JPH06206858A - Tricyclic compound - Google Patents

Abstract

PURPOSE:To provide a tricyclic compound having an acylcoenzyme A: cholesterol-acyltransferase-inhibiting action and useful as a therapeutic medicine for hyperlipemia and arterial sclerosis. CONSTITUTION:The tricyclic compound of formula I [X<1>, X<2> are CH=CH-CH= CH, S-CH=CH, etc.; Y-Z is CH2-O, CH=CH, etc.; L-M is C=CR<9> (R<9> is H, lower alkyl), etc.; W is NR<4> (R<4> is H, lower), O; R<1> to R<3> are H, lower alkyl, halogen, amino, etc.;], e.g. N-(2,6-diisopropylphenyl)-N'-(2-methyl-6,11- dihydrobenzo[b,e]oxepin-11-ylmethyl)urea. The compound of formula I is obtained by converting a compound of formula II (Q is -COOH) with an isocyanate derivative (Q is -NCO) and subsequently reacting the reaction product with a compound of formula III in the presence of a base in a solvent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tricyclic compound having an inhibitory effect on acylcoenzyme A: cholesterol acyltransferase (hereinafter referred to as ACAT) and useful as a therapeutic drug for hyperlipidemia and a therapeutic drug for arteriosclerosis.

[0002]

2. Description of the Related Art Myocardial infarction and cerebral infarction caused by arteriosclerosis occupy the top cause of death along with cancer in developed countries, and an effective therapeutic agent for arteriosclerosis is desired. The results of numerous epidemiologic studies have already pointed out that hypercholesterolemia is one of the risk factors for arteriosclerosis, and lowering serum cholesterol levels, especially low-density lipoprotein (LDL) cholesterol levels It has been reported that the onset of hardening is suppressed. In the body, cholesterol is supplied by two pathways of biosynthesis and absorption, and it is possible to lower the cholesterol level in serum by a drug that inhibits these pathways. As a drug having an absorption inhibitory action, for example, a nicotinic acid drug or a plant sterol is used, but its action is weak and not always sufficient.

Cholesterol is absorbed in free form in intestinal epithelial cells, then esterified by ACAT, taken up by chylomicrons, released into blood, and transported to the liver. Furthermore, ACAT is involved in macrophage foaming, which plays an important role in the accumulation of cholesterol in the liver and the development of arteriosclerosis [J. Lipi
d Res., 26 , 647 (1985) and Japanese Clin, 47 , 554 (198).
9)]. Therefore, a drug that inhibits this enzyme inhibits the absorption of cholesterol, promotes excretion by inhibiting the accumulation of cholesterol in the liver, lowers the cholesterol level in serum, and further suppresses the production of foam cells. Therefore, it is expected as a therapeutic drug for hyperlipidemia and arteriosclerosis. As the compound having an ACAT inhibitory action,
The compound represented by the following formula (A) is described in JP-A-2-6457.

[0004]

[Chemical 2]

[0005]

An object of the present invention is to provide a tricyclic compound having a strong ACAT inhibitory action and useful as a therapeutic drug for hypercholesterolemia and a therapeutic drug for arteriosclerosis.

[0006]

The present invention provides a compound of formula (I)

[0007]

[Chemical 3]

[Wherein, X ¹ -X ² is CH = CH-CH
= CH, represent CH = CH-CH = N or S-CH = CH, Y- Z _{is, CH 2 -O, CH = CH} , CH 2 -C
Represents H ₂ or CH ₂ —S, LM is C = CR
⁹ (in the formula, R ⁹ represents hydrogen or lower alkyl) or CH—CR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different and represent hydrogen or lower alkyl), and W is NR ⁴ (wherein R ⁴ represents hydrogen or lower alkyl) or O, R ¹ , R ² and R ³ are the same or different and are hydrogen, lower alkyl, lower alkoxy, halogen, nitro, amino or Represents mono- or di-lower alkyl-substituted amino, R ⁵ represents hydrogen or lower alkyl, R ⁶ , R ⁷ and R ⁸ are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy, provided that Y -Z is CH = CH or CH
When representing _2- CH ₂ , LM is C = CR ⁹ (in the formula, R
⁹ is as defined above) or CH-CR ^10a R ^11a
(Wherein, R ^10a and R ^11a are the same or different R ¹⁰
And (representing a lower alkyl in the definition of R ¹¹ )] [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] or a pharmaceutically acceptable salt thereof.

In the definition of each group of the formula (I), the alkyl moiety of lower alkyl and lower alkoxy, mono- or di-lower alkyl-substituted amino has 1 to 6 carbon atoms which may be linear or branched, for example, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like are included. Halogen means each atom of fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salts of the compound (I) include pharmaceutically acceptable acid addition salts such as inorganic acid salts such as hydrochlorides, sulfates and phosphates and maleate salts.
Examples thereof include organic acid salts such as fumarate and citrate.

Next, a method for producing the compound (I) will be described. Manufacturing method A

[Chemical 4]

(Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ ,
R < ⁷ >, R < ⁸ >, X < ¹ >, X < ² >, LM and YZ have the same meanings as described above.) Compound (Ia) wherein W is NH in compound (I)
Is a compound of the isocyanate derivative (IIa).
It can be obtained by converting to b) and then reacting with compound (III).

For example, compound (IIa), 1 to 20 equivalents of diphenylphosphoryl azide and 1 to 20 equivalents of a base such as triethylamine or pyridine in an inert solvent such as dichloromethane, toluene or xylene are used. Compound (IIb) is obtained by reacting at -60 ° C for 0.1-24 hours. Then, the compound (IIb) and 1
To 10 equivalents of compound (III) in an inert solvent such as dichloromethane, toluene or xylene, if necessary in the presence of 1 to 20 equivalents of a base such as triethylamine or pyridine, from -78 ° C to the boiling point of the solvent used. By reacting the compound (I
a) can be obtained.

Carboxylic acid (II used as a raw material
In a), the compound in which L-M is C = CR ⁹ (wherein R ⁹ has the same meaning as described above) can be produced by a known method [Bul.
l. Soc. Chim. Fr., 4364 (1972)]. In the carboxylic acid (IIa), L-
M is CH-CR ^10b R ^11b (wherein R ^10b and R ^11b
Is hydrogen in the definition of R ¹⁰ and R ¹¹ ) and the compound (IIaa) can be obtained by the following reaction steps.

[0015]

[Chemical 5]

(In the formula, R ¹ , R ² , R ³ , X ¹ , X ² and YZ have the same meanings as described above, R represents lower alkyl, and lower alkyl in the definition of R is the above lower alkyl. Is equivalent to the definition of

Step 1: A known method (JP-A-2-250) or a compound (A) obtained according to the method and 1
~ 20 equivalents of diethyl malonate in dichloromethane in the presence of a catalytic to large excess of a Lewis acid, e.g. titanium tetrachloride, and if necessary in the presence of 1 to 20 equivalents of an amine, e.g. triethylamine, at -78 ° C. The compound (B) can be obtained by reacting at an appropriate temperature between 1 and room temperature for 1 to 24 hours.

Step 2: Compound (B) is subjected to an ordinary hydrolysis reaction, for example, in the presence of 10N sodium hydroxide aqueous solution, in methanol or ethanol at a suitable temperature between 0 ° C. and the boiling point of the solvent for 1 to 20 hours. By doing so, the compound (C) can be obtained.

Step 3: Compound (C) is added in a pyridine in the presence of a catalytic amount to a large excess of amine such as piperidine.
Compound (IIaa) can be obtained by reacting at an appropriate temperature between 0 ° C. and the boiling point of the solvent for 1 to 20 hours.

In the carboxylic acid (IIa), L
-M is CH-CR ^10a R ^11a (wherein R ^10a and R ^10a
11a represents the same meaning as described above) (IIa
b) can be obtained by the following reaction step.

[0021]

[Chemical 6]

(Wherein R, R ¹ , R ² , R ³ , R ^10a ,
(R ^11a , X ¹ , X ² and YZ have the same meanings as described above)

Step 1: A known method (JP-A-2-250) or a compound (A) obtained according to the method and 1
-20 equivalents of the appropriate silyl ketene acetals (D) in dichloromethane in the presence of a catalytic amount to a large excess of Lewis acid, such as titanium tetrachloride, relative to compound (A), -7
Compound (E) can be obtained by reacting at an appropriate temperature between 8 ° C. and room temperature for 1 to 24 hours.

Step 2: Compound (E) is subjected to a conventional hydrolysis reaction, for example, in the presence of 1 to 20 equivalents of potassium t-butoxide in dimethyl sulfoxide at a suitable temperature between 0 ° C. and the boiling point of the solvent. Compound (IIab) can be obtained by reacting for 20 hours.

Manufacturing method B

[Chemical 7]

(Wherein R ^4a represents lower alkyl in the definition of R ⁴ , Hal represents chlorine, bromine or iodine, R ¹ , R ² , R ³ , R ⁵ , R ⁶ and R ⁷ , R ⁸ ,
X ¹ , X ² , LM and YZ have the same meanings as above.)

In compound (I), W is NR ^4a (in the formula,
R ^4a has the same meaning as defined above, and the compound (Ib) is
Compound (Ia) in which R ⁴ is hydrogen and 1-10 equivalents of compound (IV) are added in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or toluene, if necessary 1-20 It can be obtained by reacting in the presence of an equivalent amount of a base such as potassium t-butoxide, sodium hydride or silver oxide at a suitable temperature between -78 ° C and the boiling point of the solvent used for 0.1 to 24 hours.

Production Method C

[Chemical 8]

(Wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ ,
^{R 8, R 10, R 11} , X 1, X 2 and Y-Z represents the same meanings as defined above)

In the compound (I), LM is CH-C.
The compound (Ic) which is R ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ have the same meanings as described above) and W is O reacts the compound (V) with the compound (VI). Can be obtained.

For example, compound (V) and 1 to 10 equivalents of compound (VI) in an inert solvent such as dichloromethane, toluene or xylene, and if necessary the presence of 1 to 20 equivalents of a base such as triethylamine or pyridine. Down, -7
0.1 to 24 at a suitable temperature between 8 ° C and the boiling point of the solvent used.
Compound (Ic) can be obtained by reacting for a time. Of the alcohol (V) used as a raw material, the compound (Va) in which R ¹⁰ and R ¹¹ are hydrogen can be obtained by the following reaction step.

[0032]

[Chemical 9]

(In the formula, R ¹ , R ² , R ³ , X ¹ , X ² and YZ have the same meanings as described above.)

Step 1: Known method (West German Patent 1,294,970)
Alternatively, the compound (VIII) obtained according to it and an ylide obtained by treating trimethylsulfonium iodide with 1 to 2 equivalents of sodium hydride in a mixed solvent of dimethylsulfoxide-tetrahydrofuran at −78 ° C. to room temperature. Compound (IX) can be obtained by reacting at an appropriate temperature for 1 to 12 hours.

Step 2: Compound (IX) is reacted in dichloromethane with a catalytic amount of a Lewis acid, eg boron trifluoride-ether complex, at a suitable temperature between -78 and 0 ° C for 10 minutes to 6 hours, Then, the compound (X) can be obtained by treating with water.

Step 3: Compound (X) and 1 to 10 equivalents of sodium borohydride in a solvent such as methanol or ethanol at a suitable temperature of from -30 ° C to room temperature of 0.1 to 24.
Compound (Va) can be obtained by reacting for a time.

In the alcohol (V), a compound (Vb) in which R ¹⁰ is hydrogen and R ¹¹ is lower alkyl, and a compound (Vb) in which R ¹⁰ and R ¹¹ are lower alkyl (V
c) can be obtained by the following reaction steps.

[0038]

[Chemical 10]

(Wherein R ¹ , R ² , R ³ , R ^10a , R
^11a , X ¹ , X ² and YZ are as defined above)

Step 1: Compound (X) can be obtained by a conventional oxidation method using an oxidizing agent such as chromium oxide or potassium permanganate. For example, compound (X) can be obtained by reacting compound (X) with an excess of Jones reagent in acetone at a suitable temperature between -60 and 0 ° C.

Step 2: Compound (XII) is obtained by reacting compound (XI) with an excess of an organometallic reagent such as alkyl lithium reagent R ^10a Li in tetrahydrofuran at a suitable temperature between −78 ° C. and 0 ° C. be able to.

Step 3: Compound (XII) and 1 to 10 equivalents of sodium borohydride in a solvent such as methanol or ethanol at a suitable temperature between -30 ° C and room temperature.
Compound (Vb) can be obtained by reacting for -24 hours.

Step 4: Compound (XII) in tetrahydrofuran in the presence of a catalytic amount of cerium trichloride, with an excess of an organometallic reagent such as an alkyllithium reagent R ^11a Li and -7.
Compound (Vc) can be obtained by reacting at an appropriate temperature between 8 and 0 ° C.

Production Method D

[Chemical 11]

(In the formula, R ^5a represents lower alkyl in the definition of R ⁵ , and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ and R 5
¹⁰ , R ¹¹ , X ¹ , X ² , Hal and YZ have the same meanings as described above.) In the compound (I), the compound (Id) in which R ⁵ is lower alkyl is the compound (Ic) or the compound (Ic). VII)
It can be obtained according to the method of production method B.

The intermediates and the target compounds in the above-mentioned production methods are purified by conventional purification methods in synthetic organic chemistry, for example,
It can be isolated and purified by subjecting it to filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. In addition, the intermediate may be subjected to the next reaction without being particularly purified.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is, and when it is obtained in a free form, it is dissolved in a suitable solvent. Or suspended and isolated the salt formed by adding acid,
It may be purified.

Some compounds (I) may have geometrical isomers of E / Z , for example, but the present invention also includes all possible isomers including these geometrical isomers and mixtures thereof. To be done. If the separation of E / Z is desired,
For example, it may be isolated and purified by a fractionation method such as fractional crystallization, fractional precipitation and fractional dissolution. Further, the compound (I) and a pharmacologically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

Specific examples of the compound (I) obtained by each production method are shown in Table 1.

[0050]

[Table 1]

In the table, Me represents methyl, iPr represents isopropyl and tBu represents tert-butyl. Further, the compound numbers in the table correspond to the example numbers described later. Next, the pharmacological action of compound (I) will be described.

Test Example 1 Acute toxicity test A test compound was orally administered to one group of 3 ddY male mice having a body weight of 20 ± 1 g. The mortality situation 7 days after administration was observed and the minimum mortality (MLD) value was calculated. The results are shown in Table 2.

[0053]

[Table 2]

Test Example 2 ACAT Inhibitory Activity Test The ACAT inhibitory activity test using the human cultured cell line HepG2 was carried out by the method of Goldstein et al. [Methods Enzymology, 98].
Vol., Pp. 241 (1983)]. Cultured human cell line HepG2 (5 × 10 ⁵ cells / well) overnight in 5% LPDS
(Rabbit lipoprotein-depleted serum) -After preculture in DMEM medium (Dulbecco's modified Eagle medium), 5% LPDS-DME was newly added.
The medium was replaced with M medium (1 ml / well). To the medium were added cholesterol dissolved in ethanol and 25-OH-cholesterol total 3 µl (final concentration 10 µg / ml, 5 µg / ml) and test compound 10 µl dissolved in methanol (final concentration 10 ^-6 M).
After incubation for 10 hours, [ ¹⁴ C] -oleic acid-BSA (bovine serum albumin) complex 10 μl (0.42 μCi / 0.1 μmol / we
ll) was added and the cells were further cultured for 2 hours. After washing the cells, the lipids of the cells were extracted with 0.5 ml / well of hexane: isopropanol (3: 2) containing 2000 dpm of [3H] -cholesterol oleate. The extract was dried under reduced pressure and fractionated by silica gel thin-layer chromatography using petroleum ether: diethyl ether: acetic acid (170: 30: 1) as a developing solvent, and the radioactivity of cholesterol ester spots was measured with a liquid scintillation counter. did. The value obtained by subtracting the radioactivity of the blank experiment in which cholesterol and 25-OH-cholesterol were not added from this radioactivity was defined as the radioactivity of the test compound. AC of each test compound
The AT inhibitory activity is based on the radioactivity of a control (control) obtained through the same procedure without using a test compound,
It was calculated from the following formula.

[0055]

[Equation 1]

The results are shown in Table 3.

[0057]

[Table 3]

Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations.
Further, those pharmaceutical preparations are used for animals and humans.

The administration route is preferably the one which is most effective for the treatment, and it may be oral or parenteral such as rectal, buccal, subcutaneous, intramuscular and intravenous.

The dosage form includes capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.

Liquid preparations such as emulsions and syrups suitable for oral administration include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. It can be produced by using oils such as, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Capsules, tablets, powders, granules, etc. are lactose,
Excipients such as glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, fatty acid esters, etc. It can be produced using a surfactant, a plasticizer such as glycerin, or the like.

Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared by using a carrier such as a salt solution, a glucose solution or a mixture of salt water and a glucose solution.

Formulations for rectal administration include conventional carriers,
For example, it is provided as a suppository with cocoa butter, hydrogenated fat, hydrogenated fatty carboxylic acid or the like.

Also in these parenteral agents, diluents, fragrances, preservatives, antioxidants, excipients, etc.
It is also possible to add one or more auxiliary components selected from disintegrants, lubricants, binders, surfactants, plasticizers and the like.

The effective dose and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the administration form, age of the patient, body weight, nature or severity of symptoms to be treated. For oral administration, 1 mg to 1 g per adult is administered once or several times a day. For parenteral administration (eg intravenous administration) 0.1 per adult
~ 100 mg once or several times daily. However, these doses vary depending on the various conditions described above.

Examples and formulation examples are shown below.

[0067]

【Example】

Example 1: N- (2,6-diisopropylphenyl) -N '-(2-methyl-6,1
1-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 1)

2-methyl-6,11-dihydrodibenzo [b, e]
2.0 g of oxepin-11-acetic acid was dissolved in 40 ml of toluene, 2.52 ml of diphenylphosphoryl azide and 3.12 ml of triethylamine were added at room temperature, and the mixture was stirred at the same temperature for 3.5 hours and further at 100 ° C. for 1 hour. After cooling the reaction solution to room temperature,
After adding 2.92 g of 2,6-diisopropylaniline hydrochloride and 5.0 ml of triethylamine and stirring for 30 minutes, the mixture was stirred at 100 ° C. for 4 hours. The reaction mixture was cooled to room temperature, 150 ml of water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane (1: 3 v / v). The obtained crude product was recrystallized from ethyl acetate to obtain 1.16 g of compound 1.

IR (KBr tablet; cm ^-1 ): 3416,3286,2962,286
6,1650,1537,1461,1250 NMR (δ, ppm, CDCl ₃ ): 2.21 (s, 3H), 4.87 and 5.26 (q, 2
(H, ABtype, J = 15.1Hz)

Example 2: N- (2,6-diisopropylphenyl) -N '-(2-bromo-6,1
1-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 2)

Compound 2 was prepared according to the method of Example 1 by using 2.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and 1.54 g of 2,6-diisopropylaniline hydrochloride. 2.03 g was obtained.

IR (KBr tablet; cm ^-1 ): 3416,3278,2962,164
2,1533,1255 NMR (δ, ppm, CDCl ₃ ): 4.88 and 5.31 (q, 2H, ABtype, J = 1
(4.9Hz)

Example 3: N- (2,6-diisopropylphenyl) -N '-(2-bromo-1,3
-Dimethyl-6,11-dihydrodibenzo [b, e] oxepin
-11-ylmethyl) urea (Compound 3)

According to the method of Example 1, 2-bromo-1,3-dimethyl-6,11-dihydrodibenzo [b, e] oxepin-11-
2.0 g of acetic acid and 2,6-diisopropylaniline hydrochloride 1.
By using 82 g, 1.87 g of compound 3 was obtained.

IR (KBr tablet; cm ^-1 ): 3248,3062,2960,165
0,1639,1544,1304 NMR (δ, ppm, CDCl ₃ ): 2.33 (s, 3H), 2.52 (s, 3H), 4.88 and 5.28 (q, 2H, ABtype, J = 15.6Hz)

Example 4: N- (2,6-diisopropylphenyl) -N '-(6,11-dihydrodibenzo [b, e] oxepin-11 (6H) -ylidene) urea (Compound 4)

According to the method of Example 1, (6,11-dihydrodibenzo [b, e] oxepin-11 (6H) -ylidene) acetic acid 0.59
0.40 g of compound 4 was obtained by using g and 2,6-diisopropylaniline hydrochloride 0.60 g.

IR (KBr tablet; cm ^-1 ): 3390,3216,2966,169
2,1635,1507,1309,1222 NMR (δ, ppm, CDCl ₃ ): 5.11 (brs, 2H), 5.93 and 6.00
(Each s, 1H in total)

Example 5 N- (2,6-Diisopropylphenyl) -N '-(10,11-dihydrodibenzo [a, d] cycloheptene-5 (10H) -ylidene)
Urea (Compound 5)

By following the procedure of Example 1 and using 2.0 g of (10,11-dihydrodibenzo [a, d] cycloheptene-5 (10H) -ylidene) acetic acid and 2.0 g of 2,6-diisopropylaniline hydrochloride. 2.30 g of compound 5 was obtained.

IR (KBr tablet; cm ^-1 ): 3386,3212,2964,168
8,1632,1505,1478,1276 NMR (δ, ppm, CDCl ₃ ): 6.03 (s, 1H)

Example 6: (6,11-Dihydrodibenzo [b, e] oxepin-11-ylmethyl)-(2,6-diisopropylphenyl) carbamate (Compound 6)

1.1 g of 6,11-dihydrodibenzo [b, e] oxepin-11-methanol was dissolved in 30 ml of dichloromethane,
2.7 ml of triethylamine and 2.3 ml of 2,6-diisopropylisocyanic acid were added under ice cooling. After stirring at room temperature for 15 hours, 100 ml of water was added to the reaction solution and extracted with dichloromethane. The obtained organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate-toluene (1: 9 v / v)]. The obtained crude product was recrystallized from ethyl acetate to give 0.97 g of compound 6.
Obtained.

IR (KBr tablet; cm ^-1 ): 3310,2962,1705,169
3,1510,1493,1243 NMR (δ, ppm, CDCl ₃ ): 4.97 and 5.40 (q, 2H, ABtype, J = 1
(9.0Hz)

Example 7: N- (2,6-diisopropylphenyl) -N '-(6,11-dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 7)

Compound 7 was prepared according to the method of Example 1 by using 2.0 g of 6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and 1.67 g of 2,6-diisopropylaniline.
2.20 g of was obtained.

IR (KBr tablet; cm ^-1 ): 3418,2932,1637,154
3,1491,1260 NMR (δ, ppm, CDCl ₃ ): 4.12 (t, 1H, J = 7.6Hz), 4.90 and
5.30 (q, 2H, ABtype, J = 15.2Hz)

Example 8: N- (2,4-difluorophenyl) -N '-(2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 8)

According to the method of Example 1, 1.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
0.71 g of compound 8 was obtained by using 0.46 g of 2,4-difluoroaniline.

IR (KBr tablet; cm ^-1 ): 3278,2608,1642,161
4,1509,1432,1228 NMR (δ, ppm, CDCl ₃ ): 4.07 (t, 1H, J = 7.6Hz), 4.95 and
5.40 (q, 2H, ABtype, J = 14.8Hz)

Example 9: N- (2,4,6-trifluorophenyl) -N '-(2-methyl-6,1
1-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 9)

According to the method of Example 1, 1.0 g of 2-methyl-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
1.08 g of compound 9 was obtained by using 0.66 g of 2,4,6-trifluoroaniline.

IR (KBr tablet; cm ^-1 ): 3372,1638,1546,152
5,1504,1447,1254 NMR (δ, ppm, CDCl ₃ ): 4.20 (t, 1H, J = 7.8Hz), 4.96 and
5.41 (q, 2H, ABtype, J = 14.8Hz)

Example 10: N- (2,4,6-trifluorophenyl) -N '-(2-bromo-6,1
1-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 10)

According to the method of Example 1, 1.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
0.44 g of compound 10 was obtained by using 0.53 g of 2,4,6-trifluoroaniline.

IR (KBr tablet; cm ^-1 ): 3252,1614,1543,152
3,1484,1451,1231 NMR (δ, ppm, CDCl ₃ ): 4.19 (t, 1H, J = 7.8Hz), 4.96 and
5.44 (q, 2H, ABtype, J = 14.7Hz)

Example 11: N- (2,4,6-trimethylphenyl) -N '-(2-bromo-6,11-
Dihydrodibenzo [b, e] oxepin-11-ylmethyl)
Urea (Compound 11)

According to the method of Example 1, 1.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
0.81 g of compound 11 was obtained by using 0.49 g of 2,4,6-trimethylaniline.

IR (KBr tablet; cm ^-1 ): 2918,1635,1610,156
2,1484,1233 NMR (δ, ppm, CDCl ₃ ): 4.10 (t, 1H, J = 7.8Hz), 4.90 and
5.34 (q, 2H, ABtype, J = 14.9Hz)

Example 12: N- (2,4,6-trimethoxyphenyl) -N '-(2-bromo-6,1
1-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 12)

According to the method of Example 1, 1.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
1.0 g of compound 12 was obtained by using 0.66 g of 2,4,6-trimethoxyaniline.

IR (KBr tablet; cm ^-1 ): 3314,1656,1543,150
8,1453,1416,1228 NMR (δ, ppm, CDCl ₃ ): 4.08 (t, 1H, J = 7.4Hz), 4.92 and
5.37 (q, 2H, ABtype, J = 14.8Hz)

Example 13: N- (2,6-diisopropylphenyl) -N '-(2-methoxy-
6,11-Dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea (Compound 13)

According to the method of Example 1, 2-methoxy-6,11-
0.92 g of compound 13 was obtained by using 1.0 g of dihydrodibenzo [b, e] oxepin-11-acetic acid and 0.75 g of 2,6-diisopropylaniline.

IR (KBr tablet; cm ^-1 ): 3360,2964,1728,152
4,1494,1442,1260 NMR (δ, ppm, CDCl ₃ ): 4.06 (t, 1H, J = 7.6Hz), 4.99 and
5.40 (q, 2H, ABtype, J = 15.5Hz)

Example 14: N- (3,5-di-tert-butyl-4-hydroxyphenyl) -N '
-(2-Bromo-6,11-dihydrodibenzo [b, e] oxepin
-11-ylmethyl) urea (Compound 14)

Following the procedure of Example 1, 1.0 g of 2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-acetic acid and
1.09 g of compound 14 was obtained by using 0.80 g of 3,5-di-tert-butyl-4-hydroxyaniline.

IR (KBr tablet; cm ^-1 ): 3734,3292,2960,163
9,1607,1559,1484,1228 NMR (δ, ppm, CDCl ₃ ): 4.15 (t, 1H, J = 7.6Hz), 4.92 and
5.37 (q, 2H, ABtype, J = 14.8Hz)

Example 15: N- (2,6-diisopropylphenyl) -N '-(2-bromo-4-
Dimethylamino-6,11-dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea hydrochloride (Compound 15)

2-Bromo-4-dimethylamino-6,11-dihydrodibenzo [b, e] oxepin was prepared according to the method of Example 1.
-11-acetic acid 2.26 g and 2,6-diisopropylaniline 1.28
By using g, N- (2,6-diisopropylphenyl) -N '-(2-bromo-4-dimethylamino-6,11-dihydrodibenzo [b, e] oxepin-11-ylmethyl) urea was converted to 1 .
I got 98g.

IR (KBr tablet; cm ^-1 ): 3408, 2962, 1652, 1
590, 1529, 1252 NMR (δ, ppm, CDCl ₃ ): 2.81 (s, 6H), 4.01 (t, 1H, J = 7.6H
z), 4.87 and 5.28 (q, 2H, ABtype, J = 15.2Hz)

The above compound (1.78 g) was dissolved in ethanol (10 ml), and 7.34 M hydrochloric acid ethanol solution (0.7 ml) was added, and the mixture was concentrated under reduced pressure. The obtained crude crystals were recrystallized from isopropanol-isopropyl ether to obtain 1.33 g of compound 15.

Example 16: N- (2,4,6-trimethoxyphenyl) -N '-[1-methyl-1
-(6,11-Dihydrodibenzo [b, e] oxepin-11-yl) ethyl] urea (Compound 16)

According to the method of Example 1, 2-methyl-2- (6,11
-Dihydrodibenzo [b, e] oxepin -11-yl) propionic acid 2.0 g and 2,4,6-trimethoxyaniline 1.56
0.85 g of compound 16 was obtained by using g.

IR (KBr tablet; cm ^-1 ): 3320,2936,1634,159
4,1541,1509,1229 NMR (δ, ppm, CDCl ₃ ): 1.29 (s, 3H), 1.44 (s, 3H), 3.66 (s, 6
H), 3.84 (s, 3H), 4.80 and 4.91 (q, 2H, ABtype, J = 15.7H
z)

Example 17: N- (2,4,6-trimethoxyphenyl) -N '-[1-methyl-1
-(2-Bromo-6,11-dihydrodibenzo [b, e] oxepin
-11-yl) ethyl] urea (Compound 17)

According to the method of Example 1, 2.0 g of 2-methyl-2- (2-bromo-6,11-dihydrodibenzo [b, e] oxepin-11-yl) propionic acid and 2,4,6- 1.63 g of compound 17 was obtained by using 1.22 g of trimethoxyaniline.

IR (KBr tablet; cm ^-1 ): 3328,2936,1638,159
4,1543,1229 NMR (δ, ppm, CDCl ₃ ): 1.27 (s, 3H), 1.40 (s, 3H), 3.69 (s, 6
H), 3.83 (s, 3H), 4.80 and 4.99 (q, 2H, ABtype, J = 15.5H
z)

Formulation Example 1: Tablet A tablet having the following composition is prepared by a conventional method. Compound 2: 100 mg Lactose: 60 mg Potato starch: 30 mg Polyvinyl alcohol: 2 mg Magnesium stearate: 1 mg Tar pigment: Trace amount

Formulation Example 2: Powder A powder having the following composition is prepared by a conventional method. Compound 3: 150 mg lactose: 280 mg

[0121]

INDUSTRIAL APPLICABILITY According to the present invention, compound (I) and its pharmacologically acceptable salts have an ACAT inhibitory action and are useful as therapeutic drugs for hyperlipidemia and arteriosclerosis. Be expected.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location // A61K 31/17 9283-4C 31/22 9283-4C 31/335 ADN 7431-4C 31/38 AED 7431-4C 31/435 ABX 7431-4C

Claims (1)

[Claims] 1. Formula (I): [In formula, X < ¹ > -X < ² > is CH = CH-CH = CH, CH.
= CH-CH = N or S-CH = CH, YZ
_{Is, CH 2 -O, CH = CH} , CH 2 -CH 2 or C
It represents H ₂ -S, L-M is, C = CR ⁹ (wherein, R
⁹ represents hydrogen or lower alkyl) or CH-C
R ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different and represent hydrogen or lower alkyl), and W is NR ⁴
(In the formula, R ⁴ represents hydrogen or lower alkyl) or O, R ¹ , R ² and R ³ are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, halogen,
Represents nitro, amino or mono- or di-lower alkyl-substituted amino, R ⁵ represents hydrogen or lower alkyl, R ⁶ , R ⁷ and R ⁸ are the same or different and represent hydrogen, halogen, lower alkyl or lower alkoxy. but provided that Y-Z is CH = CH or CH ₂ -CH ₂
When LM represents C = CR ⁹ (wherein R ⁹ is as defined above) or CH—CR ^10a R ^11a (wherein R ^9
10a and R ^11a are the same or different and are R ¹⁰ and R ¹¹
Represents a lower alkyl in the definition of], or a pharmaceutically acceptable salt thereof.