JPH05208964A - Dicarboxylic acid and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a therapeutic agent for hypertension and cardiac incompetence, having inhibitory action on neutral metallo-end opeptidase. CONSTITUTION:A compound of formula I (R is H, lower alkyl, phenyl or OH; R<1> is substituted lower alkyl; R<2> is phenyl, etc.; X is S, O, imino, etc.; when Y<1> is imino, O or S, Y<2> is N and when Y<1> is vinylene, Y<2> is CH; (m) is 0-3; (n) is 0 or l) such as 4-benzyloxycarbonyl-5-{2-[N-((1S)-benzyloxycarbonyl-3- phenylpropyl)-(L)-phenylalanyl]aminoethyl}oxazole. The compound of formula I is obtained by condensing a carboxylic acid of formula II (X<1> is as shown for X) with an amine of formula III (R<4> is carboxyl-protecting group) in the presence of a dehydrating agent (e.g. dicyclohexylcarbodiimide) and optionally carrying out deprotection and lower alkylation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel dicarboxylic acid derivative having an antihypertensive and / or heart failure therapeutic action and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Atrial natriuretic peptide (ANP), which is secreted from the heart and has potent diuretic action, natriuretic action, vasodilatory action, and renin-angiotensin-aldosterone inhibitory action, is effective in treating hypertension and heart failure. Known to be. However, since ANP itself is a polypeptide and is poorly absorbed in the digestive tract,
The route of administration is limited to parenteral. On the other hand, since ANP is decomposed in vivo by neutral metalloendopeptidase, it is known that this enzyme inhibitor also increases the blood concentration of ANP and can be used as a therapeutic agent for hypertension and / or heart failure. ..

[0003]

The present invention provides a novel dicarboxylic acid derivative having an excellent neutral metalloendopeptidase inhibitory action and useful as an antihypertensive drug and / or a drug for treating heart failure.

[0004]

The present invention has the general formula [I]

[0005]

[Chemical 8]

[Wherein R is a hydrogen atom, a lower alkyl group,
Phenyl group or hydroxyl group, R ¹ is selected from a linear or branched alkyl group having 1 to 10 carbon atoms, an aryl group, a sulfur-containing or nitrogen-containing heteromonocyclic group, and a cycloalkyl group having 4 to 8 carbon atoms. A lower alkyl group substituted with a group, R ² is an aryl group which may have a substituent, a cycloalkyl group having 4 to 8 carbon atoms, or a sulfur-containing or nitrogen-containing heterocyclic group, X
Is a sulfur atom, an oxygen atom, or an optionally substituted imino group, Y ¹ and Y ² are Y ¹ being an imino group, an oxygen atom or a sulfur atom, and Y ² is a nitrogen atom, or Y ¹ is a vinylene group and Y ² is a group: -CH =, m is 0 to 3, n
Represents 0 or 1. ] A dicarboxylic acid derivative represented by
It relates to its ester or a pharmacologically acceptable salt thereof.

As specific examples of the object of the present invention, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group-substituted lower alkyl group, a thienyl group-substituted lower alkyl group or a cyclohexyl group-substituted lower alkyl group. An alkyl group, R ² is a phenyl group, a lower alkoxy group-substituted phenyl group, a cyclohexyl group, a thienyl group or an indolyl group, X is a sulfur atom,
Examples thereof include compounds having an oxygen atom, an imino group, or a lower alkyl group-substituted imino group.

Of these, preferred compounds in view of their medicinal effects include R ¹ as a linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group-substituted lower alkyl group or a thienyl group-substituted lower alkyl group, and R ² as a phenyl group. , A lower alkoxy group-substituted phenyl group or an indolyl group, X is an imino group or a lower alkyl group-substituted imino group, Y ¹ is an imino group, an oxygen atom or a sulfur atom, Y ² is a nitrogen atom, m is 2, and n is 0. Examples of the compound include, R is a hydrogen atom, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms or a phenyl group-substituted lower alkyl group, R ² is a phenyl group or an indolyl group, Examples include compounds in which X is an imino group, Y ¹ is an oxygen atom or a sulfur atom, Y ² is a nitrogen atom, m is 2 and n is 0.

The object [I] of the present invention is that free carboxylic acid has excellent pharmacological activity, while its ester is metabolized in vivo and hydrolyzed into free carboxylic acid to exert its activity. It is a professional drug. Therefore, any such ester residue can be used as long as it is not involved in the manifestation of drug effects when it is hydrolyzed in vivo and is pharmacologically acceptable. Specific examples of the ester compound include, for example, mono C _1-8 alkyl ester, di C _1-8 alkyl ester, mono (phenyl lower alkyl) ester, di (phenyl lower alkyl) ester, mono C _1-8 alkyl-mono. Examples thereof include (phenyl lower alkyl) ester. Of these, preferred ester compounds are mono- or di-C _1-8 alkyl ester compounds, and mono- or diethyl ester compounds are particularly preferred. Furthermore, the object of the present invention [I]
Or, as the pharmacologically acceptable salt of its ester, for example, inorganic acid addition salts such as hydrobromide, hydrochloride, sulfate, phosphate, nitrate, methanesulfonate, p-toluenesulfonate, oxalate, etc. Examples thereof include organic acid addition salts such as acid salts, fumarate salts, maleate salts, tartrate salts, and citrate salts.

The object [I] of the present invention includes any of four types of optically active compounds based on two asymmetric carbon atoms and a mixture thereof, in which two asymmetric carbon atoms are both S.
Those having a configuration (hereinafter referred to as (S-S) form) are particularly preferable in terms of efficacy. In the object [I] of the present invention, the lower alkyl group and the lower alkoxy group have 1 carbon atoms.
It means an alkyl group having 6 to 6 and an alkoxy group having 1 to 6 carbon atoms.

The object [I], its ester or salt thereof can be administered orally or parenterally, and it is used as a pharmaceutical preparation by mixing with an excipient suitable for oral or parenteral administration. be able to. Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, a solution,
It may be a liquid preparation such as a suspension or an emulsion. When administered parenterally, it can be used in the form of injection. The dose varies depending on the administration method, age of the patient, weight, condition and kind of disease to be treated, but is usually about 1 to 100 mg / kg, especially 3 to 30 mg per day.
/ Kg is preferable.

According to the present invention, the object compound [I] is (1) the general formula [II]

[0013]

[Chemical 9]

[Wherein R ³ is a protecting group for a carboxyl group,
X ¹ represents a sulfur atom, an oxygen atom or an imino group which may have a substituent, and R ¹ and R ² have the same meaning as described above. ] A carboxylic acid compound represented by the following formula or a salt thereof or a reactive derivative at a free carboxyl group thereof and a general formula [III]

[0015]

[Chemical 10]

[Wherein R ⁴ represents a protecting group for a carboxyl group, and R, Y ¹ , Y ² , m and n have the same meanings as described above. ] Or by a condensation reaction with an amine compound represented by the formula: or (2) the general formula [IV]

[0017]

[Chemical 11]

[Wherein Z ¹ represents a reactive residue, and other symbols have the same meanings as described above. ] And an acetic acid compound represented by the general formula [V]

[0019]

[Chemical 12]

[Wherein X ² represents a thiol group, a hydroxyl group, or an amino group which may have a substituent, and other symbols have the same meanings as described above. ] After condensation reaction with the compound represented by or a salt thereof, (3) when X ¹ is an unsubstituted imino group or X ² is an unsubstituted amino group, the product is optionally lower alkylated, ) Further, if desired, a protecting group R
It can be produced by removing ³ and / or R ⁴ . Examples of the protecting groups R ³ and R ⁴ for the carboxyl group include lower alkyl ester, halogen-substituted lower alkyl ester, phenyl lower alkyl ester, phenacyl ester and the like. Further, as the reactive residue Z ¹ , a halogen atom, a lower alkylsulfonyloxy group, a lower alkylphenylsulfonyloxy group (for example, p-toluenesulfonyloxy group) or the like can be preferably used.

As the salt of the carboxylic acid compound [II], for example, an alkali metal salt and an alkaline earth metal salt can be appropriately used, and as the salt of the amine compound [III] and the compound [V], for example, a mineral acid salt. Inorganic acid salts and organic acid salts such as can be appropriately used. The condensation reaction between the carboxylic acid compound [II] or its salt and the amine compound [III] or its salt can be appropriately carried out in the presence of a dehydrating agent. As the dehydrating agent, any one that can be used for peptide synthesis can be used, and for example, 1-ethyl-
Water-soluble carbodiimides such as 3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide and the like can be mentioned.

On the other hand, the reactive derivative at the carboxyl group of the carboxylic acid compound [II] and the amine compound [II]
The condensation reaction of I] or its salt and the condensation reaction of acetic acid compound [IV] and compound [V] or its salt can be appropriately carried out in the presence or absence of a deoxidizing agent. Examples of the deoxidizing agent include organic bases such as tri-lower alkylamine, N, N-di-lower alkylamine and pyridine, alkali metal hydroxides,
Any inorganic base such as alkali metal hydrogen carbonate, alkali metal carbonate, and alkali metal hydride can be preferably used. Further, as the reactive derivative at the carboxyl group of the carboxylic acid compound [II], any of those commonly used in peptide synthesis, for example, acid halides, active esters, mixed acid anhydrides, azides and the like can be used. All of these reactions are preferably carried out in a suitable solvent or without solvent under cooling to room temperature, especially at -30 ° C to 30 ° C. The solvent is not particularly limited as long as it is a solvent inert to the reaction, for example, dimethylformamide,
Tetrahydrofuran, dioxane, acetonitrile, hexamethylphosphoric triamide or a mixed solvent thereof may be used.

In the starting compound [II] or [V], when X ¹ is an unsubstituted imino group and X ² is an unsubstituted amino group, the product obtained above may be further alkylated. Lower alkylation can be carried out by a conventional method, for example, by reacting the product with a lower alkyl halide. The reaction with a lower alkyl halide can be suitably carried out in a solvent in the presence of a deoxidizing agent. As the lower alkyl halide, methyl iodide, ethyl iodide and the like can be preferably used. As the deoxidizing agent and the solvent, any of those mentioned above can be used. The reaction is preferably carried out under cooling to heating, especially at around room temperature. The removal of the protecting groups R ³ and / or R ⁴ from the product thus obtained can be carried out according to a conventional method such as catalytic reduction, acid hydrolysis or the like depending on the kind of the protecting group.

Of the above reactions, the reactions (1), (3) and (4) proceed without racemization,
When the optically active starting material compound is used, the corresponding optically active target compound [I] can be obtained. Further, in the condensation reaction (2), a nucleophilic substitution reaction (SN2 reaction) on the asymmetric carbon atom
However, for example, by appropriately selecting the reaction conditions such as the type of deoxidizing agent, the reaction proceeds without racemization. Therefore, by using an optically active raw material compound having an appropriate configuration in advance, An optically active target product having a configuration is obtained. When the obtained target product is a racemate, it can be separated into each optically active substance by a conventional method (for example, chromatography). The starting compound [II] of the present invention is the same as the acetic acid compound [IV] and the general formula [VI].

[0025]

[Chemical 13]

[However, R ⁵ represents a protecting group for a carboxyl group, and R ² and X ² have the same meanings as described above. ] The protective group R ⁵ can be removed after condensation with an acetic acid compound represented by the following in the presence of a deoxidizing agent (such as potassium carbonate) in a solvent (such as hexamethylphosphoric triamide). .. In the amine compound [III], R is a hydrogen atom, Y ¹ is an oxygen atom, Y ² is a nitrogen atom,
The compound in which n is 0 is, for example, a compound represented by the general formula [VII]

[0027]

[Chemical 14]

[Wherein R ⁶ represents a protecting group for an amino group,
m has the same meaning as described above. ] And an amino acid compound represented by the general formula [VIII]

[0029]

[Chemical 15]

[However, R ⁴ and n have the same meanings as described above. ] In the presence of a deoxidizing agent (such as triethylamine) in the presence of a deoxidizing agent (such as triethylamine), a cyclization reaction in a solvent (such as dimethylformamide), then the protecting group R
It can be manufactured by removing ⁶ . Further, the compound thus obtained can be produced by reacting the product thus obtained with diazomethane and then treating with silver benzoate.

On the other hand, the amine compound [III] in which Y ¹ is a sulfur atom or a nitrogen atom and Y ² is a nitrogen atom is
The amine compound [III] obtained above is treated with an acid (hydrochloric acid, etc.) in an oxazole ring in a solvent (methanol, etc.) to open the ring, and then a sulfidizing agent (p-methoxyphenylthionophosphine sulfide dimer) Etc.) or an iminating agent (ammonium acetate, etc.) again to perform ring closure. Furthermore, after the ring-opening of the oxazole ring is carried out, when the re-ring-closing reaction is carried out, a raw material compound [III] having a substituent (R) on the ring is obtained by appropriately selecting an acylating agent, a sulfiding agent or an iminating agent Be done. In addition, Y ¹ is a sulfur atom, Y ²
Is a nitrogen atom, m is 0, and n is 1 [III]
Can be produced by the method described in Weilstein, Vol. 27, p. 336 or in accordance therewith, and a compound [III] in which Y ¹ is a vinylene group and Y ² is a group: —CH═.
Can be produced by the method described in Weilstein, Vol. 14, p. 383, or according thereto. The amine compound [V] has the general formula [IX]

[0032]

[Chemical 16]

[Wherein X ³ represents a protected, substituted or unsubstituted amino group or a protected thiol group. ] After the condensation reaction of the acetic acid compound represented by the formula [1] or its reactive derivative at the carboxyl group with the amine compound [III] is conducted by the method described in the reaction of the compounds [II] and [III], for example, X ³ Can be produced by removing the protecting group in.

In the above reaction, acetic acid compound [I
X], an amine compound [III], and an acetic acid compound [I
The reaction of V] with the acetic acid compound [VI] can be proceeded without racemization as in the case of the above-mentioned reaction (1) and reaction (2). By using the compound, an optically active compound [II] or [V] can be obtained, and when the obtained compound is a racemate, each optical isomer can be obtained by a conventional method (for example, chromatography). It can also be separated into the body.

[0035]

【Example】

Example 1 (1) A mixture of 33 g of 2-bromo-4-phenylbutyric acid benzyl ester, 22.1 g of (L) -phenylalanine tert-butyl ester, 13.8 g of potassium carbonate and 30 ml of hexamethylphosphoric triamide at room temperature. After stirring overnight, ethyl acetate is added and the insoluble matter is filtered off. The filtrate was washed and dried, the solvent was distilled off, and the residue was purified by silica gel to obtain N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanine tert-butyl ester. 16.6g and N
-((1R) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanine tert
9.9 g of butyl ester are each obtained as an oil.

(SS) Form NMR (CDCl ₃ ) δ: 1.31 (s, 9H), 1.
76-2.06 (m, 3H), 2.51-2.70
(M, 2H), 2.78 to 2.97 (m, 2H), 3.
30 to 3.49 (m, 2H), 5.10 (s, 2H),
7.07 to 7.28 (m, 10H), 7.34 (s, 5
H)

(2) 4.73 g of the (SS) compound and 30 ml of trifluoroacetic acid were stirred under ice cooling for 10 minutes and then at room temperature for 50 minutes, and the solvent was distilled off. 10 to the balance
% Potassium carbonate aqueous solution is added for neutralization, and the resulting crystals are collected by filtration to obtain 3.09 g of N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanine. M. P. 141-143.5 ° C

(3) 4.2 g of this product, 4-benzyloxycarbonyl-5- (2-aminoethyl) oxazole.
Monobromide 3.27 g, 1-hydroxybenzotriazole monohydrate 1.53 g, triethylamine 1.4 m
1, 1-ethyl-3- (3-dimethylaminopropyl)
A mixture of 1.9 g carbodiimide hydrochloride and 30 ml dimethylformamide is stirred at -20 ° C for 1 hour and then at room temperature overnight. After distilling off the solvent, ethyl acetate was added to the residue, washed and dried, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (solvent: chloroform-
Ethyl acetate) to give 4-benzyloxycarbonyl-5- {2- [N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] aminoethyl}. 4.52 g of oxazole is obtained as a colorless oil.

NMR (CDCl ₃ ) δ: 1.68-1.
97 (m, 2H), 2.38 to 2.76 (m, 3H),
2.97 to 3.59 (m, 7H), 4.95, 5.06
(ABq, 2H), 5.33 (s, 2H), 7.02 ~
7.42 (m, 20H), 7.67 (s, 1H)

Examples 2 to 4 (1) The corresponding starting compounds [IV] and [VI] are treated in the same manner as in Example 1- (1) to obtain the compounds shown in Table 1 below.

[0041]

[Table 1]

(2) The product of (SS) configuration obtained in (1) above was treated in the same manner as in Example 1- (2) to give the following second
The (S-S) compound shown in the table is obtained.

[0043]

[Table 2]

(3) The product obtained in (2) above was used in Example 1.
-Treatment in the same manner as in (3), and (S-
S) form compound is obtained.

[0045]

[Table 3]

Examples 5 to 14 The corresponding starting compounds [II] and [III] were prepared in Example 1-
The same treatment as in (3) was carried out, and (S-
S) Obtain the target object of the body.

[0047]

[Table 4]

[0048]

[Table 5]

[0049]

[Table 6]

Example 15 4-benzyloxycarbonyl-5- {2- [N-
1.8 g of ((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] aminoethyl} oxazole was added to dimethylformamide 5
Catalytic reduction is carried out in the presence of 100 mg of palladium-black in 0 ml at 3 atm for 5 hours. After removing the catalyst by filtration, the solvent was evaporated and the obtained crystals were recrystallized from methanol to give 4-carboxy-5- {2- [N-((1S) -1-carboxy-3-phenylpropyl)- 1.1 g of (L) -phenylalanyl] aminoethyl} oxazole are obtained. M. P. 179-181 ° C (decomposition)

Examples 16 to 22 The products obtained in Examples 3 to 6, 8, 9 and 13 were used in Example 1
The same treatment as described in No. 5 and (S-
S) Obtain the target object of the body.

[0052]

[Table 7]

[0053]

[Table 8]

Example 23 4-benzyloxycarbonyl-5- {2- [N-
((1S) -1-Ethoxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] aminoethyl}
2.2 g of thiazole and 25% hydrogen bromide-acetic acid solution 30
The ml mixture is stirred at room temperature for 1 day. After distilling off the solvent, the solution was neutralized with a 10% aqueous potassium carbonate solution, and the obtained crystals were recrystallized from a mixed solution of methanol-isopropyl ether to give 4-carboxy-5- {2- [N-((1S) -1-
Ethoxycarbonyl-3-phenylpropyl)-(L)
-Phenylalanyl] aminoethyl} thiazole 1.2
7 g are obtained. M. P. 121-124 ° C

Examples 24 and 25 The products obtained in Examples 11 and 14 are treated in the same manner as in Example 23 to obtain the desired product in the (S-S) form shown in Table 9 below.

[0056]

[Table 9]

Examples 26-35 (1) 5.19 g of (2R) -3-phenyl-2-p-toluenesulfonyloxy-ethyl propionate, (L)
-A mixture of 15.74 g of phenylalanine benzyl ester, 2.91 g of di (isopropyl) ethylamine and 5 ml of hexamethylphosphoric triamide is stirred at 70 ° C for 2 days and then ethyl acetate is added. Wash the mixture,
After drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate = 9: 1) to give N-((1S) -1-ethoxycarbonyl-2-phenylethyl)-. 4.45 g of (L) -phenylalanine benzyl ester is obtained as an oil. NMR (CDCl ₃ ) δ: 1.08 (t, 3H), 2.
95 (t, 4H), 3.55 to 3.69 (m, 2H),
3.99 (q, 2H), 5.01 (ABq, 2H),
7.08-7.33 (m, 15H)

The corresponding starting compound was treated as described above,
The compounds listed in Table 10 below are obtained.

[0059]

[Table 10]

(2) The product obtained above was used in Example 1
(2) or treated in the same manner as in Example 15, to obtain the compounds shown in Table 11 below.

[0061]

[Table 11]

(3) The product obtained above was used in Example 1
Treated in the same manner as (3), the compounds shown in Tables 12 to 15 below are obtained.

[0063]

[Table 12]

[0064]

[Table 13]

[0065]

[Table 14]

[0066]

[Table 15]

Examples 36 to 47 The corresponding starting compounds were treated in the same manner as in Example 1- (3),
The compounds shown in Tables 16 to 19 below are obtained.

[0068]

[Table 16]

[0069]

[Table 17]

[0070]

[Table 18]

[0071]

[Table 19]

Example 48 (1) 2.56 g of (2S) -3- (2-thienyl) -2- (benzyloxycarbonylamino) propionic acid,
A mixture of 2.39 g of 4-benzyloxycarbonyl-5- (2-aminoethyl) oxazole-hydrobromide, 1.42 g of 1-hydroxybenzotriazole hydrate and 30 ml of dimethylformamide was cooled to -20 ° C. , 1-ethyl-3- (3-dimethylaminopropyl)
Add 1.77 g of carbodiimide hydrochloride. After 10 minutes, 0.93 g of triethylamine was added, the temperature was gradually returned to room temperature, and the mixture was stirred overnight. The solvent is distilled off, and ethyl acetate is added to the residue. After washing and drying the mixture, the solvent is distilled off,
The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate = 19: 1) and 4-benzyloxycarbonyl-5- {2- [N-((2S) -3-
3.5 g of (2-thienyl) -2- (benzyloxycarbonylamino) propionyl) amino] ethyl} oxazole are obtained as a syrup.

NMR (CDCl ₃ ) δ: 3.15-3.
28 (m, 4H), 3.46 to 3.59 (m, 2H),
4.35 (m, 1H), 5.09 (s, 2H), 5.3
1 (s, 3H), 6.47 (brs, 1H), 6.75
(M, 1H), 6.83 to 6.88 (m, 1H), 7.
09 to 7.12 (m, 1H), 7.32 to 7.42
(M, 10H), 7.69 (s, 1H)

(2) A mixture of 2.67 g of this product and 20 ml of 25% hydrogen bromide-acetic acid solution was stirred at room temperature for 10 minutes, and then
The solvent is distilled off, and the residue is pulverized by adding ethyl ether. A mixture of 1.67 g of the obtained powder, 1.67 g of (1R) -1-benzyloxycarbonyl-1- (p-toluenesulfonyloxy) -3-phenylpropane, 1.75 ml of triethylamine and 20 ml of hexamethylphosphoric triamide. After stirring at 75 ° C. overnight, ethyl acetate is added. After washing and drying the mixture, the solvent was evaporated and the residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate = 98: 2) to give 4-benzyloxycarbonyl-5- {2- [N-(( 2.1 g of 2S) -3- (2-thienyl) -2- (N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl) amino) propionyl) amino] ethyl} oxazole are obtained. M. P. 81-83 ° C

Examples 49 to 51 (1) The corresponding starting material compounds are treated in the same manner as in Example 48- (1) to obtain the following compounds.

49- (1): 4-benzyloxycarbonyl-5- {2- (N-benzyloxycarbonyl-
(L) -Phenylalanyl) aminoethyl} oxazole M.I. P. 148-149 ° C

50- (1): 3-benzyloxycarbonyl-1-{(N-benzyloxycarbonyl- (L)
-Phenylalanyl) amino} benzene M.I. P. 141-143 ° C

51- (1): 4-benzyloxycarbonylmethyl-2-{(N-benzyloxycarbonyl-
(L) -Phenylalanyl) amino} thiazole NMR (CDCl ₃ ) δ: 3.03 to 3.38 (m, 2)
H), 3.69 (s, 2H), 4.73 to 4.89.
(M, 1H), 5.07 to 5.09 (m, 2H), 5.
14 (s, 2H), 5.55 to 5.70 (m, 1H),
6.78 (s, 1H), 7.04 to 7.41 (s, 1
H)

(2) The compound obtained in (1) above and the corresponding starting compound are treated in the same manner as in Example 48- (2) to give the following compound.

49- (2): 4-benzyloxycarbonyl-5- {2- [N-((1S) -1-benzyloxycarbonyl-3- (2-thienyl) propyl)-
(L) -Phenylalanyl] aminoethyl} oxazole Properties: Syrup NMR (CDCl ₃ ) δ: 1.66 (brs, 1H),
1.50 to 1.90 (m, 2H), 2.31 to 2.39
(M, 2H), 2.60 (dd, 1H), 3.13 ~
3.33 (m, 5H), 3.33 to 3.49 (m, 2
H), 5.02 and 5.11 (ABq, 2H), 5.3.
5 (s, 2H), 6.53 (m, 1H), 6.85
(M, 1H), 7.08 (m, 1H), 7.16 to 7.
52 (m, 16H), 7.69 (s, 1H)

50- (2): 3-benzyloxycarbonyl-1-{[N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] amino} benzene : syrup _{NMR (CDCl 3) δ: 1.60~2.25} (m, 4
H), 2.51 to 3.22 (m, 2H), 3.13 to
3.45 (m, 2H), 4.98 and 5.08 (AB
q, 2H), 5.32 and 5.41 (ABq, 2H),
6.85-7.44 (m, 24H), 7.70-8.0
1 (m, 1H)

51- (2): 4-benzyloxycarbonylmethyl-2-{(N-((1S) -1-benzyloxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl) amino} thiazole Property: Syrup NMR (CDCl ₃ ) δ: 1.85 to 2.06 (m, 2
H), 2.07 to 2.28 (m, 2H), 2.53 to
2.76 (m, 2H), 2.81 to 3.00 (m, 1
H), 3.44 to 3.56 (m, 1H), 3.76.
(S, 2H), 5.15 to 5.17 (m, 4H), 6.
80-7.42 (m, 21H)

Examples 52-68 Examples 26-32, 36-39, 41-43, 46-4
The products obtained in Nos. 7 and 49 are treated in the same manner as in Example 15 to obtain compounds shown in Tables 20 to 24 below.

[0084]

[Table 20]

[0085]

[Table 21]

[0086]

[Table 22]

[0087]

[Table 23]

[0088]

[Table 24]

Example 69 2.6 g of the compound obtained in Example 1, 0.4 m of methyl iodide
After stirring a mixture of 1, 1, 0.83 g of potassium carbonate and 3 ml of hexamethylphosphoric triamide overnight at room temperature, ethyl acetate is added. The insoluble matter is filtered off, the filtrate is washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate = 95: 5), and 4-benzyloxycarbonyl-5- {2- [N
1.81 g of-((1S) -1-benzyloxycarbonyl-3-phenylpropyl) -N-methyl- (L) -phenylalanyl] aminoethyl} oxazole are obtained as an oil. NMR (CDCl ₃ ) δ: 1.65 (s, 1H), 1.
65-1.97 (m, 2H), 2.35 (s, 3H),
2.35 to 2.54 (m, 2H), 2.65 to 2.82
(M, 1H), 3.00 to 3.56 (m, 7H), 4.
92-5.17 (m, 2H), 5.32 (s, 2H),
6.99 to 7.43 (m, 20H), 7.65 (s, 1
H)

Examples 70 to 71 The compounds obtained in Examples 50 and 69 are treated in the same manner as in Example 15 to obtain the following compounds.

70: 3-carboxy-1-{[N-
((1S) -1-carboxy-3-phenylpropyl)
-(L) -phenylalanyl] amino} benzene is obtained. M. P. 201-202 ℃ (decomposition)

71: 4-carboxy-5- {2- (N-
((1S) -1-carboxy-3-phenylpropyl)
-N-methyl- (L) -phenylalanyl] aminoethyl} oxazole M.I. P. 104-106 ° C

Examples 72 to 73 The compounds obtained in Examples 49 and 51 are treated in the same manner as in Example 23 to obtain the following compounds.

72: 4-carboxy-5- {2- [N-
((1S) -1-Carboxy-3- (2-thienyl) propyl)-(L) -phenylalanyl] aminoethyl}
Oxazole M. P. 125-127 ° C (decomposition)

73: 4-carboxymethyl-2-{[N
-((1S) -1-carboxy-3-phenylpropyl)-(L) -phenylalanyl] amino} thiazole M.I. P. 178 ℃ (decomposition)

Example 74 Compound (0.35 g) obtained in Example 35, 2N-NaOH
After stirring 0.88 ml and 20 ml of methanol at room temperature overnight, water is added to the mixture. Methanol is distilled off, the residue is extracted with ethyl ether, the aqueous layer is neutralized with 1N-HCl, and extracted with ethyl acetate. The extract was washed and dried, the solvent was evaporated, isopropyl ether was added, and the mixture was pulverized to give 4-carboxy-5- {2- [N-((1
S) -1-carboxy-2-phenylethyl)-(O-
0.18 g of methyl)-(L) -tyrosyl] aminoethyl} oxazole is obtained. M. P. 103 ~ 106 ℃

Examples 75 to 80 The compounds obtained in Examples 26, 33 to 35 and 46 are treated in the same manner as in Example 74 to give compounds shown in Table 25 below.

[0098]

[Table 25]

Example 81 (1) 1.2 g of 1-tert-butoxycarbonyl-2-phenylethanethiol, sodium hydride (60%)
Oil) 0.22 g and dimethylformamide 20 ml
The mixture was stirred at room temperature for 30 minutes, and then cooled with ice under 2-bromo-.
A solution of 4-phenylbutyric acid benzyl ester (1.7 g) in dimethylformamide (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Ethyl ether was added to the mixture, and after washing, the solvent was distilled off, and the residue was purified by silica gel chromatography (solvent: hexane-ethyl ether = 95: 5) to give 1-benzyloxycarbonyl-3-phenylpropyl = 1. -Tert
-1.25 g of butoxycarbonyl-2-phenylethyl sulphide are obtained as an oil. NMR (CDCl ₃ ) δ: 1.30 (m, 9H), 1.
96-2.24 (m, 2H), 2.59-3.14
(M, 4H), 3.35 to 3.66 (m, 2H), 5.
12 (m, 2H), 7.06 to 7.36 (m, 15H)

(2) 1.47 g of this product, 1.7 of anisole
A mixture of 1 g and 10 ml trifluoroacetic acid was added at room temperature to 1
After stirring for an hour, the solvent is distilled off. Toluene is added to the residue and the solvent is distilled off again. The operation is repeated twice. The resulting product 0.86 g, 1-hydroxybenzotriazole hydrate 0.55 g, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.69 g and triethylamine 0.5 ml were added at -20 ° C. After mixing with, stir overnight while gradually returning to room temperature. The solvent was distilled off, ethyl acetate was added to the residue, washed and dried, then the solvent was distilled off, and the residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate = 5: 1) to give 4-benzyl. Oxycarbonyl-5-{[(2S) -3-phenyl-2-
1.13 g of (1-benzyloxycarbonyl-3-phenylpropylthio) propionyl] aminoethyl} oxazole are obtained as an oil. NMR (CDCl ₃ ) δ: 1.89 (m, 1H), 2.
12 (m, 1H), 2.60 (m, 2H), 2.82
(M, 1H), 2.99 to 3.52 (m, 7H), 5.
10 (m, 2H), 5.30 (m, 2H), 6.93-
7.41 (m, 20H), 7.65 (s, 1H)

(3) A mixture of 1.00 g of this product, 2 g of palladium black and 50 ml of methanol is stirred under a hydrogen atmosphere (3 atm) overnight. After the catalyst was filtered off, the solvent was distilled off to give 4-carboxy-5-{[(2S) -3-phenyl-2- (1-carboxy-3-phenylpropylthio) propionyl] aminoethyl} oxazole 0.6.
9 g are obtained as an oil. NMR (CDCl ₃ ) δ: 1.75 to 1.98 (m, 2
H), 2.22 to 2.39 (m, 1H), 2.50
2.62 (m, 2H), 2.73 to 2.89 (m, 2)
H), 3.01 to 3.36 (m, 5H), 3.36 to
3.66 (m, 1H), 7.15 to 7.37 (m, 10
H), 8.25 and 8.26 (s, s, 1H)

Reference Example 1 (1) N-benzyloxycarbonyl-β-alanine 3
3.5 g, isocyanoacetic acid methyl ester 15 g, diethylphosphoryl cyanide 31.8 g, 1,8-diazabicyclo [5,4,0] undec-7-ene 23 g, triethylamine 42 ml and dimethylformamide 300.
Stir the ml mixture at room temperature overnight. After that, the solvent was distilled off, ethyl acetate was added, and after washing and drying, the solvent was distilled off, the residue was purified with silica gel, crystallized with isopropyl ether, and recrystallized from an ethyl acetate-isopropyl ether mixed solution to obtain 4 -Methoxycarbonyl-5- {2-
22.6 g of (benzyloxycarbonylamino) ethyl} oxazole are obtained. M. P. 68-70 ° C

(2) 5 g of this product and 50 ml of 25% hydrogen bromide-acetic acid solution are stirred at room temperature for 15 minutes, and then the solvent is distilled off. The residue was crystallized with diethyl ether and 4
-Methoxycarbonyl-5- (2-aminoethyl) oxazole monohydrobromide is obtained as crude crystals and used in the next reaction without purification.

Reference Example 2 (1) The corresponding starting material compound is treated in the same manner as in Reference Example 1- (1) to obtain the following compound. 4-benzyloxycarbonyl-5- {3- (tert
-Butoxycarbonylamino) propyl} oxazole M.I. P. 124-126 ° C (2) This product was treated in the same manner as in Reference Example 1- (2), and 4
-Benzyloxycarbonyl-5- (3-aminopropyl) oxazole monohydrobromide is obtained.

Reference Examples 3 to 9 (1) The corresponding starting material compounds are treated in the same manner as in Reference Example 1- (1) to obtain the compounds shown in Table 26 below.

[0106]

[Table 26]

(2) The compound obtained in (1) was used in Reference Example 1-
Treated in the same manner as (2), the compounds shown in Table 27 below are obtained.

[0108]

[Table 27]

Reference Example 10 (1) 4-Methoxycarbonyl-5- {2- (benzyloxycarbonylamino) ethyl} oxazole 30
g, a mixture of 75 ml of 2N aqueous sodium hydroxide solution and 75 ml of methanol is stirred at room temperature for 3 hours. After distilling off methanol, 1N hydrochloric acid was added dropwise under ice cooling, and the obtained crystals were collected by filtration to give 4-carboxy-5- {2- (benzyloxycarbonylamino) ethyl} oxazole 2
5.8 g are obtained and used in the next reaction without purification.

(2) A mixture of 2.9 g of this product, 1.81 g of dicyclohexylamine, 2.33 g of ethyl iodide and 20 ml of dimethylformamide was stirred overnight at room temperature. After distilling off the solvent, 30 ml of ethyl acetate was added to the residue,
After washing and drying, the solvent was distilled off, the residue was purified by silica gel and crystallized with isopropyl ether, and ethyl acetate-n
It is recrystallized from a mixed solution of hexane to obtain 2.89 g of 4-ethoxycarbonyl-5- {2- (benzyloxycarbonylamino) ethyl} oxazole. M. P. 46-48 ° C

(3) 3.18 g of this product was used in Reference Example 1- (2)
Treated in a similar manner to 4-ethoxycarbonyl-5- (2
-Aminoethyl) oxazole monohydrochloride is obtained as crude crystals and used in the next reaction without purification.

Reference Example 11 (1) 4-methoxycarbonyl-5- {2- (benzyloxycarbonylamino) ethyl} oxazole 36.
A mixture of 5 g, 90 ml of concentrated hydrochloric acid and 270 ml of methanol is stirred at 55 ° C. for 6 hours. After the solvent was distilled off, the residue was dissolved in tetrahydrofuran and triethylamine 21
Neutralize with ml. The solution is further cooled to 0 ° C. and formic acid 45
0 ml is added and 150 ml of acetic anhydride is added dropwise at the same temperature. After stirring at 10 ° C for 3 hours, ice water was added, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed and dried, the solvent was distilled off, and the residue was purified on silica gel to give 3-oxo-5. −
20 g of (benzyloxycarbonylamino) -2- (formylamino) pentanoic acid methyl ester are obtained as a colorless oil.

NMR (CDCl ₃ ) δ: 2.86-3.
13 (m, 2H), 3.45 to 3.53 (m, 2H),
3.79 (s, 3H), 5.09 (s, 2H), 5.2
9 (d, 1H), 5.1-5.5 (br, 1H), 6.
8 to 7.0 (m, 1H) 7.34 (s, 5H), 8.2
2 (s, 1H)

(2) A mixture of 20 g of this product, 12.5 g of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide and 300 ml of toluene for 30 minutes. Bring to reflux. After evaporation of the solvent,
The residue was purified by silica gel, crystallized with isopropyl ether, and recrystallized from a mixed solution of ethyl acetate-isopropyl ether to give 4-methoxycarbonyl-5- {2- (benzyloxycarbonylamino) ethyl} thiazole 1
Obtain 0.5 g. M. P. 108-110 ° C

(3) This product was treated in the same manner as in Reference Example 10- (1) to give 4-carboxy-5- {2- (benzyloxycarbonylamino) ethyl} thiazole as crude crystals and purified. No, use in the next reaction.

Reference Examples 12 to 16 (1) The corresponding compounds are treated in the same manner as in Reference Examples 11- (1) and (2) to obtain the compounds shown in Table 28 below.

[0117]

[Table 28]

(2) The corresponding compound is treated in the same manner as in Reference Example 1- (2) to give the compounds shown in Table 29 below.

[0119]

[Table 29]

Reference Example 17 (1) The corresponding starting compound was treated in the same manner as in Reference Example 11- (1) to give 1-tert-butoxy-5-benzyloxycarbonyl-4- {2- (tert-butoxycarbonylamino). ) Obtaining ethyl} imidazole M. P. 124-126 ° C (2) This product was treated in the same manner as in Reference Example 1- (2), and 5
-Benzyloxycarbonyl-4- {2-aminoethyl} imidazole monohydrobromide is obtained.

Reference Example 18 (1) -10 g of a mixture of 2.9 g of 4-carboxy-5- {2- (benzyloxycarbonylamino) ethyl} oxazole, 4.9 g of pyridine, 6 ml of tert-butyl alcohol and 50 ml of chloroform was added. 1.84 g of phosphoryl chloride is added dropwise at 0 ° C, and the mixture is stirred at the same temperature for 1 hour and at room temperature overnight. After washing and drying, the solvent was distilled off, and the residue was purified by silica gel to obtain 2.85 g of 4-tert-butoxycarbonyl-5- {2- (benzyloxycarbonylamino) ethyl} oxazole as a colorless oil. NMR (CDCl ₃ ) δ: 1.58 (s, 9H), 3.
22-3.28 (m, 2H), 3.50-3.59
(M, 2H), 5.08 (s, 2H), 7.33 (s,
5H), 7.74 (s, 1H)

(2) 3.45 g of this product and 0.9 oxalic acid
g was treated in the same manner as in Reference Example 1- (2), and the obtained crystals were recrystallized from a tetrahydrofuran-isopropyl ether mixed solution to give 4-tert-butoxycarbonyl-5-.
(2-Aminoethyl) oxazole / 1 oxalate salt 2.
8 g are obtained. M. P. 116-120 ° C

[0123]

The dicarboxylic acid derivative [I], the ester thereof and the pharmacologically acceptable salts thereof, which are the objects of the present invention, have an excellent neutral metalloendopeptidase inhibitory action and their atrial sodium Diuretic peptide (ANP)
It exhibits excellent diuretic action, vasodilatory action, renin secretion inhibitory action, aldosterone secretion inhibitory action, etc. based on its inhibitory effect on the decomposition of lactocin, and has low toxicity and high safety as a medicine. Therefore, it can be used as a therapeutic and / or prophylactic drug for diseases such as hypertension, heart failure, and renal insufficiency. Especially for the treatment of hypertension, currently captopril,
Although angiotensin converting enzyme inhibitors (ACE inhibitors) such as delapril hydrochloride are clinically used, the object of the present invention, the esters and their pharmacologically acceptable salts are relatively low in these ACE inhibitors. It has excellent properties that it is ineffective and is effective for hyporenic hypertension.

For example, when the antihypertensive effect was examined in hypertension model rats, 4-ethoxycarbonyl-5- {2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl), which is the object of the present invention, was examined. )-(L) -Phenylalanyl] aminoethyl} thiazole, 4-carboxy-
5- {2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] aminoethyl} thiazole, 4-ethoxycarbonyl-5- {2- [N- ((1S) -1-carboxy-3
-Phenylpropyl)-(L) -phenylalanyl] aminoethyl} thiazole or 4-carboxy-5- {2
A group of 30 mg / kg of [[N-((1S) -1-ethoxycarbonyl-3-phenylpropyl)-(L) -phenylalanyl] aminoethyl} oxazole was orally administered, and purified water was orally administered as a control. Significant hypotension was observed in all compared to the groups. Further, some known ANP enhancers have both an angiotensin-converting enzyme inhibitory activity together with a neutral metalloendopeptidase inhibitory activity, but the object of the present invention is that the angiotensin-converting enzyme inhibitory activity is weak and a more selective neutral It also has the feature of having metalloendopeptidase inhibitory activity.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location C07D 413/12 209 8829-4C 263 8829-4C (72) Inventor Koji Yano 3 Hibarigaoka, Hoya-shi, Tokyo 5-chome 72-307 (72) Inventor Isao Yamaguchi 3-16-8 Ogikubo, Suginami-ku, Tokyo

Claims (13)

[Claims] 1. A compound represented by the general formula [I]: [Wherein R is a hydrogen atom, a lower alkyl group, a phenyl group or a hydroxyl group, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, or an aryl group, a sulfur-containing or nitrogen-containing heteromonocyclic group, and A lower alkyl group substituted with a group selected from a cycloalkyl group having 4 to 8 carbon atoms, R ² is an aryl group which may have a substituent, a cycloalkyl group having 4 to 8 carbon atoms, or a sulfur-containing or sulfur-containing group. Nitrogen heterocyclic group, X is a sulfur atom,
An imino group which may have an oxygen atom or a substituent, Y ¹
And ^{Y 2} is ^{Y 1} is an imino group, or is ^{Y 2} is oxygen atom or sulfur atom is a nitrogen atom, or ^{Y 1} is a vinylene group ^{Y 2} is a group: -CH =, m is 0 to 3, n Represents 0 or 1. ] The dicarboxylic acid derivative shown by these, its ester, or those pharmacologically acceptable salts. 2. R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group-substituted lower alkyl group, a thienyl group-substituted lower alkyl group or a cyclohexyl group-substituted lower alkyl group, and R ² is a phenyl group. The compound according to claim 1, wherein a phenyl group substituted with a lower alkoxy group, a cyclohexyl group, a thienyl group or an indolyl group, and X is a sulfur atom, an oxygen atom, an imino group or a lower alkyl group-substituted imino group. 3. The compound according to claim 2, wherein X is a sulfur atom, an imino group or a lower alkyl group-substituted imino group. 4. R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group-substituted lower alkyl group or a thienyl group-substituted lower alkyl group, R ² is a phenyl group, a lower alkoxy group-substituted phenyl group or An indolyl group, X is an imino group or a lower alkyl group-substituted imino group, Y ¹ is an imino group,
The compound according to claim 3, wherein an oxygen atom or a sulfur atom, Y ² is a nitrogen atom, m is 2 and n is 0. 5. R is a hydrogen atom, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms or a phenyl group-substituted lower alkyl group, R ² is a phenyl group or an indolyl group, X is an imino group, and Y. The compound according to claim 4, wherein ¹ is an oxygen atom or a sulfur atom, and Y ² is a nitrogen atom. 6. R is hydrogen atom, methyl group, phenyl group or hydroxyl group, R ¹ is sec-butyl group, sec-pentyl group, n-octyl group, benzyl group, phenylethyl group,
A thienylethyl group or a cyclohexylethyl group, R ² is a phenyl group, a methoxyphenyl group, a cyclohexyl group,
The compound according to claim 3, wherein a thienyl group or an indolyl group and X is a sulfur atom, an imino group or a methylimino group. 7. R is a hydrogen atom, a methyl group or a phenyl group, R ¹ is an n-octyl group, a phenylethyl group or a thienylethyl group, R ² is a phenyl group, a methoxyphenyl group or an indolyl group, and X is an imino group or The compound according to claim 4, which is a methylimino group. 8. R is hydrogen atom, R ¹ is n-octyl group or phenylethyl group, R ² is phenyl group or indolyl group, X is imino group, Y ¹ is oxygen atom or sulfur atom, Y ²
8. The compound according to claim 7, wherein is a nitrogen atom. 9. The compound according to claim 1, which is a linear or molecular chain alkyl ester having 1 to 10 carbon atoms or a phenyl lower alkyl ester of the dicarboxylic acid derivative. 10. The compound according to claim 9, which is a mono- or di-lower alkyl ester. 11. The compound according to claim 1, wherein the two asymmetric carbon atoms each have an absolute configuration of S configuration. 12. A compound represented by the general formula [II]: [Wherein R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, or a group selected from an aryl group, a sulfur-containing or nitrogen-containing heteromonocyclic group, and a cycloalkyl group having 4 to 8 carbon atoms] Substituted lower alkyl group, R ² is an aryl group which may have a substituent, a cycloalkyl group having 4 to 8 carbon atoms or a sulfur-containing or nitrogen-containing heterocyclic group, and R ³ is a carboxyl-protecting group. , X ¹ represents a sulfur atom, an oxygen atom, or an imino group which may have a substituent. ] A carboxylic acid compound represented by the following formula or a salt thereof or a reactive derivative at a free carboxyl group thereof and a general formula [III] [Wherein R is a hydrogen atom, a lower alkyl group, a phenyl group or a hydroxyl group, R ⁴ is a protective group for a carboxyl group, Y ¹ and Y
² is ^{Y 1} is an imino group, an oxygen atom or a sulfur atom ^{Y 2}
Is a nitrogen atom, or Y ¹ is a vinylene group and Y ²
Is a group: -CH =, m is 0 to 3, and n is 0 or 1. ]
A condensation reaction with an amine compound or salt thereof represented by
When X ¹ is an unsubstituted imino group it is optionally lower alkylated and optionally the protecting groups R ³ and / or R ⁴ are removed and, if desired, the product is its ester or pharmacologically acceptable thereof. And a general formula [I] [However, the symbols have the same meanings as described above. ] The manufacturing method of the dicarboxylic acid derivative shown by these, its ester, or those pharmacologically acceptable salt. 13. A compound represented by the general formula [IV]: [Wherein R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, or a group selected from an aryl group, a sulfur-containing or nitrogen-containing heteromonocyclic group, and a cycloalkyl group having 4 to 8 carbon atoms] A substituted lower alkyl group, R ³ represents a protecting group for a carboxyl group, and Z ¹ represents a reactive residue. ] And an acetic acid compound represented by the general formula [V] [Wherein R is a hydrogen atom, a lower alkyl group, a phenyl group or a hydroxyl group, R ² is an aryl group which may have a substituent, a cycloalkyl group having 4 to 8 carbon atoms or a sulfur-containing or nitrogen-containing heterocyclic group Group, R ⁴ is a carboxyl-protecting group, Y
¹ and ^{Y 2 Y 1} is an imino group, or is ^{Y 2} is oxygen atom or sulfur atom is a nitrogen atom, or ^{Y 1} is a vinylene group ^{Y 2} is a group: -CH =, ^{X 2} is a thiol group, Hydroxyl group,
Or an amino group which may have a substituent, m is 0 to 3,
n represents 0 or 1. ] After the condensation reaction with the compound [V] represented by the following or a salt thereof, when X ² is an unsubstituted amino group, it is optionally lower alkylated, and further, if desired, the protecting groups R ³ and / or R ⁴ are removed. Further, if necessary, the product is a ester thereof or a pharmacologically acceptable salt thereof, and is represented by the general formula [I]: [However, the symbols have the same meanings as described above. ] The manufacturing method of the dicarboxylic acid derivative shown by these, its ester, or those pharmacologically acceptable salt.