JPH06287182A - Alkylglycine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having antagonistic action on angiotensin II receptors and hypotensive action and useful as a therapeutic agent, etc., for circulatory diseases. CONSTITUTION:This compound is expressed by formula I [R<1> is (substituted) phenyl, naphthyl or heterocyclic ring; R<3> is H, carboxymethyl or lower alkoxycarbonylmethyl; R<3> is lower alkyl; R<4> is H or trityl; ALK is lower alkylene; n is 0 or 1], e.g. N-n-pentyl-N-[2'-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-benzylaminoacetamide. Furthermore, the compound expressed by formula I is obtained by using a compound expressed by formula II (Tr is trityl) as a starting raw material and reacting the resultant compound expressed by formula III with a compound expressed by formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel alkylglycine derivative or a salt thereof and a synthetic intermediate thereof, and more specifically, it has a potent angiotensin II receptor antagonistic action and hypotensive action, and has high blood pressure and heart disease. , An alkylglycine derivative or a salt thereof useful as a therapeutic agent for cardiovascular diseases such as arteriosclerosis and stroke, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art The renin-angiotensin system produces angiotensin II, which is one of the strong pressor substances in the body, and is considered to play an important role in the onset and maintenance of hypertension. Since angiotensin II is mainly produced via angiotensin II converting enzyme, an angiotensin II converting enzyme inhibitor shows a hypotensive action and was expected as a hypotensive agent, but recently, angiotensin II mediated angiotensin II converting enzyme. Angiotensin produced by other systems
It was found that all of II caused pressurization via receptors on the cell membrane. From this, it is expected that the antagonist has a more specific antihypertensive effect than the angiotensin II converting enzyme inhibitor.

However, it has been reported that peptidic antagonists have a short action time in parenteral administration, while they are ineffective in oral administration [N. A. Ondetti et
al. , Annual Reports in Me
dicinal Chemistry, 13 , 82-9
1, (1978)]. Therefore, at present, a search is being made for derivatives centering on an aromatic ring such as imidazole and xanthine (for example, JP-A-56-7107).
3, JP-A-56-71074, JP-A-57-9227
0, JP-A-58-157768, JP-A-62-2406
83, JP-A-63-23868, EP-323841, JP-A-11-11787, JP-A-3-223284, etc.), but these do not always show a satisfactory antagonistic action.

[0004]

Therefore, an object of the present invention is to provide a substance which has an excellent angiotensin II receptor antagonistic action and an antihypertensive action and is useful as a medicine.

[0005]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of such circumstances, and as a result, the alkylglycine derivative described below exhibits a strong angiotensin II receptor antagonistic action and a hypotensive action, thereby treating cardiovascular diseases. They found that they were useful as agents, and completed the present invention.

That is, the present invention is represented by the following general formula (1):

[0007]

[Chemical 2]

(Wherein R ¹ represents a phenyl group which may have a substituent, a naphthyl group or a heterocyclic group having 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and R ² represents a hydrogen atom. , A carboxymethyl group or a lower alkoxycarbonylmethyl group, R ³ represents a lower alkyl group, R ^3
4 represents a hydrogen atom or a trityl group, ALK represents a lower alkylene group, and n represents 0 or 1. ) Related to an alkylglycine derivative or a salt thereof.

In the present specification, "lower" has 1 carbon atom.
Means ~ 6. Examples of the "lower alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-
Butyl, isobutyl, sec-butyl, t-butyl, n
Examples thereof include linear or branched alkyl groups such as -pentyl, isopentyl and n-hexyl groups. Examples of the "lower alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy groups and the like. A straight-chain or branched alkoxy group may be mentioned.

Examples of the heterocyclic group having 1 or 2 nitrogen atom, oxygen atom or sulfur atom represented by R ¹ of the alkylglycine derivative represented by the general formula (1) or a salt thereof of the present invention include pyrrolyl, Ruffles, thienyl,
A nitrogen atom such as pyridyl, piperidyl, pyrrolidinyl, a 5- or 6-membered heterocyclic group containing one oxygen atom or a sulfur atom, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl,
Examples thereof include 5-membered or 6-membered heterocyclic groups containing two nitrogen atoms such as pyrimidinyl, pyridazinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl and morpholinyl groups, and two oxygen atoms or sulfur atoms.

The substituent of the phenyl group, naphthyl group or heterocyclic group having 1 or 2 nitrogen atom, oxygen atom or sulfur atom represented by R ¹ is, for example, fluorine atom, chlorine atom, bromine atom or iodine atom. Examples thereof include halogen atom such as atom, nitro group, lower alkyl group, lower alkoxy group, trifluoromethyl group, hydroxyl group, amino group and carboxyl group.

Examples of the lower alkylene group represented by ALK include methylene, ethylene, 1-methylethylene,
Examples thereof include linear or branched alkylene groups such as propylene, 2-ethylpropylene, butylene, pentylene, and hexylene groups.

Preferred among such R ¹ is a phenyl group, naphthyl group, pyridyl group, furyl group, thienyl group or pyrazinyl group which may have a substituent, which may have a substituent. Phenyl is preferred, in which case
As the substituent, a lower alkyl group or a lower alkoxy group is preferable. Preferred among R ² is a carboxymethyl group or a lower alkoxycarbonylmethyl group, particularly a carboxymethyl group or an ethoxycarbonylmethyl group. Particularly preferred among R ³ are n-butyl groups. A particularly preferred one of R ⁴ is a hydrogen atom. A
For LK and n, when ALK is a methylene group, n is 1
When ALK is an ethylene group, n is preferably 0.

A more preferred compound of the present invention is that in the general formula (1), R ¹ is a phenyl group which may have a substituent, a naphthyl group, a pyridyl group, a furyl group, a thienyl group or a pyrazinyl group, and R ² is hydrogen. An atom, a carboxymethyl group or a lower alkoxycarbonylmethyl group, R ³ is a lower alkyl group, R ⁴ is a hydrogen atom or a trityl group, ALK is a methylene group or an ethylene group, n is 0 or 1, and an alkylglycine derivative or a salt thereof is used. is there.

Further preferred compounds of the invention are R¹Is
A phenyl group which may have a substituent, R ²Is carboxymethy
Group or lower alkoxycarbonylmethyl group, R³Is low
Primary alkyl group, R^FourIs a hydrogen atom, ALK is a methylene group or
Is an ethylene group, alkylglycine derivative in which n is 0 or 1
It is a conductor or its salt.

A particularly preferred compound of the present invention is that R ¹ is a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, R ² is a carboxymethyl group or an ethoxycarbonylmethyl group, R ³ is an n-butyl group, R ⁴ is a hydrogen atom, ALK is a methylene group, n is 1 or ALK is an ethylene group, and n is 0, an alkylglycine derivative or a salt thereof. Of the lower alkyl groups for R ^1, a methyl group is preferred, and of the lower alkoxy groups, a methoxy group is particularly preferred.

The alkylglycine derivative represented by the general formula (1) of the present invention follows the following reaction process formula (I) when n is 1, and the following reaction process formula (V) when n is 0. Can be manufactured according to.

[0018]

[Chemical 3]

(In the formula, Tr represents a trityl group, and R ¹ ,
R ² , R ³ and ALK are as defined above. )

(Step A) A compound represented by the general formula (3) is obtained by reacting a known compound represented by the general formula (2) with a lower alkylamine in a suitable solvent, optionally in the presence of a base. To get The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, dioxane and the like. Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like. In the above reaction, it is preferable to use about 1 to 10 mol of a lower alkylamine and about 1 to 3 mol of a base for 1 mol of the compound of the general formula (2). Reaction temperature is from room temperature to 100 ° C
The reaction time is preferably about 1 to 12 hours.
The compound represented by the general formula (2) used here can be synthesized by, for example, the method described in JP-A-63-23868 or a method similar thereto.

(Step B) The general formula (3) obtained in the step A
The compound represented by the general formula (4) is obtained by reacting the compound represented by with bromoacetyl chloride in a suitable solvent. The solvent is not particularly limited as long as it does not participate in the reaction, for example, methylene chloride,
Examples include chloroform, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, dimethylformamide, dimethylsulfoxide and the like. In the reaction, it is preferable to use 1 to 5 mol of bromoacetyl chloride per 1 mol of the compound of the general formula (3). The reaction temperature is from under ice cooling to about room temperature, and the reaction time is preferably about 10 minutes to 1 hour.

(Step C) General formula (4) obtained in Step B
The desired compound represented by the general formula (1a) is obtained by reacting the compound represented by the formula (5) with a compound represented by the general formula (5) in the presence of a base in a suitable solvent. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane and the like. Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like. In the reaction, it is preferable to use about 1 to 3 mol of the compound of general formula (5) and about 1 to 3 mol of the base with respect to 1 mol of the compound of general formula (4). Reaction temperature is from room temperature to 100 ° C
The reaction time is preferably about 1 to 12 hours.
The compound represented by the general formula (5) used here is a known compound or can be synthesized by a production method according to the production method of the known compound.

(Step D) The general formula (1
The compound represented by a) is reacted according to the conditions for deprotection that are usually performed to obtain the desired general formula (1b).
A compound represented by The above-mentioned reaction is, for example, 0.5
.About.2N in hydrous alcohols containing hydrochloric acid or acetic acid (eg, methanol, ethanol, etc.) at room temperature,
The reaction proceeds advantageously for about 5 to 12 hours.

The compound in which R ² is a lower alkoxycarbonylmethyl group in the above compound (1a) can also be produced according to the following reaction process formula (II) or (III).

[0025]

[Chemical 4]

(In the formula, R ⁵ represents a lower alkyl group, and R ^5
1 , R ³ , ALK, and Tr are as defined above. ) That is, the compound represented by the general formula (1c) obtained in the step C of the above reaction process formula (I) is reacted with the compound represented by the general formula (6) in the presence of a base in a suitable solvent. By doing so, the desired compound represented by the general formula (1d) is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane and the like. Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium carbonate and the like. In the reaction, it is preferable to use about 1 to 3 mol of the compound of general formula (6) and about 1 to 3 mol of the base for 1 mol of the compound of general formula (1c). The reaction temperature is from room temperature to about 100 ° C., and the reaction time is preferably about 1 to 12 hours.

[0027]

[Chemical 5]

(Wherein R ¹ , R ³ , R ⁵ , ALK, Tr
Is as defined above. ) The compound represented by the general formula (7) is reacted with a chlorinating agent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride and the like by a known and conventional method to give an acyl chloride compound, which is represented by A in the reaction formula (I).
The desired compound represented by the general formula (1d) is obtained by reacting the compound represented by the general formula (3) obtained in the step with a suitable solvent in the presence of a base. The solvent is not particularly limited as long as it does not participate in the reaction,
Examples thereof include methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide and the like. Examples of the base include organic bases such as triethylamine and pyridine. In the reaction, it is preferable to use about 1 to 3 mol of the compound of general formula (7) and about 1 to 10 mol of the base for 1 mol of the compound of general formula (3). The reaction temperature is from under ice cooling to about room temperature, and the reaction time is preferably about 10 minutes to 1 hour.

The compound represented by the general formula (7) used here is selectively deprotected to an amine represented by, for example, R ¹ -ALK-NH ₂ (wherein R ¹ and ALK are as defined above). N, N-
After forming the bis (alkoxycarbonylmethyl) form, one ester part can be selectively deprotected to give a monocarboxylic acid.

The compound (1d) obtained by the above reaction process formula (II) or (III) can be converted into the compound (1b) by deprotecting the trityl group in the same manner as in the step D of the reaction process formula (I).
In, a compound in which R ² is a lower alkoxycarbonylmethyl group can be used.

On the other hand, the compound (1b) in which R ² is a lower alkoxycarbonylmethyl group can also be produced according to the following reaction process formula (IV).

[0032]

[Chemical 6]

(In the formula, R ¹ , R ³ , R ⁵ , and ALK have the same meanings as described above.) That is, the compound represented by the general formula (8) is prepared by the same method as in the reaction step formula (III). The compound represented by the general formula (7) is reacted with the compound represented by the general formula (7) to obtain a compound represented by the general formula (9), which is reacted with various azide compounds in a suitable solvent to obtain the desired compound represented by the general formula (1e). ) Is obtained.
The solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction, and examples thereof include dimethylformamide, dimethylacetamide, toluene and benzene. Examples of the azide compound include trialkyltin azide and hydrazoic acid. In the reaction, it is preferable to use about 1 to 5 mol of the azide compound with respect to 1 mol of the compound of the general formula (9). When using trialkyltin azide, it is preferable to react it in toluene or benzene while heating under reflux for about 4 to 48 hours. When hydrazoic acid is used, sodium azide and ammonium chloride are used in an amount of about 1 to 10 mol per 1 mol of the compound of the general formula (9), and the temperature is about 100 to 150 ° C. in dimethylformamide for about 1 to 10 days. The reaction is preferable, and the reaction can be promoted by adding an appropriate amount of sodium azide and ammonium chloride during the reaction.

[0034]

[Chemical 7]

(In the formula, R ¹ , R ² , R ³ and ALK have the same meanings as described above.) A compound obtained by reacting a compound represented by the general formula (10) with phosgene by a known and conventional method. In a suitable solvent with a compound represented by the general formula (3) obtained in step A of the reaction formula (I),
By reacting in the presence of a base, the desired compound represented by the general formula (1f) is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, benzene and toluene. Examples of the base include organic bases such as triethylamine and pyridine. In the reaction, the compound of the general formula (1
It is preferable to use about 1 to 3 mol of the compound of 0) and about 3 to 10 mol of the base. The reaction temperature ranges from under ice cooling to 100
The reaction time is preferably about 1 to 24 hours.

In the compound represented by the general formula (10) used herein, R ² is a lower alkoxycarbonylmethyl group, for example, R ¹ -ALK-NH ₂ (in the formula,
R ¹ and ALK have the same meanings as described above, and a bromoacetic acid ester is allowed to act on the amine represented by the above formula to give an N-alkylglycine ester form.

The compound (1f) obtained by the above reaction process formula (V) is a compound in which R ⁴ is a hydrogen atom by deprotecting the trityl group in the same manner as in the process step D of the reaction process formula (I). be able to.

In the compounds (1a), (1b) or (1f) obtained from the above reaction process formulas (I) to (V), R ² is a lower alkoxycarbonylmethyl group, compound (1d) or compound (1d). Deesterification of 1e) can lead to a compound of the present invention in which R ² is a carboxymethyl group. The deesterification reaction is
The reaction conditions vary depending on the alkyl group of the compound. For example, in the case of a methyl group or an ethyl group, the reaction is preferably carried out in a water-methanol system of 2 to 5 times equivalent sodium hydroxide or potassium hydroxide at room temperature for about 1 to 12 hours. In the case of, in hydrochloric acid or trifluoroacetic acid and a suitable organic solvent (eg, chloroform, methylene chloride, acetonitrile, etc.) at room temperature to about 1 to 1
It is better to react for 2 hours.

The compound (1) of the present invention obtained by the above reaction process formulas (I) to (V) and deesterification can be easily crystallized by usual separation and purification means such as recrystallization, distillation and column chromatography. Or it can be isolated as an oil.

Alkylglycine derivative of the present invention (1)
Is a salt with a physiologically acceptable acid or base by a conventional method, for example, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, acetic acid,
It can be led to salts with organic acids such as oxalic acid, succinic acid and maleic acid, salts with alkali metals such as sodium and potassium, and salts with alkaline earth metals such as calcium.

[0041]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Reference Example 1 Synthesis of Nn-pentyl- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methylamine [2'-(N-triphenylmethyltetrazole- 5-
Il) biphenyl-4-yl] methyl bromide 10.
0 g was dissolved in 100 ml of tetrahydrofuran and n was added at room temperature.
-Pentylamine (10 ml) was added and the mixture was stirred for 12 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract,
The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain an oily substance. This was crystallized from ether to obtain 8.35 g (yield 85%) of the title compound as white crystals. NMR (270 MHz, CDCl ₃ ) δ: 0.88 (t, 3H), 1.26 (m, 2H), 1.48
(m, 2H), 2.58 (t, 2H), 3.68 (s, 2H), 6.90 (m, 5H), 7.21-7.5
2 (m, 17H), 7.44 (m, 2H), 7.92 (dd, 1H)

Reference Examples 2 to 5 The compounds shown in Table 1 below were synthesized in the same manner as in Reference Example 1.

[0044]

[Table 1]

Reference Example 6 Synthesis of Nn-butyl-2'-cyano-biphenyl-4-yl-methylamine 2'-cyano-biphenyl-4-
The same procedure as in Reference Example 1 was performed using 500 mg of yl-methyl bromide and n-butylamine to obtain 460 mg (yield 95%) of the title compound as a colorless transparent oil. NMR (270MHz, CDCl ₃ ) δ: 0.93 (t, 3H), 1.37 (m, 2H), 1.54
(m, 2H), 1.81 (brs, 1H), 2.68 (t, 2H), 3.86 (s, 2H), 7.40-
7.55 (m, 6H), 7.64 (dt, 1H), 7.76 (dt, 1H)

Reference Example 7 Nn-pentyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl]
Synthesis of methyl-bromoacetamide Nn-pentyl- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-obtained in Reference Example 1
4-yl] methylamine (8.35 g) and methylene chloride (2)
It was dissolved in 00 ml, 12 ml of triethylamine was added, and the mixture was ice-cooled. 6 ml of bromoacetyl chloride was dropped into it,
The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and evaporated to give the title compound (9.63 g, yield 95%). NMR (270 MHz, CDCl ₃ ) δ: 0.88 (t, 3H), 1.18-1.37 (m, 4H),
1.53-1.60 (m, 2H), 3.09, 3.26 (each t, 2H), 3.87, 4.13 (each s, 2
H), 4.45,4.51 (each s, 2H), 6.90 (d, 6H), 7.01 (d, 1H), 7.09
(d, 1H), 7.14 (d, 1H), 7.23-7.38 (m, 11H), 7.47 (m, 2H), 7.
96 (m, 1H) Each amine compound obtained in Reference Examples 2 to 5 was bromoacetylated in the same manner.

Reference Example 8 Synthesis of N-benzylglycine ethyl ester 25.0 g of benzylamine was added to tetrahydrofuran 30
After dissolving in 0 ml and adding 35 ml of triethylamine, 26.0 ml of ethyl bromoacetate was added at room temperature and stirred for 4 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by distillation under reduced pressure to give 37.7 g of the title compound as a colorless transparent liquid.
(Yield 85%) was obtained. Boiling point: 115 ° C. (2 mmHg) NMR (270 MHz, CDCl ₃ ) δ: 1.27 (t, 3H), 1.85 (s, 1H), 3.41
(s, 2H), 3.81 (s, 2H), 4.19 (q, 2H), 7.32 (s, 5H)

Reference Examples 9 to 15 The compounds shown in Tables 2 and 3 were synthesized in the same manner as in Reference Example 8. However, purification was performed by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2).

[0049]

[Table 2]

[0050]

[Table 3]

Reference Example 16 Synthesis of N-benzyl-Nt-butoxycarbonylmethyl-glycine-ethyl ester 10 g of N-benzyl-glycine-ethyl ester obtained in Reference Example 8 was dissolved in 200 ml of tetrahydrofuran, and sodium hydrogencarbonate 5 was added. 0.2 g and 9.1 ml of t-butyl bromoacetate were sequentially added at room temperature and the mixture was refluxed for 5 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain 15.2 g (yield 96%) of the title compound as a colorless transparent liquid. NMR (270MHz, CDCl ₃ ) δ: 1.27 (t, 3H), 1.47 (s, 9H), 3.43
(s, 2H), 3.53 (s, 2H), 3.91 (s, 2H), 4.16 (q, 2H), 7.25-7.4
0 (m, 5H)

Reference Example 17 Synthesis of N-benzyl-N-carboxymethyl-glycine-ethyl ester 15 g of N-benzyl-Nt-butoxycarbonylmethyl-glycine-ethyl ester obtained in Reference Example 16 was added to 4N.
-Dissolved in hydrochloric acid-ethyl acetate solution and stirred at room temperature for 12 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate.
The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated to give the title compound as a colorless transparent oil (12.3).
g (yield 100%) was obtained. NMR (270MHz, CDCl ₃ ) δ: 1.27 (t, 3H), 3.49 (s, 2H), 3.51
(s, 2H), 3.90 (s, 2H), 4.19 (q, 2H), 7.33 (m, 5H), 8.28 (br
s, 1H)

Reference Example 18 Synthesis of N- (2-phenylethyl) -glycine ethyl ester 10.0 g of 2-phenylethylamine was dissolved in 200 ml of methylene chloride, 18 ml of triethylamine was added, and then 9.2 ml of ethyl bromoacetate was added. Add at room temperature 4
Stir for hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain 13.7 g (yield 80%) of the title compound as a colorless transparent liquid. NMR (270 MHz, CDCl ₃ ) δ: 1.26 (t, 3H), 2.78-2.92 (m, 4H),
3.41 (s, 2H), 4.17 (q, 2H), 7.17-7.33 (m, 5H)

Reference Examples 19 to 20 The compounds shown in Table 4 were synthesized in the same manner as in Reference Example 18.

[0055]

[Table 4]

Example 1 (A) Nn-pentyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl-benzylaminoacetamide Nn-pentyl-N- [2 '-(N-
Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-bromoacetamide 600 mg
Was dissolved in 10 ml of tetrahydrofuran, and 471.5 mg of benzylamine and 147.
4 mg was added and the mixture was refluxed for 4 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 4: 1) to obtain 500 mg (yield 80%) of the white amorphous title compound. NMR (270 MHz, CDCl ₃ ) δ: 0.84 (t, 3H), 1.09-1.49 (m, 6H),
2.05 (brs, 1H), 2.90,3.24 (each t, 2H), 3.36,3.44 (each s, 2H),
3.74, 3.85 (each s, 2H), 4.29, 4.52 (each s, 2H), 6.88 (m, 7H), 7.
00 (d, 1H), 7.07-7.51 (m, 19H), 7.94 (m, 1H)

(B) Nn-pentyl-N- [2'-
(1-H-tetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl-benzylaminoacetamide Nn-pentyl-N- [2 '-(N
500 mg of -triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-benzylaminoacetamide were dissolved in 2 ml of chloroform and then 10 ml of methanol were added. 0.5 ml of concentrated hydrochloric acid was added thereto at room temperature and stirred for 10 minutes. The reaction mixture was adjusted to pH = 4 with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was subjected to silica gel column chromatography (chloroform: methanol = 20:
270 mg of the white amorphous title compound purified in 1)
(Yield 83%) was obtained. NMR (270 MHz, CDCl ₃ ) δ: 0.84 (t, 3H), 1.15-1.47 (m, 6H),
3.18,3.38 (brs t, 2H), 3.90,4.01 (each s, 2H), 4.22 (s, 2H),
4.34 (s, 2H), 6.70 (d, 1H), 6.85 (m, 3H), 7.15-7.83 (m, 9H) MS ((-) FABMS m / z): 467 (M-1) ⁺

Examples 2 to 12 Tables 5, 6, 7 and 8 were prepared in the same manner as in Example 1.
The compound shown in was synthesized.

[0059]

[Table 5]

[0060]

[Table 6]

[0061]

[Table 7]

[0062]

[Table 8]

Example 13 (A) Nn-pentyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide Nn-pentyl-N- [2 '-(N-
Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-bromoacetamide 3.63 g
Was dissolved in 50 ml of dimethylformamide, and then N-benzylglycine ethyl ester 1.5 obtained in Reference Example 8 was dissolved.
g and 600 mg of sodium hydrogen carbonate were added, and the external temperature was adjusted to 10
The mixture was stirred at 0 ° C for 4 hours. Next, the reaction solution was distilled off using a vacuum pump and then extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate and evaporated. The obtained crude product is subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 5).
The white amorphous compound was obtained in an amount of 3.5 g (yield 83%). NMR (270 MHz, CDCl ₃ ) δ: 0.82 (t, 3H), 0.99-1.51 (m, 9H),
2.99, 3.17 (t, 2H each), 3.41 (s, 2H), 3.81 (s, 2H), 3.85, 3.93
(Each s, 2H), 4.05-4.23 (m, 2H), 4.46,4.48 (each s, 2H), 6.81 (d,
1H), 6.89 (m, 4H), 6.97 (d, 1H), 7.06 (m, 2H), 7.21-7.53
(m, 19H), 7.93 (m, 1H)

(B) Nn-pentyl-N- [2'-
(1-H-tetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide Nn-pentyl-N- [2 '-(N
-Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide (3.5 g) was used and the same procedure as in Example 1 (B) was performed to obtain a white amorphous substance. 2.12 g (yield 87%) of the title compound of was obtained. NMR (270MHz, CDCl ₃ ) δ: 0.84 (dt, 3H), 1.09-1.53 (m, 9
H), 3.19, 3.30 (each t, 2H), 3.35, 3.38 (each s, 2H), 3.40, 3.50
(Each s, 2H), 3.76 (s, 2H), 4.10 (q, 2H), 4.43,4.53 (each s, 2H),
7.08 (m, 4H), 7.01-7.26 (m, 9H), 7.40-7.63 (m, 3H), 7.98
(m, 1H) MS ((-) FABMS m / z): 553 (M-1) ⁺

Examples 14 to 24 Tables 9, 10 and 11 were prepared in the same manner as in Example 13.
The compound shown in was synthesized.

[0066]

[Table 9]

[0067]

[Table 10]

[0068]

[Table 11]

Example 25 Nn-pentyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-
Synthesis of carboxymethyl-benzylamino) acetamide Nn-pentyl-N- [2 'obtained in Example 13 (B).
-(1-H-tetrazol-5-yl) biphenyl-4
-Yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide 1.0 g methanol 10
10 ml of 1N sodium hydroxide solution
Was added and the mixture was stirred for 12 hours at room temperature. Next, the reaction solution was washed with ether, the aqueous layer was adjusted to pH = 4 with 10% aqueous hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate and evaporated to give 920 mg (yield 97%) of the white amorphous title compound. NMR (270 MHz, CDCl ₃ ) δ: 0.84 (m, 3H), 1.06-1.51 (m, 6H),
3.04,3.41 (each brs, 2H), 3.67 (s, 2H), 3.97 (s, 2H), 4.21
(s, 2H), 4.36,4.39 (each s, 2H), 6.88 (m, 4H), 7.15-7.48 (m, 8
H), 7.71,7.76 (each d, 1H) MS ((-) FABMS m / z): 525 (M-1) ⁺

Examples 26 to 36 Tables 12, 13 and 1 were prepared in the same manner as in Example 25.
The compound shown in 4 was synthesized.

[0071]

[Table 12]

[0072]

[Table 13]

[0073]

[Table 14]

Example 37 Nn-pentyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-
Separate Synthesis Method of Carboxymethyl-benzylamino) acetamide-1 (A) Nn-pentyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide Nn-pentyl-N- [2'- obtained in Example 1 (A)
1.0 g of (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-benzylaminoacetamide was dissolved in 10 ml of tetrahydrofuran, and then 181.0 mg of sodium hydrogen carbonate was added, and then bromoacetic acid ethyl ester was added. 0.3 ml was added and the mixture was refluxed for 12 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
1: 5) to obtain 92 of the title compound as a white amorphous substance.
3.4 mg (yield 82%) was obtained. Hereinafter, Example 1 (B),
The title compound was obtained in the same manner as in Example 25 to give 479.1.
mg (yield 81%) was obtained. The NMR spectra were in agreement with the data of the corresponding compounds, respectively.

Examples 38 to 43 In the same manner as in Example 37, the compounds shown in Tables 15 and 16 were synthesized.

[0076]

[Table 15]

[0077]

[Table 16]

Example 44 Nn-pentyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-
Separate Synthesis Method of Carboxymethyl-benzylamino) acetamide-2 (A) Nn-pentyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-
Synthesis of [yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide 1.0 g of N-benzyl-N-carboxymethyl-glycine-ethyl ester obtained in Reference Example 17 was converted into methylene chloride 3
After being dissolved in 0 ml and adjusted to 0 ° C, oxalyl chloride was added to 0.
5 ml was added and then triethylamine 1.7 ml was added dropwise. After stirring the reaction solution at room temperature for 15 minutes, Reference Example 1
2.0 g of Nn-pentyl- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methylamine obtained in 1. was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate: n-
Purification with hexane = 1: 5) gave 2.26 g (yield 80%) of the title compound as a white amorphous substance. Hereinafter, Example 1
(B) In the same manner as in Example 25, 1.17 g (yield 81%) of the title compound was obtained. The NMR spectrum is
Each was in agreement with the data for the corresponding compound.

Example 45 Separate synthesis of N-n-butyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-carboxymethyl-benzylamino) acetamide Method (A) Synthesis of N-n-butyl-N- [2'-cyano-biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide By a method similar to that in Example 44 (A). , Nn-pentyl- [2 '-(N-triphenylmethyltetrazole-
620 mg of the oily title compound was obtained by using 460 mg of Nn-butyl-2'-cyano-biphenyl-4-yl-methylamine obtained in Reference Example 6 instead of 5-yl) biphenyl-4-yl] methylamine. (Yield 72%) was obtained. NMR (270 MHz, CDCl ₃ ) δ: 0.87 (m, 3H), 1.10-1.64 (m, 7H),
3.20, 3.36 (each t, 2H), 3.55 (m, 2H), 3.90 (m, 2H), 4.15 (q, 2
H), 4.64 (m, 2H), 7.12-7.68 (m, 12H), 7.77 (m, 1H) MS (EIMS m / z): 497 (M ⁺ )

(B) Nn-butyl-N- [2 '-(1
Synthesis of -H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide Nn-butyl-N- [2'-cyano obtained in (A) above. -Biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide 600 mg
Was dissolved in 200 ml of benzene, 1.2 g of tri-n-butyl-tin-azide was added, and the mixture was refluxed for 16 hours. After allowing to cool, 10% hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate and evaporated. The obtained crude product was subjected to silica gel column chromatography (chloroform: methanol = 10:
Purified in 1) and 455 mg of the white amorphous title compound.
(Yield 70%) was obtained. The NMR spectrum is shown in Example 16.
The data were in agreement with the compound data of.

(C) Nn-butyl-N- [2 '-(1
Synthesis of —H-tetrazol-5-yl) biphenyl-4-yl] methyl- (N-carboxymethyl-benzylamino) acetamide Nn-butyl-N- [2 ′-(1 obtained in (B) above. −
H-tetrazol-5-yl) biphenyl-4-yl]
Using methyl- (N-ethoxycarbonylmethyl-benzylamino) acetamide and in the same manner as in Example 25, 417 mg (yield 97%) of the title compound was obtained. NM
The R spectrum was in agreement with the data for the compound of Example 28.

Example 46 (A) Nn-butyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-N- Two
Synthesis of -phenylethyl) urea 16.0 g of N- (2-phenylethyl) -glycine ethyl ester obtained in Reference Example 18 was dissolved in 200 ml of methylene chloride, 11.5 ml of triethylamine was added, and triphosgene was added at room temperature. 1 g was added. Reference example 4 there
15.0 g of Nn-butyl-N- [2 '-(N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methylamine obtained in 1. was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and evaporated.
The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give 16.7 g (yield 78%) of the title compound as a white amorphous substance.
Obtained. (B) Nn-butyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl (N
-Synthesis of ethoxycarbonylmethyl-N-2-phenylethyl) urea Nn-butyl-N- [2 '-(N- obtained in (A) above.
Using 16.7 g of triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl- (N-ethoxycarbonylmethyl-N-2-phenylethyl) urea, the same operation as in Example 1 (B) was performed. This gave 9.46 g (yield 82%) of the title compound as a white amorphous substance. NMR (270MHz, CDCl ₃ ) δ: 0.90 (t, 3H), 1.20-1.28 (m, 5H),
1.54 (m, 2H), 2.83 (t, 2H), 3.07 (m, 2H), 3.46 (t, 2H), 3.9
0 (s, 2H), 4.14 (q, 2H), 4.23 (s, 2H), 7.10-7.61 (m, 12H),
8.00 (d, 1H), MS [(-) FABMS m / z]: 539 (M-1) ⁺

Examples 47 to 48 The compounds shown in Table 17 were synthesized in the same manner as in Example 46.

[0084]

[Table 17]

Example 49 Nn-butyl-N- [2 '-(1-H-tetrazol-5-yl) biphenyl-4-yl] methyl (N-carboxymethyl-N-2-phenylethyl) urea Synthesis of Nn-butyl-N- [2 '-(1-
H-tetrazol-5-yl) biphenyl-4-yl]
Using 5.4 g of methyl (N-ethoxycarbonylmethyl-N-2-phenylethyl) urea, the white amorphous title compound of 5.1 was obtained in the same manner as in Example 25.
g (quantitative) was obtained. NMR (270MHz, CDCl ₃ ) δ: 0.92 (t, 3H), 1.26 (m, 2H), 1.55
(m, 2H), 2.84 (t, 2H), 3.10 (t, 2H), 3.48 (t, 2H), 3.83 (s, 2
H), 4.23 (s, 2H), 7.07-7.60 (m, 12H), 8.08 (m, 1H) MS [(-) FABMS m / z]: 511 (M-1) ⁺

Examples 50 to 51 The compounds shown in Table 18 were synthesized in the same manner as in Example 49.

[0087]

[Table 18]

Example 52 Pharmacological test (aortic angiotensin II contraction inhibitory effect) <Test method> Using rat thoracic aortic spiral specimens, 3
Krebs-Henseleit solution (pH = 7.
4) In The Journal of Pharm
acology and Experimental
Therapeutics, 247 , 1-7, (198
The experiment was conducted according to the method described in 8). That is, angiotensin II was administered from 1 × 10 ⁻¹⁰ M until cumulative maximum contraction was obtained, and a dose-effect curve was obtained to calculate ED ₅₀ (control). Next, the compound (drug) of the present invention (1 × 10 ⁻⁹ to 1 × 10 ⁻⁶ M) was pretreated for 10 minutes, and similarly, a dose-effect curve of angiotensin II was obtained to obtain ED.
₅₀ (drug) was calculated. The pA ₂ value was calculated from these ED ₅₀ values using the following formula. pA ₂ = −log (drug concentration) + log {[ED ₅₀
(Drug) / ED ₅₀ (Control)] − 1} The results are shown in Table 19. Du, which is currently well known as a compound showing angiotensin II receptor antagonistic action,
Since the pA ₂ value of p-753 is 8.48, [Ti
PS, 12 , February (1991)], it is clear that the compounds of the present invention exhibit a stronger angiotensin II receptor antagonistic action.

[0089]

[Table 19]

[0090]

EFFECT OF THE INVENTION The alkylglycine derivative of the present invention or a salt thereof has a strong angiotensin II receptor antagonism which has never been obtained. Therefore, it can be used in circulation of hypertension, heart disease, arteriosclerosis, stroke, etc. It is useful as a therapeutic agent for organ diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location // A61K 31/41 ABU 7431-4C 31/44 AEQ 7431-4C 31/495 ABN 7431-4C

Claims (4)

[Claims] 1. The following general formula (1): (In the formula, R ¹ represents a phenyl group which may have a substituent, a naphthyl group or a heterocyclic group having 1 or 2 nitrogen atoms, oxygen atoms or sulfur atoms, and R ² represents a hydrogen atom or carboxymethyl. Group or a lower alkoxycarbonylmethyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a trityl group, ALK represents a lower alkylene group, and n represents 0 or 1.). An alkylglycine derivative or a salt thereof. 2. In the above formula (1), R ¹ is a phenyl group which may have a substituent, a naphthyl group, a pyridyl group, a furyl group, a thienyl group or a pyrazinyl group, and R ² is a hydrogen atom or a carboxymethyl group. 2. An alkylglycine derivative or a salt thereof according to claim 1, wherein R ³ is a lower alkyl group, R ³ is a lower alkyl group, R ⁴ is a hydrogen atom or a trityl group, ALK is a methylene group or an ethylene group, and n is 0 or 1. 3. In the above formula (1), R ¹ is a phenyl group which may have a substituent, R ² is a carboxymethyl group or a lower alkoxycarbonylmethyl group, R ³ is a lower alkyl group, and R ⁴ is hydrogen. The alkylglycine derivative or a salt thereof according to claim 1, wherein the atom, ALK is a methylene group or an ethylene group, and n is 0 or 1. 4. In the above formula (1), R ¹ is a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, R ² is a carboxymethyl group or an ethoxycarbonylmethyl group, and R ³ is an n-butyl group. , R ⁴ is a hydrogen atom, A
LK is a methylene group, n is 1 or ALK is an ethylene group, n
Is 0. The alkylglycine derivative or salt thereof according to claim 1.