JPH08301841A - Squalene-epoxydase activity inhibitor - Google Patents

Abstract

PURPOSE: To obtain a new squalene-epoxydase activity inhibitor having high safety and excellent anticholesterol action and useful for treating and preventing hypercholesterolemia, hyperlipemia and arterial sclerosis. CONSTITUTION: This squalene-epoxydase inhibitor contains a compound of formula I [Q, V and W are each O, S, etc.; Z is CH or N; (m), (n), (p) and (g) are each 0 or 1; A is a group of formula II (R<6> to R<7> are H, a lower alkyl, an aralkyloxy, a halogen, hydroxyl group, etc.); R<1> to R<3> are each H, a lower alkyl, an alkylthio, a halogen, formyl, etc.,] or its pharmaceutical permissible salt as active ingredients. For example, O-p-t-buthylphenyl=N-m- tolylthiocarbamate is obtained by dropping acetonirile solution of p-t- butylphenylchlorothio-formate to acetonitrile solution of m-toluidine and potassium carbonate under ice cooling and reacting these components.

Description

Detailed Description of the Invention

[0001]

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

[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 may be considered for the occurrence of this arteriosclerosis, in particular, an increase in blood cholesterol is one of the most important risk factors, and therefore, blood cholesterol lowering is required for the prevention and treatment of arteriosclerosis. The drug is said to be effective. Also,
Among these blood cholesterol lowering agents, cholesterol biosynthesis inhibitors in vivo have been 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 enzyme 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 (HMG-CoA).
reductase) is 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. In addition, triparanol, which is known as an inhibitor of an enzyme located in the latter stage of the cholesterol biosynthesis system, has been reported to accumulate desmosterol, which causes cataract.

On the other hand, a squalene epoxidase inhibitor whose target enzyme is squalene epoxidase located in the middle stage of the cholesterol biosynthesis system is a risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the body. It is expected to provide a safer anti-cholesterol agent. As such a squalene epoxidase inhibitor, (E) -N- (6,6-dimethyl-2-heptene-4-ynyl) -N-ethyl-3- [4- (3-thienyl) -2- Allylamine compounds such as 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 thiocarbamic acid ester derivatives having antifungal activity show weak activity against squalene epoxidase in mammals [Drugs of the
Future (Drugs of the future), 18 (10), 911 (199
3)].

Further, as urea compounds, it is known that benzoylureas are useful as insecticides, and allylurea and sulfonylureas are useful as herbicides in the agricultural field.

[0007]

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 intended to provide a therapeutic and preventive agent for arteriosclerosis.

[0008]

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

That is, the present invention has the general formula [I] [Wherein Q, V and W are the same or different from each other and are an oxygen atom, a sulfur atom, NR ⁴ , NR ⁵ (R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group). ), Z represents CH or a nitrogen atom, and m, n, p, q
Represents 0 or 1. A is the formula [II] (Wherein R ⁶ and R ⁷ are the same or different from each other, a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkylthio group, an aralkyloxy group,
A lower hydroxyalkyl group, a halogen atom, a hydroxyl group, a phenyl group, an alkoxyalkyl group, or a compound represented by the formula [III] (CH ₂ ) _t1 O (CH ₂ ) _t2- A ₁ -A ₂ [III] (t1 and t2 are 0 to 3). A ₁ is a phenylene group or a heterocyclic group, A ₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or an unsubstituted or lower alkyl group, a halogen atom, a lower alkoxy group. Represents a phenyl group or a heterocyclic group which may be substituted with, and is represented by the formula [IV] (In the formula, r represents 0 or 1) or a lower alkylene group, a lower cycloalkylene group or R ⁶ and R ⁷ linked to each other. May form a ring). R ¹ , R ² , R ³
Are the same or different from each other, a hydrogen atom, a lower alkyl group, an alkylthio group, a halogen atom, a lower alkoxy group, a hydroxyl group, a hydroxy lower alkyl group, a formyl group,
The substituent represented by the above formula [III] or the formula [V] (In the formula, R ⁸ represents a lower alkyl group.) E-
Alternatively, it represents a Z-aminomethyl group. ] The squalene epoxidase inhibitor characterized by containing the compound represented by these or its pharmaceutically acceptable salt as an active ingredient, and the prevention of arteriosclerosis containing this squalene epoxidase activity inhibitor Alternatively, it is to provide a therapeutic agent or a blood cholesterol lowering agent.

The compound represented by the general formula [I] will be described more specifically. [In the formula, Z, q, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷
Represents the same meaning as described above. W ₁ and Q ₁ are the same or different and each represents an oxygen atom or a sulfur atom. ] Carbamates represented by or general formula [VII] [In the formula, r, q, Z, R ¹ , R ² and R ⁴ have the same meanings as described above. ] Or a thiocarbamate represented by the general formula [VIII] [In the formula, W ₁ , Z, q, R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as described above. ] Or a general formula [IX] [In the formula, m, q, R ¹ , R ² , R ⁴ and Z have the same meanings as described above. ] Or general formula [X] [In the formula, m, q, R ¹ , R ² , R ⁵ and Z have the same meanings as described above. ] Or a general formula [X
I] [Wherein R ¹ , R ² and Z have the same meanings as described above. ] The O, O-diallyl thiocarbonic acid ester represented by these can be mentioned.

Hereinafter, 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. Therefore, 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 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 and the like are preferable, and methyl group and ethyl are preferable. Group, propyl group, isopropyl group, t-butyl group and the like.

Examples of the lower alkylene include straight chain alkylene groups such as methylene, ethylene, propylene, butylene and pentamethylene, and cyclic alkylene groups such as 1,3-cyclopentalene and 1,4-cyclohexalene.

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 benzyloxy group, o-xylyloxy group, m-xylyloxy group, p-xylyloxy group, o-chlorophenylmethoxy group, m-chlorophenylmethoxy group, p-chlorophenylmethoxy group and o-methoxyphenyl group. Methoxy 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.

Examples of the alkoxyalkyl group include methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group and ethoxypropyl group.

As the phenyl group which is unsubstituted or has a substituent, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4- Methoxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group,
Examples thereof include a lower alkyl group such as a 4-chlorophenyl group, a lower alkoxy group, and a phenyl group substituted with a halogen atom. Preferable examples include a phenyl group, a methyl group, and a phenyl group in which a methoxy group is substituted at an arbitrary position.

The heterocyclic group includes oxygen atom, nitrogen atom,
A 5- or 6-membered heterocyclic ring containing one or more of any one of the sulfur atoms in combination with each atom can be mentioned, and specific examples thereof include a furyl group, a thienyl group, a pyrrolyl group and a pyrazolyl group. Group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group and other 5-membered heterocyclic rings, and a pyridyl group and other 6-membered heterocyclic rings. Preferably a furyl group, a thienyl group, a pyrrolyl group,
It is a 5-membered heterocyclic ring such as a pyrazolyl group.

Examples of the substituent which may have a double bond and / or a triple bond include a 4,4-dimethyl-2-pentynyl group and a 6,6-dimethylpent-2-en-4-ynyl group. be able to. 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 [VI], Q ₁ is preferably an oxygen atom, and W ₁ is preferably a sulfur atom.

R ¹ , R ² and R ³ are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group,
Lower alkyl groups such as isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group,
Alkoxy group such as propyl group, isopropyl group, halogen atom such as chlorine atom, bromine atom, hydroxy group, hydroxymethyl group, hydroxyethyl group, hydroxyalkyl group such as hydroxypropyl group, benzyloxy group, xylyloxy group, anisidylmethoxy group , Aralkyloxy groups such as chlorophenylmethoxy group, 3- (3-thienyl)
A substituent containing a heterocycle such as 2-thienylmethoxy group, 3- (3-thienyl) phenylmethoxy group, 3- (1-pyrrolyl) phenylmethoxy group, 3- (2-oxazolyl) phenylmethoxy group, E or N-ethyl-N- of Z
(6,6-dimethyl-2-hepten-4-ylaminomethyl group and the like can be mentioned.

Preferably, R ¹ and R ² are the same or different and a lower alkyl group such as a methyl group, an ethyl group and a propyl group, a halogen atom such as a chlorine atom and a bromine atom, a lower alkoxy group such as a methoxy group and an ethoxy group. , Or R ² , R
³ is a hydrogen atom and R ¹ is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom, a lower alkoxy group such as a methoxy group or an ethoxy group,
Hydroxyalkyl group such as hydroxyl group, hydroxymethyl group, hydroxyethyl group, benzyloxy group, xylyloxy group, aralkyloxy group such as anisidylmethoxy group, chlorophenylmethoxy group, 3- (3-thienyl)-
Substituent containing a heterocycle such as 2-thienylmethoxy group, 3- (3-thienyl) phenylmethoxy group, 3- (1-pyrrolyl) phenylmethoxy group, 3- (2-oxazolyl) phenylmethoxy group, E or Z N-ethyl-N-
(6,6-dimethyl-2-hepten-4-yl) aminomethyl group and the like.

R ⁴ and R ⁵ are preferably a hydrogen atom, a methyl group, an ethyl group or an n-propyl group. R ⁶ , R
⁷ are the same or different and each is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, lower alkyl group such as t-butyl group, methoxy group, ethoxy group, propoxy group. , Alkoxy group such as isopropoxy group, lower alkylthio group such as methylthio group, ethylthio group, propylthio group, halogen atom such as chlorine atom and bromine atom, hydroxyalkyl group such as hydroxymethyl group, hydroxyethyl group, hydroxypropyl group and the like Group, lower cycloalkyl group such as cyclopentyl group, cyclohexyl group, phenyl group, benzyloxy group, xylyloxy group, aralkyloxy group such as anisidylmethoxy group, chlorophenylmethoxy group, 3- (3-thienyl) -2-thienylmethoxy group Base,
3- (3-thienyl) phenylmethoxy group, 3- (1-
A substituent containing a heterocycle such as a pyrrolyl) phenylmethoxy group and a 3- (5-oxazolyl) phenylmethoxy group,
The substituents R ^6, R ⁷ are taken together to form a ring, propylene, butylene, -CH = CH-CH =
Examples thereof include CH-, 1,3-cyclopentalene group and 1,4-cyclohexalene group. Preferably R
⁶ represents a hydrogen atom and R ⁷ represents an i-propyl group or a t-butyl group, or R ⁶ and R ⁷ together form a propylene group, a butylene group, —CH═CH—CH═CH—, 1, Three
Those which represent a -cyclopentalene group or a 1,4-cyclohexalene group are preferable. Alternatively, R ⁷ is preferably a chlorine atom and R ⁶ is preferably an ethyl group, an i-propyl group or a t-butyl group.

That is, as the O-substituent of the thiocarbamate represented by the general formula [VI], p-t-butylphenyl, p-i-propylphenyl, 1,2,3,4-tetrahydro-6- Naphthyl, 5-indanyl, 1,4-methano-1,2,3,4-tetrahydro-6-naphthyl group, 1,4-ethano-1,2,3,4-tetrahydro-
6-naphthyl group, 4-chloro-3-ethylphenyl group,
A 4-chloro-3-i-propylphenyl group, a 4-chloro-3-t-butylphenyl group and the like are preferable.

Representative examples of the general formula [VI] are shown in Tables 1 to 6.

[0026]

[Table 1]

[0027]

[Table 2]

[0028]

[Table 3]

[0029]

[Table 4]

[0030]

[Table 5]

[0031]

[Table 6]

As the compound represented by the general formula [VII],
R ¹ and R ² are the same or different and each is a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a t-butyl group, a methoxy group or an ethoxy group. A lower alkoxy group such as a propoxy group and an isopropoxy group, a halogen atom such as a chlorine atom and a bromine atom, a hydroxy lower alkyl group such as a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group, a benzyloxy group, a xylyloxy group,
Aralkyloxy groups such as anisidylmethoxy group and chlorophenylmethoxy group, 3- (3-thienyl) -2-thienylmethoxy group, 3- (3-thienyl) phenylmethoxy group, 3- (1-pyrrolyl) phenylmethoxy group, 3-
Substituents containing a heterocycle such as (2-oxazolyl) phenylmethoxy group, E or Z N-ethyl-N- (6,6-
A dimethyl-2-hepten-4-yl) aminomethyl group etc. can be mentioned.

Preferably, R ¹ and R ² are the same or different and each is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom, a lower alkoxy group such as a methoxy group or an ethoxy group. Or R ² is a hydrogen atom and R ¹ is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom,
Lower alkoxy groups such as methoxy group and ethoxy group, hydroxyl groups, hydroxy lower alkyl groups such as hydroxymethyl group and hydroxyethyl group, aralkyloxy groups such as benzyloxy group, xylyloxy group, anisidylmethoxy group and chlorophenylmethoxy group, 3- (3-thienyl)-
It is a substituent containing a heterocycle such as a 2-thienylmethoxy group, a 3- (3-thienyl) phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group, and a 3- (2-oxazolyl) phenylmethoxy group. R ⁴ is preferably a hydrogen atom, a methyl group, an ethyl group or an n-propyl group.

Representative examples of the compound represented by the general formula [VII] are shown in Tables 7 and 8.

[0035]

[Table 7]

[0036]

[Table 8]

In the urea represented by the general formula [VIII], W ₁ is an oxygen atom or a sulfur atom, q is 1 or 0, and Z is a nitrogen atom or CH.

R ¹ and R ² are the same or different and each is a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group or a methoxy group. , An ethoxy group, a propoxy group, a lower alkoxy group such as an isopropoxy group, a halogen atom such as a chlorine atom and a bromine atom, a hydroxyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxy lower alkyl group such as a hydroxypropyl group, a benzyloxy group, Aralkyloxy groups such as xylyloxy group, anisidylmethoxy group, chlorophenylmethoxy group, 3- (3-thienyl) -2-thienylmethoxy group, 3- (3-thienyl)
Examples of the substituent include a heterocyclic ring-containing substituent such as a phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group, and a 3- (2-oxazolyl) phenylmethoxy group.

Preferably, R ¹ and R ² are the same or different and a lower alkyl group such as a methyl group, an ethyl group and a propyl group, a halogen atom such as a chlorine atom and a bromine atom, a lower alkoxy group such as a methoxy group and an ethoxy group. Or R ² is a hydrogen atom and R ¹ is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom,
Lower alkoxy group such as methoxy group and ethoxy group, hydroxyl group, hydroxyalkyl group such as hydroxymethyl group and hydroxyethyl group, aralkyloxy group such as benzyloxy group, xylyloxy group, anisidylmethoxy group and chlorophenylmethoxy group, 3- ( 3-thienyl) -2-
A thienylmethoxy group, a 3- (3-thienyl) phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group,
And a substituent containing a heterocycle such as a 3- (2-oxazolyl) phenylmethoxy group. R ⁴ and R ⁵ are the same or different from each other and are preferably a hydrogen atom, a methyl group or an ethyl group.

Representative examples of ureas represented by the general formula [VIII] are shown in Tables 9 to 11.

[0041]

[Table 9]

[0042]

[Table 10]

[0043]

[Table 11]

In the thioamide represented by the general formula [IX] or [X], Z represents a nitrogen atom or CH, and R ¹ , R ²
Are the same or different and each is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a lower alkyl group such as a t-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isoalkyl group. Alkoxy group such as propoxy group, halogen atom such as chlorine atom and bromine atom,
Hydroxy lower alkyl groups such as hydroxyl group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, benzyloxy group, xylyloxy group, anisidylmethoxy group, aralkyloxy groups such as chlorophenylmethoxy group, 3- (3-thienyl) -2 -Thienylmethoxy group,
3- (3-thienyl) phenylmethoxy group, 3- (1-
Examples include substituents containing a heterocycle such as a pyrrolyl) phenylmethoxy group and a 3- (2-oxazolyl) phenylmethoxy group.

Preferably, R ¹ and R ² are the same or different and a lower alkyl group such as a methyl group, an ethyl group and a propyl group, a halogen atom such as a chlorine atom and a bromine atom, a lower alkoxy group such as a methoxy group and an ethoxy group. Or R ² is a hydrogen atom and R ¹ is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom,
Lower alkoxy groups such as methoxy group and ethoxy group, hydroxyl groups, hydroxy lower alkyl groups such as hydroxymethyl group and hydroxyethyl group, aralkyloxy groups such as benzyloxy group, xylyloxy group, anisidylmethoxy group and chlorophenylmethoxy group, 3- (3-thienyl)-
Examples of the substituent include a heterocyclic ring-containing substituent such as a 2-thienylmethoxy group, a 3- (3-thienyl) phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group, and a 3- (5-oxazolyl) phenylmethoxy group.

Representative examples of the thioamide represented by the general formula [IX] or [X] are shown in Table 12 (Compound Nos. 131 to 140).

[0047]

[Table 12]

As the substituent of the O, O-diarylthiocarbonate represented by the general formula [XI], Z is a nitrogen atom or CH, and R ¹ and R ² are the same or different and each is a hydrogen atom. , Methyl group, ethyl group, propyl group,
Lower alkyl groups such as isopropyl group, n-butyl group, isobutyl group, t-butyl group, methoxy group, ethoxy group,
Lower alkoxy group such as propoxy group and isopropoxy group, halogen atom such as chlorine atom and bromine atom, hydroxy lower alkyl group such as hydroxyl group, hydroxymethyl group, hydroxyethyl group and hydroxypropyl group, benzyloxy group, xylyloxy group, aniline Aralkyloxy groups such as sidylmethoxy group and chlorophenylmethoxy group, 3-
(3-thienyl) -2-thienylmethoxy group, 3- (3
Examples of the substituent include a heterocyclic ring such as -thienyl) phenylmethoxy group, 3- (1-pyrrolyl) phenylmethoxy group, and 3- (2-oxazolyl) phenylmethoxy group.

Preferably, R ¹ and R ² are the same or different and a lower alkyl group such as a methyl group, an ethyl group and a propyl group, a halogen atom such as a chlorine atom and a bromine atom, a lower alkoxy group such as a methoxy group and an ethoxy group. Or R ² is a hydrogen atom and R ¹ is a lower alkyl group such as a methyl group, an ethyl group or a propyl group, a halogen atom such as a chlorine atom or a bromine atom,
Lower alkoxy groups such as methoxy group and ethoxy group, hydroxyl groups, hydroxy lower alkyl groups such as hydroxymethyl group and hydroxyethyl group, aralkyloxy groups such as benzyloxy group, xylyloxy group, anisidylmethoxy group and chlorophenylmethoxy group, 3- (3-thienyl)-
Examples of the substituent include a heterocyclic ring-containing substituent such as a 2-thienylmethoxy group, a 3- (3-thienyl) phenylmethoxy group, a 3- (1-pyrrolyl) phenylmethoxy group, and a 3- (2-oxazolyl) phenylmethoxy group.

Representative examples of the compound represented by the general formula [XI] are shown in Table 13 (Compound Nos. 141 to 144).

[0051]

[Table 13]

The compounds of the present invention [I], [VI] to [X]
[I] may contain an asymmetric carbon. Therefore, these compounds of the present invention include a mixture of various optical isomers such as an optically active substance, a racemate and a diastereomer, and their isolated ones. The compounds of the present invention [I], [VI] to [XI]
Has an amine residue and therefore 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 [VI] to [XI] of the present invention are also included.

Since the compound of the formula [I] inhibits the activity of squalene epoxidase in a living body very selectively, it can be used as an antihypercholesterolemic agent, an antihyperlipidemic agent and an antiarteriosclerotic agent. It is an expected useful compound.

The compound of the present invention can be administered orally or parenterally, and by formulating into a form suitable for such administration, hypercholesterolemia, hyperlipidemia, arteriosclerosis, etc. Can be used for the treatment and prevention of. When the compound of the present invention is used clinically, it is also possible to add pharmaceutically acceptable additives in accordance with the dosage form and to administer it after various preparations. As the additive in that case, various additives usually used in the pharmaceutical field can be used, for example, gelatin, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminometasilicate, 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, benzyl alcohol,
Examples thereof include gum arabic, propylene glycol, hydroxypropyl cyclodextrin and the like.

Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories, or liquid preparations such as syrups, elixirs or injections. And these can be prepared according to the usual methods in the field of formulation. The liquid preparation may be in a form that can be dissolved or suspended in water or another suitable medium before use.
Further, particularly in the case of an injectable solution, it may be dissolved or suspended in physiological saline or a glucose solution, if necessary, and a buffer and a preservative may be added.

The formulation of the present invention comprises the compound of the present invention
It can be contained in a proportion of 1.0 to 100% by weight, preferably 1.0 to 6% by weight. These formulations may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, an antiarteriosclerotic agent or an antihypercholesterolemic agent, the dose and frequency of administration are the sex, age, weight and degree of symptoms of the patient. In general, when administered orally, the daily dose for adults is 0.01
It is preferable to administer -20 mg / kg in 1 to several times, and in the case of parenteral administration, 0.01 to 2 mg / kg in 1 to several times.

[0058]

【Example】

[Reference Example] The compounds used in the experiments were prepared according to the above-mentioned prior documents or as follows.

Synthesis of O-pt-butylphenyl = Nm-tolylthiocarbamate (Compound No. 29)

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 (s, 3H),
6.95-7.58 (m, 8H), 8.1-8.6 (m, 1H)

Synthesis of O-pt-butylphenyl = N-methyl-N-3-hydroxyphenylthiocarbamate (Compound No. 33) Synthesis was carried out in the same manner as in Compound No. 29.

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)

O-pt-butylphenyl = N- (m-
Xylyl) -N-methylthiocarbamate (compound number
Synthesis of 34) The compound was synthesized by the same method as for Compound No. 29.

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)

Synthesis of O-pt-butylphenyl = N-methyl-N-3-formylphenylthiocarbamate (Compound No. 39)

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 crystals 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)

O-pt-butylphenyl = N-methyl-N- (6- (2-xylyloxy) -2-pyridyl)
Synthesis of thiocarbamate (Compound No. 49) It was synthesized by a method similar to that of Compound No. 29.

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)

Synthesis of O-pt-butylphenyl = N-methyl-N-3- (2-methylphenylmethyloxy) phenylthiocarbamate (Compound No. 50) Synthesis was carried out in the same manner as in Compound No. 29.

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)

O-pt-Butylphenyl = N-methyl-N-4- (2-xylyloxy) phenylthiocarbamate (Compound No. 51) was synthesized by the same method as that for Compound No. 29.

Properties colorless crystals 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)

O-pt-butylphenyl = N- [3-
Synthesis of (o-xylyloxy) phenylmethyl) -N-methylthiocarbamate (Compound No. 53) It was synthesized by a method similar to that of Compound No. 29.

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)

O-pt-butylphenyl = N-methyl-N- [3-Z- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate Synthesis of (Compound No. 57)

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.

(E) / (Z) -N- [2- (6,6-Dimethylheptene-4-niyl)]-N-ethylamine 76
mg ((E) / (Z) = 1/1) in 4 ml tetrahydrofuran solution under ice-cooling 60% oily sodium hydride 22 mg, O-pt-butylphenyl = N-methyl-N prepared above
-3-Bromomethylphenyl thiocarbamate 89mg 5
ml 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-Z- (N-6,6-dimethyl-2-heptene-4
33 mg of (-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound No. 57) was obtained as a light brown viscous substance.

O-pt-butylphenyl = N-methyl-N- [3-Z- (N-6,6-dimethyl-2-hepten-4-yl) -N-ethylaminomethyl] phenylthiocarbamate (Compound number 57)

IR (NaCl, cm ^-1 ) 2970, 2210, 149
0,1475,1380,1200,1180 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)

Synthesis of O-6- (1,2,3,4-tetrahydronaphthyl) = Nm-xylyl-N-methylthiocarbamate (Compound No. 69) Synthesis was carried out in the same manner as in Compound No. 29.

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)

O-6- (1,2,3,4-tetrahydronaphthyl) = N- [3- (o-xylyloxy) phenylmethyl] -N-methylthiocarbamate (Compound No.
Synthesis of 71) Synthesized by the same method as for Compound No. 29.

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], 4.80-5.2
0 (m, 4H), 6.72-7.42 (m, 11H)

Synthesis of O- (4,4-dimethyl-2-pentynyl) = Nm-chlorophenyl-N-methylthiocarbamate (Compound No. 80)

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)

Synthesis of O- (4,4-dimethyl-2-pentynyl) = Nm-tolyl-N-methylthiocarbamate (Compound No. 81)

To a 5 ml dimethylformamide solution of 343 mg of 4,4-dimethyl-2-pentyn-1-ol 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)

O- (4,4-dimethyl-2-pentynyl) = N- [3- (o-tolylmethoxy) phenyl]-
Synthesis of N-methylthiocarbamate (Compound No. 83)

To a 10 ml ether solution of 712 mg of 60% oily sodium hydride was added a 10 ml ether solution of 2 g of 4,4-dimethyl-2-pentyn-1-ol 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. Then, a solution of 84 mg of 60% oily sodium hydride in 15 ml of tetrahydrofuran was added with N- (3-
o-xylyloxyphenyl) -N-methylamine 408
A 5 ml tetrahydrofuran solution containing 5 mg of tetrahydrofuran was added dropwise, and the mixture was stirred for 5 minutes. Then, a solution of 358 mg of 4,4-dimethyl-2-pentynylchlorothioformate prepared above 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 subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 20:
Purification in 1) yielded 60 mg of the desired product as a yellow viscous product.

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)

Synthesis of N-pt-butylphenyl-N'-methyl-N'-m-tolylthiourea (Compound No. 98)

A solution of 314 mg of pt-butylaniline and 304 mg of anhydrous potassium carbonate in 10 ml of acetonitrile was added with N-chloride.
3-methylphenyl-N-methylthiocarbamoyl 400
A 10 ml acetonitrile solution of mg was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into 100 ml of water, extracted with ethyl acetate, and the organic layer was washed with saturated saline,
It was 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),
I got the object.

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)

N-pt-butylphenyl-N '-(3
Synthesis of -o-xylyloxyphenylmethyl) -N, N'-dimethylurea (Compound No. 129)

A solution of 166 mg of triphosgene in 20 ml of methylene chloride was added with 10% 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, and the mixture was 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 distilling off 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)

O-pt-butylphenyl-O'-m-
Synthesis of tolyl thiocarbonate (Compound No. 141)

M-cresol 241 mg, potassium carbonate 304
To a solution of 5 ml of acetonitrile in 5 ml of pt-butylphenylchloroformate was added dropwise a solution of 490 mg of 5 ml of acetonitrile in acetonitrile. 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)

The squalene epoxidase inhibitory action and cholesterol biosynthesis inhibitory action of the compound in the present invention were confirmed by the following methods.

[Pharmaceutical efficacy test] (1) Preparation of 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 these results, Table 14 shows the inhibition rate of squalene epoxidase activity at 10 ⁻⁴ M in the representative examples of the compound of the present invention.

[0108]

[Table 14]

As is clear from the above results, since the compound of the present invention inhibits squalene epoxidase to inhibit cholesterol biosynthesis, it is caused by enhancement of cholesterol biosynthesis mechanism and / or excessive intake of cholesterol. It is effective for treating and preventing various diseases such as anti-hypercholesterolemia, anti-hyperlipidemia and anti-atherosclerosis.

[0110]

INDUSTRIAL APPLICABILITY The compound used in the present invention is a substance having a skeleton completely different from that of the conventionally known amine-based or allylamine-based compounds, and has a high inhibitory activity against squalene epoxidase derived from mammals. Have. 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.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/38 ABN A61K 31/38 ABN 31/44 AED 31/44 AED C07C 271/58 9451-4H C07C 271/58 275/28 9451-4H 275/28 327/44 7106-4H 327/44 327/48 7106-4H 327/48 329/04 7106-4H 329/04 333/08 7106-4H 333/08 335 / 16 7106-4H 335/16 C07D 213/75 C07D 213/75 333/18 333/18 401/12 207 401/12 207 409/12 213 409/12 213 413/12 213 413/12 213 C12N 9/99 C12N 9/99 // (C07D 401/12 207: 32 213: 75) (C07D 409/12 213: 75 333: 08) (C07D 413/12 213: 75 263: 32) (72) Inventor Yasunari Yamaura Osaka 2-25-1 Otani, Otsuya, Hirakata-shi, Japan Midori Central Research Institute Ltd. (72) Akito Inoue Yoshihisa Inoue 2-25-1 Shoutsutsumi Otani, Hirakata-shi, Osaka, Ltd. Midori Cross Central Research Institute Co., Ltd. (72) Inventor Kenfumi Nakamura 2-25-1 Shoutsutsumi Otani, Hirakata-shi, Osaka Midori Cross Co., Ltd. Central Research Institute (72) Inventor Kimio Katsuura 2-23-3 Nishiochiai, Shinjuku-ku, Tokyo (72) Inventor Kenji Tokuhisa 1-39-302 Okada, Atsugi City, Kanagawa Prefecture (72) Takumi Tokunaga Atsugi, Kanagawa Prefecture Ichikada 1-1039-105 (72) Inventor Yasuaki Hanasaki 4-26-204 Shonandai, Fujisawa, Kanagawa

Claims (10)

[Claims] 1. The general formula [I] [Wherein Q, V and W are the same or different from each other and are an oxygen atom, a sulfur atom, NR ⁴ , NR ⁵ (R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group). ), Z represents CH or a nitrogen atom, and m, n, p, q
Represents 0 or 1. A is the formula [II] (Wherein R ⁶ and R ⁷ are the same or different from each other, a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkylthio group, an aralkyloxy group,
A lower hydroxyalkyl group, a halogen atom, a hydroxyl group, a phenyl group, an alkoxyalkyl group, or a compound represented by the formula [III] (CH ₂ ) _t1 O (CH ₂ ) _t2- A ₁ -A ₂ [III] (t1 and t2 are 0 to 3). A ₁ is a phenylene group or a heterocyclic group, A ₂ is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, or an unsubstituted or lower alkyl group, a halogen atom, a lower alkoxy group. Represents a phenyl group or a heterocyclic group which may be substituted with, and is represented by the formula [IV] (In the formula, r represents 0 or 1) or a lower alkylene group, a lower cycloalkylene group or R ⁶ and R ⁷ linked to each other. May form a ring). R ¹ , R ² , R ³
Are the same or different from each other, a hydrogen atom, a lower alkyl group, an alkylthio group, a halogen atom, a lower alkoxy group, a hydroxyl group, a hydroxy lower alkyl group, a formyl group,
The substituent represented by the above formula [III] or the formula [V] (In the formula, R ⁸ represents a lower alkyl group.) E-
Alternatively, it represents a Z-aminomethyl group. ] The squalene epoxidase inhibitor containing the compound represented by these or its pharmaceutically acceptable salt as an active ingredient. 2. A squalene epoxidase activity inhibitor is represented by the general formula [VI] [In the formula, Z, q, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷
Represents the same meaning as described above. W ₁ and Q ₁ are the same or different and each represents an oxygen atom or a sulfur atom. ] The squalene epoxidase inhibitor of Claim 1 which is a carbamate represented by these. 3. A squalene epoxidase activity inhibitor is represented by the general formula [VII] [In the formula, r, q, Z, R ¹ , R ² and R ⁴ have the same meanings as described above. ] The squalene epoxidase inhibitor of Claim 1 which is a thiocarbamate represented by these. 4. A squalene epoxidase activity inhibitor is represented by the general formula [VIII] [In the formula, W ₁ , Z, q, R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as described above. ] The squalene epoxidase inhibitor of Claim 1 which is a urea compound represented by these. 5. A squalene epoxidase activity inhibitor is represented by the general formula [IX] [In the formula, m, q, R ¹ , R ² , R ⁴ and Z have the same meanings as described above. ] Or general formula [X] [In the formula, m, q, R ¹ , R ² , R ⁵ and Z have the same meanings as described above. ] The squalene epoxidase inhibitor of Claim 1 which is thioamide represented by these. 6. The squalene-epoxidase activity inhibitor is represented by the general formula [XI] [Wherein R ¹ , R ² and Z have the same meanings as described above. ] The squalene epoxidase inhibitor of Claim 1 which is an O, O-diaryl thiocarbonic acid ester represented by these. 7. A preventive or therapeutic agent for arteriosclerosis or a blood cholesterol lowering agent, which comprises the squalene epoxidase activity inhibitor according to any one of claims 1 to 6. 8. General formulas [I], [VI], [VII] and [VII]
7. The compound of [I], [IX], [X] or [XI] is a mixture or isolate of optical isomers such as an optically active substance, a racemate or a diastereomer. The squalene epoxidase inhibitor described. 9. General formulas [I], [VI], [VII] and [VII]
The squalene epoxidase inhibitor according to any one of claims 1 to 6, wherein the compound of [I], [IX], [X] or [XI] contains an acid adduct thereof. 10. General formulas [I], [VI], [VII] and [VII]
The compound of [I], [IX], [X] or [XI] is a hydrate, solvate or polymorph thereof.
7. The squalene-epoxidase inhibitor according to any one of 6 to 6.