JP2019147748A - Compound or pharmaceutically acceptable salt, optical active body, pharmaceutical composition, and manufacturing method of compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having a physiological activity or a pharmacologically acceptable salt thereof, an optically active substance thereof, a pharmaceutical composition containing the compound having the physiological activity, and a method for producing the compound having the physiological activity. SOLUTION: A compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof is provided. [In the above general formula (1), R1 and R2 represent an alkyl group, an alkoxyl group, or an aryl group, R1 and R2 are different groups from each other, and FG represents an amino group or a carboxymethyl group. ] [Selection diagram] None

Description

  The present invention relates to a compound or a pharmacologically acceptable salt thereof, an optically active substance, a pharmaceutical composition, and a method for producing the compound.

  Optically active organosilicon compounds having a silicon atom as an asymmetric center are expected to be used in the field of functional materials and the like. Optically active organosilicon compounds are also expected to be used as biologically active substances in the fields of medicine and agricultural chemicals.

  A method for synthesizing a silicon compound in which a silicon atom is an asymmetric center and a method for selectively synthesizing an enantiomer of an optically active organosilicon compound have been studied. For example, Non-Patent Document 1 discloses a chiral cyclopentene skeleton having a chiral cyclopentene skeleton having an asymmetric center at a silicon atom by causing β-hydrogen elimination of an achiral silacyclopentene oxide in the presence of a specific chiral lithium amide. A method for selectively synthesizing pentenol is disclosed.

Kazunobu Igawa, et al. , “Enantioselective Synthesis of Silicate lentanes”, Angew. Chem. Int. Ed. 2016, 55, p. 5814-5818

  However, there are few examples of evaluating functions such as physiological activity that are considered to be possessed by compounds having a chiral cyclopentenol skeleton. Moreover, it cannot be said that a method for selectively producing an optically active organosilicon compound having physiological activity has been sufficiently studied.

  The present invention provides a physiologically active compound or a pharmacologically acceptable salt thereof, an optically active isomer thereof, a pharmaceutical composition containing the physiologically active compound, and a method for producing the physiologically active compound. For the purpose.

In one aspect, the present invention provides a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group.

  The compound or a pharmacologically acceptable salt thereof has a silicon atom as an asymmetric center (has an asymmetric silicon), and is used as a material used in medicines, functional materials, and the like. There is expected. Moreover, since the said compound or its pharmacologically acceptable salt has the amino group or carboxymethyl group which is a partial structure of an amino acid, or these salts, it is anticipated to have a bioactive function. .

In one aspect, the present invention provides an optically active substance comprising a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group.

In one aspect, the present invention provides a pharmaceutical composition comprising a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group.

In one aspect of the present invention, an intermediate represented by the following general formula (3) is prepared by subjecting an alicyclic alcohol having a structure represented by the following general formula (2) and a reaction substrate to Mitsunobu reaction or 辻 -Trost reaction. And a process for obtaining a compound having a structure represented by the following general formula (1) from an intermediate represented by the following general formula (3).

In the general formula (2), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In the general formula (3), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and Nu represents a substituent derived from a reaction substrate.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group.

  In the above production method, since Mitsunobu reaction or 辻 -Trost reaction is used, the stereochemistry in the alicyclic alcohol having the structure represented by the general formula (2) (particularly the stereochemistry on the 4-position carbon of the silacyclopentene skeleton) The compound having asymmetric silicon can be produced by inverting or maintaining the chemistry. For example, it is possible to selectively synthesize one enantiomer contained in a compound having a structure represented by the general formula (1).

  In one aspect, the present invention provides a compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof.

In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In one aspect, the present invention provides an optically active substance comprising a compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof.

In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In one aspect of the present invention, a compound having a structure represented by the following general formula (4) is obtained by subjecting a silacyclopentenol oxide having a structure represented by the following general formula (5) and an amine compound to a nucleophilic substitution reaction. The manufacturing method of a compound including the process of obtaining is provided.

In the general formula (5), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

  Since the above production method uses a nucleophilic substitution reaction, the stereochemistry in the alicyclic alcohol having the structure represented by the general formula (5) (particularly the stereochemistry on the 2-position carbon of the silacyclopentane skeleton) Can be reversed to produce a compound having asymmetric silicon. For example, it is possible to selectively synthesize one enantiomer contained in a compound having a structure represented by the general formula (4).

  According to the present invention, a compound having physiological activity or a pharmacologically acceptable salt thereof, an optically active isomer thereof, a pharmaceutical composition containing the compound having physiological activity, and a method for producing a compound having physiological activity. Can be provided.

  Hereinafter, embodiments of the present invention will be described. However, the following embodiments are examples for explaining the present invention, and are not intended to limit the present invention to the following contents.

  One embodiment of the present invention is a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof. In the present specification, a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof is also referred to as “compound (I)”. As shown by the following general formula (1), since compound (I) has asymmetric silicon, it can be applied to general reagents, test agents, medicines, diagnostic agents, test agents, and contrast agents. .

In General Formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. As an alkyl group, a C1-C10 alkyl group may be sufficient, and a C1-C7 alkyl group may be sufficient. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-butyl group, an s-butyl group, and a t-butyl group. The alkoxyl group may be an alkoxyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 4 carbon atoms. Examples of the alkoxyl group include a methoxy group, an ethoxy group, an n-butoxy group, an s-butoxy group, and a t-butoxy group. The aryl group may have a substituent, may be an aryl group having 6 to 20 carbon atoms, or may be an aryl group having 6 to 14 carbon atoms. Examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group.

  In General formula (1), FG is an amino group or a carboxymethyl group. When FG is an amino group, the compound (I) has a strong binding force to an adrenergic receptor protein, a noradrenergic receptor protein, a glutamate receptor protein, a histamine receptor protein, an opioid receptor protein, a sigma receptor protein, a sodium channel protein, and the like. Can have physiological activity. When FG is a carboxymethyl group, compound (I) has a strong binding force to an adrenergic receptor protein and the like and can have physiological activity.

  One embodiment of the present invention is a compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof. In the present specification, a compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof is also referred to as “compound (II)”. As shown by the following general formula (4), since the compound (II) has asymmetric silicon like the compound (I), the general reagent, test agent, medicine, diagnostic agent, test agent, contrast agent, etc. Application to is possible.

In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. As an alkyl group, a C1-C10 alkyl group may be sufficient, and a C1-C7 alkyl group may be sufficient. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-butyl group, an s-butyl group, and a t-butyl group. The alkoxyl group may be an alkoxyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 4 carbon atoms. Examples of the alkoxyl group include a methoxy group, an ethoxy group, an n-butoxy group, an s-butoxy group, and a t-butoxy group. The aryl group may have a substituent, may be an aryl group having 6 to 20 carbon atoms, or may be an aryl group having 6 to 14 carbon atoms. Examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group.

  Compound (I) or Compound (II) may be a single optical isomer (stereoisomer and optically active isomer of any one of enantiomers and diastereomers), and a plurality of optical isomers It may be a mixture of bodies. In the case of a mixture of a plurality of optical isomers, the mixing ratio is not particularly limited, and may be, for example, an equivalent mixture of enantiomers (racemate), or a mixture in which R and S isomers are mixed in an arbitrary ratio. It may be.

In compound (I) or compound (II), one or more of the constituent atoms may be substituted with an atomic isotope, and the substitution ratio may exceed the natural abundance ratio of isotopes. The atomic isotopes such as deuterium ⁽² H), tritium ⁽³ H), carbon ^{-11 (11} C), carbon ^{-14 (14} C), fluorine ^{-18 (18} F), sulfur -35 ⁽³⁵ S), iodine-125 ( ¹²⁵ I) and the like. These isotope variants are included in Compound (I) regardless of whether they are radioactive or not. Isotope variants can be used particularly as therapeutic agents, prophylactic agents, research reagents, test agents, and the like.

  The “pharmacologically acceptable salt” according to the present embodiment means a pharmaceutically acceptable salt, and includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphates. Salt with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, trifluoroacetic acid, etc .; salt with methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, salts with organic sulfonic acids such as p-toluenesulfonic acid and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonia, morpholine, glucosamine, Ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine, piperazine, etc. Include quaternary ammonium salts of. Pharmacologically acceptable salts may form hydrates or solvates, and these hydrates and solvates may be used alone or in combination of two or more. .

  One embodiment of the present invention is a composition (eg, pharmaceutical composition) comprising compound (I) or compound (II). In addition to compound (I) or compound (II), the above composition comprises an excipient, a lubricant, a binder, a disintegrant, a coating agent, a stabilizer, an isotonic agent, a buffer, a pH adjuster, Other components such as solubilizers, thickeners, preservatives, antioxidants, sweeteners, colorants, fragrances may be included. The pharmaceutical composition may be appropriately prepared by methods known to those skilled in the art. When the pharmaceutical composition contains other components in addition to compound (I) or compound (II), the content of the other components can be adjusted according to the individual to be treated and the dosage form. For example, it may be 0.001 to 95% by mass or 0.01 to 50% by mass based on the total amount of the pharmaceutical composition.

  The pharmaceutical composition may be for oral administration such as tablets, capsules, granules, and agents, and includes injections, eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, It may be used for parenteral administration such as inhalants and transdermal absorption preparations.

  A method for producing compound (I) will be described. In one embodiment of the method for producing compound (I), an alicyclic alcohol having a structure represented by general formula (2) and a reaction substrate are subjected to Mitsunobu reaction or 辻 -Trost reaction, and represented by general formula (3). A step of obtaining an intermediate having a structure and a step of obtaining a compound having a structure represented by general formula (1) from an intermediate having a structure represented by general formula (3) are included.

In the general formula (2), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In the general formula (3), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and Nu represents a substituent derived from a reaction substrate.

In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² are groups different from each other, and FG is an amino group or a carboxymethyl group.

  The production method according to the present embodiment is a step of obtaining an intermediate having a structure represented by the general formula (3) by causing Mitsunobu reaction between an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate. And an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate are subjected to 辻 -Trosst reaction to obtain an intermediate having the structure represented by the general formula (3) There is a method.

  An example of a method including the step of Mitsunobu reaction of an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate to obtain an intermediate having a structure represented by the general formula (3) Shown in (1). The production method shown in Reaction Formula (1) includes Step A1 and Step A2. Step A1 corresponds to the step of Mitsunobu reaction of the alicyclic alcohol having the structure represented by the general formula (2) and the reaction substrate to obtain an intermediate having the structure represented by the general formula (3). This corresponds to the step of obtaining the compound having the structure represented by the general formula (1) from the intermediate having the structure represented by the general formula (3).

[Step A1: Mitsunobu Reaction]
In step A1, the compound having the structure represented by the general formula (2) and the reaction substrate are subjected to a Mitsunobu reaction, whereby the stereochemistry at the 4-position carbon of the silacyclopentene skeleton in the structure represented by the general formula (2). An intermediate having the structure represented by the general formula (3) is produced.

  The reaction substrate (NuH) in the Mitsunobu reaction is not particularly limited. The nucleophile (Nu) constituting the reaction substrate may be amine, alcohol, carbanion, phenol, carboxylic acid, indole, nucleobase, thiocarboxylic acid and the like. The amount of the reaction substrate used may be 1.0 to 100 times mol, or 1.1 to 10.0 times mol for 1 mol of the compound having the structure represented by the general formula (2). 1.2-2.0 times mole may be sufficient.

As the catalyst in the Mitsunobu reaction, a catalyst known to those skilled in the art can be used. For example, a combination of azodicarboxylic acid ester and phosphine, a combination of azodicarboxylic acid amide and phosphine, or the like can be used. it can. Examples of the azodicarboxylic acid ester include diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD). Examples of the azodicarboxylic acid amide include 1,2-bis (piperidinocarbonyl) diazene. As the phosphine, triarylphosphine, trialkylphosphine and the like are used, and examples thereof include triphenylphosphine (PPh ₃ ) and tributylphosphine.

  The amount of azodicarboxylic acid ester or azodicarboxylic acid amide used is 1.0 to 100 times mol or 1.4 to 5.0 times mol for 1 mol of the compound having the structure represented by the general formula (2). It may be. The usage-amount of a phosphine may be 1.0-100 times mole with respect to 1 mol of compounds which have a structure shown by General formula (2), and may be 1.4-5.0 times mole. .

As the reaction solvent in the Mitsunobu reaction, for example, at least one solvent selected from chloroform, dioxane, xylene, diethyl ether, tetrahydrofuran (THF), dichloromethane (CH ₂ Cl ₂ ), toluene and the like can be used. . From the viewpoint of suppressing side reactions and improving the yield of compound (I), the reaction solvent may be dichloromethane or toluene, or may be toluene. The usage-amount of a solvent may be 10-100L with respect to 1 mol of compounds which have a structure shown by General formula (2), or 20-30L, for example.

  The reaction temperature in the Mitsunobu reaction can be appropriately adjusted depending on the compound having the structure represented by the general formula (2), the reaction substrate, the reaction solvent, and the like, and may be, for example, 20 to 40 ° C. It may be 35 ° C.

[Step A2]
In step A2, a compound having a structure represented by general formula (1) is obtained from an intermediate having a structure represented by general formula (3). For example, in General Formula (3), when Nu is an imide group, an amine body is obtained by performing a hydrolysis reaction. Moreover, in General formula (3), when Nu is a malonic acid ester group, a carboxymethyl body is obtained by performing a decarboxylation reaction after a hydrolysis reaction.

  An example of a method including a step of subjecting an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate to a Trost reaction to obtain an intermediate represented by the general formula (3) is represented by the following reaction formula ( 2). The production method shown in Reaction Formula (2) includes Step B1, Step B2, and Step B3. Steps B1 and B2 correspond to the step of obtaining an intermediate having the structure represented by the general formula (3) by subjecting the alicyclic alcohol having the structure represented by the general formula (2) and the reaction substrate to the Trost reaction. And process B3 respond | corresponds to the process of obtaining the compound which has a structure shown by General formula (1) from the intermediate body which has a structure shown by General formula (3).

[Step B1]
In Step B1, a hydroxyl group is substituted with the substituent G in the compound having the structure represented by the general formula (2), and partial structures such as allyl halide, allyl ester, allyl carbonate, and allyl phosphonate are introduced. In the reaction formula (2), G may be X—, RCO ₂ —, RO ₂ CO—, RO—, R ₂ N—, RSO ₃ —, ArSO ₃ — or the like. Here, X represents a halogen atom, Ar represents an aromatic ring, and R represents an alkyl group having 1 to 4 carbon atoms.

[Step B2: 辻 -Trost reaction]
In step B2, the stereochemistry at the 4-position carbon of the silacyclopentene skeleton was maintained in the structure represented by the general formula (2) by subjecting the compound obtained in step B1 to 辻 -Trosst reaction with the reaction substrate (NuH). The intermediate which has a structure shown by General formula (3) is manufactured as it is.

  In order to substitute the hydroxyl group with the substituent G in the compound having the structure represented by the general formula (2), for example, methyl chloroformate (MeOCOCl), isopropyl chloroformate, benzyl chloroformate, acetic anhydride, acetyl chloride, Fluoroacetic acid, methanesulfonyl chloride, benzenesulfonyl chloride, paratoluenesulfonyl chloride, and the like can be used.

  The reaction substrate (NuH) in the 辻 -Trost reaction is not particularly limited. The nucleophile (Nu) constituting the reaction substrate may be amine, alcohol, carbanion, phenol, carboxylic acid, indole, nucleobase, thiocarboxylic acid and the like. The amount of the reaction substrate used may be 1.0 to 100 times mol, or 1.3 to 20 times mol based on 1 mol of the compound having the structure represented by the general formula (2). Or 1.5-3.0 times mole may be sufficient.

A catalyst well known to those skilled in the art can be used as the catalyst in the 辻 -Trost reaction. For example, a combination of a palladium complex and a phosphine can be used. Examples of the palladium complex include tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) and the like. Examples of the phosphine include triphenylphosphine and tris (orthotolyl) phosphine (P (o-tolyl) ₃ ). The phosphine may be tris (orthotolyl) phosphine from the viewpoint of suppressing side reactions, improving the yield of the compound (I), and being excellent in stereoselectivity.

  The usage-amount of a palladium complex may be a catalytic amount, may be 0.01-10 times mole with respect to 1 mol of compounds which have a structure shown by General formula (2), or 0.05-1 It may be 0.0 mole. The amount of phosphine used may be a catalytic amount, and may be 0.01 to 10 times the mole of the compound having the structure represented by the general formula (2), or 0.05 to 1. It may be 0 times mole.

As a reaction solvent in the 辻 -Trost reaction, for example, at least one solvent selected from chloroform, dimethyl sulfoxide, dioxane, xylene, diethyl ether, tetrahydrofuran (THF), dichloromethane (CH ₂ Cl ₂ ), toluene and the like is used. Can be used. From the viewpoint of the solubility of carbanion, the reaction solvent may be tetrahydrofuran. The usage-amount of a solvent may be 5-100L with respect to 1 mol of compounds which have a structure shown by General formula (2), or may be 8-20L, for example.

  The reaction temperature in the 辻 -Trost reaction can be appropriately adjusted depending on the compound having the structure represented by the general formula (2), the reaction substrate, the reaction solvent, and the like, and may be, for example, 20 to 60 ° C. It may be 25 to 55 ° C.

[Step B3]
In step B3, a compound having a structure represented by general formula (1) is obtained from the intermediate having the structure represented by general formula (3) obtained in step B2. For example, in the general formula (3), when Nu is an imide group, an amine body is obtained by hydrolysis. Moreover, in General formula (3), when Nu is a malonic ester group, a carboxymethyl body is obtained by performing a decarboxylation reaction after hydrolysis.

  In the above reaction formulas (1) and (2), an example in which one enantiomer is used as the alicyclic alcohol having the structure represented by the general formula (2) is shown. Stereomers or mixtures thereof can also be used.

  As the alicyclic alcohol having the structure represented by the general formula (2), for example, a compound obtained by the method disclosed in Non-Patent Document 1 can be used. More specifically, an alicyclic alcohol (compound A1, compound A2, compound B1, and compound B2) obtained by the following reaction formula (3) or reaction formula (4) can be used. In Reaction Formula (3) and Reaction Formula (4), one enantiomer (either Compound A1 or Compound A2 or Compound B1 or Compound B2) is selectively used by using a specific chiral lithium amide. Can be synthesized. When synthesizing Compound A2 or Compound B2, for example, enantiomers of chiral lithium amides described in Reaction Formula (3) and Reaction Formula (4) are used.

  According to the above production method, various optical isomers (compound Ia, compound Ib, compound Ic, and compound Id) included in the structure represented by the general formula (1) can be selectively produced. Such optical isomers can be represented by the following general formula.

  The above production method may further comprise a step of further purifying the obtained compound (I). The purification step is performed using, for example, high performance liquid chromatography. The optical purity of the optically active substance can be, for example, 80% ee or more, 90% ee or more, or 100% ee. Optical purity can be measured by HPLC analysis using a chiral stationary phase.

A method for producing compound (II) will be described. In one embodiment of the method for producing compound (II), a silacyclopentenol oxide having a structure represented by general formula (5) and an amine compound are subjected to a nucleophilic substitution reaction to form a structure represented by general formula (4) A step of obtaining a compound having

In the general formula (5), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other.

  An example of the production method according to this embodiment is shown in the following reaction formula (5). The manufacturing method shown in Reaction Formula (5) includes Step C1 and Step C2. Step C1 is a step of performing epoxidation reaction of an alicyclic alcohol having a structure represented by the general formula (2) to obtain a silacyclopentenol oxide having a structure represented by the general formula (5). Corresponds to a step of reacting a silacyclopentenol oxide having a structure represented by the general formula (5) with an amine compound to obtain a compound having a structure represented by the general formula (4).

[Step C1: Epoxidation reaction]
In step C1, an epoxide intermediate having a structure represented by general formula (5) is produced by reacting a compound having the structure represented by general formula (2) with metachloroperbenzoic acid (mCPBA). . As the reaction solvent, for example, dichloromethane, toluene and the like can be used. The reaction temperature may be, for example, 20 to 40 ° C, or 25 to 35 ° C.

[Step C2: Nucleophilic substitution reaction]
In step C2, silacyclopentenol oxide having a structure represented by general formula (5) is reacted with an amine compound (R ³ NH ₂ ) to obtain a compound having a structure represented by general formula (4). . In Step C2, the reaction substrate (R ³ NH) is subjected to a nucleophilic substitution reaction with the above-mentioned silacyclopentenol oxide, whereby the 2-position carbon of the silacyclopentane skeleton in the structure represented by the general formula (5) A compound having the structure represented by the general formula (4) is produced while reversing the stereochemistry. In the step C2, the selection of the catalyst is important, and for example, Eu (OTf) ₃ or the like can be used. In the conventional method using BF ₃ · OEt ₂ as a catalyst, it is difficult to obtain a compound having a structure represented by the general formula (4).

As the amine compound (R ³ NH ₂ ) used in the reaction formula (3), alkylamine, alkanolamine, arylamine and the like can be used. The amount of the amine compound used may be 1.0 to 100 times mol, or 2.0 to 20 times mol based on 1 mol of the compound having the structure represented by the general formula (5). 2.0-3.0 times mole may be sufficient.

As the reaction solvent in the step C2, for example, at least one solvent selected from chloroform, xylene, diethyl ether, dichloromethane (CH ₂ Cl ₂ ), toluene and the like can be used. From the viewpoint of suppressing side reactions and improving the yield of compound (II), the reaction solvent may be dichloromethane or toluene, or may be toluene. The usage-amount of a solvent may be 10-100L with respect to 1 mol of compounds which have a structure shown by General formula (5), or 20-30L, for example.

  Although the reaction temperature in process C2 can be suitably adjusted with the compound which has a structure shown by General formula (5), an amine compound, a reaction solvent, etc., it may be 20-40 degreeC, for example, may be 25-25. It may be 35 ° C.

  In the above-described reaction formula (5), an example in which one enantiomer is used as the alicyclic alcohol having the structure represented by the general formula (2) is shown. However, the above-described reaction formulas (1) and (2) Similarly, the other enantiomers, diastereomers, or mixtures thereof can be used. As the alicyclic alcohol having the structure represented by the general formula (2), those exemplified as the alicyclic alcohol usable in the above reaction formulas (1) and (2) can be used.

  As mentioned above, although embodiment of this invention was described, this invention is not limited to the said embodiment at all.

  Hereinafter, the contents of the present invention will be described in more detail with reference to Examples and Comparative Examples. However, the present invention is not limited to the following examples.

In the examples described below, the obtained compounds were identified and confirmed in structure by the following method.
[IR spectrum analysis]
The obtained compound was applied to a sodium chloride (NaCl) plate to prepare a measurement sample, and transmitted light was measured using a spectroscope (Perkin One, manufactured by PerkinElmer Co., Ltd.).
[NMR spectrum analysis]
The obtained compound is dissolved in a heavy solvent, put into a 5 mm diameter sample tube to prepare a measurement sample, and using a spectroscope (Varian, Mercury ( ¹ H: 300 MHz, ¹³ C: 75 MHz)), Measurements were made at room temperature.
[Optical rotation analysis]
The obtained compound was dissolved in chloroform and put into a cylindrical cell having an optical path length of 100 mm to prepare a measurement sample. Using a spectroscope [manufactured by JASCO Corporation, polarimeter DIP-370] with visible light of 589 nm Measurements were made.
[Mass spectrum analysis]
The obtained compound was measured in EI or FAB mode using a mass spectrometer (JEOL Ltd., JMS-700).

  Moreover, about the obtained compound, a compound is melt | dissolved in a developing solution using high performance liquid chromatography (HPLC) (The JASCO Corporation make, a liquid feed pump: PU-2089, a detector: CD-2095), and chiral. Reaction yield and purity were measured by separating enantiomers on a column packed with a stationary phase.

Example 1
[Synthesis of Compound 3 (Synthesis of Compound (I) Having Amino Group)]
Compound 3 was synthesized according to the following reaction formula.

50.0 mg (0.22 mmol) of Compound 1 (optical purity: 98% ee or higher), 38.0 mg (0.26 mmol) of phthalimide, 0.15 mL (0.32 mmol) of diazodigalbonate diethyl (DEAD) And 84.6 mg (0.32 mmol) of triphenylphosphine (PPh ₃ ) were dissolved in 5 mL of toluene, and Mitsunobu reaction was carried out at 25 ° C. for 6 hours to synthesize compound 2 as an intermediate. After isolating Compound 2 by silica gel chromatography (using a mixed solvent of hexane: ethyl acetate = 40: 1 as an eluent), 50.9 mg (0.14 mmol) of Compound 2 obtained, and 33. 0 μL (0.68 mmol) of hydrazine monohydrate (H ₂ NNH ₂ .H ₂ O) was dissolved in 5 mL of methanol and reacted for 20 hours while refluxing. After performing Celite filtration, the crude product obtained by acid-base extraction was subjected to silica gel chromatography (using a mixed solvent of chloroform: methanol = 20: 1 as an eluent) to obtain purified compound 3. (Reaction yield: 93%, optical purity: 98% ee).

The spectral data for Compound 3 was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ):
δ 7.51-7.48 (m, 2H), 7.36-7.31 (m, 3H), 6.85 (dd, J = 10.5, 1.8Hz, 1H), 6.25 (dd, J = 10.5, 1.8 Hz, 1H), 3.94 (brs , 1H), 2.60 (br, 1H), 1.63 (dd, J = 15.0, 8.1 Hz, 1H), 0.98 (s, 9H), 0.72 (dd, J = 15.0, 6.0 Hz, 1H).
¹³ C-NMR (75 MHz, CDCl ₃ ):
δ 159.1, 136.0, 134.8, 129.1, 127.7, 126.9, 56.5, 27.0, 18.1, 17.0.
HRMS (EI, positive):
Exact mass calc. For C ₁₄ H ₂₁ NSi [M] ⁺ , requires m / z: 231.1443, found m / z: 231.1442.

<Bioactivity evaluation>
About the compound 3 obtained above, physiological activity was evaluated. An evaluation test was performed using a standard protein known to bind to a given protein. For example, when compound 3 acts more strongly on the test protein than the standard ligand, the standard ligand is detected in a free state because the binding of the standard ligand to the test protein is inhibited. A specific test was performed by dissolving compound 3 and a standard ligand labeled with tritium or iodine 125 in DMSO, and allowing the DMSO solution to act on the test protein. The bioactivity was evaluated by determining the amount of standard ligand displaced by radiation dosimetry.

  Thirty test proteins including adrenergic receptor protein, noradrenaline receptor protein, sodium channel receptor protein, glutamate receptor protein, histamine receptor protein, opioid receptor protein, and sigma receptor protein were used as test proteins.

As a result of the measurement, the racemate of Compound 3 was adrenoceptor protein (standard ligand: 0.25 nM, “ ³ H-labeled”, Prazosin, inhibition rate: 90%), noradrenaline receptor protein (standard ligand: 0) at a concentration of 10 μM. 20 nM, “ ¹²⁵ I-labeled”, RTI-55, inhibition rate: 97%, sodium channel receptor protein (standard ligand: 5.0 nM, “ ³ H-labeled”, Batrachoxinin, inhibition rate: 98%), glutamate receptor protein (Standard ligand: 4.0 nM, “ ³ H-labeled”, TCP, inhibition rate: 80%), histamine receptor protein (standard ligand: 1.20 nM, “ ³ H-labeled”, Pyrilamine, inhibition rate: 65%), opioid receptor protein (standard ligand: 0.60nM, "the ³ H-labeled" Diprenorphine, inhibition rate: 65%), and sigma receptor protein (standard ligand: 8.0 nM, ^"3 H-labeled", Haloperidol, inhibition rate: to have physiological activity have been confirmed against 55%). Among these test proteins, the racemate of Compound 3 was confirmed to exhibit particularly strong activity against sodium channel receptor protein.

Furthermore, Compound 3 in which the stereochemistry on silicon is S-form and R-form was prepared as an optically active form. Each of the prepared S-form and R-form was evaluated for physiological activity. By adjusting the concentration of the target S-form and R-form to concentrations of 100 μM, 10 μM, 1 μM, and 0.1 μM, respectively, and examining the concentration dependence of physiological activity, 50% inhibitory concentration (IC ₅₀ )It was determined. As a result, when the S form of Compound 3 is used, the IC ₅₀ is 0.33 μM, and the enantiomer R form has an IC ₅₀ of 0.96 μM, which is 3 times higher. It was confirmed that

(Example 2)
[Synthesis of Compound 5 (Synthesis of Compound (I) Having Carboxymethyl Group)]
Compound 5 was synthesized according to the following reaction formula.

  38.0 mg (0.16 mmol) of Compound 1 (optical purity: 98% ee or higher), 27.7 mg (0.19 mmol) of Meldrum's acid, 0.11 mL (0.24 mmol) of diazodigalbonate diethyl, and 63. Compound 4 as an intermediate was synthesized by dissolving 0 mg (0.24 mmol) of triphenylphosphine in 3 mL of toluene and subjecting it to Mitsunobu reaction at 25 ° C. for 6 hours. After isolating compound 4 by silica gel chromatography (using a mixed solvent of hexane: ethyl acetate = 40: 1 as an eluent), 15.0 mg (42.0 μmol) of the obtained compound 4 was obtained. 1 mL of 1N hydrochloric acid aqueous solution was dissolved in 3 mL of 1,4-dioxane, and reacted at 100 ° C. for 20 hours. The crude product was subjected to silica gel chromatography (using a mixed solvent of hexane: ethyl acetate = 5: 1 as an eluent) to obtain the purified compound 5 (reaction yield: 87%, optical purity: 98%). ee).

The spectral data for Compound 5 was as follows:
¹ H-NMR (300 MHz, CDCl ₃ ):
δ 7.52 (m, 2H), 7.36-7.32 (m, 3H), 6.81 (dd, J = 10.2, 2.1 Hz, 1H), 6.24 (dd, J = 10.2, 2,4 Hz, 1H), 3.15-3.10 (M, 1H), 2.60 (dd, J = 14.7, 6.3 Hz, 1H), 2.37 (dd, J = 14.7, 9.0 Hz, 1H), 1.39 (dd, J = 15.3, 8.4 Hz, 1H), 0.95 ( s, 9H), 0.62 (dd, J = 15.3, 8.4 Hz, 1H).
¹³ C-NMR (75 MHz, CDCl ₃ ):
δ 178.2, 157.2, 136.3, 134.8, 129.0, 127.7, 127.3, 42.1, 41.0, 27.1, 17.0, 11.9.
IR (neat, cm ⁻¹ ):
2926, 2855, 1708, 1469, 1427, 1110, 822, 733, 699.
HRMS (EI, positive):
Exact mass calc. _{for C 12 H 13 O 2 Si} [M-tBu] +, requires m / z: 217.0684, found m / z: 217.0685.
[Α] _D ²⁸ :
−71.0 (c 0.66, CHCl ₃ ) for> 98% ee.

<Bioactivity evaluation>
About the compound 5 obtained above, it carried out similarly to Example 1, and evaluated bioactivity.
From the results of the evaluation, the racemate of Compound 5 has a physiological activity against an adrenergic receptor protein (standard ligand: 0.25 nM, “ ³ H-labeled”, Prazosin, inhibition rate: 19%) at a concentration of 10 μM. Was confirmed.

(Example 3)
[Synthesis of Compound 8 (Synthesis of Compound (I) Having Carboxymethyl Group)]
Compound 8 was synthesized according to the following reaction formula.

  50 mg (0.22 mmol) of compound 1 (optical purity: 98% ee or more), pyridine 0.25 mL, and 33.3 μL (0.44 mmol) of methyl chloroformate at 0 ° C. Compound 6 was obtained by dissolving in dichloromethane and reacting at 25 ° C. 48.5 μL (0.42 mmol) of dimethyl malonate, 16.1 mg (0.42 mmol) of sodium hydride was dissolved in 1 mL of tetrahydrofuran and stirred for 20 minutes, then 11.0 mg (10.6 μmol) of Tris. (Dibenzylideneacetone) dipalladium and 16.1 mg (52.8 μmol) of tri (orthotrityl) phosphine and 61.3 mg (0.21 mmol) of compound 6 were dissolved in 2 mL of tetrahydrofuran under the conditions of 50 ° C. The compound 7 which is an intermediate was synthesized by performing a 辻 -Trosst reaction for 6.5 hours below. Compound 7 was isolated by silica gel chromatography (using a mixed solvent of hexane: diethyl ether = 20: 1 as an eluent). 62.7 mg (0.18 mmol) of the obtained compound 7 and 1 mL of 1N aqueous sodium hydroxide solution were added and stirred in 3 mL of 1,4-dioxane for 7 hours, and then 2 mL of 1N aqueous hydrochloric acid solution was added. In addition, the reaction was allowed to proceed for 20 hours at 100 ° C. The crude product was subjected to silica gel chromatography (using a mixed solvent of hexane: ethyl acetate = 3: 1 as an eluent) to obtain purified compound 8 (reaction yield: 77%, optical purity: 98%). ee).

The spectral data for Compound 8 was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ):
δ 7.53-7.50 (m, 2H), 7.37-7.32 (m, 3H), 6.84 (dd, J = 10.2, 2.1 Hz, 1H), 6.24 (dd, J = 10.2, 2.4 Hz, 1H), 3.20 (m , 1H), 2.50 (dd, J = 15.0, 6.3 Hz, 1H), 2.24 (dd, J = 15.3, 8.7 Hz, 1H), 1.44 (dd, J = 15.3, 8.1 Hz, 1H), 0.94 (s, 9H), 0.62 (dd, J = 15.0, 5.4 Hz, 1H).
¹³ C-NMR (75 MHz, CDCl ₃ ):
δ 178.6, 157.1, 136.8, 134.6, 129.0, 127.7, 127.4, 42.3, 41.7, 26.7, 15.7, 12.8.
IR (neat, cm ⁻¹ ):
2926, 1707, 1427, 1285, 1111, 822, 728, 699, 522.
HRMS (EI, positive):
Exact mass calc. for C ₁₂ H ₁₃ O ₂ Si [M-tBu] ⁺ , requirements m / z: 217.0068, found m / z: 217.0068.
[Α] _D ²⁸ :
−16.7 (c 1.33, CHCl ₃ ) for> 98% ee.

(Reference example)
[Synthesis of Compound 12]
Compound 12 was synthesized according to the following reaction formula.

50.1 mg (0.22 mmol) of compound 9 (optical purity: 98% ee or higher) and 77.7 mg (0.32 mmol) of metachloroperbenzoic acid (mCPBA) were dissolved in 2 mL of dichloromethane, The compound 10 was obtained by making it react on conditions of these. Compound 10 and 2.5 μL (0.02 mmol) of boron trifluoride diethyl ether complex were dissolved in 1 mL of allyl alcohol and reacted for 24 hours at 60 ° C. to obtain Compound 11. Compound 11 and 11.8 mg (12.8 μmol) of tris (triphenylphosphine) rhodium (I) chloride (RhCl (PPh ₃ ) ₃ ), 4.3 mg (38.4 μmol) of 1,4-diazabicyclo [2, 2,2] octane (DABCO) was dissolved in 0.9 mL of ethanol and 0.1 mL of water and reacted for 2 hours while refluxing, and then 1 mL of 1N aqueous hydrochloric acid was added. The crude product was subjected to silica gel chromatography (using a mixed solvent of hexane: ethyl acetate = 1: 1 as an eluent) to obtain the purified compound 12 (reaction yield: 57%, optical purity: 98%). ee).

The spectral data for Compound 12 was as follows:
¹ H-NMR (300 MHz, CDCl ₃ ):
δ 7.64-7.61 (m, 2H), 7.38-7.35 (m, 3H), 4.36 (brs, 1H), 4.15 (brd, J = 9.3 Hz, 1H), 4.02 (d, J = 3.9 Hz, 1H), 2.49 (br, 1H), 1.99 (br, 2H), 1.28 (dd, J = 15.6, 3.0 Hz, 1H), 1.21 (dd, J = 15.6, 5.1 Hz, 1H), 1.02 (s, 9H).
¹³ C-NMR (75 MHz, CDCl ₃ ):
δ 135.3, 134.7, 129.3, 127.7, 82.8, 72.4, 69.8, 26.6, 17.6, 13.7.
IR (reflection, cm ⁻¹ ):
3307, 2856, 1873, 1428, 1326, 1111, 824, 699, 497.
HRMS (EI, positive):
_{Exact mass calcd for C 10 H 13} O 3 Si [M-tBu] +, requires m / z: 209.0634, found m / z: 209.0634.
[Α] _D ²⁸ :
+27.5 (c 0.38, CHCl ₃ ) for> 98% ee ( _{Si 2} S).

<Bioactivity evaluation>
About the compound 12 obtained above, it carried out similarly to Example 1, and evaluated bioactivity.
From the results of the evaluation, it was confirmed that the racemate of Compound 12 has physiological activity against the serotonin receptor protein (standard ligand: 1.20 nM, “ ³ H label”, Lysic acid dietylamide, inhibition rate: 44%). It was. On the other hand, it showed no physiological activity against adrenergic receptor protein, noradrenaline receptor protein, sodium channel receptor protein, glutamate receptor protein, histamine receptor protein, opioid receptor protein, and sigma receptor protein.

Furthermore, as an optical activity, a compound 12 in which the stereochemistry on silicon is S-form and R-form was prepared. About each of the adjusted said S body and R body, the density | concentration dependence of the physiological activity evaluation with respect to a serotonin receptor protein was examined. The 50% inhibitory concentration was determined by adjusting the concentrations of the S-form and R-form to concentrations of 100 μM, 10 μM, 1 μM, and 0.1 μM and examining the concentration dependence of physiological activity. As a result, the IC ₅₀ of the S form of Compound 12 is 6.4 μM, and the R ₅₀ which is the enantiomer has an activity of 1.6 times higher than that of the IC ₅₀ of 10.3 μM. It was confirmed.

(Example 3)
[Synthesis of Compound 13]
Compound 8 was synthesized according to the following reaction formula.

  100.0 mg (0.43 mmol) of compound 9 (optical purity: 98% ee or more) and 154.6 mg (0.64 mmol) of metachloroperbenzoic acid (mCPBA) were dissolved in 10 mL of dichloromethane, The compound 10 was obtained by making it react on conditions of these. Compound 10, 88.0 mL (0.81 mmol) of benzylamine, and 48.2 mg (80.5 μmol) of europium (III) triflate were dissolved in 2 mL of toluene and reacted at 100 ° C. for only 24 hours. Compound 13 was synthesized. The crude product was subjected to silica gel chromatography (a mixed solvent of hexane: diethyl ether = 2: 1 to 1: 1 was used as an eluent) to obtain a purified compound 13 (reaction yield: 49%, optical Purity: 98% ee).

The spectral data for Compound 13 was as follows:
¹ H-NMR (300 MHz, CDCl ₃ ):
δ 7.66-7.63 (m, 2H), 7.40-7.37 (m, 3H), 4.27 (ddd, J = 6.0, 3.6, 3.3 Hz, 1H), 4.03 (d, J = 8.4 Hz, 1H), 3.80 (dd , J = 8.4, 3.3 Hz, 1H), 2.37 (br, 3H), 1.36 (dd, J = 15.6, 6.0 Hz, 1H), 1.20 (dd, J = 15.6, 3.3 Hz, 1H), 1.01 (s, 9H).
¹³ C-NMR (150 MHz, CDCl ₃ ):
δ 140.6, 135.4, 134.8, 129.2, 128.6, 128.3, 127.8, 127.2, 81.7, 72.3, 56.0, 54.0, 27.3, 17.9, 14.1.
IR (neat, cm ⁻¹ ):
3369, 2927, 1470, 1427, 1109, 1050, 822, 756, 699, 496.

Claims (7)

A compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

[In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group. ] An optically active substance comprising a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

[In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group. ] A pharmaceutical composition comprising a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

[In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group. ] A step of obtaining an intermediate represented by the following general formula (3) by subjecting an alicyclic alcohol having a structure represented by the following general formula (2) and a reaction substrate to Mitsunobu reaction or 辻 -Trosst reaction; The manufacturing method of a compound including the process of obtaining the compound which has a structure shown by the following general formula (1) from the intermediate body represented by (3).

[In the general formula (2), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. ]

[In the general formula (3), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and Nu represents a substituent derived from a reaction substrate. . ]

[In the general formula (1), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, R ¹ and R ² represent different groups, and FG represents an amino group or a carboxymethyl group. ] A compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof.

[In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. ] An optically active substance comprising a compound having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof.

[In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. ] A compound comprising a step of reacting a silacyclopentenol oxide having a structure represented by the following general formula (5) with an amine compound to obtain a compound having a structure represented by the following general formula (4): Production method.

[In the general formula (5), R ¹ and R ² represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. ]

[In the general formula (4), R ¹ , R ² and R ³ represent an alkyl group, an alkoxyl group, or an aryl group, and R ¹ and R ² are groups different from each other. ]