JP3387948B2 - Novel phenylalanine derivative or salt thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an acyl-coenzyme A:
Has inhibitory activity of resterol acyltransferase (ACAT)
New phenylalanine derivatives or their salts
You. [0002] Acyl-coenzyme A: cholesterol reed
Dietary cholesterol is inhibited by inhibiting
Intestine of cholesterol excreted from rolls and liver
Suppresses absorption and reabsorption from
Can reduce macrophage foam
Cholesterol ester in the arterial wall
Atherosclerotic lesions that reduce accumulation and storage
Formation or progress can be suppressed. Accordingly
And acyl-coenzyme A: cholesterol acyltransferase
A substance that inhibits
Related disorders, such as transient ischemic attacks, angina,
Useful for prevention and treatment of myocardial infarction, peripheral thrombus and occlusion
-Coenzyme A: Cholesterol
Research on inhibitors of luacyltransferases has been conducted [The
The Lipid, Volume 2, Issue 1, Pages 43-54 (1991
Year)]. [0003] The object of the present invention is to provide an
-Coenzyme A: Inhibition of cholesterol acyltransferase
The object of the present invention is to provide a novel compound having a utility. [0004] Under such circumstances, the inventor of the present invention.
Et al. Have conducted intensive studies and found that the general formula [1] "Where R ¹ Is an optionally substituted aralkyl
A xy, arylamino or alkenyl group; ^Two Is
An alkyl group which may be substituted; and A is of the formula: Or the formula: (Where R ^Three Represents an aryl group which may be substituted
You. ) Are shown. Phenylalani represented by
Derivative or a salt thereof is a remarkable acyl-coenzyme A:
Has the inhibitory effect of resterol acyltransferase
Heading, the present invention has been completed. Next, the present invention will be described in detail. In addition,
Unless otherwise specified in this specification, a halogen atom
Is a fluorine, chlorine, bromine or iodine atom
An alkyl group is, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, 2-methylbutyl, 3-methyl
Butyl, pentyl, hexyl, 2-ethylhexyl, f
C such as butyl, octyl or nonyl _1-10 Alkyl group
An alkenyl group is, for example, vinyl, allyl,
1-propenyl, 1-butenyl, 9-tridecenyl, 9
-Pentadecenyl, 9-heptadecenyl, 2,4-pen
Such as tadienyl or 9,12-heptadecadienyl
C _2-22 An alkenyl group; an aryl group is phenyl or
Is naphthyl or the like; an arylamino group is aryl-
An aralkyloxy group is, for example, a benzyl group.
Aryl- such as benzyloxy or phenethyloxy
C _1-5 An alkyl-O- group; a lower alkyloxy group;
Is, for example, methyloxy or ethyloxy
C _1-5 Alkyl-O- group; lower alkyloxycarbo
A nyl group is, for example, methyloxycarbonyl or
C such as ethyloxycarbonyl _1-5 Alkyl-OC
O-groups are each meant. [0006] R ¹ Aralkyloxy group, aryl
Mino group, alkenyl group and R ^Three Substituents of the aryl group of
Is, for example, substituted with a halogen atom or alkyl.
Amino group, nitro group, lower alkyloxy
And the like. Each of the above groups is
It may be substituted with one or more kinds of substituents. Ma
R ^Two Examples of the substituent of the alkyl group of
Reel group and lower alkyloxycarbonyl group
No. The phenylalanine derivative of the general formula [1]
Salts include, for example, mineral acids such as hydrochloric acid or sulfuric acid.
Salt of formic acid, citric acid, trichloroacetic acid or trif
Salts with organic carboxylic acids such as fluoroacetic acid; or methane
Sulfonic acid, benzenesulfonic acid, p-toluene sulfone
Acid, mesitylene sulfonic acid or naphthalene sulfone
And salts with sulfonic acids such as acids. Also one
The phenylalanine derivative of the general formula [1] and a salt thereof
And isomers (eg, optical isomers, geometric isomers and
And tautomers), the present invention
Includes all isomers and also all crystal forms, hydration
And solvates. Among the compounds of the present invention, preferred compounds
Include the following compounds.・ N-benzyloxycarbonyl-L-phenylalani
Le-propylamide / N-benzyloxycarbonyl-L-phenylalani
Le-tert-butylamide / N-benzyloxycarbonyl-L-phenylalani
2-ethylhexylamide / N-benzyloxycarbonyl-L-phenylalani
Le-hexylamide / N-benzyloxycarbonyl-L-phenylalani
Ru-heptylamide / N-benzyloxycarbonyl-L-phenylalani
Le-octylamide / N-benzyloxycarbonyl-L-phenylalani
-Benzylamide N-2,4-difluorophenylamino
Carbonyl-L-phenylalanyl-L-leucine methyl
Ester / N-2,4-difluorophenylaminocarbonyl-
L-phenylalanyl-L-isoleucine methyl ester
Le-N-2,4-difluorophenylaminocarbonyl-
L-phenylalanyl-2-ethylhexylamide / N-2,4-dimethoxyphenylaminocarbonyl-
L-phenylalanyl-L-leucine methyl ester N-2,4-dimethoxyphenylaminocarbonyl-
L-phenylalanyl-L-isoleucine methyl ester
Le-N-2,4-difluorophenylaminocarbonyl-
L-phenylalanyl-hexylamide / N-2,4-difluorophenylaminocarbonyl-
L-phenylalanyl-heptylamide / N-2,4-difluorophenylaminocarbonyl-
L-phenylalanyl-octylamide N-2,4-dimethoxyphenylamino
Carbonyl-L-phenylalanyl-hexylamide / N-2,4-dimethoxyphenylaminocarbonyl-
L-phenylalanyl-heptylamide / N-2,4-dimethoxyphenylaminocarbonyl-
L-phenylalanyl-octylamide allyl-L-phenylalanyl-L-leucine methyl
Ester oleyl-L-phenylalanyl-L-leucine meth
Luster oleyl-L-phenylalanyl-L-isoleucine
Methyl ester oleyl-L-phenylalanyl- (2-ethylhexyl
Sil) amide-3- [1-heptyl-3- (p-nitrophenyl) uree
Id] -2- [3- (p-nitrophenyl) ureido] p
Propylbenzene-2- [3- (p-aminophenyl) ureido] -3-
[1-Heptyl-3- (p-aminophenyl) ureido]
Propylbenzene 2- [3- (p-dimethylaminophenyl) ureido]
-3- [1-heptyl-3- (p-dimethylaminophenyl)
Ureido] propylbenzene Next, a method for producing the compound of the present invention will be described.
I will tell. A phenylalanine derivative of the general formula [1] and
The salts may be prepared by known methods or a combination thereof.
And can be obtained by, for example,
It can be synthesized according to the production route. (Equation 1) "Where R ^Four Is an amino protecting group; R ¹ , R
^Two And A have the same meaning as described above, respectively.
Shown. [0013] R ^Four Examples of the amino-protecting group include, for example,
Biochemistry Experiment Course 1 Protein Chemistry IV, pp. 207-400
(Tokyo Kagaku Dojin, 1977) Amino protecting group, specific
Typically, benzyloxycarbonyl group and tert-butoxy
Xycarbonyl group and the like. Next, a method for producing the compound of the present invention will be described.
It will be described in more detail according to the manufacturing route. (1) A compound of the general formula [2] is ^Two -NH _Two "Where R ^Two Indicates the same meaning as described above.
You. And the compound of general formula [3]
Obtainable. This reaction includes, for example,
Laboratory Experiment 1 Protein Chemistry IV, pp. 207-400 (East
Kyoto Chemical Co., 1977), Agricultural and ba
Agric. Biol. Chem. 36
Vol. 8, No. 1423-1431 (1972) and The Journal
Le of Organic Chemistry (J.Org.Chem.)
Vol. 33, No. 2, pp. 864-866 (1968)
Mixed acid anhydride method or dicyclohexylcarbodii
Known acylation methods such as the amide method are exemplified. (2) When the compound of the general formula [3] is deprotected,
The compound of the general formula [4a] can be obtained. Deprotection reaction
For example, known deprotection described in the above-mentioned document (1)
Protection. (3) The compound of the general formula [4a] is
Reduction using a reducing agent such as lithium lithium in a known manner
Then, the compound of the general formula [4b] can be obtained. (4) The compounds of the general formulas [4a] and [4b] are
General formula R ¹ —COOH “wherein, R ¹ Indicates the same meaning as described above.
You. ) Or a reactive derivative thereof.
Thus, a compound of the general formula [1] can be obtained. Reactivity induction
As the conductor, for example, acid halide, acid anhydride,
Examples include mixed acid anhydrides, active esters and active amides.
I can do it. Solvents used in this reaction include
Any solvent that does not adversely affect the solvent may be used.
Methylene, 1,2-dichloroethane and chloroform
Halogenated hydrocarbons such as diethyl ether, tet
Ethers such as lahydrofuran and dioxane;
Aromatic hydrocarbons such as benzene and toluene; N, N
-Dimethylformamide and N, N-dimethylacetate
Amides such as amides; nitrites such as acetonitrile
Pyridine; 2,4-lutidine; and water.
These solvents can be used alone or in combination of two or more.
May be used. A base can be used in this reaction.
For example, triethylamine, 1,8-dia
Zabicyclo [5.4.0] undec-7-ene or
Organic bases such as lysine; sodium hydroxide or hydroxyl
Alkali hydroxide such as potassium iodide; or sodium carbonate
Or alkali carbonates such as potassium carbonate
Can be Also, a condensing agent can be used in this reaction,
As the condensing agent, for example, N, N'-dicyclohexyl
N, N'-disubstituted carbodiimides such as carbodiimides
Is mentioned. General formula R ¹ -COOH compounds or
The amount of the reactive derivative used depends on the general formula [4a] or [4b]
It is 1 to 10 times the molar amount of the compound. This reaction is usually -2
It may be carried out at 0 to 150 ° C. for 30 minutes to 24 hours. (5) The compounds of the general formulas [4a] and [4b]
General formula R ¹ -NCO where R ¹ Indicates the same meaning as described above.
You. The compound of general formula [1]
Can be obtained. As the solvent used in this reaction
Can be any solvent that does not adversely affect the reaction.
For example, methylene chloride, 1,2-dichloroethane and
Halogenated hydrocarbons such as loroform; diethyl ether
Ethers such as ter, dioxane and tetrahydrofuran
Ters; esters such as ethyl acetate;
These solvents are used alone or as a mixture of two or more.
You may. General formula R ¹ -The amount of the NCO compound used is
1-5 times the molar amount of the compound of the general formula [4a] or [4b]
You. This reaction is usually performed at -20 to 150 ° C for 5 minutes to 24 hours.
do it. In the above production method, the general formulas [2], [3], [4]
The compounds of a] and [4b] have been described with the salts of general formula [1]
The same salts as above can be used.
When having an active group, these groups are protected in advance,
It may be eliminated after the reaction. After the reaction is complete,
Can be used for the next reaction without isolation.
You. Compounds of general formula [1] are, for example,
Appropriate reduction, hydrolysis, alkylation, etc.
This can lead to other target compounds. General formula
Compounds [1], [3], [4a] and [4b] are recrystallized and
It may be isolated and purified by a conventional method such as lamb separation. When the compound of the present invention is used as a medicament,
Excipients usually used in formulation, ordinary pharmaceutical carriers and
A formulation auxiliary such as a diluent may be appropriately mixed,
Are tablets, soft or hard capsules
Preparation, powder, syrup, granule, fine granule, pill, suspension
Preparations, emulsions, solutions, powder formulations, suppositories, ointments or subcutaneous,
Oral or intramuscular, intravenous or infusion form
Can be administered parenterally. Also, the method of administration,
The dosage and frequency of administration depend on the patient's age, weight and symptoms.
Can be selected appropriately according to
Can be administered orally or parenterally (eg, by injection, infusion, or
Administration to the intestinal site, etc.)
0 mg / kg may be administered in one to several divided doses. Next, the acyl-coenzyme of the compound of the present invention
A: Explain the inhibitory effect of cholesterol acyltransferase
You. Test Example Goodman's method [The Journal of
Biological Chemistry (J. Biol. Chem) Vol. 239,
No. 5, pp. 1335-1345 (1964)]. (1) Acyl-coenzyme A: cholesterol acyltransferase
Preparation of rat liver 20 g with sucrose buffer [0.2M sucrose
Buffer, 0.05M potassium chloride, 0.1M potassium phosphate buffer (pH
7.4)], and rat liver is cut into small pieces with scissors.
And add 50 ml of sucrose buffer, Potter-Elbe
Homogenize with Gem (Potter-Elvehjem) homogenizer
(10 round trips with Teflon Pistol). The obtained homogene
The solution is filtered through gauze (6-fold) to obtain a filtrate. Filtrate
Was centrifuged at 10,000 xg for 20 minutes, and the supernatant was
Ultracentrifuge at xg for 45 minutes to obtain a precipitate. Shu to the precipitate
Homogenized homogenized again by adding 20 ml of close buffer
The rat solution was subjected to rat liver microsomal fractionation (hereinafter referred to as enzyme preparation).
Called. ). (2) Acyl-coenzyme A: cholesterol
Measurement of syltransferase inhibitory activity 0.1 M potassium phosphate buffer (pH 7.4) (hereinafter referred to as buffer)
I do. ) Dissolve the sample in 1.59 ml and remove fatty acids from bovine blood
1.5ml of clear albumin (700mg / 100ml buffer), cholesterol
(7.2 mg / ml acetone) 50 μl, oleyl-CoA
(2.6 mg / ml buffer) 360 μl and 1.5 ml of enzyme preparation
Then, react at 30 ° C for 2 hours in a total volume of 5.0 ml. Test as control
Those without the body are similarly reacted. Click on the reaction mixture.
The reaction was stopped by adding 5 ml of roloform: methanol = 2: 1 (v / v).
To stop. Furthermore, chloroform: methanol = 2: 1 is 24ml
After addition, mix well and centrifuge at 3,000 rpm for 5 minutes.
Remove 20 ml and dry under reduced pressure. Add 10 ml of n-hexane to this.
Eh, sep-pak cartridg
e, Waters). with 10 ml of n-hexane
After washing once, n-hexane: diethyl ether = 75:25 (v /
v) Elution was performed with 10 ml, and the solvent was distilled off under reduced pressure.
100% of 1: 1 (v / v)
0 μl was analyzed by high performance liquid chromatography (HPLC).
Quantify rail cholesterol. From this, the sample concentration is 30
The inhibition rate in μg / ml was calculated. Table 1 shows the results.
The number of the test object is the number of the embodiment. (Hereinafter referred to as blank space) The phenylalanine derivative of the present invention or
The salt is acyl-coenzyme A: cholesterol acyl conversion.
Related to atherosclerosis
It is useful for prevention and treatment of various diseases. Next, the present invention will be described in detail with reference to Examples and Examples.
The present invention will be described by way of examples, but the present invention is not limited thereto.
Not. In addition, in column chromatography
The carrier used silica gel 60, No.7734 (manufactured by Merck)
Was. All mixing ratios in the eluent are volume ratios.
You. In addition, the abbreviations used below have the following meanings:
I do. Me: methyl Reference Example 1 N-benzyloxycarbonyl-L-phenylalanine
Dissolve 6.74 g in anhydrous dichloromethane and add -15
6.28 ml of triethylamine are added at ℃, and then chlorocarbonate is added.
2.14 ml of ethyl are added dropwise. The resulting mixture is kept at -15 ° C for 5 minutes
After stirring for 4.5 minutes, 4.5 g of L-leucine methyl ester was added.
After stirring at the temperature for 20 minutes, the temperature is raised to room temperature. Release overnight at 4 ° C
After the addition, add water to the reaction mixture and adjust the pH to 1.5 with 1N hydrochloric acid.
Separate the organic layer. Add water to the separated organic layer, and add
The pH is adjusted to 7.5 with sodium oxyacid, and the organic layer is separated.
The separated organic layer was washed with water and brine sequentially, and then dried.
Dry over sodium sulfate. The solvent is distilled off under reduced pressure,
Diethyl ether is added to the obtained residue, and the mixture is filtered.
For example, N-benzyloxycarbonyl-L-phenylara
6.18 g of white crystals of nyl-L-leucine methyl ester
obtain. Melting point: 105-107 ° C IR (KBr) cm-1: 3291,2958,1749,1694,1652,1548,1440,126
5,1224,1153,1057,736,701 In the same manner, the following compound is obtained. N-benzyloxycarbonyl-L-phenylalanyl
-L-isoleucine methyl ester Melting point: 100-102 ° C IR (KBr) cm-1: 3273,3065,2965,1750,1704,1660,1551,145
4,1382,1273,1202,1055,736,700 Reference Example 2 N-benzyloxycarbonyl-L-phenylalanyl
4.0 g of L-isoleucine methyl ester in methanol 4
0 ml, and add 0.23 g of 5% palladium carbon and
And 1.05 ml of concentrated hydrochloric acid, and perform catalytic reduction under normal temperature and normal pressure.
After completion of the reaction, the catalyst is removed by filtration, and the solvent is distilled off under reduced pressure.
For example, L-phenylalanyl-L-isoleucine methyl
2.8 g of the hydrochloride of the ester are obtained. Melting point: 138-143 ° C IR (KBr) cm-1: 3418,2966,1741,1682,1552,1498,1457,121
Example 1 N-benzyloxycarbonyl-L-phenylalanine
Dissolve 3.7 g in anhydrous dichloromethane and add -15
1.72 ml of triethylamine was added at ℃, and then chlorocarbonic acid was added.
1.18 ml of ethyl are added dropwise. Stir the mixture at -15 ° C for 5 minutes
Thereafter, 2 ml of 2-ethylhexylamine was added, and the mixture was added at the same temperature for 20 minutes.
After stirring for 2 minutes, warm to room temperature and stir at the same temperature for 2 hours.
You. Then, water was added to the reaction mixture, and the mixture was adjusted to pH 1.5 with 1N hydrochloric acid.
Adjust and separate the organic layer. Add water to the separated organic layer.
Adjust the pH to 7.5 with aqueous sodium hydrogen carbonate
Separate the layers. Separate the separated organic layer with water and brine.
After the next washing, it is dried with anhydrous sodium sulfate. Under reduced pressure
The solvent was distilled off, and diethyl ether was added to the obtained residue.
And N-benzyloxycarbonyl-L-
Phenylalanyl-2-ethylhexylamide white color
3.8 g of crystals are obtained. Melting point: 104-106 ° C IR (KBr) cm-1: 3310,2964,2926,1688,1652,1526,1454,138
Examples 2 to 4 In the same manner as in Example 1, the compounds shown in Table 2 are obtained. The table
A, R in 2 ¹ And R ^Two Is the following formula: Represents a substituent of the compound represented by [Table 2] The physical properties of the compounds shown in Table 2 are shown below.
Shown. No.2: Melting point: 119-121 ℃ IR (KBr) cm-1: 3312,2930,1687,1653,1533,1455,1383,128
7,1243,1041,744,698 No.3: Melting point: 128-131 ℃ IR (KBr) cm-1: 3307,2927,1687,1654,1527,1453,1382,128
6,1235,1038,749,698 No.4: Melting point: 125-127 ℃ IR (KBr) cm-1: 3306,2925,1687,1655,1527,1453,1375,128
7,1236,1038,749,698 Example 5 N-benzyloxycarbonyl-L-phenylalanyl
-695 mg of L-leucine methyl ester in 20 ml of methanol
And added to this solution 60 mg of 5% palladium on carbon,
The catalytic reduction is performed at normal temperature and normal pressure. After completion of the reaction, the catalyst is removed by filtration.
Then, the solvent is distilled off under reduced pressure. The resulting residue is
Dissolve in chloromethane and stir under ice-cooling for 2,4
-0.18 ml of difluorophenyl isocyanate is added dropwise,
Stir at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain
Column chromatography (eluent; Benze)
N: 2,4-diphenyl.
Fluorophenylaminocarbonyl-L-phenylalani
400 mg of le-L-leucine methyl ester are obtained. Melting point: 186-188 ° C IR (KBr) cm-1: 3299,2958,1749,1645,1558,1550,1431,125
2,1201,1140,962,846,699 Examples 6 to 16 In the same manner as in Example 5, compounds in Tables 3 and 4 were obtained.
You. In addition, A, R in Table 3 and Table 4 ¹ And R ^Two Is
Each of the following formulas Represents a substituent of the compound represented by [Table 3] [Table 4] The physical properties of the compounds shown in Tables 3 and 4 below
Are respectively shown. No. 6: Melting point: 185-187 ° C IR (KBr) cm-1: 3318,2966,1740,1652,1613,1540,1501,143
0,1290,1255,1204,1148,962 No.7: Melting point: 143-146 ° C IR (KBr) cm-1: 3298,2929,1638,1560,1500,1430,1286,125
1,1202,1139,962,845,697 No.8: Melting point: 188-190 ° C IR (KBr) cm-1: 3306,2957,1747,1651,1619,1532,1497,145
6,1418,1282,1212,1160,1032,668 No.9: Melting point: 183-185 ° C IR (KBr) cm-1: 3311,2965,1742,1646,1619,1532,1497,145
6,1263,1211,1160,1033,668 No.10: Melting point: 164-167 ℃ IR (KBr) cm-1: 3295,2930,1670,1636,1558,1450,1431,128
5,1252,1202,1140,1097,962,845,698 No.11: Melting point: 154-156 ° C IR (KBr) cm-1: 3298,2928,1670,1635,1558,1506,1456,143
1,1284,1251,1202,1140,1098,963,846,698 No.12: Melting point: 148-151 ℃ IR (KBr) cm-1: 3292,2927,1700,1636,1560,1499,1457,143
0,1283,1242,1202,1140,1097,962,845,699 No.13: Melting point: 166-169 ° C IR (KBr) cm-1: 3289,2930,1636,1616,1558,1497,1456,141
7,1282,1209,1159,1034,698 No.14: Melting point: 165-167 ° C IR (KBr) cm-1: 3289,2928,1637,1616,1558,1498,1456,141
7,1282,1209,1159,1034,698 No.15: Melting point: 161-163 ° C IR (KBr) cm-1: 3290,2926,1637,1616,1560,1498,1457,141
8,1282,1209,1159,1033,698 Example 16 0.38 ml of oleic acid was dissolved in anhydrous dichloromethane.
0.34 ml of triethylamine was added to the solution at -15 ° C.
0.12 ml of ethyl chlorocarbonate is added dropwise. Stir at -15 ° C for 5 minutes
After stirring, L-phenylalanine-L-isoleucine methyl
After adding 396 mg of the ester hydrochloride and stirring at the same temperature for 20 minutes,
After warming to room temperature, it is left at 4 ° C for two nights. Then
Water was added to the reaction mixture, and the pH was adjusted to 1.5 with 1N hydrochloric acid.
Separate the layers. Water is added to the separated organic layer,
The pH is adjusted to 7.5 with an aqueous thorium solution, and the organic layer is separated.
The separated organic layer was washed with water and brine sequentially, and then dried.
Dry over sodium sulfate. The solvent is distilled off under reduced pressure,
The obtained residue is subjected to column chromatography (eluent;
If purified with benzene: ethyl acetate = 20: 1), oleyl
-L-phenylalanyl-L-isoleucine methyles
You get 454 mg of tel. IR (neat) cm-1: 3278,2925,2854,1750,1639,1553,1456,138
Example 17 (1) N-benzyloxycarbonyl-L-phenylala
500 mg of nil- (2-ethylhexyl) amide in methanol
Dissolved in 0.15 ml of concentrated hydrochloric acid and 5%
Add 50 mg of radium carbon and perform catalytic reduction at normal temperature and pressure.
U. After completion of the reaction, the catalyst is filtered off, and the solvent is distilled off under reduced pressure.
You. Isopropyl ether was added to the obtained residue to solidify
Then, L-phenylalanyl- (2-ethylhexyl
381 mg of the hydrochloride of the amide are obtained. (2) Oleic acid is converted to L-phenylalanyl- (2-ethyl
Hexyl) amide hydrochloride was prepared in the same manner as in Example 16.
Oleyl-L-phenylalanyl- (2-ethyl
(Hexyl) amide. IR (neat) cm-1: 3269,2926,2855,1638,1561,1456,1379,124
Example 18 (1) N-benzyloxycarbonyl-L-phenylala
Dissolve 4 g of nilheptylamide in 120 ml of methanol,
200 mg of 5% palladium carbon was added to this solution,
To perform catalytic reduction. After completion of the reaction, the catalyst was removed by filtration, and
When the solvent is distilled off, L-phenylalanylheptyla
2.7 g of amide are obtained. (2) 2.7 g of L-phenylalanylheptylamide
Dissolve in 150 ml of Luther ether, and add
2.3 g of lithium aluminum chloride and stirred at room temperature for 5 hours
I do. Then, under ice-cooling, add methanol until foaming stops.
, The insoluble material is removed by filtration, and the solvent is distilled off under reduced pressure.
You. The residue obtained is extracted with ethyl acetate. Extract
After washing with water and drying over magnesium sulfate,
The solvent is distilled off. The obtained residue is treated with anhydrous dichlorometa.
Dissolved in 20 ml of p-nitrophenyl under ice-cooling.
1.23 g of isocyanate are added. Stir at room temperature for 2 hours
Thereafter, the solvent is distilled off under reduced pressure. The obtained residue is
Chromatography (eluent; benzene: ethyl acetate = 5:
Purification in 1) gives 3- [1-heptyl-3- (p-nitro)
Rophenyl) ureido] -2- [3- (p-nitrophenyl)
2.6 g of ureido] propylbenzene are obtained. Melting point: 138-140 ° C IR (KBr) cm-1: 3367,2928,2856,1686,1648,1615,1599,156
0,1506,1330,1302,1246,1178,1112,851,751 Example 19 3- [1-Heptyl-3- (p-nitrophenyl) urey
Do] -2- [3- (p-nitrophenyl) ureido] pro
8 g of pyrbenzene were dissolved in 140 ml of methanol.
Add 500 mg of 5% palladium carbon to the liquid and contact at normal temperature and normal pressure
Perform reduction. After completion of the reaction, the catalyst was removed by filtration and the solvent was removed under reduced pressure.
Is distilled off. Column chromatography of the resulting residue
-(Eluent; chloroform: methanol = 5: 1)
Then, 2- [3- (p-aminophenyl) ureido] -3
-[1-heptyl-3- (p-aminophenyl) urey
6.6 g of propylbenzene are obtained. Example 20 2- [3- (p-aminophenyl) ureido] -3- [1
-Heptyl-3- (p-aminophenyl) ureido] pro
Dissolve 6.6 g of pyrbenzene in 100 ml of methanol.
20.7 ml of 37% formaldehyde and 500 mg of platinum oxide in the solution
And catalytic reduction is performed under normal temperature and normal pressure. After the reaction, touch
The medium is filtered off and the solvent is distilled off under reduced pressure. The residue obtained
Column chromatography (eluent; benzene: acetic acid)
Purification by chill = 1: 1) yields 2- [3- (p-dimethyla
Minophenyl) ureido] -3- [1-heptyl-3-
(P-Dimethylaminophenyl) ureido] propylben
1.03 g of Zen is obtained. Melting point: 91-94 ° C IR (KBr) cm-1: 3311,2927,2855,1637,1519,1355,1318,124
Example 21 2- [3- (p-dimethylaminophenyl) ureido]-
3- [1-heptyl-3- (p-dimethylaminophenyl)
Le) ureido] propylbenzene 500mg and ethanol 5ml
And then add 0.19 ml of concentrated hydrochloric acid to the solution,
When the solvent is distilled off, 2- [3- (p-dimethylaminophen)
Nil) ureido] -3- [1-heptyl-3- (p-dim
Tylaminophenyl) ureido] propylbenzene
529 mg of the hydrochloride are obtained. Melting point: 143-145 ° C IR (KBr) cm-1: 3316,2926,2856,2619,1675,1558,1516,131
8,1244,837,702

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI // A61K 31/165 A61K 31/165 31/17 31/17 31/27 31/27 A61P 9/10 101 A61P 9/10 101 43/00 111 43/00 111 (56) References JP-A-2-117625 (JP, A) Appl. Organomet. Chem. , (1988), Vol. 2, No. 6, p. 557-560 (58) Field surveyed (Int. Cl. ⁷ , DB name) CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] [Claim 1] The general formula: Wherein R ¹ is a benzyloxy group, phenethyloxy
Group or a halogen atom or an alkyl group
Good amino group, nitro group, lower alkyloxy group,
One or more selected from a nyl group and a naphthyl group
Phenylamino optionally substituted with the above substituents, na
The Fuchiruamino or alkenyl group; ^{R 1} is benzyl
When it is a ruoxy group or a phenethyloxy group , R ²
Is an alkyl group; R ¹ is ^one or more substituents selected from a halogen atom, an amino group optionally substituted by an alkyl group, a nitro group, a lower alkyloxy group , a phenyl group and a naphthyl group May be substituted
When it is a phenylamino, naphthylamino or alkenyl group, R ² is an alkyl group optionally substituted by a lower alkyloxycarbonyl group; and A is a group represented by the formula: Or the formula: (In the formula, R ³ is substituted with one or more substituents selected from a halogen atom, an amino group optionally substituted with an alkyl group, a nitro group, a lower alkyloxy group, a phenyl group and a naphthyl group. Phenyl may be
Or a naphthyl group. ) Are shown. However,
Excluding N-benzyloxycarbonyl-L-phenylalanyl-hexylamide. Or a salt thereof.