JPH03220168A - 1-phenylalkyl-3-phenylurea derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1>, R<3> and R<6> are H, 1-5C alkyl, 1-5C alkoxy, 1-5C alkylthio, halogen, nitro, CF3 or (substituted) amino; R<2> is H or 1-5C alkyl; R<4> and R<5> are 1-15C alkyl, 1-5C alkoxy or halogen; X is O or S; l and (m) are 0-5; (n) is 0-3; (p) is 1-3 when R<1> is 1-5C alkyl or halogen and 1 when R<1> is other substituent groups]. EXAMPLE:1-(2,2-Diphenylethyl)-3-(2,6-dimethylphenyl)urea. USE:A medicine. A therapeutic agent for hyprelipemea or atherosclerosis having lowering action on blood cholesterol due to inhibition of an enzyme, acyl- coenzyme-cholesterol acyltransferase. PREPARATION:For example, a phenylalkylamine derivative expressed by formula II is subjected to a reaction with a phenyl iso(thio)cyanate derivative expressed by formula III in an inert solvent at 0-150 deg.C to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application 1] The present invention provides a therapeutic agent for hyperlipidemia having a strong lipid-lowering effect;
and 1 useful as a treatment for atherosclerosis.
-phenylalkyl-3-phenylurea derivatives and 1-
This invention relates to phenylalkyl-3-phenylthiourea derivatives.

[Prior Art and Problems to be Solved by the Invention] Hyperlipidemia caused by abnormal lipid metabolism is considered to be a cause of arteriosclerosis, and is also considered to be a risk factor for ischemic heart disease, cerebral infarction, and the like. Recently, it has been revealed that the enzyme acyl coenzyme cholesterol acyltransferase (ACAT) plays an important role in cholesterol metabolism, especially in cholesterol metabolism.
Compounds with inhibitory activity inhibit cholesterol absorption in the intestinal tract, lower cholesterol in the blood, and inhibit the deposition of cholesterol esters in arterial walls. It has been reported that it is useful as a therapeutic agent for the disease (Japanese Patent Application Laid-open No. 63-316761,
Publication No. 3569).

[Means for Solving the Problems 1] As a result of searching for a compound that exhibits an even better lipid-lowering effect on top of these prior art techniques, the present inventors discovered a novel and useful urea derivative, and completed the present invention. I came to the conclusion.

That is, the gist of the present invention is the following general formula (I) (wherein R1,
R3 and R6 are each independently a hydrogen atom, a carbon number of 1-
5 alkyl group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a halogen atom, a nitro group, a trifluoromethyl group, or an optionally substituted amino group, and R2 is a hydrogen atom. or represents an alkyl group having 1-5 carbon atoms, R4 and R5 each independently represent an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, or a halogen atom, and X is an oxygen atom or a sulfur atom. represents. e represents an integer of 0-5, m represents an integer of 0-5, and n represents an integer of 0-3. Further, p represents an integer of 1-3 only when R1 represents an argyl group having 1-5 carbon atoms or a halogen atom, and represents 1 in the case of other substituents. ) 1-phenylalkyl-3 represented by
- consists in phenylurea derivatives.

Hereinafter, the present invention will be explained in detail.

The compound of the present invention is represented by the above general formula (I). In the formula, the alkyl group having 1 to 5 carbon atoms in R1, R2, R3, R4, R5 and R6 includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, 5eC- butyl group, tert-butyl group,
Examples include n-pentyl group, 5ee-pentyl group, neopentyl group, etc., and examples of the alkoxy group having 1-5 carbon atoms in R1, R3, R4, R5 and R6 include methoxy group,
Ethoxy group, n-propoxy group, isopropoxy group, n
-butoxy group, 5ee-butoxy group, tert-butoxy group, n-pentoxy group, 5ee-pentoxy group, neopentyl group and the like.

Examples of the alkylthio group having 1 to 5 carbon atoms in R1, R3 and R6 include methylthio group, ethylthio group, isopropylthio group, etc., and halogen atoms in R1, R3, R4, R5 and R6 include fluorine atom and chlorine atom. , bromine atom, etc. In addition, examples of the optionally substituted amine group include an alkylamino group substituted with an alkyl group having 1 to 5 carbon atoms, such as an amine group, a methylamine group, a dimethylamino group, an ethylamino group, a diethylamino group, and a dialkylamino group. Examples include groups.

Representative compounds of the present invention represented by formula (I) are illustrated in Table 1 below.

The 1-phenylalkyl-3-phenylurea derivatives of the present invention are not limited to specific isomers, but include all optical isomers and mixtures thereof, such as racemates.

Next, a method for producing the compound of the present invention will be explained.

(II), (III)
(In the formula, R1, R2, R3, R4, R5, R6,
l, m and n are as defined above. ) Phenylalkylamine derivative (II) and phenyl isocyanate derivative (III) (or phenyl inthiocyanate derivative) in benzene, toluene, xylene, hexane, heptane, diethyl ether, tetrahydrofuran (THF), dioxane, N,N-dimethyl In a solvent that does not participate in the reaction such as formamide, from 0°C
Compound (I) of the present invention is obtained by condensation in a temperature range of 150°C.

b (IV) (V) (wherein,
R1, R2, R3, R4, R5, R6, X, l! , m
and n are as defined above. ) The compound (I) of the present invention can be obtained by reacting the phenylalkyl isocyanate derivative (■) (or the phenylalkyl inthiocyanate derivative) and the aniline derivative (V) under the same conditions as in Method A above.

(VI) (wherein R1,)j2, R3, R4, R5, R6, X,
e, m and n? , has already been defined. ) Kenpo is a method for synthesizing the compound represented by the above general formula (I) in which X is an oxygen atom, and is basically the same as the above method B, except that phenylalkyl isocyaner F as
Derivative IVa) and phenylalkylcarboxylic acid derivative (
The compound (■a) of the present invention can be obtained by producing it from VI) and then condensing it with the aniline derivative (V).

As a method for converting a phenylalkyl carboxylic acid derivative (VI) into a phenylalkyl isocyanate derivative (IVa), for example, an organic amine that does not participate in the reaction such as triethylamine and diphenylphosphoryl azide (DPP) are used.
Examples include a method in which the reaction is carried out in the presence of A) in an inert solvent such as benzene, toluene, or xylene at a temperature range from room temperature to 150°C.

<D> (■) (IIIa) (In the formula, R4, R5 and R6 are as defined above.) Kenpo also uses the compound represented by the general formula (I) above, when X is an oxygen atom. Synthesis method, benzoic acid derivative (■)
to the phenyl isocyanate derivative (IIIa) above C
The compound of the present invention (
(2) This is a method to obtain a).

(V) -> (I) (wherein R1, R2, R3, R4, R5, R6, X,
e, m and n are as defined above, and Y represents a leaving group such as a halogen atom, an aryloxy group, or an alkylthio group. ) The phenylalkyl derivative (II) is converted into a reactive intermediate (■
) and then reacting with the aniline derivative (V) to obtain the compound (I) of the present invention. Examples of the above reactive intermediate (■) include phenylalkylcarbamoyl chloride (wherein Y is a chlorine atom) obtained by reacting the phenylalkylamine derivative (II) with phosgene when X in the formula is an oxygen atom; , phenylalkylcarbamoyl aryl ester (in the formula, Y is an aryloxy group) obtained by reacting the phenylalkylamine derivative (II) with an aryl chloroformate. When X in the formula is a sulfur atom, examples include phenylalkylthiocarbamic acid alkylthioester (Y in the formula is an alkylthio group).

<F> A method for obtaining the compound (I) of the present invention by reaction.

Examples of the reactive intermediate (IX) include phenylcarbamoyl chloride (Y in the formula is a chlorine atom) obtained by reacting the aniline derivative (V) with phosgene, when X in the formula is an oxygen atom, and aniline Examples include phenylcarbamoyl aryl ester (in the formula, Y is an aryloxy group) obtained by reacting the derivative (V) with an aryl chloroformate.

Also, when X in the formula is a sulfur atom, phenylthiocarbamic acid alkylthioester (Y in the formula is an alkylthio group)
etc.

(V) (IX) (wherein, R4
, R5, R6, X and Y are as defined above. ) Conversion of aniline derivative (V) to reactive intermediate (IX) -
Afterwards, phenylalkylamine derivative (II) and (
In the formula, R1, R2, R3, R4, R5, R6, X, e
, m and n are as defined above. ) Illegal is the synthesis method of compound (Ib) in which X is an oxygen atom among the compounds of the present invention. This is a method for converting a so-called urea derivative into a thiourea derivative (Ib).

The compounds of the present invention are administered to humans, preferably by oral administration, as a therapeutic agent for hyperlipidemia and atherosclerosis. Dosage forms for oral administration include tablets, granules, powders, capsules, etc., which contain the compound of the present invention and conventional excipients such as glucose, lactose, corn starch, or mannitol. It can be produced by adding agents, binders such as hydroxypropyl cellulose (RPC) and carboxymethyl cellulose (CMC), disintegrants such as starch and seratine powder, and lubricants such as talc and magnesium stearate.

In the case of oral administration, the dosage of the compound of the present invention is about 0.1 mg to 300 mg per day for adults. However, the specific dosage employed can vary depending on the needs of the patient, the extent of the disease being treated and the activity of the compound used.

[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited in any way by these Examples unless the gist of the present invention is exceeded.

Example 1 Synthesis of l-(2,2-diphenylethyl)-3-(2,6-dimethylphenyl)urea (compound No. 5 in Table 1) 2.2-diphenylethylamine 0.99g (5m
mol) to 10 ml of ethyl ether, then 2
, 6-dimethylphenyl isocyanate 0.73g (
A solution of 5 mmol) in ethyl ether (10 ml) was added dropwise at room temperature. After stirring the reaction mixture overnight at room temperature, the precipitated crystals were ? 1-(2,2-diphenylethyl)-3-(2,6-dimethylphenyl)urea 0.99
g (yield 58%) was obtained.

Melting point: 182-183°C (recrystallization solvent: ethyl acetate) IR (KBr) cm-': 3320.2930.
1620.1580.1260.695NMR (CDC
13) 6: 2.02 (s, 6H), 3.81
(q, 2H).

4.15 (t, 5.53 (s, LH) with 2H).

6.97-7.26 (m, 13H) Example 1 Row 2-9 Using the corresponding diphenylalkylamine in place of 2-diphenylethylamine in Example 1, 2,6-
The corresponding substituted phenyl isocyanate was used instead of dimethyl phenyl isocyanate;
The compounds shown in Tables 2 and 3 below were synthesized in the same manner as above.

Example 10 1-(3,3-diphenylpropyl)-3-(2,6-
diituprobylphenyl) urea (compound No. in Table 1,
Synthesis of 59) 3.3-diphenylpropylamine 1.05g (5m
mol) was added to 20 ml of ether, and 10 ml of 0.5 mol of 2,6-diituprobylphenyl isocyanate in hexane was added at room temperature. This mixed solution was stirred for 5 hours, and the precipitated crystals were collected. 2.00 g of 1-(3,3-diphenylpropyl)-3-(2,6-dibutylphenyl)urea (yield: $97%).

Melting point: 211-212°C (recrystallization solvent: ethyl acetate)
IR (KBr) cm-': 3320.2950.1
640.1560.1280.705NMR (CDC1
3) 6: 1.19 (brs, 12H), 2.
18 (m, 2H) 3.12 (m, 2H), 3
．． 28 (m, 2H).

3.85 (t, LH), 4.17 (brs,
LH).

5.71 (s, LH), 7.12-7.35 (
m, 13H) Example 11 1-(2,2-diphenylethyl)-3-(2,6-dimethylphenyl)thiourea (Compound No. 67 in Table 1
) synthesis 2.2-cyphenylethylamine 0.28g
(1,4 mmol) and 0.23 g (1,4 mmol) of 2,6-dimethylphenylinthiocyanate were added to 5 ml of dimethylformamide (DMF) and heated at 60°C for 3 hours.
heated for an hour. After cooling the reaction solution, 50 ml of water was added, extracted with ether, dried over anhydrous magnesium sulfate, filtered, concentrated the resulting solution, and then subjected to silica gel column chromatography (eluent/n-'\xane:acetic acid). Ethyl = 4
: 1) to obtain 0.15 g (yield 30%) of oily 1-(2,2-diphenylethyl)3-(2,6-dimethylphenyl)thiourea.

Melting point: 151-153°C (recrystallization solvent: ethanol)
IR (KBr) cm-': 3250.2930.1
530.1260.705NMR(CDCl2)δ:
1.96 (s, 6H), 4.10 (m, 2H
)4.30 (t, IH), 5.26 (s, L
H) 6.96 (d, 2H), 7.06-7.27
(m, IIH) 7.63 (s, LH) Example 12 1-(2,2-diphenylethyl)-3-(2,6-diitupropylphenyl)thiourea (Compound No. in Table 1
, 69) The title compound was synthesized in the same manner as in Example 11, except that 2,6-diisopropylphenyl thiocyanate was used instead of 2,6-dimethylphenyl thiocyanate.

Yield: 29% Melting point: 141-143°C (recrystallization solvent: ethanol) IR (KBr) cm-': 3160.2970.
1535.1270.70ONMR(CDC13)6
: 0.91 (d, 6H), 1.09 (d,
6H).

2.95 (m, 2H), 4.16 (d, 3H
).

5.14 (s, IH), 5.25 (s, IH
).

7.03-7.34 (m, 13H) Example 13 1-(2,2-diphenylethyl)-3-(2,6-simethoxyphenyl) urine! (Compound No. 21 in Table-1)
Synthesis of 2.6-dimethoxybenzoic acid 1.82g (10
mmol), diphenylphosphoryl azide (DPPA
) 2.75 g (10 mmol) and triethylamine 1.21 g (12 mmol) were added to 20 ml of benzene, stirred at room temperature for 1 hour, and then heated and stirred at 80°C for 2 hours. After cooling the reaction solution to room temperature, 1.97 g (10 mmol) of 2,2-diphenylethylamine was added to the room temperature.
Stir overnight with ML. This reaction mixture was purified by silica gel column chromatography (eluent: dichloromethane), and 1-(2,2-diphenylethyl)-3-(2
,6-Simethoxyphenyl)urea 1.70g (yield 4
5%).

Melting point: 163-165°C (Recrystallization solvent: ethyl acetate / ethanol) IR (KBr
) cm-': 3330.2930.1655.15
45.1255.1105゜0O NMR (CDC13) δ:3.58 (s, 6H)
, 3.83 (q, 2H).

4.19 (t, LH), 5.13 (t, IH
).

5.81 (s, IH), 6.48 (d, 2H
)7.08 (t, IH), 7.15-7.31
(m, l0H) Example 14 1-(2-(2-methylphenyl)-2-phenylethyl)-3-(2,6-diitubrobylphenyl)urea (
Synthesis of Compound No. 36 in Table 1 3-(2-methylphenyl)-3-phenylpropionic acid 0.72 g (3 mmol), diphenylphosphoryl azide 0.83 g (3 mmol) and triethylamine 0.36 g ( 3.6mmof) toluene 30ml
After stirring at room temperature for 1 hour, the mixture was heated and stirred at 80°C for 2 hours. After cooling, 0.54 g (3 mmol) of 2,6-dipropylaniline was added under water cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate = 4:1) to obtain 1-(2-(2-methylphenyl)-2-phenylethyl)-3-(2,6 0.78 g (yield: 63%) of diitubrobylphenyl)urea was obtained.

Melting point: 176-178°C (recrystallization solvent: ethyl acetate)
IR (KBr) cm-': 3300.2960.16
35.1560.1260.70ONMR(CDC13
) 6: 0.90-1.10 (brs, 12H
), 2.15 (s, 3H) 3.10 (m, L
H), 3.77 (q, IH).

4.16 (t, LH), 4.27 (t, IH
).

5.57 (s, LH), 7.02-7.26 (
m, 12H) Examples 15-29 In Example 14, 3-(2-methylphenyl)-3
- Synthesize the compounds in Cloth-4 and Table-5 below in the same manner as in Example 14, except that the corresponding phenylalkylcarboxylic acid was used instead of phenylpropionic acid.

Example 30 1-(3,3-bis(4-methoxyphenyl',)phthyl)-3-(2,6-diituprobylphenyl)urea (
Synthesis of compound No. 70) in Table 1 4.4-bis(4-methoxyphenyl)pentanoic acid 0.
95 g (3 mmol), 0.83 g (3 mmol) of azidihydriphenylphosphoryl (DPPA), and 0.36 g (3.6 mmol) of triethylamine were added to 30 ml of toluene, stirred at room temperature for 2 hours, and then heated to 80°C.
It was heated for 3 hours. After cooling, 0.54 g (3 mmol) of 2,6-diitubropylaniline was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was subjected to silica gel chromatography (eluent; n-hexane:ethyl acetate = 4:
1) to obtain 1.OOg (yield 68%) of 1-(3,3-bis(4-methoxyphenylbutyl)-3-(2,6-diitupropylphenyl)urea.

Melting point: 167-169°C (recrystallization solvent: ethanol)
IR (KBr) cm-': 3320, 2960, 1
630,1515,1250,1180゜103083
O NMR (CDC13) 6:1.18 (d, 12
H), 1.58 (s, 3H).

2.04 (m, 2H) 2.98 (m, 2H)
.

3.30 (m, 2H, 3.75 (s, 6H).

4.08 (t, LH), 5.98 (s, LH
).

6.74 (d, 4H), 7.05 (d, 4H
).

7.17 (d, 2H), 7.35 (t, LH
) Test side 1 The blood cholesterol lowering effect of the compound of the present invention was measured by the following method.

Randomly divided Goalten hamster C bodies (N80-100 g) into groups and raised for 3 days on normal diet (fixed feed for laboratory animals, MF-1, manufactured by Oriental Yeast Co., Ltd. for breeding mice, rats, and hamsters). did. Thereafter, the above diet was changed to a diet containing 1% cholesterol and 0.5% cholic acid and fed ad libitum. 181 times at the same time indicated dose (1mg/10ml ofwat)
The test drug was administered orally by gavage, adjusted to a concentration of 1.5 er/kg). To the control group, 10 ml of water per 1 kg of body weight was orally administered by force. Five days later, 3 hours after administering the test drug, blood was collected from the abdominal vena cava under Sibutal anesthesia (Nembutal injection, manufactured by Dynabo), and serum was separated by centrifugation. Cholesterol concentration in serum was determined using a blood cholesterol 1llll constant kit (Tetaminar TC5 manufactured by Kyowa Medics), and the results are shown in Table 6 below as a percent inhibition of serum cholesterol concentration compared to a control.

Table 6 Experimental Example 2 The ACAT inhibitory effect of the compounds of the present invention was measured by the following method.

The activity of ACAT was measured in tissue samples containing hamster liver microsomes using radiolabeled cholesterol protein A-1, formed from radiolabeled oleic acid coenzyme A.
It was determined by measuring the leaves of Therefore, the A.C.A.
The activity of the compound of the present invention to inhibit T is determined by determining the percent reduction in cholesterol oleate formation in a control group that does not tolerate the test drug by adding each concentration (uM) of the test drug, and The results are expressed as IC50 values, that is, the concentration of the test compound required to inhibit 50% of the enzyme expression, and the results are shown in Table 7 below.

Since the compound has a blood cholesterol lowering effect by inhibiting ACAT, it is expected to be used as a therapeutic agent for hyperlipidemia or atherosclerosis.

Claims (1)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^3 and R^6 are each independently a hydrogen atom, carbon number 1-5 represents an alkyl group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a halogen atom, a nitro group, a trifluoromethyl group, or an optionally substituted amino group, and R^2 is hydrogen. Represents an atom or an alkyl group having 1-5 carbon atoms, R^4 and R^
5 each independently represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or a halogen atom;
represents an oxygen atom or a sulfur atom. l represents an integer of 0-5, m represents an integer of 0-5, and n represents an integer of 0-3. Further, p represents an integer of 1-3 only when R^1 represents an alkyl group having 1-5 carbon atoms or a halogen atom, and represents 1 in the case of other substituents. ) A 1-phenylalkyl-3-phenylurea derivative represented by: