JP2009040743A - METALLO-beta-LACTAMASE INHIBITOR - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a metallo-β-lactamase inhibitor which becomes a medicine inhibiting deactivation of a β-lactam-based antibody substance and recovering antibacterial activity. <P>SOLUTION: A maleic acid derivative having a structure represented by general formula (I) has a metallo-β-lactamase inhibiting activity. The combined use of the compound represented by the general formula (I) with a β-lactam-based antibody substance enables recovery of antibacterial activity of β-lactam-based antibody substance to metallo-β-lactamase-producing bacterium. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

Background of the Invention

The present invention relates to a metallo-β-lactamase inhibitor comprising a maleic acid compound as an active ingredient, and more particularly, the present invention relates to β-lactam antibiotics in the treatment of bacterial infections in animals or humans. It is related with the pharmaceutical composition and its method for strengthening the effectiveness with respect to a metallo- (beta) -lactamase production resistant microbe by using together.

Background Art β-lactamase is very important in the resistance of bacteria to β-lactam antibiotics. In particular, metallo-β-lactamase having zinc at the active center and showing a wide substrate specificity is regarded as a problem because it also hydrolyzes carbapenem antibiotics that are relatively stable to serine-β-lactamase. Yes. In fact, bacteria that produce metallo-β-lactamase are a threat because they become resistant to many clinically important β-lactams. Metallo-β-lactamases are Bacillus cereus, Bacteroides fragilis, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Shigella flexneri, Alcaligenes It has been confirmed in multibacterial species such as freundii and Enterobacter cloacae. Especially in Pseudomonas aeruginosa (Pseudomonas aeruginosa), multidrug resistance has been remarkably increased, and there are significant problems. Clavulanic acid, sulbactam, and tazobactam currently used as β-lactamase inhibitors are useful for serine-β-lactamases having serine as an active center, but have no inhibitory effect on metallo-β-lactamases.

  Therefore, in order to recover the effectiveness of β-lactam antibiotics such as imipenem against resistant bacteria due to metallo-β-lactamase production, the need for metallo-β-lactamase inhibitors is increasing.

  In Pseudomonas aeruginosa, various compounds have been reported as having metallo-β-lactamase inhibitory activity since the metallo-β-lactamase encoded by the transmissible plasmid was reported. WO98 / 17639, WO97 / 30027, WO98 / 40056, WO98 / 39311, and WO97 / 10225 describe certain β-thiopropionyl-amino acid derivatives along with their use as inhibitors against metallo-β-lactamases. ing. In addition, some documents disclose thiols and thioesters as metallo-β-lactamase inhibitors (Biol. Pharm. Bull., 1997, 20, 1136, FEMS Microbiology Letters, 1997, 157, 171, Antimicrob. Agents Chemother., 1997, 41, 135, Chem. Commun., 1998, 1609, Biochem. J., 1998, 331, 703, and WO00 / 076962). Furthermore, WO01 / 030148 and WO01 / 030149 describe succinic acid compounds as metallo-β-lactamase inhibitors. In addition, there are literatures on the general status of various metallo-β-lactamase inhibitory compounds and metallo-β-lactamase producing bacteria (Clin. Microbiol. Rev., 2005, 18, 306). However, there is no description or suggestion of a maleic acid derivative which is a compound of the present invention in the above-mentioned reference.

  In order to actually exert an effect on resistant bacteria due to metallo-β-lactamase production in the medical field, it is essential to restore the effectiveness by using in combination with β-lactam antibiotics. However, there have been few reports showing such combined effects against bacterial species such as Pseudomonas aeruginosa, which are problematic in actual medical practice, and are currently effective for human and animal infections. There are no metallo-β-lactamase inhibitors.

Regarding maleic acid derivatives, dimethylmaleic acid is disclosed in JP-A-57-207245, dimethylmaleic acid and diethylmaleic acid are represented by Acta Chem. Scand., 1964, 18, 1276 (M ¹ in the general formula (I) is a hydrogen atom) Compound), and Japanese Patent Publication No. 7-91213 discloses 3-methyl-2-tetradecanylmaleic acid. However, these salts or esters having a group that can be hydrolyzed in vivo are not known.

Bioorg. Med. Chem., 2000, 8, 571 has a description of 2-hydroxymethyl-3-tetradecanylmaleic acid, but there are other disclosures of 2-hydroxymethyl-3-lower alkylmaleic acid. can not see. Furthermore, J. Am. Chem. Soc., 1955, 77, 6702 discloses a dicarboxylic acid having a cyclic alkyl group in the side chain, but it is a monosubstituted fumaric acid derivative and not a maleic acid derivative. J. Org. Chem., 1984, 49, 1985 discloses a maleic acid substituent having an alkylthio group, while the other has an alkenyl group. WO91 / 08775 and Tetrahedron Lett., 1988, 29, 3869 disclose an ester compound of maleic acid monosubstituted by an alkoxy group, but the carboxylic acid (M ¹ in the general formula (I) is a hydrogen atom) Compound), or salts thereof, is not disclosed. Further, compounds having a dihydrofuranyl group are described in Nord. Pulp Pap. Res. J., 1994, 9, 84, and compounds having a pyridinium group are described in Angew. Chem., 1990, 102, 1164. There is no suggestion regarding the metallo-β-lactamase inhibitory activity.

Summary of the Invention

  Therefore, an object of the present invention is to provide a novel metallo-β-lactamase inhibitor that is a drug that suppresses inactivation of β-lactam antibiotics and restores antibacterial activity.

  The present inventors have now found that maleic acid derivatives and pharmacologically acceptable salts thereof have an inhibitory action on metallo-β-lactamases. Furthermore, it discovered that it had the effect of recovering the activity of β-lactam antibiotics against metallo-β-lactamase producing bacteria. The present invention is based on such knowledge.

（式中、
Ｒ^１はＣ_２−６アルキル基、Ｃ_３−７環状アルキル基、ヒドロキシメチル基、−Ｃ_１−３アルキレン−フェニル基、−Ｃ_０−１アルキレン−複素環、−Ｏ−Ｃ_１−６アルキル基、または−Ｓ−Ｃ_１−６アルキル基を表し、これらはいずれも置換基を有していてもよく、
Ｒ^２はＣ_１−６アルキル基、Ｃ_３−７環状アルキル基、ヒドロキシメチル基、−Ｃ_１−３アルキレン−フェニル基、−Ｃ_０−１アルキレン−複素環、−Ｏ−Ｃ_１−６アルキル基、または−Ｓ−Ｃ_１−６アルキル基を表し、これらはいずれも置換基を有していてもよく、
二つのＭ^１は、同一または異なっていてもよく、水素原子、医薬的に許容されるカチオン、または医薬的に許容される生体内で加水分解されうる基を表す。） And according to one aspect of this invention, the metallo-beta-lactamase inhibitor containing the compound represented by the following general formula (I), its salt, or those solvates is provided.

(Where
R ¹ is a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-heterocycle, or —O—C _1-6 alkyl. Group, or —S—C _1-6 alkyl group, any of which may have a substituent,
R ² is a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-heterocycle, or —O—C _1-6 alkyl. Group, or —S—C _1-6 alkyl group, any of which may have a substituent,
Two M ¹ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. )

  According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the metallo-β-lactamase inhibitor, a β-lactam antibiotic, and optionally a pharmaceutically acceptable carrier. .

  Moreover, according to another aspect of the present invention, there is provided a method for treating bacterial infection, comprising administering a β-lactam antibiotic and the metallo-β-lactamase inhibitor in combination. Provided.

（式中、
Ｒ^３はＣ_１−６アルキル基またはＣ_３−７環状アルキル基を表し、これらはいずれも置換基を有していてもよく、ただしＣ_１−２鎖状アルキル基の場合は少なくとも1つ置換基を有していなくてはならず、
Ｒ^４はＣ_１−６アルキル基、Ｃ_３−７環状アルキル基を表し、これらはいずれも置換基を有していてもよく、
二つのＭ^２は、同一または異なっていてもよく、水素原子、医薬的に許容されるカチオン、または医薬的に許容される生体内で加水分解されうる基を表す。） Moreover, according to another aspect of this invention, the compound represented by the following general formula (II), its salt, or those solvates are provided.

(Where
R ³ represents a C _1-6 alkyl group or a C _3-7 cyclic alkyl group, any of which may have a substituent group, provided that at least one in the case of C _1-2 chain alkyl group substituted Must have a group,
R ⁴ represents a C _1-6 alkyl group or a C _3-7 cyclic alkyl group, any of which may have a substituent,
Two M ² may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. )

（式中、
Ｒ^５はエチル基を表し、
Ｒ^６はＣ_１−３鎖状アルキル基を表し、
二つのＭ^３は、同一または異なっていてもよく、医薬的に許容されるカチオン、または医薬的に許容される生体内で加水分解されうる基を表す。） Moreover, according to another aspect of this invention, the compound represented by the following general formula (III), its salt, or those solvates are provided.

(Where
R ⁵ represents an ethyl group,
R ⁶ represents a C _1-3 chain alkyl group,
The two M ³ may be the same or different and represent a pharmaceutically acceptable cation or a group that can be hydrolyzed in vivo in a pharmaceutically acceptable organism. )

（式中、
Ｒ^７はＣ_１−６アルキル基、Ｃ_３−７環状アルキル基、−Ｃ_１−３アルキレン−フェニル基、−Ｃ_１アルキレン−Ａ環、−Ｏ−Ｃ_１−６アルキル基、または−Ｓ−Ｃ_１−６アルキル基を表し、いずれも置換基を有していてもよく、
Ｒ^８は−Ｃ_１−３アルキレン−フェニル基、−Ｃ_０−１アルキレン−Ａ環、−Ｏ−Ｃ_１−６のアルキル基、または−Ｓ−Ｃ_１−６アルキル基を表し、いずれも置換基を有していてもよく、
Ａ環は窒素原子、酸素原子、および硫黄原子から選択されるヘテロ原子を１〜４個含む、５〜１０員の単環または二環性複素環を表し、
二つのＭ^４は、同一または異なっていてもよく、水素原子、医薬的に許容されるカチオン、または医薬的に許容される生体内で加水分解されうる基を表すが、
ただしＲ^７がＣ_１−６アルキル基の場合Ｒ^８はジヒドロフランは除く。） Moreover, according to another aspect of this invention, the compound represented by the following general formula (IV), its salt, or those solvates are provided.

(Where
R ⁷ represents a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a —C _1-3 alkylene-phenyl group, a —C ₁ alkylene-A ring, an —O—C _1-6 alkyl group, or —S—. _{Represents a} C _1-6 alkyl group, any of which may have a substituent,
R ⁸ represents —C _1-3 alkylene-phenyl group, —C _0-1 alkylene-A ring, —O—C _1-6 alkyl group, or —S—C _1-6 alkyl group, all of which are substituted May have a group,
Ring A represents a 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
Two of M ⁴ may be the same or different, a hydrogen atom, represents a pharmaceutically acceptable cation or a pharmaceutically acceptable hydrolyzable group in vivo,
However, when R ⁷ is a C _1-6 alkyl group, R ⁸ excludes dihydrofuran. )

（式中、
Ｒ^９はＣ_１−６アルキル基、Ｃ_３−７環状アルキル基、−Ｃ_１−３アルキレン−フェニル基、−Ｃ_０−１アルキレン−Ｂ環、−Ｏ−Ｃ_１−６アルキル基、または、−Ｓ−Ｃ_１−６アルキル基を表し、いずれも置換基を有していてもよく、
Ｒ^１０は−Ｃ_１−３アルキレン−フェニル基、−Ｃ_０−１アルキレン−Ｂ環、−Ｏ−Ｃ_１−６のアルキル基、または−Ｓ−Ｃ_１−６アルキル基を表し、いずれも置換基を有していてもよく、
Ｂ環はピリジン、ピペリジンまたはテトラヒドロピランを表し、
二つのＭ^５は、同一または異なっていてもよく、水素原子、医薬的に許容されるカチオンまたは医薬的に許容される生体内で加水分解されうる基を表すが、
ただしＲ^９がピリジニウムを表す場合は除く。） Moreover, according to another aspect of this invention, the compound represented by the following general formula (V), its salt, or those solvates are provided.

(Where
R ⁹ is a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-B ring, an —O—C _1-6 alkyl group, or -S-C _1-6 represents an alkyl group, any of which may have a substituent,
R ¹⁰ represents a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-B ring, an —O—C _1-6 alkyl group, or an —S—C _1-6 alkyl group, all of which are substituted. May have a group,
Ring B represents pyridine, piperidine or tetrahydropyran;
Two M ⁵ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation or a pharmaceutically acceptable group that can be hydrolyzed in vivo,
However, if the R ⁹ represents a pyridinium except. )

Detailed description of the invention

Definitions In this specification, unless otherwise specified, “C _1-6 ” “C _2-6 ” “C _3-7 ” “C _1-3 ” “C _0-1 ” “C _2-3 ” “C ₁ ” Etc. represent the number of carbon atoms. For example, “C _1-6 alkyl group” represents an alkyl group having 1-6 carbon atoms. C ₀ represents a bond. Lower is preferably C _1-6 , and preferably cyclic is C _3-7 .

  "Halogen atom" represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  “Heteroatom” represents a nitrogen atom, an oxygen atom, or a sulfur atom.

The “alkyl group” or “alkoxy group” as a group or a part of the group preferably means a linear or branched alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. Examples of “alkyl” include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, i-pentyl, t-pentyl, Examples include n-hexyl and i-hexyl. Examples of “alkoxy” include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, neopentyloxy, i-pentyloxy, Examples include t-pentyloxy, n-hexyloxy, i-hexyloxy and the like. The lower alkyl group preferably represents a C _1-6 alkyl group and has the same meaning as described above.

In the present specification, the term “cyclic alkyl group” as a group or part of a group preferably means a monocyclic alkyl group having 3 to 7 carbon atoms. Examples of “cyclic alkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The lower cycloalkyl group preferably represents a C _3-7 cyclic alkyl group and has the same meaning as described above.

  In the present specification, the term “alkylene” as a group or part of a group preferably means an alkylene group having 1 to 3 carbon atoms. Examples of “alkylene” include methylene, ethylene, propylene and the like.

  In the present specification, the “heterocycle” is preferably a 5- to 14-membered monocyclic to tricyclic heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. More preferably, a 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom is mentioned. Preferred examples include tetrahydrofuran, furan, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, Pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinuclidine, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, and pteridine.

  “Aryl” preferably represents an aromatic ring such as phenyl or substituted phenyl, and a condensed ring such as naphthyl, phenanthrenyl, fluorenyl, or anthryl. Preferred aryl groups are a phenyl group, a naphthyl group and a fluorenyl group.

In the present specification, the term “which may have a substituent” preferably means that it may have 1 to 6, more preferably 1 to 3 substituents. The term “substituent” refers to a hydroxyl group, a thiol group, a C _1-6 alkyl group, a C _1-6 alkoxy group, an S—C _1-6 alkyl group, an amino group, a mono-substituted amino group, a di-substituted amino group, an amide group, A guanidyl group, an N-substituted amide group, an N, N-disubstituted amide group, a halogen atom, a carboxyl group, a phenyl group, a substituted phenyl group, a C _1-6 alkylcarbonyl group, a heterocyclic ring, a heterocyclic carbonyl group, and the like. The phenyl group may be condensed. Preferred substituents include a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono-substituted amino group, a di-substituted amino group, an amide group, a guanidyl group, an N-substituted amide group, N, N -A disubstituted amide group, a halogen atom, a carboxyl group, a phenyl group (the phenyl group may be condensed), a substituted phenyl group, a C _1-6 alkylcarbonyl group, a heterocyclic ring, and a heterocyclic carbonyl group.

_{C 1-6} alkyl groups of the above-mentioned _{"substituent", C 1-6} alkoxy groups, _{S-C 1-6} alkyl _group, a _{C 1-6} alkylcarbonyl group, an alkyl group as part of the group, and an alkoxy group Is as defined above. A halogen atom is also synonymous. These C _1-6 alkyl group, C _1-6 alkoxy group, S—C _1-6 alkyl group and C _1-6 alkylcarbonyl group may be further substituted by the above-mentioned “substituent”. Especially _{C 1-6} alkyl and _{C 1-6} alkoxy groups, hydroxyl group, an amino group, monosubstituted amino group, disubstituted amino group, an amide group, a guanidyl group, N- substituted amide group, N, N- disubstituted amide Group, carboxyl group, heterocyclic ring, phenyl group, substituted phenyl group and the like.

  When the “substituent” has a carboxyl group or a carboxyl group as a part of the group, the carboxyl group is a pharmaceutically acceptable cation or a pharmaceutically acceptable group that can be hydrolyzed in vivo. For example, sodium salt, potassium salt and the like are preferable.

  “Substitution” in the above-mentioned “substituent” in the mono-substituted amino group, di-substituted amino group, amide group, N-substituted amide group, N, N-disubstituted amide group, substituted phenyl group, etc. It means having a "group".

  The heterocyclic ring in the above “substituent” and the heterocyclic ring in the heterocyclic carbonyl group have the same meaning as the above “heterocycle”.

  Preferable examples of the heterocyclic carbonyl include morpholylcarbonyl, piperazylcarbonyl, piperidylcarbonyl and the like, preferably morpholyl-4-yl-carbonyl, piperazin-4-ylcarbonyl, (4-hydroxypiperazine) -1 -Ylcarbonyl and the like.

Metallo-β-lactamase inhibitor comprising a compound represented by the general formula (I) According to one embodiment of the present invention, the compound represented by the general formula (I), a salt thereof, or a salt thereof A metallo-β-lactamase inhibitor comprising a solvate is provided.

  The compound represented by the general formula (I) has a metallo-β-lactamase inhibitory action, and the compound itself can be used as a metallo-β-lactamase inhibitor.

  As described above, metallo-β-lactamase hydrolyzes many β-lactam antibiotics and deactivates their effectiveness. Here, if the compound represented by the general formula (I) is used in combination with a β-lactam antibiotic, the activity can be recovered.

  The compound represented by the general formula (I) can be used as a metallo-β-lactamase inhibitor, or can be used in combination with a carrier and further with a pharmaceutical composition described below in combination with a β-lactam antibiotic. It is preferable to be used.

The “C _2-6 alkyl group” represented by R ¹ may be either a straight chain or branched chain, and is preferably a C _2-4 alkyl group, for example, an ethyl group, an n-propyl group, an i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, neopentyl group, i-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group, etc. Is mentioned. More preferred are ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group and t-butyl group. This alkyl group may be substituted, and examples of the substituent include the above-mentioned “substituent”, and more preferable examples of the substituent include a hydroxyl group, a thiol group, an amino group, and a halogen atom.

The “C _1-6 alkyl group” represented by R ² may be linear or branched, and is preferably a C _1-4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, neopentyl group, i-pentyl group, t-pentyl group, n-hexyl group, i- A hexyl group etc. are mentioned. More preferred are methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group and t-butyl group. This alkyl group may be substituted, and examples of the substituent include the above-mentioned “substituent”, and more preferable examples of the substituent include a thiol group, an amino group, and a halogen atom.

The “C _3-7 cyclic alkyl group” represented by R ¹ or R ² preferably includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and more preferably a cyclopentyl group, a cyclohexyl group. And cycloheptyl group. This C _3-7 cyclic alkyl group may be substituted, and examples of the substituent include the above-mentioned “substituent”. More preferable substituents include a hydroxyl group, a thiol group, a C _1-6 alkyl group, an amino group. Group and halogen atom. The C _3-7 cyclic alkyl group may also be condensed with other rings such as aryl, preferably phenyl.

Examples of the —C _1-3 alkylene-phenyl group represented by R ¹ or R ² include a benzyl group, a phenethyl group, and a phenylpropyl group. The phenyl group of the —C _1-3 alkylene-phenyl group may be substituted, and examples of the substituent include the above-mentioned “substituent”. More preferable substituents include a hydroxyl group, a C _1-6 alkyl group, -COOM (M represents a cation hydrogen atom or a pharmaceutically ^{acceptable), - CO-NR 22 R} 23 ( ^{wherein, R 22} and ^{R 23} may be the same or different, a hydrogen atom or a _{C 1 Represents a -6} alkyl group (preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group) (this alkyl group may be further substituted with an aminocarbonyl group), or R ²² and R ²³ is a 5- or 6-membered saturated heterocycle comprising 1 to 2 oxygen atoms or nitrogen atoms, preferably together with the nitrogen atom to which they are attached (preferably morpholinyl Group, a piperazyl group, or a piperidyl group) (this heterocyclic ring, especially a piperidyl group may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)), —O—R ²⁴ ( Here, R ²⁴ represents a C _1-6 alkyl group (preferably a C _1-4 alkyl group) (this alkyl group may be substituted, and as a substituent, —COOM (M is a hydrogen atom, C _{1 A -6} alkyl group or a pharmaceutically acceptable cation), an aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocycle comprising 1-2 nitrogen atoms (preferably Imidazole), a 5- or 6-membered saturated heterocycle (preferably pyrrolidine) comprising 1 to 2 nitrogen atoms, and a hydroxymethyl group.

“—C _0-1 alkylene-heterocycle” represented by R ¹ or R ² represents —bonded-heterocycle or —methylene-heterocycle, and “heterocycle” has the same meaning as above, and preferred examples As, examples thereof include a 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and more preferably a nitrogen atom or an oxygen atom. 5-6 membered saturated or unsaturated heterocycles comprising Specific examples of the “heterocycle” include tetrahydrofuran, furan, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, Pyridazine, pyrimidine, pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinuclidine, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine and the like. The bond or methylene group may be bonded to any of the heterocyclic rings. One or more hydrogen atoms on the heterocycle of the —C _0-1 alkylene-heterocycle may be substituted, and examples of the substituent include the above-mentioned “substituent”. Examples include a hydroxyl group, a thiol group, a C _1-6 alkyl group, an amino group, and a halogen atom.

The “—O—C _1-6 alkyl group” represented by R ¹ or R ² is a C _1-6 alkoxy group which may be linear, branched or cyclic, preferably —O—C _1-4 alkyl. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy and the like, more preferably methoxy, ethoxy, propoxy, isopropoxy, t-butoxy and the like. This alkyl group moiety may be substituted, and examples of the substituent include the above-mentioned “substituent”, and more preferable substituents include a hydroxyl group, a thiol group, a C _1-6 alkyl group, an amino group, and a halogen atom. And a phenyl group.

The “—S—C _1-6 alkyl group” represented by R ¹ or R ² is a C _1-6 alkylthio group which may be linear, branched or cyclic, and preferably —S—C _1-4. Examples of the alkyl group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, and the like, more preferably methylthio, ethylthio, propylthio, isopropylthio, t-butylthio and the like. This alkyl group moiety may be substituted, and examples of the substituent include the above-mentioned “substituent”, and more preferable substituents include a hydroxyl group, a thiol group, a C _1-6 alkyl group, an amino group, and a halogen atom. And a phenyl group.

M ¹ represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo.

  “Pharmaceutically acceptable cation” is a cation capable of forming a salt with one or both of the carboxyl groups of the general formula (I), and examples thereof include alkali metals, alkaline earth metals, ammonium, organic bases and the like. Preferably, lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethylamine, triethylamine, diisopropylamine and the like can be mentioned.

  “Pharmaceutically acceptable in vivo hydrolyzable group” refers to a detachable group bonded to one or both carboxyl groups of general formula (I), which undergo metabolism in vivo. Represents a group which becomes a carboxyl group upon hydrolysis and elimination.

  In the compound of the general formula (I), the “pharmaceutically acceptable group that can be hydrolyzed in vivo” is preferably an ester residue, and examples thereof include a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyloxy group. Lower alkyl group, lower cycloalkylcarbonyloxy lower alkyl group, lower cycloalkylmethylcarbonyloxy lower alkyl group, lower alkenylcarbonyloxy lower alkyl group, arylcarbonyloxy lower alkyl group, tetrahydrofuranylcarbonyloxymethyl group, lower alkoxy lower alkyl group , Lower alkoxy lower alkoxy lower alkyl group, arylmethyloxy lower alkyl group, arylmethyloxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy carbo Ruoxy lower alkoxy group, lower cycloalkoxycarbonyloxy lower alkyl group, lower cycloalkyl methoxycarbonyloxy lower alkyl group, aryloxycarbonyloxy lower alkyl group, 3-phthalidyl group optionally having a substituent on the aromatic ring, aromatic 2- (3-phthalidylidene) ethyl group, 2-oxotetrahydrofuran-5-yl group, mono-lower alkylaminocarbonyloxymethyl group, di-lower alkylaminocarbonyloxymethyl group, 2 which may have a substituent on the ring, 2 -Oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group, piperidinylcarbonyloxy lower alkyl group optionally having substituent, lower alkyl lower cycloalkylaminocarbonyloxy lower alkyl group, etc. Can be mentioned.

  As the “pharmaceutically acceptable group that can be hydrolyzed in vivo”, preferably a methyl group, an ethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, an acetoxymethyl group, a 1- (isopropyloxycarbonyloxy) ethyl group 1- (ethoxycarbonyloxy) ethyl group, pivaloyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropane- 1-yl group, isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butan-1-yl) oxycarbonyloxymethyl The group (1-ethylpropyl Pan-1-yl) oxycarbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, methoxycarbonyloxymethyl group , Cyclopentyloxycarbonyloxymethyl group, t-butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyl Oxymethyl group, 1- (neopentyloxycarbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, allyl group, 1- (t-butoxycarbonyloxy) ethyl group, (N, N-di-) n-propylamino D) Carbonyloxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylpiperidin-1-yl) Carbonyloxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl group, N, N-diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-ylaminocarbonyloxymethyl group, N- Cyclohexyl-N-ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropyla Nocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl group, 1- (N, N -Diisopropylaminocarbonyloxy) ethyl group, N-ethyl-N-isoamylaminocarbonyloxymethyl group and the like.

According to a preferred embodiment of the present invention, in the general formula (I), R ¹ is a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a benzyl group, a phenethyl group, —C _0-1. Alkylene-heterocycle (heterocycle represents tetrahydropyran, pyridine, or piperidine), —O—C _1-6 alkyl group, or —S—C _1-6 alkyl group, each of which represents a substituent. R ² may be a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a benzyl group, a phenethyl group, a —C _0-1 alkylene-heterocycle (the heterocycle is tetrahydropyran). , Pyridine, or piperidine), —O—C _1-6 alkyl group, or —S—C _1-6 alkyl group, all of which may have a substituent, and M ¹ is same It may be one or different and represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo.

In this embodiment, the “substituent” has the same meaning as described above, and more preferably a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a carboxy group, an amide group, a phenyl group (which is condensed to a ring). A heterocyclic carbonyl group which may have a substituent (for example, a piperidine carbonyl group, an acyloxypiperidine carbonyl group, a hydroxypiperidine carbonyl group, a piperazine carbonyl group, a morpholine carbonyl group, etc.), a heterocyclic ring. A C _1-6 alkoxy group (such as imidazolyl C _1-6 alkoxy group), a heterocyclic oxy group (such as pyrrolidineoxy group), an aminooxo C _1-6 alkylcarbamoyl group, a carboxyl group, Amino C _1-6 alkoxy group, guanidyl group, guanidyl C _1-6 a Alkyl group, guanidyl _{C 1-6} alkoxy _group, and _{C 1-6} alkoxy-oxo _{C 1-6} alkoxy group.

M ¹ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo.

  The “pharmaceutically acceptable cation” preferably includes lithium, sodium, potassium, magnesium, calcium, ammonium, ethanolamine, triethanolamine, trimethylamine, triethylamine, diisopropylamine and the like.

  The “pharmaceutically acceptable group capable of being hydrolyzed in vivo” refers to a detachable group bonded to one or both carboxyl groups of the general formula (I), which are metabolized in vivo. Represents a group which becomes a carboxyl group upon hydrolysis and elimination.

  In the compound of the general formula (I), “a pharmaceutically acceptable group that can be hydrolyzed in vivo” is preferably a methyl group, an ethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, an acetoxymethyl group, 1 -(Isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, pivaloyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxy) (Carbonyloxy) -2-methylpropan-1-yl group, isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butane -1-yl) oxycarbonylo Cymethyl group, (1-ethylpropan-1-yl) oxycarbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl Group, methoxycarbonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, t-butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran -4-yl) oxycarbonyloxymethyl group, 1- (neopentyloxycarbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, allyl group, 1- (t-butoxycarbonyloxy) ethyl group, ( , N-di-n-propylamino) carbonyloxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6 -Dimethylpiperidin-1-yl) carbonyloxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N -Methylaminocarbonyloxymethyl group, N, N-diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-yl Aminocarbonyloxymethyl group, N-cyclohexyl-N-ethylaminocarbonyloxymethyl group, N-I Butyl-N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl group, 1 -(N, N-diisopropylaminocarbonyloxy) ethyl group, N-ethyl-N-isoamylaminocarbonyloxymethyl group and the like.

As a preferred compound group of the present invention,
R ¹ is
A _C2-6 alkyl group,
C _3-7 cyclic alkyl group (this ring may be substituted with a hydroxyl group and may be condensed with aryl, preferably phenyl),
A hydroxymethyl group,
-C _1-3 alkylene - phenyl (the phenyl group may be substituted, the substituent, a hydroxyl _{group, C 1-6} alkyl group, a hydroxymethyl group, -COOM (M represents a hydrogen atom or a pharmaceutically Represents an acceptable cation), —CO—NR ²² R ^23, wherein R ²² and R ²³ may be the same or different and are each a hydrogen atom or a C _1-6 alkyl group (preferably C _1-4 An alkyl group, more preferably a C _1-2 alkyl group) (this alkyl group may be further substituted with an aminocarbonyl group), or R ²² and R ²³ are the nitrogen atom to which they are attached. Together with a 5- or 6-membered saturated heterocyclic ring containing 1 to 2 oxygen or nitrogen atoms (preferably morpholyl, piperazyl, or piperidyl (This heterocyclic ring, especially piperidyl group may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)), —O—R ²⁴ (wherein R ²⁴ is C _1-6 alkyl group (preferably C _1-4 alkyl group) (this alkyl group may be substituted, and as a substituent, -COOM (M is a hydrogen atom, C _1-6 alkyl group or pharmaceutical) ), An aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms (preferably imidazole), or And a 5- or 6-membered saturated heterocyclic ring (preferably pyrrolidine) comprising 1 to 2 nitrogen atoms).
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
R ² is
A C _1-6 alkyl group,
C _3-7 cyclic alkyl group (this ring may be substituted with a hydroxyl group and may be condensed with aryl, preferably phenyl),
A hydroxymethyl group,
-C _1-3 alkylene - phenyl (the phenyl group may be substituted, the substituent, a hydroxyl _{group, C 1-6} alkyl group, a hydroxymethyl group, -COOM (M represents a hydrogen atom or a pharmaceutically Represents an acceptable cation), —CO—NR ²² R ^23, wherein R ²² and R ²³ may be the same or different and are each a hydrogen atom or a C _1-6 alkyl group (preferably C _1-4 An alkyl group, more preferably a C _1-2 alkyl group) (this alkyl group may be further substituted with an aminocarbonyl group), or R ²² and R ²³ are the nitrogen atom to which they are attached. Together with a 5- or 6-membered saturated heterocyclic ring containing 1 to 2 oxygen or nitrogen atoms (preferably morpholyl, piperazyl, or piperidyl (This heterocyclic ring, especially piperidyl group may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)), —O—R ²⁴ (wherein R ²⁴ is C _1-6 alkyl group (preferably C _1-4 alkyl group) (this alkyl group may be substituted, and as a substituent, -COOM (M is a hydrogen atom, C _1-6 alkyl group or pharmaceutical) ), An aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms (preferably imidazole), or And a 5- or 6-membered saturated heterocyclic ring (preferably pyrrolidine) comprising 1 to 2 nitrogen atoms).
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
And a group of compounds representing —O—C _1-6 alkyl group or —S—C _1-6 alkyl group.

More preferred compounds of the formula (I) include
R ¹ is
A _C2-6 alkyl group,
C _3-7 cyclic alkyl group (this ring may be substituted with a hydroxyl group and may be condensed with aryl, preferably phenyl),
A hydroxymethyl group,
—C _1-3 alkylene-phenyl group (this phenyl group is a hydroxyl group, a C _1-6 alkyl group, a hydroxymethyl group, —COOM (M represents a hydrogen atom or a pharmaceutically acceptable cation), —CO— NR ²² R ²³ (wherein R ²² and R ²³ may be the same or different and are each a hydrogen atom or a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group). Group) (this alkyl group may be further substituted with an aminocarbonyl group), or R ²² and R ²³ together with the nitrogen atom to which they are attached, an oxygen atom or a nitrogen atom Or a 5- or 6-membered saturated heterocycle comprising 1 to 2 (preferably a morpholinyl group, a piperazyl group, or a piperidyl group). Ring, especially piperidyl group may be substituted by a hydroxyl group or a _{C 1-6} alkanoyloxy ^{group)), - O-R 24} ( ^{wherein, R 24} _{is C 1-6} alkyl group (preferably _{C 1- 4} alkyl group) (this alkyl group may be substituted, -COOM (M represents a hydrogen atom, a C _1-6 alkyl group or a pharmaceutically acceptable cation), aminocarbonyl group , An amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring (preferably imidazole) comprising 1 to 2 nitrogen atoms, or 5 or 1 to 2 nitrogen atoms 6-membered saturated heterocycle (preferably pyrrolidine)).
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
R ² is
A C _1-6 alkyl group,
A C _3-7 cyclic alkyl group (this ring may be substituted with a hydroxyl group and may be condensed with aryl, preferably phenyl), or a C _1-2 alkylene-phenyl group,
The compound group which represents is mentioned.

As a more preferred compound group,
R ¹ is
A C _2-6 alkyl group (which may be substituted with a hydroxyl group),
A C _3-7 cyclic alkyl group (which may be substituted with a hydroxyl group or condensed with a phenyl group);
A hydroxymethyl group,
C _1-2 alkylene-phenyl group (this phenyl group is a hydroxyl group, a C _1-6 alkyl group, a hydroxymethyl group, —COOM (M represents a hydrogen atom or a pharmaceutically acceptable cation), —CO—NR ²² R ²³ (wherein R ²² and R ²³ may be the same or different and are each a hydrogen atom or a C _1-6 alkyl group (preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group). ) (This alkyl group may be further substituted with an aminocarbonyl group), or R ²² and R ²³ together with the nitrogen atom to which they are attached represent an oxygen atom or a nitrogen atom. It may represent a 5- or 6-membered saturated heterocycle comprising 1 or 2 (preferably morpholinyl, piperazyl or piperidyl group) (this heterocycle In particular, the piperidyl group may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group), —O—R ²⁴ (wherein R ²⁴ is a C _1-6 alkyl group (preferably C _1-4). An alkyl group) (this alkyl group may be substituted, -COOM (M represents a hydrogen atom, a C _1-6 alkyl group or a pharmaceutically acceptable cation), an aminocarbonyl group, An amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring (preferably imidazole) comprising 1 to 2 nitrogen atoms, or 5 or 6 comprising 1 to 2 nitrogen atoms Membered saturated heterocycle (preferably pyrrolidine)).
-C _0-1 alkylene-heterocycle (wherein this heterocycle represents pyridine, morpholine, piperidine, tetrahydropyran and may be substituted with a hydroxyl group),
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
Represents
R ² is
A C _1-6 alkyl group,
A C _3-7 cyclic alkyl group,
The compound group which represents is mentioned.

As a more preferred compound group,
R ¹ is
A _C2-4 alkyl group,
C _3-7 cyclic alkyl group (may be substituted with a hydroxyl group or condensed with a phenyl group)
R ² is
A _C1-4 alkyl group,
A C _3-7 cyclic alkyl group,
The compound group which represents is mentioned.

Preferable specific examples of R ¹ or R ² are preferably ethyl, n-propyl, i-propyl, cyclopentyl, 2,3-dihydro-1H-inden-2-yl, cyclohexyl, 2- (Trans-4-hydroxycyclohexyl), 2- (cis-4-hydroxycyclohexyl), 2- (tetrahydropyran-4-yl), 2-[(piperidin-1-yl) methyl], (pyridin-3-yl) ) Methyl group, (4-hydroxypiperidin-1-yl) methyl, hydroxymethyl group, (2-methylphenyl) methyl group, methoxy group, methylthio group, isopropylthio group, benzyl group, 2- (4-hydroxybenzyl) Group, 4-methoxybenzyl group, 4-carboxybenzyl group, 4-carbamoylbenzyl group, 4- (4-acetoxypiperidine-1-carbonyl) Benzyl group, 4- (4-hydroxypiperidine-1-carbonyl) benzyl group, 4- (2-amino-2-oxoethylcarbamoyl) benzyl group, 4-hydroxybenzyl group, 4-oxidebenzyl (sodium salt) group, 4- (carboxylatemethoxy) benzyl group, 4- (2-methoxy-2-oxoethoxy) benzyl group, 4- (2-amino-2-oxoethoxy) benzyl group, 4- (2-amino-2-oxo) Ethoxy) benzyl group, 4- (2-aminoethoxy) benzyl group, 4- (morpholine-1-carbonyl) benzyl group, 4- (piperazine-1-carbonyl) benzyl group, 4- [2- (1H-imidazole- 1-yl) ethoxy] benzyl group, 4- (2-guanidinoethoxy) benzyl group, 4- (pyrrolidin-3-yloxy) benzyl group, phenethyl group and the like. That. However, R ¹ does not represent a methyl group.

In the general formula (I), R ¹ is preferably an ethyl group, an n-propyl group, an i-propyl group, a cyclopentyl group, a 2,3-dihydro-1H-inden-2-yl group, a cyclohexyl group, 2- (trans-4-hydroxycyclohexyl), 2- (cis-4-hydroxycyclohexyl), 2- (tetrahydropyran-4-yl), 2-[(piperidin-1-yl) methyl], (4-hydroxy Piperidin-1-yl) methyl, hydroxymethyl group, methoxy group, methylthio group, isopropylthio group, benzyl group, 2- (4-hydroxybenzyl) group, 4-carboxybenzyl group, 4-carbamoylbenzyl group, 4- ( 4-acetoxypiperidine-1-carbonyl) benzyl group, 4- (4-hydroxypiperidine-1-carbonyl) benzyl group, 4- (2 Amino-2-oxoethylcarbamoyl) benzyl group, 4-hydroxybenzyl group, 4-oxidebenzyl (sodium salt) group, 4- (carboxylatemethoxy) benzyl group, 4- (2-amino-2-oxoethoxy) benzyl Group, 4- (2-amino-2-oxoethoxy) benzyl group, 4- (2-aminoethoxy) benzyl group, 4- [2- (1H-imidazol-1-yl) ethoxy] benzyl group, 4- ( 2-guanidinoethoxy) benzyl group, phenethyl group and the like, and R ² is methyl group, ethyl group, n-propyl group, i-propyl group, cyclopentyl group, benzyl group, phenethyl group, (2-methylphenyl) methyl group , (Pyridin-3-yl) methyl group, 4- (morpholine-1-carbonyl) benzyl group, 4- (piperazine-1-carbonyl) benzyl group, 4-metho Shibenjiru represents group, 4- (2-methoxy-2-oxo-ethoxy) benzyl group, and 4- (pyrrolidin-3-yloxy) benzyl group.

Furthermore, specific examples of the general formula (I) are as follows.
2-ethyl-3-methylmaleic acid dimethyl ester 2-ethyl-3-methylmaleic acid disodium 2,3-diethylmaleic acid diethyl ester 2,3-diethylmaleic acid disodium 2,3-diethylmaleic acid dipotassium 2, 3-di-n-propyl maleic acid diethyl ester 2,3-di-n-propyl maleic acid disodium 2-benzyl-3-methyl maleic acid dimethyl ester 2-benzyl-3-methyl maleic acid disodium 2-benzyl- Disodium 3-ethyl maleate 3-ethyl-2- (4-hydroxybenzyl) disodium 2,3-dibenzyl disodium maleate 2-benzyl-3-phenethyl disodium maleate 2,3-diphenethyl Maleic acid diethyl ester 2,3-diphenethylma Disodium inodium 2-isopropyl-3-methylmaleate disodium 3-ethyl-2-isopropylmaleate disodium 2,3-diisopropylmaleate disodium 3-benzyl-2-isopropylmaleate disodium 2-isopropyl- Disodium 3- (2-methylphenyl) methyl maleate 2-cyclopentyl-3-ethyl disodium 2-cyclopentyl-3-isopropyl maleate disodium 3-benzyl-2-cyclopentyl maleate disodium 2,3- Disodium dicyclopentyl maleate 2- (2,3-dihydro-1H-inden-2-yl) -3-isopropyl disodium 2-cyclohexyl-3-isopropyl disodium maleate 2- (trans-4-hydroxy Cyclohexyl) -3-isopropylmaleate disodium 2- (cis-4-hydroxycyclohexyl) -3-isopropylmaleate disodium 3-isopropyl-2- (tetrahydropyran-4-yl) maleate disodium 2-isopropyl- 3-[(Pyridin-3-yl) methyl] maleic acid disodium 3-methyl-2-[(piperidin-1-yl) methyl] maleic acid dimethyl ester 3-methyl-2-[(piperidin-1-yl) Methyl] disodium maleate 2-[(4-hydroxypiperidin-1-yl) methyl] -3-methylmaleic acid dimethyl ester 2-[(4-hydroxypiperidin-1-yl) methyl] -3-methylmaleic acid Disodium 2-hydroxymethyl-3-methylmaleate disodium 3-ethyl-2-methoxymale Disodium 3-ethyl-2-methylthiomaleate disodium 3-ethyl-2-isopropylthiomaleate disodium 2- (4-carboxybenzyl) -3-isopropylmaleate dimethyl ester 2- (4-carboxybenzyl) Trisodium-3-isopropylmaleate 2- (4-carbamoylbenzyl) -3-isopropylmaleic acid dimethyl ester 2- (4-carbamoylbenzyl) -3-isopropylmaleate disodium 2-isopropyl-3- [4- (morpholine) -1-carbonyl) benzyl] maleic acid dimethyl ester 2-isopropyl 3- [4- (morpholine-1-carbonyl) benzyl] disodium maleate 2-isopropyl 3- [4- (piperazine-1-carbonyl) benzyl] malein Acid dimethyl ester hydrochloride 2- Isosodium 3- [4- (piperazine-1-carbonyl) benzyl] maleate 2- [4- (4-acetoxypiperidine-1-carbonyl) benzyl] -3-isopropylmaleate dimethyl ester 2- [4- ( 4-hydroxypiperidine-1-carbonyl) benzyl] -3-isopropylmaleate disodium 2- [4- (2-amino-2-oxoethylcarbamoyl) benzyl] -3-isopropylmaleic acid dimethyl ester 2- [4- (2-Amino-2-oxoethylcarbamoyl) benzyl] -3-isopropylmaleate disodium 2-isopropyl-3- (4-methoxybenzyl) maleate disodium 2- (4-hydroxybenzyl) -3-isopropylmalein Acid dimethyl ester 2- (4-oxidebenzyl) -3-isopropylmale Trisodium acid 2-sodium-3- [4- (2-methoxy-2-oxoethoxy) benzyl] maleic acid dimethyl ester 2- [4- (carboxylatemethoxy) benzyl] -3-isopropyltrisodium maleate 2 -[4- (2-Amino-2-oxoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester 2- [4- (2-amino-2-oxoethoxy) benzyl] -3-isopropylmaleic acid disodium 2 -[4- (2-Aminoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester 2- [4- (2-aminoethoxy) benzyl] -3-isopropylmaleate disodium 2- {4- [2- ( 1H-imidazol-1-yl) ethoxy] benzyl} -3-isopropylmaleic acid dimethyl ester 2- {4- [2- (1H-imida) Zol-1-yl) ethoxy] benzyl} -3-isopropyl maleate disodium 2-isopropyl-3- [4- (pyrrolidin-3-yloxy) benzyl] dimethyl 2-isopropyl-3- [4- (pyrrolidine) -3-yloxy) benzyl] maleic acid disodium 2- [4- (2-guanidinoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester hydrochloride 2- [4- (2-guanidinoethoxy) benzyl] -3- Isosodium maleate disodium

  The compound of the general formula (I) is preferably a pharmaceutically acceptable salt, and such a salt includes an acid addition salt. Accordingly, the compound of the general formula (I) can be used in the form of a salt derived from an inorganic acid or an organic acid. Such salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, Cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrogen bromide Acid salt, hydroiodide salt, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinic acid Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate There is a fine undecanoate salts and the like.

  The compound of general formula (I) may be a solvate.

  Examples of the solvate solvent include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform and the like.

  The compound of the general formula (I) or a salt thereof may have an asymmetric carbon in the molecule, and each of them or a mixture thereof is included in the present invention. Moreover, the compound of general formula (I) may be used in the form of the prodrug. Prodrugs are hydrolysable in the body and are preferred for oral administration due to good absorption from the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors.

Medicinal Use and Pharmaceutical Composition As described above, the compound of the general formula (I) has a metallo-β-lactamase inhibitory action, and is therefore used for inhibiting metallo-β-lactamase. One specific application mode is that it is used in combination with an antibiotic that is inactivated by metallo-β-lactamase, particularly a β-lactam antibiotic, to restore the activity of such an antibiotic and to prevent infection. It can be used for therapeutic applications.

  Therefore, according to one aspect of the present invention, there are provided a metallo-β-lactamase inhibitor and a pharmaceutical composition comprising a compound of the general formula (I) as an active ingredient in combination with a β-lactam antibiotic. Is done. That is, the metallo-β-lactamase inhibitor and the pharmaceutical composition according to the present invention are used by being administered simultaneously or sequentially with the β-lactam antibiotic.

  Examples of β-lactam antibiotics include carbapenem, penicillin, cephem, or prodrugs thereof.

  Specific examples of carbapenems include imipenem, meropenem, biapenem, doripenem, ertapenem, tevipenem (pivaloyloxymethyl (4R, 5S, 6S) -6-[(R) -1-hydroxyethyl] -4-methyl- 7-oxo-3-{[1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio})-1-azabicyclo [3.2.0] hept-2-en-2-carboxy Rate), CS-023 ((-)-(4R, 5S, 6S) -3-[[(3S, 5S) -5-[(S) -3- (2-guanidinoacetylamino) pyrrolidin-1-yl] Carbonyl] -1-methylpyrrolidin-3-yl] thio] -6-[(R) -1-hydroxyethyl] -4-methyl-7-oxo-azabicyclo [3.2.0] hept-2-ene- 2-carboxylic acid) and ME1036 ((1S, 5 , 6S) -2- [7- (1-carbamoylmethylpyridinium-3-yl) carbonylimidazo [5,1-b] thiazol-2-yl] -6-((1R) -1-hydroxyethyl) -1 -Methyl-1-carbapene-2-em-3-carboxylate) and the like. Carbapenems particularly preferred for use in combination with the compound of general formula (I) are imipenem, meropenem, biapenem and doripenem.

  Examples of penicillins include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azurocillin, mezlocillin, sulbenicillin, and other piperacillins. These penicillins are also in their prodrug form in vivo such as ampicillin, benzylpenicillin and amoxicillin acetoxymethyl, pivaloyloxymethyl, 1- (ethoxycarbonyloxy) ethyl and phthalidyl esters. Further as 6-α-carboxyacetamide as an ester that can be hydrolyzed or as an aldehyde or ketone adduct of penicillins having a 6-α-aminoacetamide side chain (for example similar derivatives of hetacillin, metampicillin and amoxicillin) It can also be used as an ester of penicillins having a side chain (for example, carbenicillin and ticarcillin) (for example, phenyl, indanyl ester, etc.). Penicillins that are particularly preferably used in combination with the compound of the general formula (I) are ampicillin, amoxicillin, carbenicillin, piperacillin, azurocillin, mezlocillin and ticarcillin. These penicillins can be used in the form of their pharmaceutically acceptable salts, such as the sodium salt. In another form, ampicillin or amoxicillin is in the form of microparticles of the zwitterionic form (ampicillin trihydrate or amoxicillin trihydrate) for injectable suspensions or infusion suspensions. It can be used in combination with I).

  Examples of cephems include cephatridine, cephalolidine, cephalotin, cephazoline, cephalexin, cefacetril, cephapilin, cefamandole nafeto, cefradine, 4-hydroxycephalexin, cefoperazone, latamoxef, cefminox, flomoxef, ceftrosine ceftazidime, Examples include cefmetazole, cefotaxime, ceftriaxone, cefepime, cefpirom, cefozopran, and other known cephems, all of which can be used in the form of a prodrug thereof. Cephems that are particularly preferred in combination with the compound of general formula (I) are cefotaxime, ceftriaxone, ceftazidime and cefepime, which can be used in the form of pharmaceutically acceptable salts such as sodium salts. .

  According to a preferred embodiment of the present invention, when a compound of general formula (I) and a carbapenem antibiotic are combined, it is also preferable to use a dehydropeptidase (DHP) inhibitor in combination. This is because many carbapenems are susceptible to degradation by DHP. Preferred DHP inhibitors include cilastatin or a salt thereof.

  According to a preferred embodiment of the present invention, it is preferable to further use another serine-β-lactamase inhibitor in addition to the compound of the general formula (I). Preferred examples include clavulanic acid, sulbactam or tazobactam. Can be mentioned.

  Preferred metallo-β-lactamase producing strains in which antibiotics and compounds of the general formula (I) are used in combination include, for example, Bacillus cereus, Bacteroides fragilis, Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomona, Shigella flexneri, Alcaligenes xylosoxidans, Legionella gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Acinetobacter baumannii, Citrobacter freundii, and Enterobacter cloacae.

  The dose of the compound of the general formula (I) and the antibiotic can vary within a wide range, but for example, a weight ratio of about 1: 0.5 to 20, preferably 1: 1 to 8 is common. .

  The compound of general formula (I) and the β-lactam antibiotic can be administered separately or can be administered in the form of a single composition comprising both active ingredients. In any embodiment, the compound of the general formula (I) and / or the antibiotic is preferably in the form of a pharmaceutical composition by combining with a pharmaceutically acceptable carrier (that is, a pharmaceutical additive). .

  The pharmaceutical composition according to the present invention can be administered orally or parenterally. Examples of parenteral administration include administration routes such as intranasal, eye drop, ear drop, transdermal, respiratory tract, intrarectal, intraurological, subcutaneous, intramuscular, and intravenous. Examples of preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, chewables, suspensions, etc., and are suitable for parenteral administration. Examples of preparations include, for example, injections, drops, inhalants, sprays, suppositories, vaginal suppositories, transdermal absorbents, transmucosal absorbents, eye drops, ear drops, nasal drops, or patches. Etc. Liquid preparations such as injections and infusions are provided as powdered pharmaceutical compositions in, for example, lyophilized form, and water or other suitable media (for example, physiological saline, glucose infusion solution, buffer solution, etc.) can be mentioned at the time of use. ) May be used by dissolving or suspending in a).

  The carrier, that is, the additive for formulation, can be appropriately selected depending on the form of the pharmaceutical composition, and the kind thereof is not particularly limited. For example, the stabilizer, surfactant, plasticizer, lubricant, solubilizer, buffer Agent, sweetener, base, adsorbent, flavoring agent, binder, suspending agent, brightener, coating agent, flavoring agent / fragrance, wetting agent, wetting regulator, filler, antifoaming agent, chewing agent Agent, refreshing agent, coloring agent, sugar-coating agent, tonicity agent, pH adjusting agent, softening agent, emulsifier, adhesive, adhesion enhancer, thickener, thickener, foaming agent, excipient, dispersion Agents, propellants, disintegrating agents, disintegrating aids, fragrances, desiccants, preservatives, preservatives, soothing agents, solvents, solubilizers, solubilizing agents, fluidizing agents, etc. You may use in combination of a seed or more. Specific examples of these pharmaceutical additives are described, for example, in the Pharmaceutical Additives Encyclopedia (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo Co., Ltd.), and those skilled in the art can use appropriate formulations according to the form of the pharmaceutical composition. A pharmaceutical composition in a desired form can be produced according to a method commonly used in the art. In general, the pharmaceutical composition can be prepared so that the substance as an active ingredient is 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W).

  Preferred examples of the carrier include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystal wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid , Trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polyisobate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, Arabia Rubber, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextri Can be used pharmaceutical additives etc., it is not limited thereto.

  The dosage and number of administrations of the pharmaceutical composition according to the present invention are not particularly limited, but appropriate dosages and administrations according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, and symptoms of patients. The number of times can be determined. In the case of oral administration, it can be administered once or several times per day so that it is 1 to 100 mg / kg as a compound of general formula (I) per day for adults. 0.1-100 mg / kg is preferably administered once or divided into several times per day.

  According to another aspect of the present invention, a compound of general formula (I), a β-lactam antibiotic, and optionally a β-lactamase inhibitor or a dehydropeptidase (DHP) inhibitor, Sequentially, there is provided a method of treating an infection comprising administering to an animal, including a human.

  Furthermore, according to another aspect of the present invention, a pharmaceutical composition comprising a β-lactam antibiotic and optionally further a β-lactamase inhibitor or a dehydropeptidase (DHP) inhibitor, particularly a therapeutic agent for infectious diseases There is provided the use of a compound of general formula (I) for the preparation of

Manufacture of a compound The compound of general formula (I) by this invention can be preferably manufactured, for example by the scheme AH shown below, or the method according to these.

  In the present specification, Me represents a methyl group, Et represents an ethyl group, TBS represents a t-butyldimethylsilyl group, TBDPS represents a t-butyldiphenylsilyl group, Ac represents an acetyl group, and Bn represents a benzyl group. .

During the above scheme ^{A~H, R 1, R 2,} M 1 are each the general formula ^{R 1, R 2, M} 1 in the formula (I) synonymous. Compounds (Ia), (Ib) and (Ic) represent the case where M ¹ of the general formula (I) is a pharmaceutically acceptable cation. R ¹¹ is hydroxyl group, thiol group, —O—C _1-6 alkyl group, —S—C _1-6 alkyl group, amino group, N-monosubstituted amino group, N, N-disubstituted amino group, nitrogen. Represents a heterocycle containing atoms. X ¹ represents a halogen atom, and P ¹ and P ² represent a protecting group for a carboxyl group.

  In Schemes A-H, if necessary, the desorption step of the protecting group is introduced in the form of a protected form, for example, if the desired substituent is incompatible with the reaction conditions of the synthesis used. It can be deprotected after completion. In addition, if necessary, the substituent itself can be converted through a desorption step of the protecting group.

  The protecting group may be appropriately determined with reference to Protective Groups in Organic Synthesis (T. W. Greene et al., Wiley, New York (1999)).

  In the present invention, the required protecting groups are mainly a hydroxyl protecting group, an amino group protecting group, or a carboxyl protecting group.

  Examples of the hydroxyl protecting group include silyl groups such as acetyl group, pivaloyl group, triethylsilyl group, t-butyldimethylsilyl (TBS) group, t-butyldiphenylsilyl (TBDPS) group, benzyl group, trityl group, and o-nitro group. Examples include benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, t-butyloxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group and the like.

  Examples of the amino protecting group include acetyl group, t-butoxycarbonyl group, benzyl group, benzyloxycarbonyl group, benzenesulfonyl group, o-nitrobenzenesulfonyl group, p-nitrobenzenesulfonyl group and the like.

  Examples of carboxyl protecting groups include silyl groups such as methyl, ethyl, t-butyl, allyl, benzhydryl, 2-naphthylmethyl, benzyl and t-butyldimethylsilyl (TBS) groups, and phenacyl groups. P-methoxybenzyl group, o-nitrobenzyl group, p-methoxyphenyl group, p-nitrobenzyl group, 4-pyridylmethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyl Examples include an oxycarbonyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group, a pivaloyloxymethyl group, a cyclohexyloxycarbonyloxymethyl group, and the like.

Scheme A
This scheme is preferred when the maleic acid diester raw material A1 is readily available from commercial sources or can be readily produced by various methods known in the art.

Conversion of the compound A1 to compound (I-a), after the M ¹ if necessary, a metal cation, tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n- propanol, water and the like, or In these mixed solvents, an alkali hydroxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) of 2 equivalents or more is allowed to act on the compound A1, and from 5 minutes at 0 ° C to 90 ° C. After reacting for 48 hours, the compound (Ia) can be obtained by vacuum concentration and vacuum drying.

Scheme B
This scheme is preferred when the maleic anhydride raw material B1 is readily available from commercial sources or can be readily produced by various methods known in the art.

The compound (Ia) is obtained by ring-opening reaction of the acid anhydride of compound B1 by a standard method. If necessary, M ¹ is converted to a metal cation, and then, in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof, 2 equivalents or more of compound B1 are added. By reacting an alkali hydroxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, and then concentrating under reduced pressure and vacuum drying. Compound (Ia) can be obtained.

Scheme C
Conversion of compound C1 to compound C2 in this scheme can be performed by the following method based on a known literature method (ES Ratemi et al., J. Org. Chem., 1996, 61, 6296).

  The acetylene dicarboxylic acid ester raw material C1 can be easily obtained from commercial sources, or can be easily produced by various methods known in the art.

One equivalent or an excess amount of bromo (dimethyl sulfide) in Compound C1, in tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane, or a mixed solvent thereof. In the presence of copper (I), one equivalent or an excess amount of the halogenated alkyl halide magnesium R ^{1 or 2} MgX ¹ is allowed to act at −80 ° C. to 0 ° C. and reacted for 5 minutes to 5 hours. Thereafter, hexamethylphosphoric triamide and alkyl halide R ^{1 or 2} X ¹ were reacted with the obtained 2-position anion body at −80 ° C. to 50 ° C. for 5 minutes to 5 hours, and then C2 was obtained by a conventional post-treatment. Can be obtained.

R ^{1 or 2} MgX ¹ is, for example, benzylmagnesium bromide, benzylmagnesium chloride, n-propylmagnesium chloride, t-butylmagnesium chloride, s-butylmagnesium bromide, c-hexylmagnesium bromide, c-pentylmagnesium bromide, Ethylmagnesium bromide, ethylmagnesium chloride, n-heptylmagnesium bromide, n-hexylmagnesium bromide, i-propylmagnesium bromide, i-propylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, n- bromide Octyl magnesium, n-pentadecyl magnesium bromide, n-pentyl magnesium bromide, phenyl magnesium bromide, phenyl magnesium chloride, phenyl magnesium iodide, n-propyl magnesium bromide, n-tetrade chloride Le magnesium bromide o- - up reel magnesium bromide m- - up reel magnesium bromide p- - up reel magnesium, vinylmagnesium bromide and the like.

R ^{1 or 2} X ¹ is, for example, methyl iodide, ethyl iodide, n-propyl iodide, i-propyl iodide, n-butyl iodide, s-butyl iodide, i-butyl iodide, bromide. Examples thereof include methyl, ethyl bromide, n-propyl bromide, i-propyl bromide, n-butyl bromide, s-butyl bromide and i-butyl bromide.

Next, the conversion of compound C2 to compound (Ia) can be carried out by the following method. Here, M ¹ is converted to a metal cation, and then at least 2 equivalents of water relative to Compound C2 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali oxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, concentration under reduced pressure and vacuum drying are performed. Compound (Ia) can be obtained.

Scheme D
This scheme is a succinic acid in which the succinic acid raw material D1 is easily available from commercial sources or can be produced by various methods known in the art (for example, JP 2003-513890 A). This is the preferred method. Conversion of compound D1 to compound D3 can be performed by the following method based on a known literature method (MJ Kates et al., J. Org. Chem., 1996, 61, 4164). That is, tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane, or a mixed solvent thereof with respect to D1 in the presence of one equivalent or an excess amount of base, One equivalent or an excess amount of a halogenated formate (for example, methyl chloroformate and ethyl chloroformate) is allowed to react and react at −80 ° C. to 80 ° C. for 5 minutes to 8 hours, and then concentrated to dryness under reduced pressure. By doing so, D2 can be obtained. Examples of the base include diisopropylethylamine, triethylamine, 2,6-lutidine, pyridine, N-methylmorpholine and the like as organic bases, and sodium hydride, sodium hydroxide, potassium hydroxide and sodium methoxy as inorganic bases. And sodium ethoxide, potassium-t-butoxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.

  Next, the conversion from compound D2 to compound D3 can be carried out by the following method. That is, the presence of one equivalent or an excess amount of base in Compound D2, in tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane, or a mixed solvent thereof. Then, one equivalent or an excess amount of trimethylsilyl trifluoromethanesulfonic acid is allowed to act, and the reaction is carried out at −80 ° C. to 100 ° C. for 5 minutes to 5 hours. Thereafter, a catalytic amount or more of tetrabutylammonium bromide and one equivalent or an excess amount of bromine are allowed to act, and after reacting at −80 ° C. to 100 ° C. for 5 minutes to 8 hours, it is subjected to a conventional post-treatment, Compound D3 can be obtained. Examples of the base include diisopropylethylamine, triethylamine, 2,6-lutidine, pyridine, N-methylmorpholine and the like as organic bases, and sodium hydride, sodium hydroxide, potassium hydroxide and sodium methoxy as inorganic bases. And sodium ethoxide, potassium-t-butoxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.

And compound (Ia) is obtained by the ring-opening reaction of the acid anhydride of compound D3 by a standard method. If necessary, M ¹ is converted to a metal cation, and then 2 equivalents or more of compound D3 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali hydroxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, and then concentrating under reduced pressure and vacuum drying. Compound (Ia) can be obtained.

Scheme E
Conversion of compound E1 to compound E2 can be performed by the following method based on a known literature method (H. Hagiwara et al., Synthetic Commun., 1984, 14, 1193). The α-halogenated carboxylic acid derivative E1 is readily available from commercial sources, or is easily produced by various methods known in the art. For compound E1, one equivalent or an excess of a strong base (for example, in tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane, or a mixed solvent thereof (for example, Lithium diisopropylamide, lithium hexamethyldisilazane, potassium hexamethyldisilazane, sodium hydride, potassium hydride) and a catalytic amount or more of copper (I) halide (for example, copper (I) chloride, Copper bromide (I) and copper iodide (I) can be mentioned.) And reacted at −90 ° C. to 20 ° C. for 5 minutes to 5 hours, and then compound E2 is obtained by a conventional post-treatment. Can do. Since this scheme is based on a dimerization reaction, it is most suitable for the synthesis of symmetrically 2,3-disubstituted maleic acids.

Next, the conversion of compound E2 to compound (Ia) can be carried out by the following method. If necessary, M ¹ is converted to a metal cation, and 2 equivalents or more of compound E2 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali hydroxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, and then concentrating under reduced pressure and vacuum drying. Compound (Ia) can be obtained.

Scheme F
Conversion from Compound F1 and Compound F2 to Compound F5 can be performed by the following method based on a known literature method (SB Singh et al., Bioorg. Med. Chem., 2000, 8, 571). The pyruvic acid derivative F1 and the compound F2 are easily available from commercial sources, or are easily produced by various methods known in the art. That is, one equivalent or excess of compound F2 in tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane, or a mixed solvent thereof. An excess amount of a strong base (for example, lithium diisopropylamide, lithium hexamethyldisilazane, potassium hexamethyldisilazane, sodium hydride, potassium hydride, etc.) is allowed to act, and at −90 ° C. to 20 ° C. for 5 minutes to 5 hours. React. The produced enolate is allowed to act on compound F1, reacted at −90 ° C. to 20 ° C. for 5 minutes to 5 hours, and then subjected to a conventional post-treatment to give compound F3.

  Next, the conversion of compound F3 to compound F4 can be performed by the following method. In an tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof, two or more equivalents of an alkali hydroxide aqueous solution (for example, sodium hydroxide, hydroxide) with respect to the compound F3 Compound F4 can be obtained by reacting at 70 ° C. to 100 ° C. for 1 hour to 48 hours and then subjecting to a conventional post-treatment.

When P ¹ in compound F3 is a protecting group that can be removed by a hydrogenation reaction (for example, a benzyl group), conversion to compound F4 can also be performed by the following method. That is, in a methanol, ethanol, tetrahydrofuran, dioxane, diethyl ether, hexane, toluene, water or a mixed solvent thereof, a catalytic amount of a metal catalyst such as nickel or palladium with respect to the compound F3 (for example, Raney nickel, palladium hydroxide-carbon). And palladium-carbon, etc.) is added, and the mixture is allowed to react for 1 to 48 hours at 0 ° C. to 50 ° C. under a hydrogen stream with vigorous stirring, and then subjected to conventional post-treatment to give compound F4. Obtainable.

  Next, the conversion of compound F4 to compound F5 can be performed by the following method. Compound F5 can be obtained by allowing an excess amount of acetic anhydride to act on compound F4, reacting at 70 ° C. to 140 ° C. for 1 hour to 48 hours, and subjecting it to conventional post-treatment.

Compound (Ia) is obtained by ring opening reaction of acid anhydride of compound F5 by standard methods. If necessary, M ¹ is converted to a metal cation, and then 2 equivalents or more of compound F4 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. An aqueous alkali hydroxide solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) is allowed to react and react at 0 ° C. to 90 ° C. for 5 minutes to 48 hours. -A) can be obtained.

Scheme F '
The conversion from Compound F1 and Compound F2 to Compound F5 can be performed by the method described in the description of Scheme F. R ^{1 ′} and R ^{2 ′} have the same meanings as R ¹ or R ² , respectively, and one or both of R ^{1 ′ and} R ^{2 ′} represent a substituent different from R ¹ or R ² .

  Next, conversion of compound F5 to compound F6 can be carried out by the following method. By allowing compound F5 to react with an equivalent amount or an excess amount of trimethylsilyldiazomethane in an alcohol such as methanol, reacting at 0 ° C. to 20 ° C. for 5 minutes to 8 hours, and then subjecting it to a conventional post-treatment, Compound F6 can be obtained.

The compound F6 can be converted into the compound F7 by using R ¹ and R ² in the compound F6 as different R ^{1 ′} and R ^{2 ′} using various methods known in the art. .

Next, the conversion of compound F7 to compound (Ia) can be carried out by the following method. Here, M ¹ is converted to a metal cation, and then at least 2 equivalents of water relative to Compound F7 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali oxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, concentration under reduced pressure and vacuum drying are performed. Compound (Ia) can be obtained.

Scheme G
Conversion of compound G1 to compound G2 can be carried out by the following method. That is, it can be easily obtained from a commercial source, or can be produced by various methods known in the art (for example, ES Ratemi et al., J. Org. Chem., 1996, 61, 6296). One equivalent or an excess of N-halogenated succinimide (for example, N-bromosuccinimide, N-chlorosuccinimide, etc.) and a catalytic amount or a catalytic amount or more with respect to compound G1 in carbon tetrachloride. And a radical initiator (for example, 2,2′-azobisisobutyronitrile, dibenzoyl peroxide, etc.) are allowed to react and react at 0 ° C. to 80 ° C. for 5 minutes to 48 hours, and then used conventionally. Compound G2 can be obtained by post-treatment.

  Next, the conversion of compound G2 to compound G3 can be carried out by the following method. That is, primary amine, secondary amine (cyclic amine is added to compound G2 in tetrahydrofuran, dioxane, diethyl ether, toluene, benzene, hexamethylphosphoric triamide, dimethylformamide, dichloromethane, dichloroethane, hexane or a mixed solvent thereof. Compound G3 by reacting with water, hydrogen sulfide, alcohol, thiol, etc. in the presence of a base and reacting at −80 ° C. to 100 ° C. for 5 minutes to 48 hours, followed by conventional post-treatment. Can be obtained.

Next, conversion of compound G3 to compound (Ib) can be carried out by the following method. Here, M ¹ is converted to a metal cation, and then at least 2 equivalents of water relative to compound G3 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali oxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, concentration under reduced pressure and vacuum drying are performed. Compound (Ib) can be obtained.

Scheme H
Compound H1 in this scheme is readily available from commercial sources or is readily prepared by various methods known in the art (eg, AM Despande et al., Synthesis, 2001, 5, 702). . Conversion from compound H1 to compound H2 can be carried out by the following method. That is, an excess amount of water is allowed to act on Compound H1 in tetrahydrofuran, dioxane, diethyl ether, hexamethylphosphoric triamide, dimethylformamide or a mixed solvent thereof in the presence of a base, and from 0 ° C. to 100 ° C. for 5 minutes. After reacting for 48 hours, compound H2 can be obtained by subjecting to conventional post-treatment.

Next, conversion of compound H2 to compound (Ic) can be carried out by the following method. Here, M ¹ is converted to a metal cation, and then at least 2 equivalents of water relative to Compound H2 in tetrahydrofuran, dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof. By reacting an alkali oxide aqueous solution (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) and reacting at 0 ° C. to 90 ° C. for 5 minutes to 48 hours, concentration under reduced pressure and vacuum drying are performed. Compound (Ic) can be obtained.

  As described above, the compounds (Ia), (Ib) and (Ic) obtained in the schemes A to H are subjected to chromatography or sephadex using a nonionic macroporous resin as necessary. It can be purified by using methods such as gel filtration, normal phase and reverse phase chromatography, and crystallization.

Conversion of M ¹ of the general formula (I) The compound (Ia), (Ib) or (Ic) which is an alkali metal salt such as sodium salt or potassium salt obtained by the above method is converted to tetrahydrofuran. , Dioxane, diethyl ether, acetonitrile, dimethylformamide, methanol, ethanol, n-propanol, water, or a mixed solvent thereof, for compound (Ia), (Ib) or (Ic), 2 or more equivalents of amine (for example, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine) hydrochloride are allowed to react and react at 0 ° C to 90 ° C for 5 minutes to 48 hours, and then concentrated under reduced pressure and vacuum dried. Thus, an ammonium salt of the general formula (I) can be obtained.

  The ammonium salt of the general formula (I) thus obtained is also optionally subjected to chromatography using a nonionic macroporous resin, gel filtration using Sephadex, etc., normal phase and reverse phase chromatography, It can be purified by using a method such as crystallization.

Further, when a group M ¹ can be hydrolyzed in vivo, the general formula (I) is obtained by the following method.

M ¹ obtained by the above method can be hydrolyzed in vivo with alkali metal salts (Ia), (Ib) or (Ic) such as sodium salt and potassium salt, which are metal cations. It is obtained by reacting a halide compound (represented as M ⁶ -X ² here) of the group.

M ⁶ has the same meaning as the group that can be hydrolyzed in the living body of the general formula (I), and X ² is chlorine, bromine, iodine, —OSO ₂ CF ₃ , —OSO ₂ CH ₃ , —OSO ₂ PhCH _3, etc. Represents a leaving group. In an alkyl halide (M ⁶ -X ² :) of 2 equivalents or more in the presence of a catalytic amount or an excess amount of a base as necessary with respect to (Ia), (Ib) or (Ic), By reacting at -70 ° C to 50 ° C (preferably, -30 ° C to 30 ° C) for 10 minutes to 24 hours, general formula (I) in which M ¹ is a group that can be hydrolyzed in vivo can be obtained. . Examples of the base include diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, 2,6-lutidine and the like as organic bases, and inorganic bases such as sodium hydroxide and potassium hydroxide. Sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like. Wherein the alkyl halide is represented by M ⁶ -X ^2, X ² represents a halogen atom or a leaving group, preferably iodine, bromine or chlorine, for example methyl iodide, ethyl iodide, 1- (cyclohexyloxy Carbonyloxy) ethyl iodide, bromomethyl acetate 1- (isopropyloxycarbonyloxy) ethyl iodide, 1- (ethoxycarbonyloxy) ethyl iodide, iodomethyl pivalate, cyclohexyloxycarbonyloxymethyl iodide, 1- (isobutyloxy) Carbonyloxy) ethyl iodide, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl iodide, isobutyloxycarbonyloxymethyl iodide, isopropyloxycarbonyloxymethyl iodide, isobutyl Ruoxymethyl iodide, (pentan-1-yl) oxycarbonyloxymethyl iodide, (butan-1-yl) oxycarbonyloxymethyl iodide, (1-ethylpropan-1-yl) oxycarbonyloxymethyl iodide , Isopentyloxycarbonyloxymethyl iodide, (propan-1-yl) oxymethyl iodide, ethoxycarbonyloxymethyl iodide, neopentyloxycarbonyloxymethyl iodide, methoxycarbonyloxymethyl iodide, cyclopentyloxycarbonyloxymethyl Iodide, t-butoxycarbonyloxymethyl iodide, 3-bromophthalide, 1- (methoxycarbonyloxy) ethyl iodide, 1- (cyclopentyloxycarbonyloxy) ethyl iodide Id, (tetrahydropyran-4-yl) oxycarbonyloxymethyl iodide, 1- (neopentyloxycarbonyloxy) ethyl iodide, (piperidin-1-yl) carbonyloxymethyl iodide, allyl iodide, 1- ( t-butoxycarbonyloxy) ethyl iodide, N, N-di (propan-1-yl) aminocarbonyloxymethyl iodide, phenyloxycarbonyloxymethyl iodide, (5-methyl-2-oxo-1,3- Dioxolen-4-yl) methyl bromide, (Z) -2- (3-phthalidylidene) ethyl bromide, (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl chloride, N, N-di-n- Chloromethyl butylcarbamate, 1-iodohexane, Nn-hexyl-N-methyl carbonate Chloromethyl vamate, chloromethyl N, N-diisobutylcarbamate, chloromethyl N, N-diisopropylcarbamate, chloromethyl N-cyclohexyl-N-methylcarbamate, chloromethyl N-pentan-1-ylcarbamate, N- Cyclohexyl-N-ethylcarbamate chloromethyl, N-isobutyl-N-isopropylcarbamate chloromethyl, Nt-butyl-N-ethylcarbamate chloromethyl, N, N-diisopropylcarbamate-1-chloroethyl, 1- [(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride, N-ethyl-N-isoamylcarbamate chloromethyl, etc.), alone or in combination with an inert solvent (eg, N, N- Dimethylformamide, N, N-dimethylacetate Amide, N, N-diethylformamide, N, N-diethylacetamide, N-methylpyrrolidinone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, Examples include diethyl ether, anisole, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphoric triamide, methanol, ethanol and the like. In addition, a group that can be hydrolyzed in vivo in a portion corresponding to M ¹ is introduced in advance at the initial stage of the processes of Schemes A to H, and can be obtained according to each scheme.

  The ester (I) obtained as above can be isolated and purified by precipitation, gel filtration using Sephadex, etc., normal phase and reverse phase silica gel column chromatography, etc. .

Novel compounds represented by general formula (II), formula (III), formula (IV), and formula (V) The compound group represented by general formula (I) includes new compounds. Therefore, according to another aspect of the present invention, novel 2,3-disubstituted maleic acid derivatives are provided, specifically the general formulas (II), (III), (IV), and A novel compound represented by the formula (V) is provided.

Compound of General Formula (II) In the above formula (II), R ³ represents a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, or a hydroxymethyl group, all of which have a substituent. R ⁴ represents a C _1-6 alkyl group or a C _3-7 cyclic alkyl group, any of which may have a substituent. Here, the “C _1-6 alkyl group” or “C _2-6 alkyl group” represented by R ³ or R ⁴ may be either linear or branched, preferably C _1-4 alkyl. Or a _C2-4 alkyl group, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl Group, neopentyl group, i-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group and the like. The “C _3-7 cyclic alkyl group” represented by R ³ or R ⁴ preferably includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and more preferably a cyclopentyl group, a cyclohexyl group. And cycloheptyl group.

  Any of these may have a substituent described for the general formula (I), and preferred examples thereof are the same as those for the general formula (I).

M ² represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo.

The “pharmaceutically acceptable cation” represented by M ^{2 has} the same meaning as in general formula (I).

Compounds R ⁵ of formula (III), represents an ethyl group, ^{R 6} is _{C 1-3} chain alkyl groups, i.e. methyl, ethyl, represents a propyl group.

M ³ may be the same or different and represents “pharmaceutically acceptable cation” or “pharmaceutically acceptable group capable of being hydrolyzed in vivo”. That is, it represents a salt or an ester having a group that can be hydrolyzed in vivo.

The “pharmaceutically acceptable cation” represented by M ^{3 has} the same meaning as in general formulas (I) and (II).

The “pharmaceutically acceptable in-vivo hydrolyzable group” represented by M ³ represents a detachable group bonded to one or both carboxyl groups of the general formula (III), which are in vivo Represents a group which undergoes metabolism, is hydrolyzed and eliminated, and becomes a carboxyl group, and is synonymous with the general formula (II).

The “C _1-6 alkyl group” represented by the compound R ⁷ of the general formula (IV) and the “C _3-7 cyclic alkyl group” represented by R ⁷ are as defined in the general formulas (I) and (II), and The preferable example is the same as that of general formula (I).

The “—C _1-3 alkylene-phenyl group” represented by R ⁷ or R ⁸ has the same meaning as in general formula (I), and preferred examples thereof are also the same as in general formula (I).

The “—C ₁ alkylene-A ring” represented by R ⁷ or the “—C _0-1 alkylene-A ring” represented by R ⁸ means that the A ring is connected via methylene or methylene / bond, and the A ring is nitrogen. A 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 atoms, oxygen atoms, or sulfur atoms. More preferred is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen atom or oxygen atom. Specific examples of the “heterocycle” include tetrahydrofuran, furan, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, Pyridazine, pyrimidine, pyrazine, triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinuclidine, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine and the like. The bond or methylene group may be bonded to any of the heterocyclic rings. However, when R ⁷ is a C _1-6 alkyl group, R ⁸ excludes dihydrofuran.

R ⁷ or ^{R 8} represents an "alkyl _{-O-C 1-6",} and ^{R 7} or ^{R 8} represents _{"-S-C 1-6} alkyl group", the general formula (I) interchangeably And preferred examples thereof are also the same as those in formula (I).

Any of these may have the aforementioned substituent.
M ⁴ may be the same or different and each represents a hydrogen atom, “pharmaceutically acceptable cation” or “pharmaceutically acceptable group that can be hydrolyzed in vivo”.

The “pharmaceutically acceptable cation” represented by M ^{4 has} the same meaning as in general formulas (I) and (II), and preferred examples thereof are also the same as in general formula (I).

The “pharmaceutically acceptable in vivo hydrolyzable group” represented by M ⁴ represents a detachable group bonded to one or both of the carboxyl groups of the general formula (IV), and these are in vivo Represents a group which undergoes metabolism, hydrolyzes and desorbs to become a carboxyl group, and is synonymous with the general formula (II).

The “C _1-6 alkyl group” represented by the compound R ⁹ of the general formula (V) and the “C _3-7 cyclic alkyl group” represented by R ⁹ have the same _{meanings as} the general formulas (I) and (II). Preferred examples thereof are also the same as those in the general formula (I).

The “—C _1-3 alkylene-phenyl group” represented by R ⁹ or R ¹⁰ has the same meaning as in formula (I), and preferred examples thereof are also the same as in formula (I).

The “—C _0-1 alkylene-B ring” represented by R ⁹ or R ¹⁰ is bonded to the B ring or via methylene, and the B ring represents pyridine, piperidine, or tetrahydropyran. However, R ⁹ and R ¹⁰ are excluded from pyridinium (when bonded on the nitrogen atom of pyridine to form a quaternary salt).

The “—O—C _1-6 alkyl group” or “—S—C _1-6 alkyl group” represented by R ⁹ or R ¹⁰ has the same meaning as in the general formula (I), and preferred examples thereof are also represented by the general formula. Same as (I).

Any of these may have the aforementioned substituent.
M ⁵ may be the same or different and each represents a hydrogen atom, “pharmaceutically acceptable cation” or “pharmaceutically acceptable group that can be hydrolyzed in vivo”.

The “pharmaceutically acceptable cation” represented by M ^{5 has} the same meaning as in general formulas (I) and (II), and preferred examples thereof are also the same as in general formula (I).

The “pharmaceutically acceptable in vivo hydrolyzable group” represented by M ⁵ represents a detachable group bonded to one or both of the carboxyl groups of the general formula (V), which are in vivo. Represents a group that undergoes metabolism, hydrolyzes and desorbs to become a carboxyl group, and has the same meaning as in formula (II).

  The compounds of the general formulas (II) to (V) can be produced by a method according to the production method of the compound of the general formula (I) described above.

  The compounds of the general formulas (II) to (V) can also be produced by known methods, for example, the schemes (A to H) or a method analogous thereto, as in the case of the compounds of the general formula (I).

  Hereinafter, the present invention will be described by way of examples, but the present invention is not limited thereto. Tables 1-1 to 5 show the structures of the example compounds.

Example 1 :
2-Ethyl-3-methylmaleic acid dimethyl ester
Bromo (dimethylsulfide) copper (I) (1.08 g, 5.25 mmol) was suspended in dehydrated tetrahydrofuran (24 mL) and stirred vigorously at −50 ° C. with 1.06 M ethylmagnesium chloride-tetrahydrofuran solution (4.8 mL 5.1 mmol) was added dropwise. The mixture was stirred at the same temperature for 2 hours and further stirred at -78 ° C for 5 minutes. A solution of dimethyl acetylenedicarboxylate (563 mg, 3.96 mmol) in tetrahydrofuran (8 mL) was added dropwise thereto. After 40 minutes, a solution of hexamethylphosphoric triamide 4 mL in tetrahydrofuran (4 mL) was added dropwise at the same temperature, and a solution of methyl iodide (1.44 g, 10.1 mmol) in tetrahydrofuran (8 mL) was further added dropwise. After stirring for 20 minutes, the temperature was raised to room temperature. Saturated aqueous ammonium chloride solution (10 mL, adjusted to pH 8 with aqueous ammonia) was added at −20 ° C., and the temperature was raised to room temperature again. The reaction solvent was distilled off under reduced pressure, and diethyl ether and water were added for liquid separation. The aqueous layer was extracted three times with diethyl ether, the combined organic layer was washed with saturated aqueous ammonium chloride solution, water and saturated brine, and the organic layer was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate). 9: 1) to give 98.2 mg (yield 14%) of the title compound as a syrup.
¹ H NMR (CDCl ₃ ) δ 1.07 (t, J = 7.5 Hz, 3H), 1.95 (s, 3H), 2.37 (q, J = 7.5 Hz, 2H), 3.75 (s, 3H), 3.78 (s, 3H).

Example 2 :
Disodium 2-ethyl-3-methylmaleate
2-ethyl-3-methylmaleic acid dimethyl ester (86.5 mg, 0.465 mmol) is dissolved in 1,4-dioxane (1.0 mL), and 1 M aqueous sodium hydroxide solution (0.93 mL, 0.93 mmol) is added at room temperature. The mixture was stirred at 50 ° C. for 4 hours. The reaction solvent was distilled off under reduced pressure, and the obtained residue was vacuum-dried to obtain 93.8 mg (quantitative) of the title compound as a solid.
¹ H NMR (D ₂ O) δ 0.81 (t, J = 7.6 Hz, 3H), 1.64 (s, 3H), 2.08 (q, J = 7.6 Hz, 2H); MS (FAB +) m / z 203 [( M + H) ⁺ ].

Example 3 :
2,3-diethylmaleic acid diethyl ester
In an argon atmosphere, diisopropylamine (654 mg, 6.46 mmol) was dissolved in dehydrated tetrahydrofuran (5 mL), and 1.58 M n-butyllithium-hexane solution (3.9 mL, 6.4 mmol) was added with stirring under ice cooling. The mixture was stirred at 0 ° C. for 10 minutes and at −90 ° C. for 5 minutes. A solution of ethyl 2-bromo-n-butyrate (1.00 g, 5.13 mmol) in tetrahydrofuran (9.5 mL) was added dropwise at −90 ° C., and the mixture was stirred for 30 minutes. Copper (I) iodide (489 mg, 2.56 mmol) was added at the same temperature, and the mixture was further stirred vigorously for 5 minutes. The temperature was raised to 0 ° C. with stirring, and a saturated aqueous ammonium chloride solution (30 mL) was added. The reaction solution was filtered as it was, and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with water and saturated brine and concentrated. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) to give 368.4 mg (yield 63%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 1.07 (t, J = 7.5 Hz, 6H), 1.30 (t, J = 7.1 Hz, 6H), 2.37 (q, J = 7.5 Hz, 4H), 4.22 (q, J = 7.1 Hz, 4H); MS (ESI +) m / z 229 [(M + H) ⁺ ].

Example 4 :
Disodium 2,3-diethylmaleate
Dissolve 2,3-diethylmaleic acid diethyl ester (368 mg, 1.61 mmol) in 1,4-dioxane (3.2 mL), add 1 M aqueous sodium hydroxide solution (3.2 mL, 3.2 mmol) at room temperature, and add 50 Stir at 15 ° C. for 15 hours. The solvent of the reaction solution was concentrated under reduced pressure, and the resulting residue was vacuum-dried to obtain 346 mg (quantitative) of the title compound as a colorless solid.
¹ H NMR (D ₂ O) δ 0.83 (t, J = 7.5 Hz, 6H), 2.11 (q, J = 7.5 Hz, 4H); MS (FAB +) m / z 217 [(M + H) ⁺ ].

Example 5 :
Dipotassium 2,3-diethylmaleate
In the same manner as in Example 4, 2,3-diethylmaleic acid diethyl ester was reacted with 1 M aqueous potassium hydroxide to give a solid title compound (quantitative).
MS (FAB +) m / z 249 [(M + H) ⁺ ].

Example 6 :
2,3-di-n-propylmaleic acid diethyl ester
The oily title compound (yield 85%) was obtained from ethyl 2-bromo-n-valerate in the same manner as in Example 3.
¹ H NMR (CDCl ₃ ) δ 0.95 (t, J = 7.5 Hz, 6H), 1.30 (t, J = 7.2 Hz, 6H), 1.47 (m, 4H), 2.33 (m, 4H), 4.20 (q, J = 7.2 Hz, 4H).

Example 7 :
Disodium 2,3-di-n-propylmaleate
In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2,3-di-n-propylmaleic acid diethyl ester.
¹ H NMR (D ₂ O) δ 0.74 (t, J = 7.5 Hz, 6H), 1.20 (tq, J = 7.5, 7.8 Hz, 4H) 2.07 (t, J = 7.8 Hz, 4H); MS (FAB +) m / z 245 [(M + H) ⁺ ].

Example 8 :
2-Benzyl-3-methylmaleic acid dimethyl ester
In the same manner as in Example 1, dimethyl acetylenedicarboxylate was reacted with benzylmagnesium chloride and methyl iodide to give the oily title compound (yield 24%).
¹ H NMR (CDCl ₃ ) δ 2.04 (s, 3H), 3.66 (s, 3H), 3.72 (s, 2H), 3.78 (s, 3H), 7.15-7.32 (m, 5H).

Example 9 :
2-Benzyl-3-methyl maleate disodium
In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2-benzyl-3-methylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 1.75 (s, 3H), 3.49 (s, 2H), 7.09-7.23 (m, 5H); MS (FAB +) m / z 265 [(M + H) ⁺ ].

Example 10 (Synthesis example) :
2-Benzyl-3-ethylmaleic anhydride
a) Diisopropylamine (759 mg, 7.5 mmol) was added to dehydrated tetrahydrofuran (5 mL) under a nitrogen stream and cooled to -78 ° C. To this solution was added a 1.58 M n-butyllithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at -78 ° C for 5 minutes and at 0 ° C for 15 minutes. The prepared tetrahydrofuran solution of lithium diisopropylamide was cooled to −78 ° C., and a solution of 3-phenylpropionic acid ethyl ester (891 mg, 5.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 1 hour, and further at −78 ° C. Stir for 1 hour. Using a cannula, the prepared tetrahydrofuran solution of enolate was added dropwise to a solution of 2-ketobutyric acid ethyl ester (781 mg, 6.0 mmol) in dehydrated tetrahydrofuran (5 mL) cooled to -78 ° C. After stirring at -78 ° C for 2 hours, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) to give 1.12 g of oily 3-benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester (yield). 73%) was obtained as a mixture of diastereomers.

  b) Dissolve the resulting 3-benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester in 1,4-dioxane (5 mL), water (5 mL), 5 M aqueous sodium hydroxide solution (15 mL) And stirred at 100 ° C. for 15 hours. The reaction mixture was cooled to room temperature, adjusted to pH 1 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure to give solid 3-benzyl-2-ethyl-2-hydroxysuccinic acid 1.0 g. (Quantitative) was obtained.

c) The obtained 3-benzyl-2-ethyl-2-hydroxysuccinic acid was dissolved in acetic anhydride (35 mL) and stirred at 110 ° C. for 15 hours. Acetic anhydride in the reaction solution was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-toluene-ethyl acetate 8: 3: 1) to give 619 mg (yield 79%) of the oily title compound. Got.
¹ H NMR (CDCl ₃ ) δ 1.13 (t, J = 7.8 Hz, 3H), 2.49 (q, J = 7.8 Hz, 2H), 3.79 (s, 2H), 7.18-7.49 (m, 5H); MS ( EI) m / z 216 (M ⁺ ).

Example 11 :
2-Benzyl-3-ethylmaleic acid disodium 2-benzyl-3-ethylmaleic anhydride (619 mg, 2.86 mmol) is dissolved in 1,4-dioxane (3.0 mL) and 1 M hydroxylated at room temperature. Sodium aqueous solution (5.73 mL, 5.73 mmol) was added and stirred for 10 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was vacuum-dried to obtain 800 mg (quantitative) of the title compound as a colorless solid.
¹ H NMR (D ₂ O) δ 0.85 (t, J = 7.5 Hz, 3H), 2.20 (q, J = 7.5 Hz, 2H), 3.79 (s, 2H), 7.08-7.31 (m, 5H); MS (FAB +) m / z 279 [(M + H) ⁺ ].

Example 12 (Synthesis example) :
3- (4-t-Butyldimethylsilyloxyphenyl) propionic acid ethyl 3- (4-hydroxyphenyl) propionic acid ethyl ester (940 mg, 4.84 mmol) was dissolved in dehydrated dimethylformamide (9.4 mL) at room temperature. T-butyldimethylsilane chloride (1.0 g, 6.6 mmol) and imidazole (490 mg, 1.5 mmol) were added, and the mixture was allowed to stand at the same temperature for 14 hours. The reaction mixture was concentrated as it was and subjected to silica gel column chromatography (hexane-ethyl acetate 25: 1 → 20: 1) to obtain 1.49 g (quantitative) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 0.18 (s, 6H), 0.97 (s, 9H), 1.23 (t, J = 7.0 Hz, 3H), 2.57 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 6.57 (m, 2H), 6.87 (m, 2H).

Example 13 (Synthesis example) :
2- (4-Acetoxybenzyl) -3-ethylmaleic anhydride
a) Under an argon atmosphere, diisopropylamine (572 mg, 5.65 mmol) was dissolved in dehydrated tetrahydrofuran (7 mL), and a 1.54 M n-butyllithium-hexane solution (3.5 mL, 5.4 mmol) was added while stirring under ice-cooling. In addition, the mixture was stirred at 0 ° C. for 10 minutes and at −78 ° C. for 5 minutes. At the same temperature, a solution of ethyl 3- (4-t-butyldimethylsilyloxyphenyl) propionate (1.47 g, 4.78 mmol) in anhydrous tetrahydrofuran (7 mL) was added dropwise over 6 minutes, and the mixture was further stirred for 20 minutes. Using a cannula, the prepared tetrahydrofuran solution of enolate was added dropwise into a solution of 2-ketobutyric acid ethyl ester (518 mg, 3.98 mmol) in dehydrated tetrahydrofuran (5 mL) cooled to -78 ° C. After stirring at -78 ° C for 1 hour, acetic acid was added to adjust to pH 4, and the temperature was raised to room temperature. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The organic layer was washed with saturated brine, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1 → 5: 1) to give oily 3- (4-t-butyl). Dimethylsilyloxybenzyl) -2-ethyl-2-hydroxysuccinic acid diethyl ester 433 mg (low polar diastereomer, 25% yield) and 290 mg (high polar diastereomer, 17% yield) were obtained, respectively. .

  b) 3- (4-t-Butyldimethylsilyloxybenzyl) -2-ethyl-2-hydroxysuccinic acid diethyl ester (425 mg, 0.968 mmol) was dissolved in 1,4-dioxane (3.9 mL) at room temperature. 1 M lithium hydroxide aqueous solution (3.9 mL, 3.9 mmol) was added, and the mixture was stirred at 60 ° C. for 22 hours. While the reaction solution was stirred under ice-cooling, 1 M hydrochloric acid was added to adjust to pH 1. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was concentrated under reduced pressure and dried under vacuum to obtain 343 mg (crudely purified) of solid 3- (4-t-butyldimethylsilyloxybenzyl) -2-ethyl-2-hydroxysuccinic acid.

c) Acetic anhydride (5 mL) was added to the obtained crude 3- (4-t-butyldimethylsilyloxybenzyl) -2-ethyl-2-hydroxysuccinic acid and stirred at 115 ° C. for 3 hours. Acetic anhydride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (toluene-ethyl acetate 19: 1 → 16: 1) to give 210 mg of oily title compound (yield of 2 steps: 79%) Got. ¹ H NMR (CDCl ₃ ) δ 1.16 (t, J = 7.6 Hz, 3H), 2.30 (s, 3H), 2.51 (q, J = 7.6 Hz, 2H), 3.78 (s, 2H), 7.05 (m, 2H), 7.50 (m, 2H).

Example 14 :
3-ethyl-2- (4-hydroxybenzyl) maleate disodium In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2- (4-acetoxybenzyl) -3-ethylmaleic anhydride. Obtained.
¹ H NMR (D ₂ O) δ 0.83 (t, J = 7.6 Hz, 3H), 2.18 (q, J = 7.6 Hz, 2H), 3.40 (s, 2H), 6.66 (m, 2H), 6.99 (m , 2H); MS (FAB +) m / z 295 [(M + H) ⁺ ].

Example 15 (Synthesis example) :
2,3-dibenzylmaleic anhydride
a) (2S, 3S) -2,3-dibenzylsuccinic acid (252 mg, 0.845 mmol) was dissolved in dehydrated tetrahydrofuran (2.5 mL) and stirred under ice cooling with N-methylmorpholine (90 mg, 0.89 mmol) and ethyl chloroformate (97 mg, 0.89 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated and dried under reduced pressure as it was to obtain 340 mg (crudely purified) of solid (2S, 3S) -2,3-dibenzylsuccinic anhydride.

b) The obtained (2S, 3S) -2,3-dibenzylsuccinic anhydride was suspended in dehydrated toluene (3.5 mL), and triethylamine (361 mg, 2.54 mmol) and trimethylsilyl were stirred with stirring under ice cooling. Trifluoromethanesulfonic acid (565 mg, 2.54 mmol) was added and stirred at 90 ° C. for 2 hours. While stirring the reaction solution under ice cooling, a solution of tetrabutylammonium bromide (2.7 mg, 0.00845 mmol) in dichloromethane (3 mL) and bromine (140 mg, 0.876 mmol) were added dropwise, and the mixture was stirred at the same temperature for 30 minutes. . The residue obtained by concentrating the reaction solution as it was under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 59 mg of the title compound as a solid (2 step yield: 25%).
¹ H NMR (CDCl ₃ ) δ 3.80 (s, 4H), 7.14 (m, 4H), 7.28 (m, 6H).

Example 16 :
Disodium 2,3-dibenzylmaleate
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2,3-dibenzylmaleic anhydride.
¹ H NMR (D ₂ O) δ 3.59 (s, 4H), 7.10-7.21 (m, 10H); MS (FAB +) m / z 341 [(M + H) ⁺ ].

Example 17 (Synthesis example) :
2-Benzyl-3-phenethylmaleic anhydride
a) Under an argon atmosphere, diisopropylamine (1.44 g, 14.3 mmol) was dissolved in dehydrated tetrahydrofuran (20 mL), and 1.54 M n-butyllithium-hexane solution (8.8 mL, 13.6 mmol) was added while stirring under ice cooling. In addition, the mixture was stirred at 0 ° C for 10 minutes and at -78 ° C for 5 minutes. At the same temperature, a solution of ethyl 3-phenylpropionate (2.14 g, 12.0 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise over 6 minutes, and the mixture was further stirred for 20 minutes. Using a cannula, the prepared enolate in tetrahydrofuran was added dropwise to a solution of 2-oxo-4-phenylbutyric acid ethyl ester (2.05 g, 10 mmol) in dehydrated tetrahydrofuran (10 mL) cooled to −78 ° C. After stirring at -78 ° C for 1 hour, acetic acid was added to adjust to pH 4, and the temperature was raised to room temperature. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The organic layer was washed with saturated brine, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to give oily 3-benzyl-2-phenethyl-2-hydroxysuccinate. Acid diethyl ester 806 mg (low polarity diastereomer, yield 21%) and 412 mg (high polarity diastereomer, yield 13%) were obtained, respectively.

  b) 3-Benzyl-2-hydroxy-2-phenethylsuccinic acid diethyl ester (806 mg, 2.1 mmol) was dissolved in 1,4-dioxane (8.0 mL), and 1 M aqueous lithium hydroxide solution (8.4 mL, (8.4 mmol) was added, and the mixture was stirred at 60 ° C. for 48 hours. While the reaction solution was stirred under ice-cooling, 1 M hydrochloric acid was added to adjust to pH 1. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was concentrated under reduced pressure and vacuum dried to obtain 651 mg (crude purification) of solid 3-benzyl-2-hydroxy-2-phenethylsuccinic acid.

c) Acetic anhydride (2.5 mL) was added to the obtained crude 3-benzyl-2-hydroxy-2-phenethylsuccinic acid, and the mixture was stirred at 115 ° C. for 3 hours. Acetic anhydride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain 180 mg of the title compound as a solid (2 step yield: 81%).
¹ H NMR (CDCl ₃ ) δ 2.73 (m, 2H), 2.82 (m, 2H), 3.51 (s, 2H), 7.09 (m, 4H), 7.22-7.32 (m, 6H).

Example 18 :
2-Benzyl-3-phenethylmaleate disodium In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-benzyl-3-phenethylmaleic anhydride.
¹ H NMR (D ₂ O) δ 2.44 (m, 2H), 2.53 (m, 2H), 3.44 (s, 2H), 7.07-7.23 (m, 10H); MS (FAB +) m / z 355 [(M + H ) ⁺ ].

Example 19 :
2,3-diphenethylmaleic acid diethyl ester
In the same manner as in Example 3, an oily title compound (yield 70%) was obtained from 2-bromo-4-phenylbutyric acid ethyl ester.
¹ H NMR (CDCl ₃ ) δ 1.32 (t, J = 7.2 Hz, 6H), 2.51-2.67 (m, 8H), 4.22 (q, J = 7.2 Hz, 4H), 7.14-7.30 (m, 10H).

Example 20 :
Disodium 2,3-diphenethylmaleate
In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2,3-diphenethylmaleic acid diethyl ester.
¹ H NMR (D ₂ O) δ 2.30 (m, 4H), 2.49 (m, 4H), 7.08-7.23 (m, 10H); MS (FAB +) m / z 369 [(M + H) ⁺ ].

Example 21 (synthesis example) :
2-Isopropyl-3-methylmaleic anhydride
a) Diisopropylamine (759 mg, 7.5 mmol) was added to dehydrated tetrahydrofuran (5 mL) under a nitrogen stream and cooled to -78 ° C. To this solution was added a 1.58 M n-butyllithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at -78 ° C for 5 minutes and at 0 ° C for 15 minutes. The prepared solution of lithium diisopropylamide in tetrahydrofuran is cooled to -78 ° C, and a solution of benzyl propionate (821 mg, 5.0 mmol) in dehydrated tetrahydrofuran (10 mL) is added dropwise over 1 hour, followed by stirring at -78 ° C for 1 hour. did. The prepared enolate solution was added to a solution of 3-methyl-2-ketobutyric acid benzyl ester (1.24 g, 6.0 mmol) in dehydrated tetrahydrofuran (5 mL) cooled to −78 ° C. using a cannula. After stirring at -78 ° C for 2 hours, 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) to give 1.22 g of oily 2-isopropyl-2-hydroxy-3-methylsuccinic acid dibenzyl ester ( 66% yield) was obtained as a diastereo mixture.

  b) The obtained 2-isopropyl-2-hydroxy-3-methylsuccinic acid dibenzyl ester was dissolved in tetrahydrofuran (25 mL), 10% palladium-carbon (120 mg) was added, and the mixture was stirred at room temperature under a hydrogen stream for 15 hours. did. The catalyst was filtered, and the filtrate was concentrated under reduced pressure to obtain 748 mg (quantitative) of oily 2-hydroxy-2-isopropyl-3-methylsuccinic acid.

c) The obtained 2-hydroxy-2-isopropyl-3-methylsuccinic acid was dissolved in acetic anhydride (30 mL) and stirred at 110 ° C. for 15 hours. Acetic anhydride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 19: 1) to give 203 mg (yield 40%) of the title compound as an oil.
¹ H (CDCl ₃ ) δ 1.30 (d, J = 7.1 Hz, 6H), 2.10 (s, 3H), 2.92-3.03 (m, 1H); MS (EI) m / z 154 (M ⁺ ).

Example 22 :
2-Isopropyl-3-methyl maleate disodium
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-isopropyl-3-methylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.91 (d, J = 6.9 Hz, 6H), 1.63 (s, 3H), 2.55-2.65 (m, 1H); MS (FAB +) m / z 217 [(M + H) ⁺ ].

Example 23 (Synthesis example) :
3-ethyl-2-isopropylmaleic anhydride
The oily title compound (yield 50%) was obtained from ethyl butyrate and 3-methyl-2-ketobutyric acid ethyl ester in the same manner as in Example 10.
¹ H NMR (CDCl ₃ ) δ 1.15 (t, J = 7.6 Hz, 3H), 1.30 (d, J = 6.8 Hz, 6H), 2.54 (q, J = 7.6 Hz, 2H), 2.93-3.04 (m, 1H); MS (EI) m / z 169 [(M + H) ⁺ ].

Example 24 :
3-ethyl-2-isopropylmaleate disodium
A solid title compound (quantitative) was obtained from 3-ethyl-2-isopropylmaleic anhydride in the same manner as in Example 11.
¹ H NMR (D ₂ O) δ 0.87 (t, J = 7.5 Hz, 3H), 0.91 (d, J = 6.2 Hz, 6H), 2.09 (q, J = 7.5 Hz, 2H), 2.57-2.68 (m , 1H); MS (FAB +) m / z 231 [(M + H) ⁺ ].

Example 25 (synthesis example) :
2,3-diisopropylmaleic anhydride
In the same manner as in Example 21, a solid title compound (yield 68%) was obtained from 3-methylbutyric acid benzyl ester and 3-methyl-2-ketobutyric acid benzyl ester.
NMR (CDCl ₃ ) δ 1.30 (d, J = 6.9 Hz, 12H), 2.98-3.09 (m, 2H); MS (FAB +) m / z 183 [(M + H) ⁺ ].

Example 26 :
Disodium 2,3-diisopropylmaleate
The solid title compound (quantitative) was obtained from 2,3-diisopropylmaleic anhydride in the same manner as in Example 11.
¹ H NMR (D ₂ O) δ 0.68 (d, J = 6.8 Hz, 12H), 2.32-2.42 (m, 2H); MS (FAB +) m / z 245 [(M + H) ⁺ ].

Example 27 (synthesis example)
3-Benzyl-2-isopropylmaleic anhydride
In the same manner as in Example 10, an oily title compound (yield 27%) was obtained from phenylpropionic acid ethyl ester and 3-methyl-2-ketobutyric acid ethyl ester.
¹ H NMR (CDCl ₃ ) δ 1.27 (d, J = 6.9 Hz, 6H), 3.00-3.10 (m, 1H), 3.80 (s, 2H), 7.20-7.35 (m, 5H); MS (EI) m / z 231 [(M + H) ⁺ ].

Example 28 :
3-Benzyl-2-isopropylmaleate disodium
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 3-benzyl-2-isopropylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.91 (d, J = 7.0 Hz, 6H), 2.65-2.76 (m, 1H), 3.53 (s, 2H), 7.06-7.23 (m, 5H); MS (FAB +) m / z 293 [(M + H) ⁺ ].

Example 29 (synthesis example) :
2-Isopropyl-3- (2-methylphenyl) methylmaleic acid anhydride In the same manner as in Example 21, more oil than 3- (2-methyl) phenylpropionic acid benzyl ester and 3-methyl-2-ketobutyric acid benzyl ester Of the title compound (yield 60%).
¹ H NMR (CDCl ₃ ) δ 1.22 (d, J = 6.1 Hz, 6H), 2.35 (s, 3H), 2.83-2.94 (m, 1H), 3.79 (s, 2H), 7.00 (d, J = 6.9 Hz, 1H), 7.12-7.20 (m, 3H); MS (EI) m / z 244 (M ⁺ ).

Example 30 :
2-Isopropyl-3- (2-methylphenyl) methylmaleic acid disodium 2-isopropyl-3- (2-methylphenyl) methylmaleic anhydride as a solid title compound in the same manner as in Example 11 (quantitative) Got.
¹ H NMR (D ₂ O) δ 0.89 (d, J = 7.1 Hz, 6H), 2.19 (s, 3H), 2.54-2.65 (m, 1H), 3.47 (s, 2H), 7.00-7.15 (m, 4H); MS (FAB +) m / z 307 [(M + H) ⁺ ].

Example 31 (Synthesis example) :
2-cyclopentyl-3-ethylmaleic anhydride
In the same manner as in Example 21, an oily title compound (63% yield) was obtained from cyclopentylacetic acid benzyl ester and 2-ketobutyric acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.18 (t, J = 7.5 Hz, 3H), 1.65-1.95 (m, 8H), 2.49 (q, J = 7.5 Hz, 2H), 2.92-3.03 (m, 1H); MS (EI) m / z 195 [(M + H) ⁺ ].

Example 32 :
2-cyclopentyl-3-ethyl maleate disodium
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-cyclopentyl-3-ethylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.80 (t, J = 7.3 Hz, 3H), 1.24-1.68 (m, 8H), 2.10 (q, J = 7.3 Hz, 2H), 2.57-2.67 (m, 1H) ; MS (FAB +) m / z 257 [(M + H) ⁺ ].

Example 33 (Synthesis example) :
2-cyclopentyl-3-isopropylmaleic anhydride
In the same manner as in Example 21, an oily title compound (yield 79%) was obtained from cyclopentylacetic acid benzyl ester and 3-methyl-2-ketobutyric acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.30 (d, J = 7.1 Hz, 6H), 1.65-1.95 (m, 8H), 2.96-3.08 (m, 2H); MS (EI) m / z 208 (M ⁺ ) .

Example 34 :
2-cyclopentyl-3-isopropylmaleate disodium
A solid title compound (quantitative) was obtained from 2-cyclopentyl-3-isopropylmaleic anhydride in the same manner as in Example 11.
¹ H NMR (D ₂ O) δ 0.92 (d, J = 6.8 Hz, 6H), 1.26-1.70 (m, 8H), 2.56-2.68 (m, 2H); MS (FAB +) m / z 271 [(M + H ) ⁺ ].

Example 35 (Synthesis example) :
2-keto-2-cyclopentylacetic acid benzyl ester
a) 0.5 M potassium bistrimethylsilylamide-toluene solution (67.2 mL, 33.6 mmol) was added to dehydrated tetrahydrofuran (30 mL), and the mixture was cooled to −78 ° C. under a nitrogen stream. To this was added dropwise a solution of cyclopentylacetic acid benzyl ester (6.11 g, 28 mmol) in anhydrous tetrahydrofuran (30 mL) over 1 hour. After stirring at −78 ° C. for 30 minutes, a solution of Davis oxaziridine reagent (8.78 g, 33.6 mmol) in dehydrated tetrahydrofuran (30 mL) was added dropwise over 1 hour. After stirring at -78 ° C for 1 hour, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and then the organic solvent in the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) to obtain 6.157 g (yield 94%) of oily 2-cyclopentyl-2-hydroxyacetic acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.36-1.74 (m, 8H), 2.19-2.3 (m, 1H), 2.70 (d, J = 6.5 Hz, 1H), 4.17 (dd, J = 4.9, 6.5 Hz, 1H ), 5.19 (d, J = 12.2 Hz, 1H), 5.23 (d, J = 12.2 Hz, 1H), 7.30-7.45 (m, 5H).

b) Dess-Martin reagent (5 g, 11.8 mmol) was added to a solution of 2-cyclopentyl-2-hydroxyacetic acid benzyl ester (1.76 g, 7.5 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 15 hours. 10% sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the organic solvent in the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) to obtain 1.383 g (yield 79%) of the oily title compound.
¹ H NMR (CDCl ₃ ) δ 1.58-1.92 (m, 8H), 3.44-3.53 (m, 1H), 5.28 (s, 2H), 7.34-7.42 (m, 5H); MS (EI) m / z 232 (M ⁺ ).

Example 36 (synthesis example) :
3-Benzyl-2-cyclopentylmaleic anhydride
In the same manner as in Example 21, an oily title compound (42% yield) was obtained from 3-phenylpropionic acid benzyl ester and 2-cyclopentyl-2-ketoacetic acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.60-1.95 (m, 8H), 3.00-3.10 (m, 1H), 3.80 (s, 2H), 7.18-7.34 (m, 5H); MS (EI) m / z 256 (M ⁺ ).

Example 37 :
3-Benzyl-2-cyclopentylmaleic acid disodium In the same manner as in Example 11, the solid title compound was obtained from 3-benzyl-2-cyclopentylmaleic anhydride (quantitative).
¹ H NMR (D ₂ O) δ 1.28-1.66 (m, 8H), 2.64-2.74 (m, 1H), 3.54 (s, 2H), 7.06-7.22 (m, 5H); MS (FAB +) m / z 319 [(M + H) ⁺ ].

Example 38 (synthesis example) :
2,3-Dicyclopentylmaleic anhydride In the same manner as in Example 21, a solid title compound (yield 60%) was obtained from cyclopentylacetic acid benzyl ester and 2-cyclopentyl-2-ketoacetic acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.60-1.90 (m, 16H), 2.97-3.07 (m, 2H); MS (EI) m / z 234 (M ⁺ ).

Example 39 :
Disodium 2,3-dicyclopentylmaleate In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2,3-dicyclopentylmaleic anhydride.
¹ H NMR (D ₂ O) δ 1.26-1.68 (m, 16H), 2.57-2.67 (m, 2H); MS (FAB +) m / z 297 [(M + H) ⁺ ].

Example 40 (Synthesis example) :
2- (2,3-Dihydro-1H-inden-2-yl) -3-isopropylmaleic anhydride In a manner similar to Example 21, 2- (2,3-dihydro-1H-inden-2-yl) The oily title compound (yield 62%) was obtained from benzyl acetate and 3-methyl-2-ketobutyric acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.30 (d, J = 7.1 Hz, 6H), 2.98-3.08 (m, 1H), 3.14 (dd, J = 8.6, 15.1 Hz, 2H), 3.33 (dd, J = 10.0 , 15.1 Hz, 2H), 3.65-3.75 (m, 1H), 7.18-7.26 (m, 4H); MS (EI) m / z 256 (M ⁺ ).

Example 41 :
2- (2,3-Dihydro-1H-inden-2-yl) -3-isopropylmaleate disodium
A solid title compound (quantitative) was obtained from 2- (2,3-dihydro-1H-inden-2-yl) -3-isopropylmaleic anhydride in the same manner as in Example 11.
¹ H NMR (D ₂ O) δ 0.95 (d, J = 7.1 Hz, 6H), 2.62-2.73 (m, 1H), 2.84-2.96 (m, 4H), 3.26-3.37 (m, 1H), 7.02- 7.07 (m, 2H), 7.12-7.16 (m, 2H); MS (FAB +) m / z 319 [(M + H) ⁺ ].

Example 42 (synthesis example) :
2-Cyclohexyl-3-isopropylmaleic anhydride An oily title compound (yield 57%) was obtained from cyclohexylacetic acid benzyl ester and 3-methyl-2-ketobutyric acid benzyl ester in the same manner as in Example 21.
¹ H NMR (CDCl ₃ ) δ 1.30 (d, J = 7.0 Hz, 6H), 1.60-1.90 (m, 10H), 2.62-2.72 (m, 1H), 3.00-3.12 (m, 1H); MS (EI ) m / z 222 (M ⁺ ).

Example 43 :
2-Cyclohexyl-3-isopropylmaleate disodium In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-cyclohexyl-3-isopropylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.91 (d, J = 6.8 Hz, 6H), 0.96-1.28 (m, 5H), 1.47-1.59 (m, 5H), 2.15-2.26 (m, 1H), 2.56- 2.64 (m, 1H); MS (FAB +) m / z 285 [(M + H) ⁺ ].

Example 44 (synthesis example) :
Trans-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane and cis-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane
a) Dissolve 1,4-cyclohexanedione monoethylene acetal (5.02 g, 32.1 mmol) in toluene (150 mL) and add benzyl (triphenylphosphoranylidene) acetate (23.7 g, 57.8 mmol) and benzoic acid at room temperature. Acid (832.5 mg, 6.82 mmol) was added and stirred vigorously at 95 ° C. for 2 days. Hexane (300 mL) and diethyl ether (150 mL) were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was vigorously stirred for 10 minutes. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 6: 1 → 4: 1) to give oily 4-benzyloxycarbonylmethylidenecyclohexaneethylene. Acetal 8.53 g (yield 92%) was obtained.

  b) 4-Benzyloxycarbonylmethylidenecyclohexaneethylene acetal (8.19 g, 28.4 mmol) is dissolved in methanol, diphenyl sulfide (52 mg, 0.28 mmol) and 10% palladium-carbon (1.74 g) are added, and hydrogen is added at room temperature. Stir vigorously under atmosphere for 40 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1) to give 7.62 g (yield of oily 4-benzyloxycarbonylmethylcyclohexanone ethylene acetal). 92%).

  c) 4-Benzyloxycarbonylmethylcyclohexanone ethylene acetal (7.62 g, 26.2 mmol) was dissolved in acetone (235 mL) -water (10 mL), and p-toluenesulfonic acid monohydrate (221 mg, 1. 16 mmol) was added and the mixture was stirred at 55 ° C. for 10 hours. While stirring with ice cooling, sodium bicarbonate was added to adjust the pH to 5, and the reaction solution was concentrated under reduced pressure. After adding toluene, the residue obtained by azeotropic distillation was subjected to silica gel column chromatography (hexane-ethyl acetate 4: 1) to give 5.57 g (yield) of oily 2- (4-oxocyclohexyl) acetic acid benzyl ester. 86%).

  d) 2- (4-oxocyclohexyl) acetic acid benzyl ester (2.64 g, 10.7 mmol) was dissolved in methanol (50 mL), and sodium borohydride (393 mg, 10.4 mmol) was added while stirring under ice cooling. added. After stirring at the same temperature for 2 hours, acetic acid (1 mL) was added to adjust to pH 4. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the resulting residue, and the mixture was separated. The combined organic layers were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1 → 2: 1 → 1: 1) to give oily trans-4-benzyloxycarbonylmethyl-1-hydroxy. Cyclohexane 2.20 g (yield 82%) and cis-4-benzyloxycarbonylmethyl-1-hydroxycyclohexane 540 mg (yield 20%) were obtained.

e) Trans-4-benzyloxycarbonylmethyl-1-hydroxycyclohexane (2.20 g, 8.86 mmol) was dissolved in dimethylformamide (31 mL), and imidazole (953 mg, 14.0 mmol) and t-butyldimethylsilane chloride at room temperature. (1.60 g, 10.6 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. Water (70 mL) and hexane (200 mL) were added with stirring under ice cooling, and the layers were separated. The aqueous layer was extracted again with hexane, the combined organic layers were concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50: 1) to give oily trans-4-benzyloxycarbonylmethyl. 1.96 g (92% yield) of -1-t-butyldimethylsilyloxycyclohexane was obtained.
¹ H NMR (CDCl ₃ ) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.01 (m, 2H), 1.31 (m, 2H), 1.57-1.84 (m, 5H), 2.23 (d, J = 6.6 Hz, 2H), 3.50 (m, 1H), 5.11 (s, 2H), 7.30-7.38 (m, 5H).

f) In the same manner as in step e, cis-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane (yield 89%) is more oily than cis-4-benzyloxycarbonylmethyl-1-hydroxyxycyclohexane. )
¹ H NMR (CDCl ₃ ) δ 0.02 (s, 6H), 0.87 (s, 9H), 1.44-1.49 (m, 6H), 1.52-1.62 (m, 2H), 1.85 (m, 1H), 2.28 (d , J = 7.3 Hz, 2H), 3.92 (m, 1H), 5.11 (s, 2H), 7.30-7.38 (m, 5H).

Example 45 (synthesis example)
2- (trans-4-hydroxycyclohexyl) -3-isopropylmaleic anhydride
a) Under an argon atmosphere, diisopropylamine (418 mg, 4.15 mmol) was dissolved in 6 mL of dehydrated tetrahydrofuran, and 1.58 M n-butyllithium-hexane solution (2.5 mL, 5.4 mmol) was added while stirring under ice-cooling. The mixture was stirred at 0 ° C. for 10 minutes and at −78 ° C. for 5 minutes. A solution of trans-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane (1.36 g, 3.76 mmol) in dehydrated tetrahydrofuran (7 mL) was added dropwise at the same temperature over 7 minutes, and the mixture was further stirred for 15 minutes. . Using the cannula, the prepared enolate solution was dropped into a solution of 3-methyl-2-ketobutyric acid benzyl ester (776 mg, 3.76 mmol) in dehydrated tetrahydrofuran (4 mL) cooled to −78 ° C. After stirring at -78 ° C for 1 hour, acetic acid was added to adjust to pH 4, and the temperature was raised to room temperature. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation and extraction. The aqueous layer was extracted again with ethyl acetate, the combined organic layers were concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1) to give oily 3- (trans-4- t-Butyldimethylsilyloxycyclohexyl) -2-hydroxy-2-isopropylsuccinic acid dibenzyl ester 629 mg (low polar diastereomer, 29% yield) and 801 mg (high polar diastereomer, 37% yield) Respectively.

  b) 3- (trans-4-tert-butyldimethylsilyloxycyclohexyl) -2-hydroxy-2-isopropylsuccinic acid dibenzyl ester (801 mg, 1.41 mmol) was dissolved in ethanol (13 mL) and 10% palladium was added. -Carbon (251 mg, 50% water-containing product) was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen stream. The catalyst was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 514 mg (yield 94%) of oily 3- (trans-4-tert-butyldimethylsilyloxy) -2-hydroxy-2-isopropylsuccinic acid. Obtained.

  c) 3- (trans-4-tert-butyldimethylsilyloxycyclohexyl) -2-hydroxy-2-isopropylsuccinic acid (510 mg, 1.31 mmol) was dissolved in acetic anhydride (5.5 mL) and stirred at 120 ° C. for 18 hours. Stir. Acetic anhydride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 50: 1) to give oily 2- (trans-4-tert-butyldimethylsilyloxycyclohexyl) -3. -Obtained 293 mg (yield 63%) of isopropylmaleic anhydride.

d) 2- (trans-4-tert-butyldimethylsilyloxycyclohexyl) -3-isopropylmaleic anhydride (263 mg, 0.745 mmol) was dissolved in ethanol (7 mL) and concentrated hydrochloric acid (83 mg, 0.84 mmol). ) Was added and allowed to stand at 50 ° C for 30 minutes. The reaction mixture was concentrated as it was, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 1) to obtain 179 mg (quantitative) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 1.31 (d, J = 6.8 Hz, 6H), 1.38 (m, 2H), 1.55 (br s, 1H), 1.70 (m, 2H), 1.93 (m, 2H), 2.11 (m, 2H), 2.63 (m, 1H), 3.03 (m, 1H), 3.71 (m, 1H).

Example 46 :
2- (Trans-4-hydroxycyclohexyl) -3-isopropylmaleate disodium
In the same manner as in Example 11, a solid title compound (quantitative) was obtained from 2- (trans-4-hydroxycyclohexyl) -3-isopropylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.93 (d, J = 7.1 Hz, 6H), 1.18 (m, 2H), 1.35 (m, 2H), 1.57 (m, 2H), 1.83 (m, 2H), 2.21 (m, 1H), 2.60 (septet, J = 7.1 Hz, 1H), 3.46 (m, 1H); MS (FAB +) m / z 301 [(M + H) ⁺ ].

Example 47 (Synthesis example) :
2- (cis-4-hydroxycyclohexyl) -3-isopropylmaleic anhydride
In the same manner as in Example 45, the solid title compound (yield 42%) was obtained from cis-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane.
¹ H NMR (CDCl ₃ ) δ 1.31 (d, J = 6.8 Hz, 6H), 1.40 (br s, 1H), 1.48 (m, 2H), 1.59 (m, 2H), 1.92 (m, 2H), 2.20 (m, 2H), 2.70 (m, 1H), 3.11 (septet, J = 6.8 Hz, 1H), 4.15 (m, 1H).

Example 48 :
2- (cis-4-hydroxycyclohexyl) -3-isopropylmaleate disodium
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2- (cis-4-hydroxycyclohexyl) -3-isopropylmaleic anhydride.
¹ H NMR (D ₂ O) δ 0.92 (d, J = 7.0 Hz, 6H), 1.32 (m, 2H), 1.42-1.60 (m, 4H) ,. 1.65 (m, 2H), 2.28 (m, 1H ), 2.61 (septet, J = 7.0 Hz, 1H), 3.88 (m, 1H); MS (FAB +) m / z 301 [(M + H) ⁺ ].

Example 49 (synthesis example) :
2- (Tetrahydropyran-4-yl) acetic acid benzyl ester
2- (Tetrahydropyran-4-yl) acetic acid (325 mg, 2.26 mmol) was dissolved in dehydrated dichloromethane (10 mL) and stirred at room temperature with benzyl alcohol (439 mg, 2.94 mmol), 1-ethyl-3- (3-Dimethylammoniumpropyl) carbodiimide hydrochloride (564 mg, 2.94 mmol) and triethylamine (297 mg, 2.94 mmol) were added and stirred for 12 hours. Water (1 mL) was added to the reaction solution for liquid separation, and the organic layer was further washed with water (1 mL) and saturated brine (1 mL). The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 7: 1) to give 172 mg (yield 32%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 1.34 (m, 2H), 1.63 (m, 2H), 2.02 (m, 1H), 2.30 (d, J = 7.1 Hz, 2H), 3.39 (m, 2H), 3.93 ( m, 2H), 5.12 (s, 2H), 7.31-7.40 (m, 5H).

Example 50 (Synthesis example) :
3-Isopropyl-2- (tetrahydropyran-4-yl) maleic anhydride
a) Under an argon atmosphere, diisopropylamine (122 mg, 1.21 mmol) was dissolved in dehydrated tetrahydrofuran (2 mL), and 1.58 M n-butyllithium-hexane solution (703 μL, 1.11 mmol) was added while stirring under ice-cooling. In addition, the mixture was stirred at 0 ° C. for 10 minutes and at −78 ° C. for 5 minutes. At the same temperature, a solution of 2- (tetrahydropyran-4-yl) acetic acid benzyl ester (250 mg, 1.07 mmol) in dehydrated tetrahydrofuran (1 mL) was added dropwise over 6 minutes, and the mixture was further stirred for 15 minutes. Using the cannula, the prepared enolate solution was dropped into a solution of 3-methyl-2-ketobutyric acid benzyl ester (191 mg, 0.928 mmol) in dehydrated tetrahydrofuran (1 mL) cooled to −78 ° C. After stirring at -78 ° C for 1 hour, acetic acid was added to adjust to pH 4, and the temperature was raised to room temperature. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation and extraction. The aqueous layer was extracted again with ethyl acetate, the combined organic layers were concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 7: 1) to give oily 2-hydroxy-2-isopropyl. 3- (tetrahydro-2H-pyran-4-yl) succinic acid dibenzyl ester 115 mg (low polarity diastereomer, 29% yield) and 158 mg (high polarity diastereomer, 39% yield), respectively Obtained.

  b) 2-hydroxy-2-isopropyl-3- (tetrahydro-2H-pyran-4-yl) succinic acid dibenzyl ester (112 mg, 0.255 mmol) is dissolved in ethanol (2.8 mL) and 10% palladium-carbon is dissolved. (44 mg, 50% water-containing product) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen stream. The catalyst was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 72 mg (quantitative) of 2-hydroxy-2-isopropyl-3- (tetrahydropyran-4-yl) succinic acid in the form of foam.

c) 2-Hydroxy-2-isopropyl-3- (tetrahydropyran-4-yl) succinic acid (70 mg, 0.27 mmol) was dissolved in acetic anhydride (1 mL) and allowed to stand at 120 ° C. for 10 hours. Acetic anhydride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain 38 mg (yield 67%) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 1.32 (d, J = 7.1 Hz, 6H), 1.54 (m, 2H), 2.16 (m, 2H), 2.94 (m, 1H), 3.10 (septet, J = 7.1 Hz, 1H), 3.45 (m, 2H), 4.08 (m, 2H).

Example 51 :
3-isopropyl-2- (tetrahydropyran-4-yl) maleic acid disodium salt
The solid title compound (quantitative) was obtained from 3-isopropyl-2- (tetrahydropyran-4-yl) maleic anhydride in the same manner as in Example 11.
¹ H NMR (D ₂ O) δ 0.93 (d, J = 7.1 Hz, 6H), 1.42 (m, 2H), 1.61 (m, 2H) ,. 2.55 (m, 1H), 2.62 (septet, J = 7.1 Hz, 1H), 3.38 (m, 2H), 3.84 (m, 2H); MS (FAB +) m / z 287 [(M + H) ⁺ ].

Example 52 (synthesis example) :
3- (3-Pyridyl) propionic acid benzyl ester
3- (3-Pyridyl) propionate hydrochloride (1.51 g, 10.0 mmol) was suspended in benzyl alcohol (3.1 mL, 30 mmol), and p-toluenesulfonic acid monohydrate (181.8 mg, 0.96 mmol) And stirred at 130 ° C. for 20 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 1 → 1: 3) to give 1.69 g (yield 70%) of the title compound as an oil.

Example 53 (synthesis example) :
2-Isopropyl-3-[(pyridin-3-yl) methyl] maleic anhydride
In the same manner as in Example 50, 122 mg (yield 38%) of the oily title compound was obtained from 3- (3-pyridyl) propionic acid benzyl ester and 3-methyl-2-ketobutyric acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 1.30 (d, J = 6.8 Hz, 6H), 3.07 (septet, J = 6.8 Hz, 1H), 3.82 (s, 2H), 7.28 (m, 1H), 7.59 (m, 1H), 8.53 (m, 2H).

Example 54 :
2-Isopropyl-3-[(pyridin-3-yl) methyl] disodium maleate
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-isopropyl-3-[(pyridin-3-yl) methyl] maleic anhydride.
¹ H NMR (D ₂ O) δ 0.90 (d, J = 6.8 Hz, 6H), 2.68 (septet, J = 6.8 Hz, 1H), 3.55 (s, 2H), 7.24 (m, 1H), 7.62 (m , 1H), 8.19 (m, 1H), 8.26 (m, 1H); MS (FAB +) m / z 294 [(M + H) ⁺ ].

Example 55 :
3-methyl-2-[(piperidin-1-yl) methyl] maleic acid dimethyl ester
a) 2,3-Dimethylmaleic acid dimethyl ester (500 mg, 2.90 mmol) was dissolved in carbon tetrachloride (11 mL), and N-bromosuccinimide (803 mg, 4.51 mmol) and 2,2′- were dissolved at room temperature. Azobisisobutyronitrile (3.2 mg, 0.019 mmol) was added, and the mixture was heated to reflux with stirring for 4 hours. The reaction solution was filtered as it was, and the filtrate was washed with water and saturated brine. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1 → 8: 1) to give 191 mg (yield) of oily 2-bromomethyl-3-methylmaleic acid dimethyl ester. 26%).

b) 2-Bromomethyl-3-methylmaleic acid dimethyl ester (32 mg, 0.13 mmol) was dissolved in dehydrated dimethylformamide (450 μL), piperidine (21 mg, 0.25 mmol) was added at room temperature, and then at 50 ° C. for 4 hours. Left to stand. The residue obtained by concentrating the reaction solution as it was under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 2) to obtain 13 mg (yield 39%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 1.39 (m, 2H), 1.51 (m, 4H), 1.99 (s, 3H), 2.37 (m, 4H), 3.23 (s, 2H), 3.75 (s, 3H), 3.76 (s, 3H).

Example 56 :
3-methyl-2-[(piperidin-1-yl) methyl] maleic acid disodium salt
In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 3-methyl-2-[(piperidin-1-yl) methyl] maleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 1.26 (m, 2H), 1.38 (m, 4H), 1.74 (s, 3H), 2.33 (m, 4H), 3.10 (s, 2H); MS (FAB +) m / z 272 [(M + H) ⁺ ].

Example 57 :
2-[(4-Hydroxypiperidin-1-yl) methyl] -3-methylmaleic acid dimethyl ester
In the same manner as in Example 55, the oily title compound (43% yield) was obtained from 2,3-dimethylmaleic acid dimethyl ester and 4-hydroxypiperidine.
¹ H NMR (CDCl ₃ ) δ 1.35 (br s, 1H), 1.55 (m, 2H), 1.84 (m, 2H), 1.99 (s, 3H), 2.17 (m, 2H), 2.74 (m, 2H) , 3.27 (s, 2H), 3.68 (m, 1H), 3.76 (s, 3H), 3.78 (s, 3H).

Example 58 :
2-[(4-Hydroxypiperidin-1-yl) methyl] -3-methylmaleate disodium
In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2-[(4-hydroxypiperidin-1-yl) methyl] -3-methylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 1.34 (m, 2H,), 1.70 (m, 2H), 1.72 (s, 3H), 2.13 (m, 2H), 2.66 (m, 2H), 3.13 (s, 2H ), 3.54 (m, 1H); MS (FAB +) m / z 288 [(M + H) ⁺ ].

Example 59 (synthesis example) :
2-hydroxymethyl-3-methylmaleic anhydride
To 2-bromomethyl-3-methylmaleic anhydride (1.25 g, 6.10 mmol) was added 5 M aqueous sodium hydroxide solution (4 mL) at room temperature, and the mixture was stirred for 12 hours. 5 M hydrochloric acid (5 mL) was added to adjust to pH 1, sodium chloride was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 2: 1) to give 227 mg (yield 26%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 2.21 (t, J = 1.1 Hz, 3H), 4.63 (q, J = 1.1 Hz, 2H).

Example 60 :
2-hydroxymethyl-3-methylmaleate disodium
In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-hydroxymethyl-3-methylmaleic anhydride.
¹ H NMR (D ₂ O) δ 1.75 (s, 3H), 4.65 (s, 2H); MS (FAB +) m / z 205 [(M + H) ⁺ ].

Example 61 (synthesis example) :
3-Ethyl-2-methoxymaleic anhydride An oily title compound (yield 37%) was obtained from 2-ketobutyric acid ethyl ester and methoxyacetic acid methyl ester in the same manner as in Example 17.
¹ H NMR (CDCl ₃ ) δ 1.18 (t, J = 7.6 Hz, 3H), 2.45 (q, J = 7.6 Hz, 2H), 4.25 (s, 3H).

Example 62 :
3-ethyl-2-methoxymaleic acid disodium In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 3-ethyl-2-methoxymaleic anhydride.
¹ H NMR (D ₂ O) δ 0.82 (t, J = 7.5 Hz, 3H), 2.13 (q, J = 7.5 Hz, 2H), 3.39 (s, 3H); MS (FAB +) m / z 219 [( M + H) ⁺ ].

Example 63 (synthesis example) :
3-Ethyl-2-methylthiomaleic anhydride An oily title compound (yield 18%) was obtained from 2-ketobutyric acid ethyl ester and methylthioacetic acid ethyl ester in the same manner as in Example 17.
¹ H NMR (CDCl ₃ ) δ 1.18 (t, J = 7.5 Hz, 3H), 2.49 (q, J = 7.5 Hz, 2H), 2.77 (s, 3H).

Example 64 :
Disodium 3-ethyl-2-methylthiomaleate In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 3-ethyl-2-methylthiomaleic anhydride.
¹ H NMR (D ₂ O) δ 0.81 (t, J = 7.5 Hz, 3H), 2.05 (s, 3H), 2.22 (q, J = 7.5 Hz, 2H); MS (ESI +) m / z 235 [( M + H) ⁺ ].

Example 65 (synthesis example) :
3-Ethyl-2-isopropylthiomaleic anhydride An oily title compound (yield 26%) was obtained from 2-ketobutyric acid ethyl ester and isopropylthioacetic acid ethyl ester in the same manner as in Example 17.
¹ H NMR (CDCl ₃ ) δ 1.17 (t, J = 7.6 Hz, 3H), 1.37 (d, J = 6.8 Hz, 6H), 2.49 (q, J = 7.6 Hz, 2H), 4.38 (septet, J = (6.8 Hz, 1H).

Example 66 :
Disodium 3-ethyl-2-isopropylthiomaleate In the same manner as in Example 11, the title compound (quantitative) was obtained as a solid from 3-ethyl-2-isopropylthiomaleic anhydride.
¹ H NMR (D ₂ O) δ 1.17 (t, J = 7.6 Hz, 3H), 1.37 (d, J = 6.8 Hz, 6H), 2.49 (q, J = 7.6 Hz, 2H), 4.38 (septet, J = 6.8 Hz, 1H); MS (FAB +) m / z 263 [(M + H) ⁺ ].

Example 67 (Synthesis example) :
3- {4-[(t-Butyldiphenylsilyloxymethyl) phenyl]} propionic acid ethyl ester
a) 4- (t-Butyldiphenylsilyloxymethyl) benzaldehyde (3.26 g, 8.71 mmol) was dissolved in benzene (80 mL) and ethyl (triphenylphosphoranylidene) acetate (3.19 g, 9.14 mmol) at room temperature. And benzoic acid (116.0 mg, 0.950 mmol) were added and heated to reflux with stirring for 2 hours. Hexane (80 mL) and diethyl ether (40 mL) were added to the residue obtained by directly concentrating the reaction solution under reduced pressure, and the mixture was stirred for 8 hours. The precipitated solid was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 25: 1) to give oily (E) -3- {4-[(t There was obtained 3.47 g (yield 90%) of -butyldiphenylsilyloxy) methyl] phenyl} ethyl acrylate.

b) Dissolve ethyl (E) -3-{[(t-butyldiphenylsilyloxy) methyl] phenyl} acrylate (3.47 g, 7.80 mmol) in methanol (70 mL) and diphenyl sulfide (14 mg, 0.078 mmol). ) And 10% palladium-carbon (1.06 g) were added, and the mixture was vigorously stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 25: 1 → 10: 1) to give 3.21 g of the oily title compound (92% yield). )
¹ H NMR (CDCl ₃ ) δ 1.09 (s, 9H), 1.24 (t, J = 7.2 Hz, 3H), 2.62 (t, J = 7.8 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H) , 4.13 (q, J = 7.2 Hz, 2H), 4.74 (s, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.35-7.43 (m, 6H), 7.69 (m, 4H).

Example 68 (synthesis example) :
2- [4- (Hydroxymethyl) benzyl] -3-isopropylmaleic anhydride
a) Under an argon atmosphere, diisopropylamine (1.06 g, 0.763 mmol) was dissolved in dehydrated tetrahydrofuran (15 mL), and a 1.60 M n-butyllithium-hexane solution (4.5 mL, 7.16 mmol) was added while stirring under ice-cooling. In addition, the mixture was stirred at 0 ° C. for 10 minutes and at −78 ° C. for 5 minutes. At the same temperature, a solution of ethyl 3- {4-[(t-butyldiphenylsilyloxymethyl) phenyl]} propionate (3.20 g, 7.16 mmol) in dehydrated tetrahydrofuran (20 mL) was added dropwise over 15 minutes. Stir for 20 minutes. Using a cannula, the prepared enolate in tetrahydrofuran was added dropwise to a solution of ethyl 3-methyl-2-ketobutyrate (1.14 g, 7.88 mmol) in dehydrated tetrahydrofuran (5.5 mL) cooled to -78 ° C. After stirring at -78 ° C for 1 hour, acetic acid was added to adjust to pH 4, and the temperature was raised to room temperature. The reaction solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The organic layer was washed with saturated brine, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to give oily 3- {4-[(t-butyldiphenylsilyl). Obtained 962 mg (low-polar diastereomer, 23% yield) and 999 mg (high-polar diastereomer, 24% yield) of oxymethyl) phenyl]}-2-isopropyl-2-hydroxysuccinic acid diethyl ester, respectively It was.

  b) 3- {4-[(t-butyldiphenylsilyloxymethyl) phenyl]}-2-isopropyl-2-hydroxysuccinic acid diethyl ester (1.32 g, 1.59 mmol) obtained was dissolved in tetrahydrofuran (26 mL). 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.45 mL, 2.45 mmol) was added at room temperature, and the mixture was allowed to stand at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 2: 1 → 1: 1) to give oily 2-isopropyl-3- {4-[(hydroxymethyl) Obtained 700 mg (yield 89%) of phenyl]}-2-hydroxysuccinic acid diethyl ester.

  c) Obtained 2-isopropyl-3- {4-[(hydroxymethyl) phenyl]}-2-hydroxysuccinic acid diethyl ester (700 mg, 1.99 mmol) at 1,4-dioxane (6.0 mL) at room temperature. 1 M lithium hydroxide aqueous solution (4.0 mL, 4.0 mmol) was added, and the mixture was stirred at 60 ° C. for 16 hours. Furthermore, 5 M sodium hydroxide aqueous solution (16.5 mL, 82.5 mmol) was added, and it stirred at 90 degreeC for 24 hours. After allowing to cool, 5 N hydrochloric acid (19 mL) was added and stirred under ice-cooling, and the reaction mixture was concentrated to dryness to give crude 2-isopropyl-3- {4-[(hydroxymethyl) Phenyl]}-2-hydroxysuccinic acid was obtained.

  d) Acetic anhydride (20 mL) was added to the crude 2-isopropyl-3- {4-[(hydroxymethyl) phenyl]}-2-hydroxysuccinic acid obtained in c above, and 140 ° C. for 2 hours. Stir. The reaction solution was filtered as it was, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 6: 1) to give 2-isopropyl-3- {4-[(hydroxymethyl). Phenyl]}-2-hydroxysuccinic anhydride 302 mg (2 step yield 50%) was obtained.

e) 2-Isopropyl-3- {4-[(hydroxymethyl) phenyl]}-2-hydroxysuccinic anhydride (224 mg, 0.742 mmol) was dissolved in methanol (9 mL) and sulfuric acid (18 mg, 0.18 mmol) was added and heated to reflux with stirring for 12 hours. The reaction mixture was directly concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane-diethyl ether 1: 1) to give 101 mg (yield 52%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 1.28 (d, J = 7.0 Hz, 6H), 3.07 (septet, J = 7.0 Hz, 1H), 3.80 (s, 2H), 4.68 (d, J = 4.4 Hz, 2H) , 7.22 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H).

Example 69 :
2- (4-Carboxybenzyl) -3-isopropylmaleic acid dimethyl ester
a) 2- [4- (Hydroxymethyl) benzyl] -3-isopropylmaleic anhydride (101 mg, 0.388 mmol) was dissolved in a mixed solvent of methanol (1.0 mL) and tetrahydrofuran (1.0 mL), and the mixture was cooled with ice. A 2.0 M trimethylsilyldiazomethane-hexane solution (1.0 mL, 2.0 mmol) was added with stirring at. The mixture was stirred at room temperature for 2 hours, and the reaction solution was directly concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (toluene-ethyl acetate 4: 1 → 3: 1) to obtain 96 mg of oily 2- [4- (hydroxymethyl) benzyl] -3-isopropylmaleic acid dimethyl ester ( Yield 81%) was obtained.

  b) 2- [4- (Hydroxymethyl) benzyl] -3-isopropylmaleic acid dimethyl ester (96 mg, 0.31 mmol) is dissolved in benzene (2.0 mL), activated manganese dioxide (602 mg) is added, and the mixture is brought to room temperature. Stir vigorously for 3 hours. After the reaction solution was filtered, the filtrate was concentrated to dryness to obtain 79 mg (yield 83%) of colorless oily 2- (4-formylbenzyl) -3-isopropylmaleic acid dimethyl ester.

c) 2- (4-Formylbenzyl) -3-isopropylmaleic acid dimethyl ester (79 mg, 0.259 mmol) was suspended in a mixed solvent of dioxane (3.0 mL) and water (3.0 mL), and ice-cooled. Amidosulfuric acid (38 mg, 0.39 mmol) and sodium chlorite (35 mg, 0.39 mmol) were added with stirring, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated as it was, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 2) to give 80 mg (yield 96%) of the title compound as an oil.
¹ H NMR (CDCl ₃ ) δ 1.12 (d, J = 6.8 Hz, 6H), 2.95 (septet, J = 6.8 Hz, 1H), 3.66 (s, 3H), 3.83 (s, 5H), 7.28 (m, 2H), 8.03 (m, 2H); MS (ESI +) m / z 321 [(M + H) ⁺ ].

Example 70 :
2- (4-Carboxybenzyl) -3-isopropylmaleic acid trisodium In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2- (4-carboxybenzyl) -3-isopropylmaleic acid dimethyl ester. Obtained.
¹ H NMR (D ₂ O) δ 0.89 (d, J = 6.8 Hz, 6H), 2.67 (septet, J = 6.8 Hz, 1H), 3.55 (s, 2H), 7.18 (d, 2H), 7.61 (d , 2H); MS (FAB +) m / z 359 [(M + H) ⁺ ].

Example 71 :
2- (4-Carbamoylbenzyl) -3-isopropylmaleic acid dimethyl ester 2- (4-Carboxybenzyl) -3-isopropylmaleic acid dimethylester (7.8 mg, 0.024 mmol) was dissolved in tetrahydrofuran (400 μL), 0.5 M Ammonia-dioxane solution (600 μL) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (14.8 mg, 0.0535 mmol) were added, Stir at room temperature for 4 hours. The residue obtained by concentrating the reaction solution as it was under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 4) to obtain 7.0 mg (yield 90%) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 6.8 Hz, 6H), 2.95 (septet, J = 6.8 Hz, 1H), 3.65 (s, 3H), 3.80 (s, 2H), 3.82 (s, 3H), 5.54 (br s, 1H), 6.02 (br s, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H); MS (ESI +) m / z 320 [(M + H) ⁺ ].

Example 72 :
2- (4-carbamoylbenzyl) -3-isopropylmaleate disodium In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2- (4-carbamoylbenzyl) -3-isopropylmaleate dimethyl ester. Obtained.
¹ H NMR (D ₂ O) δ 0.87 (d, J = 6.8 Hz, 6H), 2.66 (septet, J = 6.8 Hz, 1H), 3.57 (s, 2H), 7.23 (d, J = 8.2 Hz, 2H ), 7.56 (d, J = 8.2 Hz, 2H); MS (FAB +) m / z 336 [(M + H) ⁺ ].

Example 73 :
2-Isopropyl-3- [4- (morpholine-1-carbonyl) benzyl] -maleic acid dimethyl ester 2- (4-carboxybenzyl) -3-isopropylmaleic acid dimethyl ester (9.7 mg, 0.030 mmol) was added to dichloromethane (300 1-hydroxybenzotriazole (14.1 mg, 0.104 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18.8 mg, 0.0981 mol) with stirring under ice-cooling And morpholine (12.9 mg, 0.151 mmol) was added. The mixture was warmed to room temperature for 2 hours under ice-cooling and further stirred for 1 hour, and then water and chloroform were added to the reaction solution for liquid separation. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate only) to give 11.8 mg (quantitative) of the title compound as an oil. It was.
¹ H NMR (CDCl ₃ ) δ 1.12 (d, J = 6.8 Hz, 6H), 2.95 (septet, J = 6.8 Hz, 1H), 3.35-3.82, (m, 8H), 3.66 (s, 3H), 3.78 (s, 2H), 3.82 (s, 3H), 7.22 (m, 2H), 7.34 (m, 2H).

Example 74 :
2-Isopropyl-3- [4- (morpholine-1-carbonyl) benzyl] maleic acid disodium 2-isopropyl-3- [4- (morpholine-1-carbonyl) benzyl] maleic acid in the same manner as in Example 2. The solid title compound (quantitative) was obtained from dimethyl ester.
¹ H NMR (D ₂ O) δ 0.86 (d, J = 6.8 Hz, 6H), 2.65 (septet, J = 6.8 Hz, 1H), 3.34 (m, 2H), 3.50 (m, 2H), 3.53 (s , 2H), 3.57 (m, 2H), 3.64 (m, 2H), 7.15-7.20 (m, 4H); MS (ESI +) m / z 362 {[(M-2Na + 2H) + H] ⁺ }.

Example 75 :
2-Isopropyl-3- [4- (piperazine-1-carbonyl) benzyl] maleic acid dimethyl ester hydrochloride
a) In the same manner as in Example 73, from 2- (4-carboxybenzyl) -3-isopropylmaleic acid dimethyl ester and t-butylpiperazine-1-carboxylate, 2- {4- [4- (t-butoxy Carbonyl) piperazine-1-carbonyl] benzyl} -3-isopropylmaleic acid dimethyl ester (quantitative) was obtained.

b) Dissolve 2- {4- [4- (t-butoxycarbonyl) piperazine-1-carbonyl] benzyl} -3-isopropylmaleic acid dimethyl ester (11.8 mg, 0.0302 mmol) in methanol (200 μL) Then, 5 M hydrochloric acid (200 μL) was added at room temperature, and the mixture was allowed to stand for 5 hours. The reaction solution was directly concentrated to dryness to obtain 10.2 mg (quantitative) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 0.89 (d, J = 7.0 Hz, 6H), 2.92 (septet, J = 7.0 Hz, 1H), 3.09 (br s, 2H), 3.16 (br s, 2H), 3.49 ( s, 3H), 3.58 (br s, 2H), 3.67 (s, 3H), 3.70 (s, 2H), 3.81 (br s, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.24 (d , J = 8.1 Hz, 2H).

Example 76 :
2-Isopropyl-3- [4- (piperazine-1-carbonyl) benzyl] maleic acid disodium 2-isopropyl-3- [4- (piperazine-1-carbonyl) benzyl] maleic acid in the same manner as in Example 2 The solid title compound (quantitative) was obtained from dimethyl ester.
¹ H NMR (D ₂ O) δ 0.87 (d, J = 7.0 Hz, 6H), 2.57-2.73 (m, 5H), 3.27 (m, 1H), 3.50-3.53 (m, 3H), 7.13-7.20 ( m, 4H); MS (ESI-) m / z 359 {[(M-2Na + 2H) -H] ^- }.

Example 77 :
2- [4- (4-Acetoxypiperidine-1-carbonyl) benzyl] -3-isopropylmaleic acid dimethyl ester 2- (4-carboxybenzyl) -3-isopropylmaleic acid dimethyl ester (10.3 mg, 0.0322 mmol) was dissolved in dichloromethane. 1-hydroxybenzotriazole (13.3 mg, 0.0965 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (20.8 mg, dissolved in (500 μL) and stirred under ice cooling. 0.109 mol), piperidin-4-yl acetate hydrochloride (28.8 mg, 0.161 mmol) and triethylamine (14.6 mg, 0.145 mmol) were added. After stirring at room temperature for 1 hour, water was added for liquid separation, and the aqueous layer was extracted again with ethyl acetate. The residue obtained by concentrating the combined organic layers under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 2) to give 11.1 mg (yield 78%) of the title compound as a solid.
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 7.0 Hz, 6H), 1.61 (br s, 1H), 1.74 (br s, 1H), 1.86 (br s, 1H), 1.96 (br s, 1H ), 2.08 (br s, 3H), 2.96 (septet, J = 7.0 Hz, 1H), 3.31 (br s, 1H), 3.53 (br s, 1H), 3.66 (br s, 1H), 3.66 (s, 3H), 3.78 (s, 2H), 3.82 (s, 3H), 4.07 (br s, 1H), 5.01 (m, 1H), 7.21 (m, 2H), 7.33 (m, 2H).

Example 78 :
2- [4- (4-Hydroxypiperidine-1-carbonyl) benzyl] -3-isopropylmaleate disodium In the same manner as in Example 2, 2- [4- (4-acetoxypiperidine-1-carbonyl) benzyl] The solid title compound (quantitative) was obtained from -3-isopropylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 0.89 (d, J = 7.0 Hz, 6H), 1.28-1.44 (m, 2H), 1.65-1.91 (m, 2H), 2.69 (septet, J = 7.0 Hz, 1H) , 3.04-3.12 (m, 2H) .3.55 (m, 1H), 3.56 (s, 2H), 3.82 (m, 1H), 4.04 (m, 1H), 7.15-7.23 (m, 4H); MS (ESI + ) m / z 376 {[(M-2Na + 2H) + H] ⁺ }.

Example 79 :
2- [4- (2-Amino-2-oxoethylcarbamoyl) benzyl] -3-isopropylmaleic acid dimethyl ester In the same manner as in Example 77, 2- (4-carboxybenzyl) -3-isopropylmaleic acid dimethyl ester The solid title compound (yield 84%) was obtained from glycinamide hydrochloride.
¹ H NMR (CD ₃ OD) δ 1.08 (d, J = 6.8 Hz, 6H), 3.03 (septet, J = 6.8 Hz, 1H), 3.62 (s, 3H), 3.76 (s, 3H), 3.84 (s , 2H), 4.02 (s, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H).

Example 80 :
2- [4- (2-Amino-2-oxoethylcarbamoyl) benzyl] -3-isopropylmaleate disodium In the same manner as in Example 2, 2- [4- (2-amino-2-oxoethylcarbamoyl) The solid title compound (quantitative) was obtained from benzyl] -3-isopropylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 0.87 (d, J = 6.8 Hz, 6H), 2.65 (septet, J = 6.8 Hz, 1H), 3.57 (s, 2H), 3.92 (s, 2H), 7.24 (d , J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H); MS (ESI +) m / z 349 {[(M-2Na + 2H) + H] ⁺ }.

Example 81 (synthesis example) :
2-Isopropyl-3- (4-methoxybenzyl) maleic anhydride In the same manner as in Example 50, more oily oil than 3-methyl-2-ketobutyric acid benzyl ester and 3- (4-methoxyphenyl) propionic acid benzyl ester The title compound (51% yield) was obtained.
¹ H NMR (CDCl ₃ ) δ 1.28 (d, J = 7.0 Hz, 6H), 3.05 (septet, J = 7.0 Hz, 1H), 3.74 (s, 2H), 3.79 (s, 3H), 6.85 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H).

Example 82 :
2-Isopropyl-3- (4-methoxybenzyl) maleic acid disodium In the same manner as in Example 11, the solid title compound (quantitative) was obtained from 2-isopropyl-3- (4-methoxybenzyl) maleic anhydride. Obtained.
¹ H NMR (D ₂ O) δ 0.85 (d, J = 7.0 Hz, 6H), 2.65 (septet, J = 7.0 Hz, 1H), 3.41 (s, 2H), 3.61 (s, 3H), 6.74 (m , 2H), 7.04 (m, 2H); MS (ESI +) m / z 323 [(M + H) ⁺ ].

Example 83 (synthesis example) :
3- [4- (t-Butyldimethylsilyloxy) phenyl] propionic acid benzyl ester
a) 3- (4-Hydroxyphenyl) propionic acid (1.49 g, 8.96 mmol) dissolved in dimethylformamide (21.5 mL), potassium carbonate (1.30 g, 9.41 mmol), benzyl bromide (1.69 g, 9.86 mmol) And stirred at room temperature for 12 hours. Toluene and water were added to the reaction solution to separate it. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1 → 3: 1) to give 2.16 g of oily 3- (4-hydroxyphenyl) propionic acid benzyl ester ( Yield 94%) was obtained.

b) In the same manner as in Example 12, the oily title compound (93% yield) was obtained from 3- (4-hydroxyphenyl) propionic acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 0.18 (s, 6H), 0.98 (s, 9H), 2.65 (m, 2H), 2.90 (m, 2H), 5.11 (s, 2H), 6.73 (m, 2H), 7.03 (m, 2H), 7.26-7.40 (m, 5H).

Example 84 (Synthesis example) :
2- [4- (t-Butyldimethylsilyloxy) benzyl] -3-isopropylmaleic anhydride In a manner similar to Example 50, 3-methyl-2-ketobutyric acid benzyl ester and 3- [4- (t- The oily title compound (yield 58%) was obtained from butyldimethylsilyloxy) phenyl] propionic acid benzyl ester.
¹ H NMR (CDCl ₃ ) δ 0.18 (s, 6H), 0.97 (s, 9H), 1.25 (d, J = 6.8 Hz, 6H), 3.02 (septet, J = 6.8 Hz, 1H), 3.72 (s, 2H), 6.78 (m, 2H), 7.06 (m, 2H).

Example 85 :
2- (4-Hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester
a) 2- [4- (t-Butyldimethylsilyloxy) benzyl] -3-isopropylmaleic anhydride (823 mg, 2.28 mmol) was dissolved in methanol (15 mL) and stirred at room temperature with 2.0 M Trimethylsilyldiazomethane-hexane solution (8.5 mL, 17 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1 → 8: 1) to give oily 2- [4- (t -Butyldimethylsilyloxy) benzyl] -3-isopropylmaleic acid dimethyl ester (913 mg, yield 98%) was obtained.

b) 2- [4- (t-butyldimethylsilyloxy) benzyl] -3-isopropylmaleic acid dimethyl ester (823 mg, 2.02 mmol) was dissolved in tetrahydrofuran (13 mL) and 1 M tetrabutylammonium at room temperature. A fluoride-tetrahydrofuran solution (2.1 mL, 2.1 mmol) was added. The reaction mixture was allowed to stand at room temperature for 1 hour, and the reaction solution was directly concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 2: 1) to give solid 2- (4-hydroxybenzyl) -3 -592 mg (quantitative) of isopropylmaleic acid dimethyl ester was obtained.
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 6.8 Hz, 6H), 2.98 (septet, J = 6.8 Hz, 1H), 3.65 (s, 3H), 3.68 (s, 2H), 3.80 (s, 3H), 4.98 (br s, 1H), 6.74 (m, 2H), 7.02 (m, 2H).

Example 86 :
2- (4-oxidebenzyl) -3-isopropylmaleic acid trisodium In the same manner as in Example 2, the solid title compound (quantitative) was obtained from 2- (4-hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester. Obtained.
¹ H NMR (D ₂ O) δ 0.90 (d, J = 7.0 Hz, 6H), 2.71 (septet, J = 7.0 Hz, 1H), 3.36 (s, 2H), 6.45 (m, J = 8.5 Hz, 2H ), 6.90 (d, J = 8.5 Hz, 2H); MS (FAB +) m / z 331 [(M + H) ⁺ ].

Example 87 :
2-Isopropyl-3- [4- (2-methoxy-2-oxoethoxy) benzyl] maleic acid dimethyl ester 2- (4-hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester (44.1 mg, 0.151 mmol) was converted to dimethyl It melt | dissolved in formamide (880 microliters), and potassium carbonate (34.7 mg, 0.251 mmol) and methyl bromoacetate (138.4 mg, 0.904 mmol) were added, stirring at room temperature. After stirring at room temperature for 20 hours, toluene and water were added to the reaction solution for liquid separation. The aqueous layer was extracted again with toluene, and the combined organic layers were concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (toluene-ethyl acetate 10: 1) to give 45.2 mg (yield 82) of the oily title compound. %).
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 7.0 Hz, 6H), 2.97 (septet, J = 7.0 Hz, 1H), 3.65 (s, 3H), 3.69 (s, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.61 (s, 2H), 6.83 (m, 2H), 7.09 (m, 2H).

Example 88 :
2- [4- (Carboxylatomethoxy) benzyl] -3-isopropylmaleic acid trisodium In the same manner as in Example 2, 2-isopropyl-3- [4- (2-methoxy-2-oxoethoxy) benzyl] malein The solid title compound (quantitative) was obtained from acid dimethyl ester.
¹ H NMR (D ₂ O) δ 0.89 (d, J = 7.0 Hz, 6H), 2.68 (septet, J = 7.0 Hz, 1H), 3.45 (s, 2H), 4.29 (s, 2H), 6.72 (d , J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H); MS (FAB +) m / z 389 [(M + H) ⁺ ].

Example 89 :
2- [4- (2-Amino-2-oxoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester In a manner similar to Example 87, 2- (4-hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester and From bromoacetamide, an oily title compound (yield 80%) was obtained.
¹ H NMR (CDCl ₃ ) δ 1.12 (d, J = 7.0 Hz, 6H), 2.98 (septet, J = 7.0 Hz, 1H), 3.65 (s, 3H), 3.67 (s, 2H), 3.80 (s, 3H), 4.47 (s, 2H), 5.58 (br s, 1H), 6.54 (br s, 1H), 6.84 (m, 2H), 7.12 (m, 2H); MS (FAB +) m / z 372 [( M + Na) ⁺ ].

Example 90 :
2- [4- (2-Amino-2-oxoethoxy) benzyl] -3-isopropylmaleate disodium In the same manner as in Example 2, 2- [4- (2-amino-2-oxoethoxy) benzyl] The solid title compound (quantitative) was obtained from -3-isopropylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 0.91 (d, J = 6.8 Hz, 6H), 2.70 (septet, J = 6.8 Hz, 1H), 3.48 (s, 2H), 4.47 (s, 2H), 6.81 (d , J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H); MS (FAB +) m / z 320 {[(M-2Na + 2H) + H] ⁺ }.

Example 91 :
2- [4- (2-Aminoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester
a) 2- (4-Hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester (204.5 mg, 0.6996 mmol) was dissolved in benzene (6 mL) and stirred at room temperature with N- (t-butoxycarbonyl) ethanol. Amine (343 mg, 2.13 mol), tributylphosphine (853 mg, 4.20 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (1.05 g, 4.20 mmol) were added. After stirring at room temperature for 1 hour, the reaction solution is filtered, and the residue obtained by concentrating the filtrate under reduced pressure is subjected to silica gel column chromatography (hexane-ethyl acetate 2: 1) to give oily 2- {4- 287 mg (yield 98%) of [2- (t-butoxycarbonylamino) ethoxy] benzyl} -3-isopropylmaleic acid dimethyl ester was obtained.

b) The obtained 2- {4- [2- (t-butoxycarbonylamino) ethoxy] benzyl} -3-isopropylmaleic acid dimethyl ester (287 mg, 0.659 mmol) was dissolved in methanol (6 mL), and room temperature was obtained. 5M hydrochloric acid (5.9 mL) was added and left at room temperature for 20 hours. The residue obtained by concentration under reduced pressure was dissolved in ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added. After separation, the residue obtained by concentrating the organic layer was subjected to LH-20 (dichloromethane-methanol 1: 1) to obtain 222 mg (quantitative) of the oily title compound.
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 7.0 Hz, 6H), 2.99 (septet, J = 7.0 Hz, 1H), 3.07 (t, J = 5.1 Hz, 2H), 3.65 (s, 3H) , 3.69 (s, 2H), 3.80 (s, 3H), 3.96 (t, J = 5.1 Hz, 2H), 6.82 (m, 2H), 7.08 (m, 2H).

Example 92 :
2- [4- (2-Aminoethoxy) benzyl] -3-isopropylmaleate disodium In the same manner as in Example 2, from 2- [4- (2-aminoethoxy) benzyl] -3-isopropylmaleate dimethyl ester The solid title compound (quantitative) was obtained.
¹ H NMR (D ₂ O) δ 0.89 (d, J = 7.0 Hz, 6H), 2.68 (septet, J = 7.0 Hz, 1H), 2.82 (m, 2H), 3.45 (s, 2H), 3.91 (m , 2H), 6.79 (m, 2H), 7.07 (m, 2H); MS (FAB +) m / z 352 [(M + H) ⁺ ].

Example 93 :
2- {4- [2- (1H-imidazol-1-yl) ethoxy] benzyl} -3-isopropylmaleic acid dimethyl ester In a manner similar to Example 91a, 2- (4-hydroxybenzyl) -3-isopropylmalein The title compound (yield 52%) was obtained from acid dimethyl ester and 1- (2-hydroxyethyl) imidazole.
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 7.0 Hz, 6H), 2.97 (septet, J = 7.0 Hz, 1H), 3.01 (s, 3H), 3.68 (s, 2H), 3.80 (s, 3H), 4.18 (t, J = 5.0 Hz, 2H), 4.32 (t, J = 5.0 Hz, 2H), 6.78 (m, 2H), 7.03-7.09 (m, 4H), 7.60 (m, 1H); MS (ESI +) m / z 387 [(M + H) ⁺ ].

Example 94 :
2- {4- [2- (1H-imidazol-1-yl) ethoxy] benzyl} -3-isopropylmaleate disodium 2- {4- [2- (1H-imidazole-1] The solid title compound (quantitative) was obtained from -yl) ethoxy] benzyl} -3-isopropylmaleic acid dimethyl ester.
¹ H NMR (D ₂ O) δ 0.88 (d, J = 7.0 Hz, 6H), 2.67 (septet, J = 7.0 Hz, 1H), 3.45 (s, 2H), 4.20 (m, 2H), 4.24 (m , 2H), 6.72 (m, 2H), 6.85 (m, 1H), 7.03-7.08 (m, 3H), 7.58 (s, 1H); MS (ESI +) m / z 403 [(M + H) ⁺ ] .

Example 95 :
2-Isopropyl-3- [4- (pyrrolidin-3-yloxy) benzyl] maleic acid dimethyl In a manner similar to Example 91, 2- (4-hydroxybenzyl) -3-isopropylmaleic acid dimethyl ester and N- (t -Butoxycarbonyl) -3-hydroxypyrrolidine gave the oily title compound (yield 82%).
¹ H NMR (CDCl ₃ ) δ 1.11 (d, J = 7.0 Hz, 6H), 1.93 (m, 1H), 2.07 (m, 1H), 2.84-3.02 (m, 3H), 3.15-3.20 (m, 2H ), 3.65 (s, 3H), 3.69 (s, 2H), 3.80 (s, 3H), 4.79 (m, 1H), 6.77 (m, 2H), 7.06 (m, 2H).

Example 96 :
2-Isopropyl-3- [4- (pyrrolidin-3-yloxy) benzyl] maleic acid disodium 2-isopropyl-3- [4- (pyrrolidin-3-yloxy) benzyl] maleic acid in the same manner as in Example 2. The solid title compound (quantitative) was obtained from dimethyl ester.
¹ H NMR (D ₂ O) δ 0.90 (d, J = 7.0 Hz, 6H), 1.84-1.98 (m, 2H), 2.69 (septet, J = 7.0 Hz, 1H), 2.70-3.05 (m, 4H) , 3.45 (s, 2H), 4.85 (m, 1H), 6.78 (m, 2H), 7.08 (m, 2H); MS (ESI +) m / z 334 {[(M-2Na + 2H) + H] ⁺ }.

Example 97 :
2- [4- (2-Guanidinoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester hydrochloride
a) 2- [4- (2-Aminoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester (30.2 mg, 0.0900 mmol) was dissolved in tetrahydrofuran (900 μL), and N, N′-bis ( t-Butoxycarbonyl) -1-guanylpyrazole (35.2 mg, 0.113 mmol) was added and allowed to stand for 20 hours. The reaction mixture was directly concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1) to give syrupy 2- [4- {2- [2,3-bis (t- 47.6 mg (92% yield) of butoxycarbonyl) guanidino] ethoxy} benzyl] -3-isopropylmaleic acid dimethyl ester were obtained.

b) The obtained 2- [4- (2-aminoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester hydrochloride (23.5 mg, 0.0407 mmol) was dissolved in methanol (470 μL), and 5 M at room temperature. Hydrochloric acid (407 μL) was added and allowed to stand for 4 hours. The reaction mixture was concentrated to dryness to give 17.6 mg (quantitative) of the oily title compound.
¹ H NMR (D ₂ O) δ 0.91 (d, J = 7.0 Hz, 6H), 2.94 (septet, J = 7.0 Hz, 1H), 3.43 (t, J = 5.0 Hz, 3H), 3.50 (s, 3H ), 3.57 (s, 2H), 3.68 (s, 3H), 4.02 (t, J = 5.0 Hz, 2H), 6.80 (m, 2H), 7.01 (m, 2H).

Example 98 :
2- [4- (2-Guanidinoethoxy) benzyl] -3-isopropylmaleic acid disodium salt In the same manner as in Example 2, 2- [4- (2-guanidinoethoxy) benzyl] -3-isopropylmaleic acid dimethyl ester The solid title compound (quantitative) was obtained from the hydrochloride.
¹ H NMR (D ₂ O) δ 0.92 (d, J = 6.8 Hz, 6H), 2.97 (m, 1H), 2.79 (septet, J = 6.8 Hz, 1H), 2.79 (m, 2H), 3.69 (s , 2H), 4.04 (m, 2H), 6.83 (m, 2H), 7.07 (m, 2H); MS (ESI +) m / z 350 {[(M-2Na + 2H) + H] ⁺ }.

The structure of the compound prepared above is as shown below.

The full length was amplified by PCR using bla _IMP-1 of Pseudomonas aeruginosa MSC15369 having IMP-1 which is one of the inhibitory activity metallo-β-lactamases as a template. This PCR product was incorporated into pTrcHis2 TOPO vector (Invitrogen), introduced into E. coli DH5α (TOYOBO), and induced at 0.5 ° C. for 3 hours at 37 ° C. under induction of Isopropyl-β-D-(−)-thiogalactopyranoside (Wako). IMP-1 was expressed by culture. After recovering the cells, the periplasmic fraction was extracted by osmotic shock with sucrose, and IMP-1 was purified by Ni-NTA Slurry (QIAGEN) using a C-terminal His tag. Similarly, the bla _VIM-2 gene of Pseudomonas putida MSC06534 carrying VIM-2, which is a kind of metallo-β-lactamase, was integrated and expressed in E. coli DH5α to purify VIM-2.

For measuring the metallo-β-lactamase inhibitory activity, 50 mM HEPES (pH 7.5) buffer (hereinafter referred to as “buffer”) was used, and nitrocefin (Oxoid) having a final concentration of 100 μM was used as a substrate. To each well of a 96-well plate, a test drug dissolved in a buffer solution (test substance: the compound of the example number shown in Table 2) is added, nitrocefin is added, and after mixing, a final concentration of 1 nM is added to each well. Of IMP-1 or 1.5 nM VIM-2, and allowed to react at room temperature for 20 minutes. At this time, ZnSO ₄ having a final concentration of 100 μM was added in order to remove the inhibitory effect due to chelation. The enzyme inhibitory activity was measured by measuring the nitrocefin hydrolysis activity at a wavelength of 490 nm using an ARVOsx microplate reader (Wallac). As a control, a reaction solution from which metallo-β-lactamase was removed was prepared, and the concentration of the test drug exhibiting 50% inhibition was defined as IC ₅₀ . The results were as shown in Table 2.

(Inhibitory activity)

Combined effects
Using Pseudomonas aeruginosa strain PAO1 / pMS363 (FEMS Microbiology Letters, 1994, 121, 175) producing IMP-1, the inhibitory effect of carbapenem resistance by metallo-β-lactamase in bacteria of maleic acid derivatives was evaluated. The minimum inhibitory concentration (MIC) of ceftriaxone (CTRX), ceftazidime (CAZ), and cefepime (CFPM) against IMP-1-producing Pseudomonas aeruginosa is the standard method of the Japanese Society of Chemotherapy (Chemotherapy, 1981, 29, 76) Was measured by a micro liquid dilution method. That is, the strain cultured overnight in Mueller-Hinton broth was adjusted with the same medium to 10 ⁴ CFU / well, and added to the same medium containing ceftriaxone, ceftazidime, and cefepime at various concentrations. The compound of the present invention was added to each well to a final concentration of 50 μg / ml, and the effect was confirmed by MIC of ceftriaxone, ceftazidime and cefepime. The results are shown in Table 3.

(Combination effect)

  As shown in Table 2, enzyme inhibition activity as a metallo-β-lactamase inhibitor was found in the maleic acid derivative general formula (I) of the present invention and inhibited both IMP type and VIM type enzymes. Clarified what to do. To date, there have been few reports of metallo-β-lactamase inhibitors that show a combined effect with β-lactam drugs against metallo-β-lactamase-producing Pseudomonas aeruginosa that has been difficult to treat in the medical field, As shown in Table 3, the compound of the present invention was found to have an effect of recovering the activity of imipenem when used in combination with imipenem against metallo-β-lactamase-producing Pseudomonas aeruginosa. Therefore, the compound represented by the general formula (I) of the present invention is useful in combination with a β-lactam drug or the like as a metallo-β-lactamase inhibitor against such resistant Pseudomonas aeruginosa and the like.

Claims (21)

Metallo-β-lactamase inhibitor comprising a compound represented by the following general formula (I), a salt thereof, or a solvate thereof:

(Where
R ¹ is a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-heterocycle, or —O—C _1-6 alkyl. Group, or —S—C _1-6 alkyl group, any of which may have a substituent,
R ² is a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-heterocycle, or —O—C _1-6 alkyl. Group, or —S—C _1-6 alkyl group, any of which may have a substituent,
Two M ¹ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ). R ¹ is a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a benzyl group, a phenethyl group, a —C _0-1 alkylene-heterocycle (where the heterocycle is tetrahydropyran, pyridine, or Represents a piperidine), -O-C _1-6 alkyl group, or -S-C _1-6 alkyl group, all of which may have a substituent,
R ² represents a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a hydroxymethyl group, a benzyl group, a phenethyl group, a —C _0-1 alkylene-heterocycle (the heterocycle represents tetrahydropyran, pyridine, or piperidine). ), —O—C _1-6 alkyl group, or —S—C _1-6 alkyl group, any of which may have a substituent,
2. The metallo of claim 1, wherein two M ¹ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. -Β-lactamase inhibitors. R ¹ is
A _C2-6 alkyl group,
A C _3-7 cyclic alkyl group (wherein the ring may be substituted with a hydroxyl group, or may be condensed with aryl);
A hydroxymethyl group,
-C _1-3 alkylene - phenyl group (wherein the phenyl group,
Hydroxyl group,
A C _1-6 alkyl group,
A hydroxymethyl group,
The group -COOM (M represents a hydrogen atom or a pharmaceutically acceptable cation),
A group —CO—NR ²² R ²³ (wherein R ²² and R ²³ may be the same or different and each represents a hydrogen atom or a C _1-6 alkyl group (this alkyl group is further substituted with an aminocarbonyl group); Or R ²² and R ²³ together with the nitrogen atom to which they are attached, a 5- or 6-membered saturated heterocycle comprising 1-2 oxygen or nitrogen atoms (Preferably represents a morpholinyl group, a piperazyl group, or a piperidyl group) (this heterocycle may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)),
Group —O—R ²⁴ (wherein R ²⁴ represents a C _1-6 alkyl group (this alkyl group represents —COOM (M represents a hydrogen atom, a C _1-6 alkyl group or a pharmaceutically acceptable cation)). , An aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms), or 5 or 6 containing 1 to 2 nitrogen atoms A membered saturated heterocycle (preferably pyrrolidine)
May be substituted. )
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
R ² is
A C _1-6 alkyl group,
A C _3-7 cyclic alkyl group (wherein the ring may be substituted with a hydroxyl group, or may be condensed with aryl);
A hydroxymethyl group,
-C _1-3 alkylene - phenyl group (wherein the phenyl group,
Hydroxyl group,
A C _1-6 alkyl group,
A hydroxymethyl group,
The group -COOM (M represents a hydrogen atom or a pharmaceutically acceptable cation),
A group —CO—NR ²² R ²³ (wherein R ²² and R ²³ may be the same or different and each represents a hydrogen atom or a C _1-6 alkyl group (this alkyl group is further substituted with an aminocarbonyl group); Or R ²² and R ²³ together with the nitrogen atom to which they are attached, a 5- or 6-membered saturated heterocycle comprising 1-2 oxygen or nitrogen atoms (Preferably represents a morpholinyl group, a piperazyl group, or a piperidyl group) (this heterocycle may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)),
Group —O—R ²⁴ (wherein R ²⁴ represents a C _1-6 alkyl group (this alkyl group represents —COOM (M represents a hydrogen atom, a C _1-6 alkyl group or a pharmaceutically acceptable cation)). , An aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms), or 5 or 6 containing 1 to 2 nitrogen atoms A membered saturated heterocycle (preferably pyrrolidine)
May be substituted. )
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
The metallo-β-lactamase inhibitor according to claim 1, which represents R ¹ is
A _C2-6 alkyl group,
A C _3-7 cyclic alkyl group (wherein the ring may be substituted with a hydroxyl group, or may be condensed with aryl);
A hydroxymethyl group,
-C _1-3 alkylene - phenyl group (wherein the phenyl group,
Hydroxyl group,
A C _1-6 alkyl group,
A hydroxymethyl group,
The group -COOM (M represents a hydrogen atom or a pharmaceutically acceptable cation),
A group —CO—NR ²² R ²³ (wherein R ²² and R ²³ may be the same or different and each represents a hydrogen atom or a C _1-6 alkyl group (this alkyl group is further substituted with an aminocarbonyl group); Or R ²² and R ²³ together with the nitrogen atom to which they are attached, a 5- or 6-membered saturated heterocycle comprising 1-2 oxygen or nitrogen atoms (Preferably represents a morpholinyl group, a piperazyl group, or a piperidyl group) (this heterocycle may be substituted with a hydroxyl group or a C _1-6 alkanoyloxy group)),
Group —O—R ²⁴ (wherein R ²⁴ represents a C _1-6 alkyl group (this alkyl group represents —COOM (M represents a hydrogen atom, a C _1-6 alkyl group or a pharmaceutically acceptable cation)). , An aminocarbonyl group, an amino group, a guanidino group, or a 5- or 6-membered unsaturated heterocyclic ring containing 1 to 2 nitrogen atoms), or 5 or 6 containing 1 to 2 nitrogen atoms May be substituted with a membered saturated heterocycle.)
-C _0-1 alkylene-heterocycle (wherein this heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing one nitrogen or oxygen atom, which ring is substituted with a hydroxyl group. You may)
-O-C _1-6 alkyl group, or -S-C _1-6 alkyl group,
R ² is
A C _1-6 alkyl group,
A C _3-7 cyclic alkyl group (wherein the ring may be substituted with a hydroxyl group and may be condensed with aryl), or a C _1-2 alkylene-phenyl group,
The metallo-β-lactamase inhibitor according to claim 1, which represents The metallo-β-lactamase inhibitor according to claim 1, wherein R ¹ and R ² represent a C _2-4 alkyl group.   A pharmaceutical composition comprising a compound of general formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.   The pharmaceutical composition according to claim 6, which is used as a metallo-β-lactamase inhibitor.   The pharmaceutical composition according to claim 6, which is used concurrently or sequentially with a β-lactam antibiotic.   The pharmaceutical composition according to claim 8, which is used by being administered simultaneously or sequentially with a dehydropeptidase inhibitor and / or a β-lactamase inhibitor other than the compound of general formula (I).   The pharmaceutical composition according to claim 6, wherein the β-lactam antibiotic is a carbapenem antibiotic.   A pharmaceutical composition comprising the metallo-β-lactamase inhibitor according to claim 1, a β-lactam antibiotic, and optionally a pharmaceutically acceptable carrier.   The pharmaceutical composition according to any one of claims 6 to 11, which is used as an antibacterial agent.   A method for treating bacterial infection, comprising administering a β-lactam antibiotic in combination with the metallo-β-lactamase inhibitor according to claim 1.   The method according to claim 13, wherein the β-lactam antibiotic is a carbapenem antibiotic. A compound represented by the following general formula (II), a salt thereof, or a solvate thereof.

(Where
R ³ represents a C _2-6 alkyl group, a C _3-7 cyclic alkyl group, or a hydroxymethyl group, any of which may have a substituent,
R ⁴ represents a C _1-6 alkyl group or a C _3-7 cyclic alkyl group, any of which may have a substituent,
Two M ² may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation, or a pharmaceutically acceptable group that can be hydrolyzed in vivo. ) A compound represented by the following general formula (III), a salt thereof, or a solvate thereof.

(Where
R ⁵ represents an ethyl group,
R ⁶ represents a C _1-3 chain alkyl group, and two M ³ may be the same or different, and are hydrolyzed in a pharmaceutically acceptable cation or a pharmaceutically acceptable in vivo. Represents a possible group. ) A compound represented by the following general formula (IV), a salt thereof, or a solvate thereof.

(Where
R ⁷ represents a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a —C _1-3 alkylene-phenyl group, a —C ₁ alkylene-A ring, an —O—C _1-6 alkyl group, or —S—. _{Represents a} C _1-6 alkyl group, any of which may have a substituent,
R ⁸ represents —C _1-3 alkylene-phenyl group, —C _0-1 alkylene-A ring, —O—C _1-6 alkyl group, or —S—C _1-6 alkyl group, all of which are substituted May have a group,
Ring A represents a 5- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom,
Two of M ⁴ may be the same or different, a hydrogen atom, represents a pharmaceutically acceptable cation or a pharmaceutically acceptable hydrolyzable group in vivo,
However, when R ⁷ is a C _1-6 alkyl group, R ⁸ does not represent dihydrofuran. )   Ring A is tetrahydrofuran, furan, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, The compound according to claim 17, which is triazole, tetrazole, thiadiazole, azetidine, thiazoline, quinuclidine, triazine, isobenzofuran, indole, indolizine, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine, Salts or solvates thereof. A compound represented by the following general formula (V), a salt thereof, or a solvate thereof.

(Where
R ⁹ is a C _1-6 alkyl group, a C _3-7 cyclic alkyl group, a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-B ring, an —O—C _1-6 alkyl group, or -S-C _1-6 represents an alkyl group, any of which may have a substituent,
R ¹⁰ represents a —C _1-3 alkylene-phenyl group, a —C _0-1 alkylene-B ring, an —O—C _1-6 alkyl group, or an —S—C _1-6 alkyl group, all of which are substituted. May have a group,
Ring B represents pyridine, piperidine, or tetrahydropyran;
Two M ⁵ may be the same or different and each represents a hydrogen atom, a pharmaceutically acceptable cation or a pharmaceutically acceptable group that can be hydrolyzed in vivo,
However, the case where R ⁹ and R ¹⁰ represent pyridinium is excluded. )   The compound according to any one of claims 15 to 19, wherein the pharmaceutically acceptable cation is a metal cation or an ammonium cation.   Use of a compound according to any one of claims 1 to 5 or claims 15 to 20 for the prevention or treatment of bacterial infections.