method 1 (In the formula, R ¹ , R ² , R ³ and n are the same as those described above, W ₂ represents an oxygen atom or a sulfur atom, and X represents a halogen atom such as a chlorine atom or a bromine atom.)

The compound of the present invention represented by the formula [Ia] has the formula:
It can be produced by reacting the halogenoformate represented by [VIII] with the amine represented by the formula [IX], for example, in the presence of a base at room temperature to 150 ° C. for several minutes to 24 hours in the absence or presence of a solvent.

Examples of the base include sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium carbonate,
Examples thereof include inorganic bases such as potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, and organic bases such as pyridine, triethylamine and trimethylenediamine.
As the solvent, solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, toluene can be used.

The compound [IX] is not particularly limited as long as it is equimolar or more to the compound [VIII]. The halogenoformate represented by the formula [VIII] can be produced by reacting the corresponding alcohol or phenolic compound with a halogenothiocarbonylating agent such as thiophosgene.

Production method 2 (In the formula, R ¹ , R ² , R ³ , n, W ₂ and X have the same meanings as described above, and Q ₂ represents an oxygen atom or N—R ⁴ .
R ⁴ has the same meaning as described above. )

The compound represented by the formula [Ib] has the formula [X]
It can be produced by reacting the carbamoyl halide represented by the following formula with the alcohol or amine represented by the formula [XI] in the presence of a base, without solvent or in a solvent at room temperature to 150 ° C. for several minutes to 24 hours.

Examples of the base include sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium carbonate,
Examples thereof include inorganic bases such as potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, and organic bases such as pyridine, triethylamine and trimethylenediamine.
As the solvent, solvents such as methanol, ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, toluene can be used.

The compound [XI] is not particularly limited as long as it is equimolar or more to the compound [X]. The carbamoyl halide represented by the formula [X] can be produced by reacting the corresponding amine compound with a halogenocarbonylating agent such as phosgene or a halogenothiocarbonylating agent such as thiophosgene.

Manufacturing method 3 (In the formula, R ¹ , R ² , R ³ , n and W ² have the same meanings as described above.)

The compound of the present invention represented by the formula [Ic] has the formula:
It can be produced by reacting an iso (thio) cyanate represented by [XII] with an amine represented by the formula [XIII], for example, in the presence of a base at room temperature to 150 ° C. for several minutes to 24 hours in the absence or presence of a solvent.

Examples of the base include organic bases such as pyridine, triethylamine and trimethylenediamine. As the solvent, a solvent such as isopropanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, toluene can be used. The compound [XIII] is not particularly limited as long as it is at least equimolar to the compound [XII].

[0048]

EXAMPLES Example 1 Synthesis of O-pt-butylphenyl = Nm-tolylthiocarbamate (Compound No. 1)

M-toluidine 406 mg, potassium carbonate 519
A 5 ml acetonitrile solution of 813 mg of pt-butylphenylchlorothioformate was added dropwise to a 5 ml acetonitrile solution of 5 mg under ice cooling. Then, the mixture was stirred at room temperature for 3.5 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1) to give the desired product as white crystals.
Obtained 853 mg.

Melting point 109-112 ° C. IR (NaCl, cm ⁻¹ ) 3180,3050,2960,1605,1550,1
490,1370,1210,1180 NMR (CDCl ₃ , δppm) 1.34 (s, 9H), 2.37 (2.3H),
6.95-7.58 (m, 8H), 8.1-8.6 (m, 1H)

Example 2 Synthesis of O-pt-butylphenyl = N-methyl-N-3-hydroxyphenylthiocarbamate (Compound No. 2) Synthesis was carried out in the same manner as in Example 1.

Properties Colorless crystal Melting point 161 to 163.5 ° C. IR (NaCl, cm ⁻¹ ) 3360,2960,1610,1595,1480,1
385,1300,1215,1200,1170 NMR (CDCl ₃ , δppm) 1.30 (s, 9H), 3.71 (s, 3H),
5.09 (s, 1H), 6.75-7.05 (m, 5H), 7.22-7.43 (m, 3H)

Example 3 Synthesis of O-pt-butylphenyl = N-methyl-N-3-formylphenylthiocarbamate (Compound No. 3)

O-pt-butylphenyl = N- was added to 10 ml of a methylene chloride solution containing 1.64 g of pyridinium chlorochromate.
A solution of 1 g of methyl-N-3-hydroxymethylphenylthiocarbamate in 10 ml of methylene chloride was added, and the mixture was stirred at room temperature for 1.5.
Stir for hours. Then, 80 ml of ether was added to the reaction solution, and the mixture was further stirred for 15 minutes. Chromates were filtered off, the filtrate was washed with water and saturated saline, and then the organic layer was 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 n-hexane: ethyl acetate = 6: 1) to give 829 mg of the target white crystal.
I got

Properties Colorless crystal Melting point 123 to 125 ° C. IR (KBr, cm ⁻¹ ) 2960,1700,1480,1385,1285,120
5 NMR (CDCl ₃ , δppm) 1.31 (s, 9H), 3.75 (s, 3H),
6.89-7.06 (m, 2H), 7.38 (d, J = 8.7Hz, 2H), 7.44-7.70 (m, 2
H), 7.78-7.92 (m, 2H), 10.04 (s, 1H)

Example 4 O-pt-butylphenyl = N-methyl-N-3-
Synthesis of (2-methylphenylmethyloxy) phenylthiocarbamate (Compound No. 5) Synthesis was carried out in the same manner as in Example 1.

Properties Light yellow liquid IR (NaCl, cm ⁻¹ ) 2990,3020,1620,1600 NMR (CDCl ₃ , δppm) 1.34 (s, 9H), 2.41 (s, 3H),
5.06 (s, 2H), 6.80-7.52 (m, 12H)

Example 5 O-pt-butylphenyl = N-methyl-N- (6-
Synthesis of (2-xylyloxy) -2-pyridyl) thiocarbamate (Compound No. 4) Synthesis was carried out in the same manner as in Example 1.

Properties Light yellow liquid NMR (CDCl ₃ , δppm) 1.36 (s, 9H), 2.45 (s, 3H),
3.78 (s, 3H), 5.40 (s, 2H), 6.70-7.70 (m, 11H)

Example 6 O-pt-butylphenyl = N-methyl-N-3-
Synthesis of (2-xylyloxymethyl) phenylthiocarbamate (Compound No. 6) Synthesis was carried out in the same manner as in Example 1.

Properties Light yellow viscous substance IR (NaCl, cm ⁻¹ ) 2960,1490,1475,1380,1200,1
175,1155,1120,1105,1075 NMR (CDCl ₃ , δppm) 1.30 (s, 9H), 2.32 (s, 3H),
3.73 (s, 3H), 4.56-4.62 (m, 4H), 6.87-6.98 (m, 2H), 7.12-7.
50 (m, 10H)

Example 7 O-pt-butylphenyl = N-methyl-N-4-
Synthesis of (2-xylyloxy) phenylthiocarbamate (Compound No. 7) Synthesis was carried out in the same manner as in Example 1.

Properties colorless crystal IR (NaCl, cm ⁻¹ ) 2960,1510,1490,1390,1240,1
220,1180,1165,1010 NMR (CDCl ₃ , δppm) 1.30 (s, 9H), 2.38 (s, 3H),
3.73 (s, 3H), 5.03 (s, 2H), 6.88-7.14 (m, 5H), 7.17-7.48 (m,
(7H)

Example 8 O-pt-butylphenyl = N-methyl-N- (3-
Synthesis of (4- (3-thienyl) -2-thienyl) methyloxy) phenylthiocarbamate (Compound No. 8)

To a solution of 42 mg of 60% oily sodium hydride in 4 ml of tetrahydrofuran was added dropwise a solution of 300 mg of O-pt-butylphenyl = N-methyl-N- (3-hydroxyphenyl) thiocarbamate in 18 ml of tetrahydrofuran under ice cooling. The mixture was stirred at room temperature for 10 minutes. The reaction solution was ice-cooled again, and 4-
(3-thienyl) -2-bromomethylthiophene 273 mg
Was added. After the addition is complete, return the reaction temperature to room temperature and
Stir for hours. After completion of the reaction, water was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was extracted 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, and the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 6: 1) to obtain 383 mg of light brown crystals of the target substance.

IR (NaCl, cm ^-1 ) 2960,1600,148
5,1380,1210,1175 NMR (CDCl ₃ , δppm) 1.30 (s, 9H), 3.71 (s, 3H),
5.23 (s, 2H), 6.87-7.04 (m, 5H), 7.26-7.43 (m, 8H)

Example 9 O-pt-butylphenyl = N-methyl-N- (6-
(4- (3-thienyl) -2-thienyl) methyloxy) -2-pyridylthiocarbamate (Compound No. 9)
Synthesis of the target compound was carried out in the same manner as in Example 8.

Properties Light yellow crystal IR (NaCl, cm ^-1 ) 2960,1600,1465,1460,1425,1
370,1340,1275,1180 NMR (CDCl ₃ , δppm) 1.32 (s, 9H), 3.79 (s, 3H),
5.55 (s, 2H), 6.72 (dd, J = 0.7,8.1Hz, 1H), 6.96-7.10 (m, 3
H), 7.26-7.44 (m, 7H), 7.64 (t, J = 7.7Hz, 1H)

Example 10 O-pt-butylphenyl = N-methyl-N- [3-
E- (N-6,6-Dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 10) and O-pt-butylphenyl = N-methyl-N- Synthesis of [3-Z- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 11).

O-pt-butylphenyl = N-methyl-N-3-hydroxymethylphenylthiocarbamate
394 mg of 10 ml ethyl acetate solution under ice-cooling phosphorus tribromide 390
mg was added and stirred for 20 minutes. 50 ml of saturated sodium hydrogen carbonate solution was slowly added to the reaction solution. Further, 30 ml of saturated saline was added to the reaction solution, and the reaction solution was extracted with ethyl acetate.
The organic layer was 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 = 5: 1).
Purified by O-pt-butylphenyl = N-methyl-
89 mg of N-3-bromomethylphenylthiocarbamate was obtained as a colorless viscous substance.

76 mg of (E) / (Z) -N- [2- (6,6-dimethylhepten-4-yl)]-N-ethylamine
22 mg of 60% oily sodium hydride in ice-cooled 4 ml tetrahydrofuran solution of ((E) / (Z) = 1/1), O-pt-butylphenyl = N-methyl-N-prepared above
5 ml of 89 mg of 3-bromomethylphenyl thiocarbamate
Tetrahydrofuran solution was added sequentially. After the addition is complete
After stirring for 1.5 hours, 2 ml of dimethylformamide was added, and the mixture was further stirred for 4.5 hours. After that, the reaction liquid is 200 ml of water
And extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1) to obtain the desired product, O-pt-butylphenyl = N-methyl-N-.
[3-E- (N-6,6-dimethyl-2-heptene-4
-Yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 10) as a pale yellow viscous material, 37 mg and O-pt-butylphenyl = N-methyl-N- [3
33 mg of -Z- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 11) was obtained as a light brown viscous substance.

O-pt-butylphenyl = N-methyl-N- [3-E- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 10) IR (NaCl, cm ^-1 ) 2970,2220,1490,1470,1380,1
200,1180,1160,1120,1110 NMR (CDCl ₃ , δppm) 1.03 (t, J = 7.3Hz, 3H), 1.2
4 (s, 9H), 1.30 (s, 9H), 2.51 (q, J = 7.0Hz, 2H), 3.09 (d, J = 6.4
Hz, 2H), 3.59 (s, 2H), 3.73 (s, 3H), 5.62 (dd, J = 1.4,15.9Hz,
1H), 6.06 (dt, J = 6.4,15.9Hz, 1H), 6.83-7.05 (m, 2H), 7.12-
7.45 (m, 6H)

O-pt-Butylphenyl = N-methyl-N- [3-Z- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 11) IR (NaCl, cm ^-1 ) 2970,2210,1490,1475,1380,1
200,1180 NMR (CDCl ₃ , δppm) 1.06 (t, J = 7.2Hz, 3H), 1.2
3 (s, 9H), 1.30 (s, 9H), 2.54 (q, J = 7.2Hz, 2H), 3.34 (d, J = 6.8
Hz, 2H), 3.62 (s, 2H), 3.73 (s, 3H), 5.57 (d, J = 11.0,1H), 5.8
2-6.00 (m, 1H), 6.85-7.05 (m, 2H), 7.13-7.43 (m, 6H)

Example 11 Op-t-butylphenyl = N- (m-xylyl)-
Synthesis of N-methylthiocarbamate (Compound No. 12) Synthesis was carried out in the same manner as in Example 1.

IR (NaCl, cm ^-1 ) 2940,1510,150
0,1400,1205 NMR (CDCl ₃ , δppm) 1.70-1.98 (m, 4H), 2.39
(s, 3H), 2.60-2.83 (m, 4H), 3.43 (s, 3H), 4.89 (s, 2H), 6.76-
7.36 (m, 8H)

Example 12 Synthesis of O-pt-butylphenyl = N- (3-methoxyphenylmethyl) -N-methylthiocarbamate (Compound No. 13) Synthesis was carried out in the same manner as in Example 1.

IR (NaCl, cm ^-1 ) 2950,1610,159
5,1510,1410,1220 NMR (CDCl ₃ , δppm) 1.35 (s, 9H), [3.24 (s), 3.
45 (s), 3H], 3.83 (s, 3H), [4.90 (s), 5.18 (s), 2H], 6.80 (m, 8
H)

Example 13 Synthesis of O-pt-butylphenyl = N- (3- (o-xylyloxy) phenylmethyl) -N-methylthiocarbamate (Compound No. 14) Synthesis was carried out in the same manner as in Example 1. .

IR (NaCl, cm ^-1 ) 3030,2960,160
0,1520,1500,1400,1260,1220 NMR (CDCl ₃ , δppm) 1.33 (s, 9H), 2.20 (s, 3H),
[3.21 (s), 3.42 (s), 3H], 4.89-5.17 (m, 4H), 6.84-7.48 (m, 1
2H)

Example 14 Synthesis of O-pt-butylphenyl = N- [4- (o-xylyloxy) phenylmethyl) -N-methylthiocarbamate (Compound No. 15) Synthesis was carried out in the same manner as in Example 1. .

Properties Colorless viscous substance IR (NaCl, cm ⁻¹ ) 2960,1510,1500,1395,1240,1
205,1175,1140,1100 NMR (CDCl ₃ , δppm) 1.35 (s, 9H), 2.40 (s, 3H),
[3.12 (s), 3.42 (s), 3H], [4.86 (s), 5.14 (s), 2H], 5.06 (s, 2
H), 6.95-7.10 (m, 4H), 7.18-7.32 (m, 4H), 7.34-7.48 (m, 4H)

Example 15 Om-methoxyphenyl = N- (4-t-butylphenyl) -N-methylthiocarbamate (Compound No. 16)
Synthesis was carried out in the same manner as in Example 1.

Properties Yellow solid Melting point 116 to 118 ° C. IR (KBr, cm ⁻¹ ) 2960,1605,1505,1480,1380,128
0,1170,1150,1110,1035 NMR (CDCl ₃ , δppm) 1.33 (s, 9H), 3.73 (s, 3H),
3.79 (s, 3H), 6.55-6.88 (m, 3H), 7.18-7.35 (m, 3H), 7.43 (d,
(J = 8.6Hz, 2H)

Example 16 O-3- (o-xylyloxy) phenyl = N- (4-
Synthesis of t-butylphenyl) -N-methylthiocarbamate (Compound No. 17)

To a solution of 260 mg of thiophosgene in 20 ml of methylene chloride, under ice-cooling, 3- (o-xylyloxy) phenol 512 was added.
A 10 ml methylene chloride solution of mg and a 10 ml methylene chloride solution of 230 mg of pyridine were sequentially added dropwise. After completion of dropping, the mixture was stirred at room temperature for 18 hours, then, a solution of 597 mg of N- (pt-butylphenyl) -N-methylamine in 25 ml of methylene chloride was added dropwise, and the mixture was stirred for further 5 hours. . Then, 5% aqueous ammonia was added to the reaction solution, and the reaction solution was extracted with methylene chloride. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purify with (developing solvent n-hexane: methylene chloride = 5: 2) to obtain the desired product as a yellow oil 4
82 mg was obtained.

Refractive index n ^D 24.0 1.5899 IR (NaCl, cm ^-1 ) 2960,1605,1480,1380,1255,1
170, 1145, 1115, 1015, NMR (CDCl ₃ , δppm) 1.33 (s, 9H), 2.36 (s, 3H),
3.73 (s, 3H), 5.00 (s, 2H), 6.62-6.97 (m, 3H), 7.14-7.54 (m,
9H)

Example 17 O-6- (1,2,3,4-tetrahydronaphthyl) =
Synthesis of Nm-xylyl-N-methylthiocarbamate (Compound No. 20) Synthesis was carried out in the same manner as in Example 1.

IR (NaCl, cm ^-1 ) 2930,1510,149
5,1400,1240,1220,1150 NMR (CDCl ₃ , δppm) 1.70-1.98 (m, 4H), 2.39
(s, 3H), 2.60-2.83 (m, 4H), 3.43 (s, 3H), 4.89 (s.2H), 6.76-
7.36 (m, 7H)

Example 18 O-6- (1,2,3,4-tetrahydronaphthyl) =
Synthesis of Nm-anisylmethyl-N-methylthiocarbamate (Compound No. 21) Synthesis was carried out in the same manner as in Example 1.

IR (NaCl, cm ^-1 ) 2940,1610,159
5,1520,1405,1222,1160, 1172 NMR (CDCl ₃ , δppm) 1.81 (m, 4H), 2.78 (m, 4H),
[3.23 (s), 3.43 (s), 3H], 3.84 (s, 3H), [4.88 (s), 5.17 (s), 3
H], 6.62-7.42 (m, 7H)

Example 19 O-6- (1,2,3,4-tetrahydronaphthyl) =
N- [3- (o-xylyloxy) phenylmethyl]-
Synthesis of N-methylthiocarbamate (Compound No. 22) Synthesis was carried out in the same manner as in Example 1.

IR (NaCl, cm ^-1 ) 2950,1620,160
0,1580 NMR (CDCl ₃ , δppm) 1.65-1.89 (m, 4H), 2.31-
2.42 (m, 3H), 2.75 (m, 4H), [3.20 (s), 3.41 (s), 3H], 4.80-5.
20 (m, 4H), 6.72-7.42 (m, 11H)

[0093]Example 20  O- (4,4-dimethyl-2-pentynyl) = N-m-
Trilyl-N-methylthiocarbamate (Compound No. 23)
Synthesis of

To a solution of 343 mg of 4,4-dimethyl-2-pentyn-1-ol in 5 ml of dimethylformamide was added 129 mg of 60% oily sodium hydride, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was ice-cooled and N-methyl-N-m was added to the reaction solution.
A solution of 600 mg of tolylchlorothioformate in 5 ml of dimethylformamide was added dropwise. After completion of the dropping, the reaction temperature was returned to room temperature and stirring was continued for 2.5 hours. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, 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 30: 1) gave 762 mg of the desired product as a colorless oil.

IR (NaCl, cm ^-1 ) 2970, 2240, 149
0,1475,1380,1210,1160,1135 NMR (CDCl ₃ , δppm) 1.20 (s, 9H), 2.37 (s, 3H),
3.62 (s, 3H), 5.07 (s, 2H), 6.95-7.18 (m, 3H), 7.23-7.35 (m,
1H)

Example 21 O- (4,4-dimethyl-2-pentynyl) = Nm-
Synthesis of chlorophenyl-N-methylthiocarbamate (Compound No. 24)

To a solution of 4,4-dimethyl-2-pentyn-1-ol (407 mg) and potassium carbonate (504 mg) in 5 ml of acetonitrile was added Nm-chlorophenyl-N-methylchlorothioformate (762 mg of 5 ml) in acetonitrile at room temperature. It was stirred for 21 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine, 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 −
The product was purified with hexane: ethyl acetate = 30: 1) to obtain 308 mg of the desired product as a colorless viscous substance.

IR (NaCl, cm ^-1 ) 2970, 2245, 159
5,1480,1380,1200,1135 NMR (CDCl ₃ , δppm) 1.21 (s, 9H), 3.59 (s, 3H),
5.06 (s, 2H), 7.07-7.16 (m, 1H), 7.22-7.40 (m, 3H)

Example 22 O- (4,4-dimethyl-2-pentynyl) = N- [3
Synthesis of-(o-tolylmethoxy) phenyl] -N-methylthiocarbamate (Compound No. 25)

A 10 ml ether solution of 4,4-dimethyl-2-pentyn-1-ol (2 g) was added to a 10 ml ether solution of 712 mg of 60% oily sodium hydride under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was ice-cooled again, and thiophosgene 2.05 g
10 ml of ether solution was added dropwise. After completion of the dropping, the temperature was returned to room temperature and the mixture was further stirred for 2 hours. Then, the reaction solution was poured into 100 ml of water and extracted with ether. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.09 g of 4,4-dimethyl-2-pentynylchlorothioformate as an orange oily substance.

Subsequently, 84 mg of 60% oily sodium hydride was added.
A solution of 408 mg of N- (3-o-xylyloxyphenyl) -N-methylamine in 5 ml of tetrahydrofuran was added dropwise to a solution of 15 ml of tetrahydrofuran, the mixture was stirred for 5 minutes, and then 4,4-dimethyl-2-pentynyl prepared above was prepared. A solution of 358 mg of chlorothioformate in 5 ml of dimethylformamide was added dropwise. Then, the mixture was further stirred at room temperature for 23 hours. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 20: 1) to obtain 60 mg of the desired product as a yellow viscous substance.

IR (NaCl, cm ^-1 ) 2970, 2245, 160
0,1490,1475,1380,1230 NMR (CDCl ₃ , δppm) 1.20 (s, 9H), 2.39 (s, 3H),
3.61 (s, 3H), 5.04 (s, 2H), 5.09 (s, 2H), 6.79-7.00 (m, 3H),
7.18-7.46 (m, 5H)

Example 23 O- (E)-(6,6-dimethyl-2-heptene-4-
(Ynyl) = N-3-chlorophenyl-N-methylthiocarbamate (Compound No. 26)

IR (NaCl, cm ^-1 ) 2975, 2230, 147
5,1380,1205,1140 NMR (CDCl ₃ , δppm) 1.22 (s, 9H), 3.56 (s, 3H),
4.95 (s, 2H), 5.48-5.80 (m, 1H), 5.90-6.18 (m, 1H), 7.00-7.
45 (m, 4H)

Example 24 N-3-methoxyphenyl-N-methyl-N'-pt
-Synthesis of butylphenylurea (Compound No. 27)

To a solution of 314 mg of p-t-butylaniline and 304 mg of anhydrous potassium carbonate in 10 ml of acetonitrile was added N-3 chloride.
400 mg of -methoxyphenyl-N-methylcarbamoyl
Add 10 ml of acetonitrile solution dropwise and at room temperature after the addition is complete.
It was stirred for 18 hours. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to obtain 470 mg of the desired product as a colorless solid.

IR (NaCl, cm ^-1 ) 3400, 2960, 168
0,1590,1520,1320,1230 NMR (CDCl ₃ , δppm) 1.28 (s, 9H), 3.34 (s, 3H),
3.84 (s, 3H), 6.28 (s, 1H), 6.83-6.97 (m, 3H), 7.17-7.44 (m,
5H)

Example 25 N-pt-butylphenyl-N'-methyl-N'-m
-Synthesis of tolylthiourea (Compound No. 28) Synthesis was carried out in the same manner as in Example 24.

Properties Colorless crystal Melting point 114 to 116 ° C. IR (KBr, cm ⁻¹ ) 3378,1595,1520,1340 NMR (CDCl ₃ , δppm) 1.24 (s, 9H), 2.40 (s, 3H),
3.82 (s, 3H), 6.83-7.48 (m, 9H)

Example 26 N-3-Methoxyphenyl-N-methyl-N'-pt
-Butylphenyl-N'-methylurea (Compound No. 2
Synthesis of 9) Synthesis was carried out in the same manner as in Example 24.

Melting point 121 to 123 ° C. IR (KBr, cm ⁻¹ ) 3280,2960,1625,1600,1580,148
5,1375,1295,1190 NMR (CDCl ₃ , δppm) 1.24 (s, 9H), 3.15 (s, 3H),
3.23 (s, 3H), 6.13-6.23 (m, 1H), 6.39 (t, J = 2.2Hz, 1H), 6.42
-6.52 (m, 1H), 6.72-6.89 (m, 4H), 7.09 (d, J = 8.7Hz, 2H)

Example 27 Synthesis of Npt-butylphenyl-N '-(3-o-xylyloxyphenyl) -N, N'-dimethylurea (Compound No. 30)

To a solution of 45 mg of 60% oily sodium hydride in 6 ml of tetrahydrofuran was added 320 ml of a solution of 320 mg of N-3-hydroxyphenyl-N'-pt-butylphenyl-N, N'-dimethylurea in 6 ml of tetrahydrofuran while cooling with ice. A solution of 192 mg of o-xylyl chloride in 6 ml of tetrahydrofuran and 4 ml of dimethylformamide were successively added dropwise, and then the mixture was stirred at room temperature for 43 hours. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1) to obtain 435 mg of the desired product as a colorless viscous substance.

IR (NaCl, cm ^-1 ) 2960, 1655, 159
0,1510,1485,1350,1200,1120 NMR (CDCl ₃ , δppm) 1.21 (s, 9H), 2.36 (s, 3H),
3.17 (s, 6H), 4.90 (s, 2H), 6.33-6.42 (m, 1H), 6.46 (t, J = 2.2
Hz, 1H), 6.51-6.60 (m, 1H), 6.70 (d, J = 8.7Hz, 2H), 6.91 (t, J
= 8.1Hz, 1H), 7.05 (d, J = 8.8Hz, 2H), 7.16-7.30 (m, 3H), 7.33
-7.43 (m, 1H)

Example 28 Synthesis of N-pt-butylphenyl-N '-(3-o-xylyloxyphenylmethyl) -N, N'-dimethylurea (Compound No. 31)

A solution of 166 mg of triphosgene in 20 ml of methylene chloride was added to 10 parts of N-methyl-pt-butylaniline under ice cooling.
ml methylene chloride solution and 10 ml methylene chloride solution of pyridine were sequentially added dropwise, and the mixture was stirred at room temperature for 24 hours. N- [3-
(O-Xylyloxy) phenylmethyl] methylamine
666 mg of 15 ml methylene chloride solution was added dropwise, and further at room temperature.
It was stirred for 22 hours. Aqueous 5% ammonia was added to the reaction solution, stirred for 30 minutes, and then extracted with methylene chloride. The organic layer was washed with 3% hydrochloric acid and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1) to obtain 553 mg of the desired product as a colorless viscous substance.

IR (NaCl, cm ^-1 ) 2955, 1645, 160
0,1510,1485,1445,1380,1255 NMR (CDCl ₃ , δppm) 1.28 (s, 9H), 2.38 (s, 3H),
2.48 (s, 3H), 3.22 (s, 3H), 4.35 (s, 2H), 5.01 (s, 2H), 6.73-
6.92 (m, 3H), 7.02 (d, J = 8.6Hz, 2H), 7.18-7.46 (m, 7H)

Example 29 Synthesis of N-methyl-Nm-tolyl = pt-butylphenylacetic acid thioamide (Compound No. 32)

N-methyl-Nm-tolyl = pt-butylphenylacetic acid amide 1 g, Lawesson's reagent 0.85 g 10
The ml toluene solution was heated under reflux for 20 minutes, and further stirred under heating at 90 ° C for 30 minutes. After cooling, take the supernatant of the reaction mixture and cool it to 3%.
It was washed with aqueous sodium hydroxide. The aqueous layer was extracted with benzene, and the organic layer was combined with the above organic layer, washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent).
The product was purified with n-hexane: ethyl acetate = 3: 1) to obtain 935 mg of the desired product as a yellow oil.

IR (NaCl, cm ^-1 ) 2950,1485,146
5,1375,1090 NMR (CDCl ₃ , δppm) 1.28 (s, 9H), 2.26 (s, 3H),
3.70 (s, 3H), 3.98 (s, 2H), 6.66 (s, 2H), 6.82-6.98 (m, 3H),
7.11-7.32 (m, 4H)

Example 30 Synthesis of N-methyl-Nm-xylyl = pt-butylbenzthioamide (Compound No. 33) Synthesis was carried out in the same manner as in Example 29.

Melting point 75-79 ° C. IR (KBr, cm ⁻¹ ) 2960,1490,1395,1290,1110 NMR (CDCl ₃ , δppm) [1.29 (S), 1.32 (s), 9H],
[2,36 (s), 2.36 (s), 3H], [3.04 (s), 3.46 (s), 3H], 6.91-7.0
0 (m, 1H), 7.08-7.43 (m, 7H)

Example 31 Synthesis of Opt-butylphenyl-O'-m-tolylthiocarbonate (Compound No. 34)

M-cresol 241 mg, potassium carbonate 304
A 5 ml acetonitrile solution of 490 mg of pt-butylphenylchloroformate was added dropwise to a 5 ml acetonitrile solution of mg. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The solid in the reaction solution was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 20: 1) to give the desired product as a pale yellow liquid.
I got 632 mg.

Refractive index n ^D _26.5 1.5609 IR (NaCl, cm ^-1 ) 2960,1505,1275,1205,1190,1
140,1105 NMR (CDCl ₃ , δppm) 1.35 (s, 9H), 2.41 (s, 3H),
6.98-7.18 (m, 5H), 7.29-7.39 (m, 1H), 7.45 (d, J = 8.8Hz, 2H)

Example 32 Synthesis of m-methylphenylthioacetic acid O-pt-butylphenyl ester (Compound No. 35) Synthesis was carried out in the same manner as in Example 31.

Refractive index n ^D _23.6 1.5725 IR (NaCl, cm ^-1 ) 2960,1505,1265,1205,1165,1
105 NMR (CDCl ₃ , δppm) 1.33 (s, 9H), 2.39 (s, 3H),
4.25 (s, 2H), 6.90 (d, J = 8.9Hz, 2H), 7.06-7.37 (m, 4H), 7.41
(d, J = 8.8Hz, 2H)

Example 33 Synthesis of N-methyl-Nm-xylyl = pt-butylbenzamide (Compound No. 36)

Nm-xylylmethylamine 2.79 g of 30
2.87 ml of triethylamine and 4.06 g of pt-butylbenzoyl chloride were sequentially added to the ml ether solution under ice cooling at room temperature.
It was stirred for 4.5 hours. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with 5% hydrochloric acid solution, saturated sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1) to obtain 5.57 g of the desired product as a pale yellow liquid.

Refractive index n ^D _24.4 1.5550 IR (NaCl, cm ^-1 ) 2960,1630,1395,1265,1165,1
NMR (CDCl ₃ , δppm) 1.31 (s, 9H), 2.36 (s, 3H),
2.82-3.08 (m, 3H), 4.45-4.82 (m, 2H), 6.93-7.32 (m, 4H), 7.
41 (s, 4H)

Example 34 Synthesis of N-methyl-Nm-tolyl = pt-butylphenylacetic acid amide (Compound No. 37)

N-methyl-m-toluidine (2 g) and triethylamine (2.4 ml) were added to a 10 ml ether solution under ice-cooling and p-chloride was added.
A 35 ml ether solution of 3.65 g of -t-butylphenylacetyl was added, and the mixture was stirred at room temperature for 16.5 hours. The reaction solution was poured into water and extracted with ether, and then the organic layer was added with a 3% hydrochloric acid solution,
The extract was washed with saturated sodium hydrogen carbonate solution and saturated saline and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 5: 1).
The desired product was obtained as a pale yellow liquid in an amount of 5.57 g.

Refractive index n ^D _27.5 1.5504 IR (NaCl, cm ⁻¹ ) 2955,1655,1600,1585,1490,1
370 NMR (CDCl ₃ , δppm) 1.29 (s, 9H), 2.34 (s, 3H),
3.26 (s, 3H), 3.42 (s, 2H), 6.84-7.05 (m, 4H), 7.11-7.35 (m,
4H)

[Pharmaceutical efficacy test] (1) Preparation of rat squalene epoxidase Rat squalene epoxidase
Journal of Lipid Researc
h), Vol. 31, p. 2095 (1990). After bleeding and killing male SD rats, the liver was exposed to 0.1%.
The mixture was refluxed with M Tris-hydrochloric acid (pH 7.5, 4 ° C). The liver was removed and 3 wt / vol% 0.1 M Tris-HCl (pH 7.
It was homogenized at 5, 4 ° C.) and centrifuged at 1500 × g for 15 minutes. The supernatant was further centrifuged at 105000 × g for 30 minutes, and the resulting microsomes were mixed with 0.1 M Tris-HCl (pH
The suspension was suspended at 7.5, 4 ° C), the amount of protein was quantified, and then stored at -80 ° C.

(2) Method for measuring squalene epoxidase activity The squalene epoxidase activity was measured by Journal of Lipid Resea.
rch), Vol. 31, p. 2095 (1990). Squalene-epoxidase fraction prepared in (1) (protein mass 1.0 mg / ml), 0.067M 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
NADPH, 4 μM 3H-squalene tween 80
A solution of the test drug in dimethyl sulfoxide was added to the suspension solution to make the total volume 0.3 ml, and the mixture was reacted at 37 ° C. for 60 minutes. The reaction was stopped by adding 0.3 ml of 10% potassium hydroxide / methanol solution, and the reaction was carried out at 37 ° C. for 30 minutes. The material to be saponified was extracted with petroleum ether and then concentrated to dryness. The obtained residue was dissolved in a small amount of ethyl ether and spotted on silica gel thin layer chromatography, and benzene-ethyl acetate (9
9.5: 0.5). Generated 3H-squalene-
The 2,3-epoxide portion was cut off and measured with a liquid scintillation counter. Thus, the inhibition rate of the compound of the present invention against squalene epoxidase was determined.

(3) Test Results From this, Table 4 shows the inhibition rate of squalene epoxidase activity at 10 ⁻⁴ M in the representative examples of the compound of the present invention.

[0137]

[Table 4]

[0138]

INDUSTRIAL APPLICABILITY According to the present invention, a compound useful in the field of medicine, particularly in the fields of treatment and prevention of hypercholesterolemia, hyperlipidemia, and thus arteriosclerosis can be provided. INDUSTRIAL APPLICABILITY The compound of the present invention is a novel substance having a completely different skeleton from the conventionally known amine-based or allylamine-based compounds, and has a high inhibitory activity against squalene epoxidase derived from mammals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/44 AED A61K 31/44 AED C07C 233/65 9547-4H C07C 233/65 271/44 9451 -4H 271/44 271/48 9451-4H 271/48 275/28 9451-4H 275/28 275/32 9451-4H 275/32 327/22 7106-4H 327/22 327/44 7106-4H 327/44 327/48 7106-4H 327/48 329/04 7106-4H 329/04 333/04 7106-4H 333/04 333/08 7106-4H 333/08 335/16 7106-4H 335/16 C07D 409/14 213 C07D 409/14 213 C12N 9/99 C12N 9/99 // C07D 213/75 C07D 213/75 (C07D 409/14 213: 75 333: 08) (72) Inventor Yasunari Yamaura 2 Otani Otani, Hirakata City, Osaka Prefecture Chome No. 25-1 Incorporated company Midori Cross Central Research Institute (72) Inventor Yoshihisa Inoue Osaka Prefecture No. 2-25-1, Otani, Tsutsutsumi Otani, Central Research Laboratory, Midori Cross Co., Ltd. (72) Inventor, Norifumi Nakamura, 2-25-1, Otani Ohtani, Midori Cross, Hirakata, Osaka (72) Inventor Taku Tokunaga 1-39-105 Okada, Atsugi-shi, Kanagawa Prefecture 72-72 Inventor Yasuaki Hanasaki 4-26-204, 4-47, Shonandai, Fujisawa-shi, Kanagawa Kimio Katsuura 2 Nishiochiai, Shinjuku-ku, Tokyo -23-3

Claims (10)

[Claims] 1. The general formula [I] [Wherein Q, V, W are the same or different from each other by an oxygen atom, a sulfur ^{atom, N-R 3, N-} R 4 (R 3, R 4 represents a hydrogen atom or a lower alkyl group) or an CH ₂ , L and n represent 0 or 1. R ¹ is a lower alkyl group, a lower alkylene group, a lower alkoxy group or a phenyl group which may be substituted with an aralkyloxy group, or a compound of the formula [II] (In the formula, m represents 0 or 1). R ² is the formula [II
I] (In the formula, Z represents CH or a nitrogen atom, R ⁵ is a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group,
Hydroxy lower alkyl group, formyl group or A ₁ -A
_2- R ⁶ (A ₁ represents an oxygen atom, CH ₂ or CH ₂ O, A ₂ represents CH ₂ , a nitrogen atom substituted with a lower alkyl group, a phenylene group or a 5- or 6-membered heterocyclic group,
R ⁶ is a lower alkyl group, a phenyl group which may be optionally substituted with a halogen atom or a lower alkoxy group, or 5 to
Represents a 6-membered heterocyclic group or middle of carbon chain of the double bonds and / or C ₆ may have a triple bond -C ₂₀ substituent. )). However, W and Q are the same or different and represent an oxygen atom or a sulfur atom, and V is N—R ³
When n is 0, R ¹ is a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group or a lower alkylene group and R ³ is a lower alkyl group, R ⁵ in the formula [III] is Excluding those which are C ₁ -C ₄ alkyl groups, halogen atoms and lower alkoxy groups. ] The compound and its salt represented by these. 2. The compound has the general formula [IV] [Wherein Z, A ₁ , A ₂ , R ³ and R ⁶ are the same as defined above, Q ₁ and W ₁ are different from each other and represent an oxygen atom or a sulfur atom, and R ⁷ and R ⁸ are the same or different. And a hydrogen atom, a lower alkyl group or R ⁷ and R ⁸ together represent a lower alkylene group. However, R ⁷ and R ⁸ are not hydrogen atoms at the same time. ] The compound of Claim 1 represented by these. 3. The general formula [V] The compound according to claim 1, which is represented by the formula: wherein Z, R ³ , R ⁵ , R ⁷ and R ⁸ are the same as above. 4. The general formula [VI] The compound according to claim 1, which is represented by the formula: wherein m, n, Z, R ³ and R ⁵ are the same as the above. 5. The general formula [VII] [In the formula, n ¹ represents 0 or 1, and W ₂ represents an oxygen atom or a sulfur atom. R ³ and R ⁴ are the same or different from each other and represent a hydrogen atom or a lower alkyl group, and R ⁹ is a lower alkyl group, a lower alkoxy group, an aralkyloxy group or halogen. ] The compound of Claim 1 which is a compound represented by these. 6. O-pt-butylphenyl Nm-
The compound of claim 1 which is methylphenyl thiocarbamate. 7. The compound of claim 1, which is O-pt-butylphenyl N-methyl-Nm-hydroxyphenyl thiocarbamate. 8. General formulas [I], [IV], [V] and [VI]
The compound according to any one of claims 1 to 5, wherein the compound of [VII] is a mixture or isolate of optical isomers such as an optically active substance, a racemate and a diastereomer. 9. General formulas [I], [IV], [V] and [VI]
The compound according to any one of claims 1 to 5, wherein the compound of [VII] contains an acid adduct thereof. 10. General formulas [I], [IV], [V] and [V
The compound of [I] or [VII] includes a hydrate, solvate or polymorphic form thereof.
The compound according to the item.