JP7040760B2 - A compound or a pharmacologically acceptable salt thereof, an optically active substance, a pharmaceutical composition, and a method for producing the compound. - Google Patents

Description

Article 30, Paragraph 2 of the Patent Law Applicable Website Publication Date August 25, 2017 Website Address https: // www. time-connect. com / products / maingroups / abstract / 10.1555 / s-0036-1590826 [Publications, etc.] Publication date September 7, 2017 Publications 28th Basic Organic Chemistry Discussion Meeting Abstracts [Publications, etc.] Date September 8, 2017 Meeting name 28th Main Group Organic Chemistry Discussion Venue Venue B, Ito Campus, Kyushu University (2304, 3rd floor, Center 2, Motooka, Nishi-ku, Fukuoka) [Publications, etc.] Date of publication December 2017 7th Publications Abstracts of the 44th Main Group Organic Chemistry Discussion [Publications, etc.] Date December 9, 2017 Meeting Name 44th Meeting of Main Group Organic Chemistry Venue Tokyo Institute of Technology Ookayama Campus (Tokyo) 2-12-1 Ookayama, Meguro-ku) [Publications, etc.] Publication date January 24, 2018 Publications IRCCS The 1st International Chemistry Abstracts [Publications, etc.] Publication date January 24, 2018 Publications IRCCS The 1st International Chemistry Poster

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 fields such as functional materials. Further, the optically active organosilicon compound is also expected to be used as a biologically active substance in the fields of pharmaceuticals and pesticides.

A method for synthesizing a silicon compound having a silicon atom as 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 describes a chiral cyclo having a chiral cyclopentene skeleton centered on a silicon atom by causing β-hydrogen desorption 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 Chemical Clementans”, Agew. Chem. Int. Ed. 2016, 55, p. 5814-5818

However, there are few examples of evaluating functions such as physiological activity considered to be possessed by a compound having a chiral cyclopentenol skeleton. Further, 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 pharmaceutical composition containing a compound having a physiological activity or a pharmacologically acceptable salt thereof, an optically active substance thereof, and a compound having a physiological activity, and a method for producing a compound having a physiological activity. The purpose is.

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 above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group.

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

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

In the above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group.

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

In the above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group.

In one aspect, the present invention is an intermediate represented by the following general formula (3) in which an alicyclic alcohol having a structure represented by the following general formula (2) is subjected to a Mitsunobu reaction or a Tsuji-Trost reaction with a reaction substrate. Provided is a method for producing a compound, which comprises a step of 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 above 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 different groups from each other.

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

In the above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group.

Since the above production method uses the Mitsunobu reaction or the Tsuji-Trost reaction, the stereochemistry of the alicyclic alcohol having the structure represented by the general formula (2) (particularly, the stereochemistry on the 4-position carbon of the silacyclopentene skeleton). Chemistry) can be inverted or maintained to produce compounds with asymmetric silicon. For example, it is also possible to selectively synthesize one enantiomer contained in the compound having the 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 above 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 different groups from each other.

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

In the above 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 different groups from each other.

In one aspect, the present invention is a compound having a structure represented by the following general formula (4) by subjecting an amine compound to a nucleophilic substitution reaction with a silacyclopentenol oxide having a structure represented by the following general formula (5). Provided is a method for producing a compound, which comprises a step of obtaining the compound.

In the above 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 different groups from each other.

In the above 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 different groups from each other.

Since the above production method uses a nucleophilic substitution reaction, the stereochemistry of 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 inverted to produce a compound having asymmetric silicon. For example, it is also possible to selectively synthesize one enantiomer contained in the compound having the structure represented by the general formula (4).

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

Hereinafter, embodiments of the present invention will be described. However, the following embodiments are examples for explaining the present invention, and the present invention is not intended to be limited 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, pharmaceuticals, diagnostic agents, test agents, contrast agents and the like. ..

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 different groups from each other, 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 different groups from each other. The alkyl group may be an alkyl group having 1 to 10 carbon atoms or an alkyl group having 1 to 7 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-butyl group, an s-butyl group, a t-butyl group and the like. The alkoxyl group may be an alkoxyl group having 1 to 6 carbon atoms, or may be 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, a t-butoxy group and the like. 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, an anthrasenyl group and the like.

In the general formula (1), FG is an amino group or a carboxymethyl group. When the FG is an amino group, the compound (I) has a strong binding force to an adrenaline accepting protein, a noradrenaline accepting protein, a glutamate accepting protein, a histamine accepting protein, an opioid accepting protein, a sigma accepting protein, a sodium channel protein and the like. Can have physiological activity. When the FG is a carboxymethyl group, the compound (I) has a strong binding force to an adrenergic receptor protein or the like and may have a 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 compound (II) has asymmetric silicon like compound (I), general reagents, test agents, pharmaceuticals, diagnostic agents, test agents, contrast agents, etc. Can be applied to.

In the above 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 different groups from each other. The alkyl group may be an alkyl group having 1 to 10 carbon atoms or an alkyl group having 1 to 7 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-butyl group, an s-butyl group, a t-butyl group and the like. The alkoxyl group may be an alkoxyl group having 1 to 6 carbon atoms, or may be 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, a t-butoxy group and the like. 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, an anthrasenyl group and the like.

Compound (I) or compound (II) may be a single optical isomer (a stereoisomer of any one of enantiomers and diastereomers and an optically active isomer), and may be 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 equal amount mixture of enantiomers (racemic body), or a mixture in which R-form and S-form are mixed at an arbitrary ratio. 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 abundance ratio of isotopes in nature. Examples of atomic isotopes include deuterium ( ² H), tritium ( ³ H), carbon-11 ( ¹¹ C), carbon-14 ( ¹⁴ C), fluorine-18 ( ¹⁸ F), and sulfur-35 ( ³⁵ ). S), iodine-125 ( ¹²⁵ I) and the like can be mentioned. These isotopic variants are included in compound (I), whether radioactive or not. Isotope variants can be used, in particular, 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 is an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitrate, sulfuric acid, and phosphate. Salts with; Salts with organic carboxylic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, trifluoroacetic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Salts with organic sulfonic acids such as p-toluene sulfonic acid and naphthalene sulfonic acid; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonia, morpholine, glucosamine, Examples thereof include quaternary ammonium salts with ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine, piperazine and the like. The pharmacologically acceptable salt may form a hydrate or a solvate, 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, a pharmaceutical composition) comprising compound (I) or compound (II). In addition to compound (I) or compound (II), the above composition comprises excipients, lubricants, binders, disintegrants, coating agents, stabilizers, tonicity agents, cushioning materials, pH adjusters, and the like. It may contain other components such as solubilizers, thickeners, preservatives, antioxidants, sweeteners, colorants, flavors and the like. The pharmaceutical composition may be appropriately prepared by a method known to those skilled in the art. When the pharmaceutical composition contains other components in addition to the compound (I) or the compound (II), the content of the other components can be adjusted according to the individual to be treated, the administration form and the like. 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 may be injections, eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, etc. It may be for parenteral administration such as an inhalant or a transdermal absorption preparation.

The method for producing compound (I) will be described. One embodiment of the method for producing the compound (I) is represented by the general formula (3) in which an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate are subjected to a Mitsunobu reaction or a Tsuji-Trost reaction. It includes a step of obtaining an intermediate having a structure and a step of obtaining a compound having a structure represented by the general formula (1) from an intermediate having a structure represented by the general formula (3).

In the above 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 different groups from each other.

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

In the above 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 different groups 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 Mitsunobu-reacting an alicyclic alcohol having a structure represented by the general formula (2) with a reaction substrate to obtain an intermediate having a structure represented by the general formula (3). A method comprising the above, and a step of causing a Tsuji-Trost reaction between 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). There is a method.

An example of a method including a step of Mitsunobu-reacting an alicyclic alcohol having a structure represented by the general formula (2) with a reaction substrate to obtain an intermediate having a structure represented by the general formula (3) is described below. Shown in (1). The production method shown in the reaction formula (1) includes steps A1 and A2. Step A1 corresponds to a step of Mitsunobu reaction between 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), and step A2 corresponds to the step. Corresponds to the step of obtaining a compound having a structure represented by the general formula (1) from an intermediate having a 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 to form a stereochemistry at the 4-position carbon of the silacyclopentene skeleton in the structure represented by the general formula (2). With the inversion of, 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 an amine, an alcohol, a carbanion, a phenol, a carboxylic acid, an indol, a nucleobase, a thiocarboxylic acid or 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 with respect to 1 mol of the compound having the structure represented by the general formula (2). , 1.2 to 2.0 times mol.

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

The amount of the azodicarboxylic acid ester or azodicarboxylic acid amide used is 1.0 to 100 times mol or 1.4 to 5.0 times mol with respect to 1 mol of the compound having the structure represented by the general formula (2). May be. The amount of phosphine used may be 1.0 to 100 times mol or 1.4 to 5.0 times mol with respect to 1 mol of the compound having the structure represented by the general formula (2). ..

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 amount of the solvent used may be, for example, 10 to 100 L or 20 to 30 L with respect to 1 mol of the compound having the structure represented by the general formula (2).

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., 25 to 40 ° C. It may be 35 ° C.

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

An example of a method including a step of causing a Tsuji-Trost reaction between an alicyclic alcohol having a structure represented by the general formula (2) and a reaction substrate to obtain an intermediate represented by the general formula (3) is described below (reaction formula). Shown in 2). The production method shown in the reaction formula (2) includes step B1, step B2 and step B3. Steps B1 and B2 correspond to a step of Tsuji-Trost reaction between 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). However, step B3 corresponds to a step of obtaining a compound having a structure represented by the general formula (1) from an intermediate having a structure represented by the general formula (3).

[Step B1]
In step B1, the hydroxyl group is substituted with the substituent G in the compound having the structure represented by the general formula (2) to introduce a partial structure such as allyl halide, allyl ester, allyl carbonate, and allyl phosphonate. 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: Tsuji-Trost reaction]
In step B2, the compound obtained in step B1 was subjected to Tsuji-Trost reaction with the reaction substrate (NuH) to maintain the stereochemistry at the 4-position carbon of the silacyclopentene skeleton in the structure represented by the general formula (2). As it is, an intermediate having the structure represented by the general formula (3) is produced.

In order to replace 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, trian anhydride Fluoroacetic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, paratoluenesulfonyl chloride and the like can be used.

The reaction substrate (NuH) in the Tsuji-Trost reaction is not particularly limited. The nucleophile (Nu) constituting the reaction substrate may be an amine, an alcohol, a carbanion, a phenol, a carboxylic acid, an indol, a nucleobase, a thiocarboxylic acid or the like. The amount of the reaction substrate used may be 1.0 to 100 times mol or 1.3 to 20 times mol with respect to 1 mol of the compound having the structure represented by the general formula (2). Alternatively, it may be 1.5 to 3.0 times the mole.

As the catalyst in the Tsuji-Trost reaction, a catalyst well known to those skilled in the art can be used, and for example, a combination of a palladium complex and 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 (orthotril) phosphine from the viewpoint of suppressing side reactions, improving the yield of compound (I), and having excellent stereoselectivity.

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

As the reaction solvent in the Tsuji-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 can be used. Can be used. From the viewpoint of the solubility of carbanion, the reaction solvent may be tetrahydrofuran. The amount of the solvent used may be, for example, 5 to 100 L or 8 to 20 L with respect to 1 mol of the compound having the structure represented by the general formula (2).

The reaction temperature in the Tsuji-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, but 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 the general formula (1) is obtained from the intermediate having the structure represented by the general formula (3) obtained in the step B2. For example, in the general formula (3), when Nu is an imide group, an amine compound is obtained by hydrolysis. Further, in the general formula (3), when Nu is a malonic acid ester group, a carboxymethyl compound is obtained by performing a decarboxylation reaction after hydrolysis.

In the above-mentioned 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, but the other enantiomer and diastereomer are shown. A stereomer or a mixture 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, alicyclic alcohols (Compound A1, Compound A2, Compound B1 and Compound B2) obtained by the following reaction formula (3) or reaction formula (4) can be used. In the reaction formula (3) and the reaction formula (4), one enantiomer (either compound A1 or compound A2 or any of compound B1 and compound B2) is selectively selected by using a specific chiral lithium amide. Can be synthesized into. When synthesizing compound A2 or compound B2, for example, the mirror isomers of chiral lithium amide described in the reaction formula (3) and the reaction formula (4) are used.

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

The above-mentioned production method may include a step of further purifying the obtained compound (I). The purification step is performed using, for example, high performance liquid chromatography or the like. 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 the compound (II), a nucleophilic substitution reaction is carried out between a silacyclopentenol oxide having a structure represented by the general formula (5) and an amine compound, and the structure represented by the general formula (4) is formed. Including the step of obtaining a compound having.

In the above 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 different groups from each other.

In the above 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 different groups from each other.

An example of the production method according to this embodiment is shown in the following reaction formula (5). The production method shown in the reaction formula (5) includes steps C1 and C2. Step C1 shows a step of performing an 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), and the step C2 is shown. Corresponds to the 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, the compound having the structure represented by the general formula (2) is reacted with metachloroperbenzoic acid (mCPBA) to produce an epoxide intermediate having the structure represented by the general formula (5). .. 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, the silacyclopentenol oxide having the structure represented by the general formula ( _{5) is reacted with the amine compound (R3 NH 2} ⁾ to obtain a compound having the structure represented by the general formula (4). .. In step C2, the nucleophilic substitution reaction of the reaction substrate ( ^R3NH ) with the above-mentioned silacyclopentenol oxide is carried out in the 2-position carbon of the silacyclopentane skeleton in the structure represented by the general formula (5). While reversing the stereochemistry, a compound having a structure represented by the general formula (4) is produced. In step C2, the selection of the catalyst is important, and for example, Eu (OTf) ₃ or the like can be used. It is difficult to obtain a compound having a structure represented by the general formula (4) by a conventional method using BF ₃ and OEt ₂ as a catalyst.

As the amine compound (R ³ NH ₂ ) used in the reaction formula (3), alkylamines, alkanolamines, arylamines 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 with respect to 1 mol of the compound having the structure represented by the general formula (5). It may be 2.0 to 3.0 times the mole.

As the reaction solvent in 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 amount of the solvent used may be, for example, 10 to 100 L or 20 to 30 L with respect to 1 mol of the compound having the structure represented by the general formula (5).

The reaction temperature in step C2 can be appropriately adjusted depending on the compound having the structure represented by the general formula (5), the amine compound, the reaction solvent and the like, but may be, for example, 20 to 40 ° C., and 25 to 25 to 40 ° C. It may be 35 ° C.

In the above-mentioned 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, but the above-mentioned reaction formulas (1) and (2) are used. Similarly, the other enantiomer, diastereomer, or a mixture thereof can also be used. As the alicyclic alcohol having the structure represented by the general formula (2), those exemplified as the alicyclic alcohols that can be used in the above reaction formulas (1) and (2) can be used.

Although the embodiment of the present invention has been described above, the present invention is not limited to the above embodiment.

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 compound was identified by the following method and the structure was confirmed.
[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 (Spectrum One, manufactured by PerkinElmer Co., Ltd.).
[NMR spectrum analysis]
The obtained compound is dissolved in a heavy solvent and placed in a sample tube having a diameter of 5 mm to prepare a measurement sample, and a spectroscope (Mercury ( ¹ H: 300 MHz, ¹³ C: 75 MHz) manufactured by Varian) is used. The measurement was performed at room temperature.
[Optical rotation analysis]
The obtained compound is dissolved in chloroform and placed in a cylindrical cell having an optical path length of 100 mm to prepare a measurement sample. Measurements were made.
[Mass spectrum analysis]
The obtained compound was measured in EI or FAB mode using a mass spectrometer (JMS-700, manufactured by JEOL Ltd.).

Further, with respect to the obtained compound, the compound was dissolved in a developing solution using high performance liquid chromatography (HPLC) (manufactured by Nippon Kogaku Co., Ltd., liquid feed pump: PU-2089, detector: CD-2095) and chiral. The reaction yield and purity were measured by separating the enantiomers on a column packed with a stationary phase.

(Example 1)
[Synthesis of compound 3 (synthesis of compound (I) having an amino group)]
Compound 3 was synthesized according to the following reaction formula.

50.0 mg (0.22 mmоl) of compound 1 (optical purity: 98% ee or higher), 38.0 mg (0.26 mmоl) of phthalate imide, 0.15 mL (0.32 mmоl) of diethyl diazodigalbonate (DEAD). , And 84.6 mg (0.32 mmоl) of triphenylphosphine (PPh ₃ ) were dissolved in 5 mL of toluene and Mitsunobu reacted 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 mmоl) of the obtained compound 2 and 33. 0 μL (0.68 mmоl) 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 is 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 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.

<Evaluation of bioactivity>
The bioactivity of the compound 3 obtained above was evaluated. Evaluation tests were performed using standard proteins 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. The specific test was carried out 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. Evaluation of bioactivity was performed by determining the amount of expulsed standard ligand by radiation dose measurement.

As test proteins, 30 kinds of test proteins including adrenaline accepting protein, noradrenaline accepting protein, sodium channel accepting protein, glutamic acid accepting protein, histamine accepting protein, opioid accepting protein, and sigma accepting protein were used.

As a result of the measurement, the racemic form of compound 3 was adrenaline accepting protein (standard ligand: 0.25 nM, " ^3H label", Prazosin, inhibition rate: 90%) and noradrenaline accepting protein (standard ligand: 0) at a concentration of 10 μM. .20 nM, " ¹²⁵ I labeled", RTI-55, inhibition rate: 97%), sodium channel accepting protein (standard ligand: 5.0 nM, " ^3H labeled", Batrachotoxinin, inhibition rate: 98%), glutamate accepting protein (Standard ligand: 4.0 nM, " ³ H label", TCP, inhibition rate: 80%), histamine receptor protein (standard ligand: 1.20 nM, " ³ H label", Pyrylamine, inhibition rate: 65%), opioid Receptive protein (standard ligand: 0.60 nM, " ³ H label", Diprenorfine, inhibition rate: 65%), and sigma receptor protein (standard ligand: 8.0 nM, " ³ H label", Haloperidol, inhibition rate: 55%). ) Was confirmed to have physiological activity. Among these test proteins, it was confirmed that the racemate of compound 3 showed particularly strong activity against the sodium channel accepting protein.

Further, as an optically active substance, compound 3 in which the stereochemistry on silicon is S-form and R-form was prepared. Biological activity was evaluated for each of the prepared S-form and R-form. By adjusting the concentrations of the S-form and R-form to be the concentrations of 100 μM, 10 μM, 1 μM, and 0.1 μM, respectively, and examining the concentration dependence of the physiological activity, the 50% inhibitory concentration ( _IC50 ). )It was determined. As a result, when the S-form of compound 3 is used, the IC ₅₀ is 0.33 μM, and the IC ₅₀ of the R-form, which is the enantiomer, is 0.96 μM, which is three times higher in activity. It was confirmed that

(Example 2)
[Synthesis of compound 5 (synthesis of compound (I) having a carboxymethyl group)]
Compound 5 was synthesized according to the following reaction formula.

38.0 mg (0.16 mmоl) of Compound 1 (optical purity: 98% ee or higher), 27.7 mg (0.19 mmоl) of Meldrum's acid, 0.11 mL (0.24 mmоl) of diethyl diazodigalbonate, and 63. 0 mg (0.24 mmоl) of triphenylphosphine was dissolved in 3 mL of toluene and Mitsunobu reacted at 25 ° C. for 6 hours to synthesize compound 4 as an intermediate. 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 μmоl) of the obtained compound 4 and 0. 1 mL of 1N aqueous solution of silica gel was dissolved in 3 mL of 1,4-dioxane, and the reaction was carried out under the condition of 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 purified compound 5 (reaction yield: 87%, optical purity: 98%). ee).

The spectral data for compound 5 was as follows.
^{1 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.

<Evaluation of bioactivity>
The bioactivity of the compound 5 obtained above was evaluated in the same manner as in Example 1.
From the results of the evaluation, the racemate of compound 5 has physiological activity against the adrenergic receptor protein (standard ligand: 0.25 nM, " ^3H label", Prazosin, inhibition rate: 19%) at a concentration of 10 μM. Was confirmed.

(Example 3)
[Synthesis of compound 8 (synthesis of compound (I) having a carboxymethyl group)]
Compound 8 was synthesized according to the following reaction formula.

50 mg (0.22 mmоl) of compound 1 (optical purity: 98% ee or higher) and 0.25 mL of pyridine and 33.3 μL (0.44 mmоl) of methyl chloroformate in 1.5 mL under 0 ° C. conditions. Compound 6 was obtained by dissolving in dichloromethane and reacting at 25 ° C. 48.5 μL (0.42 mmоl) of dimethyl malonate and 16.1 mg (0.42 mmоl) of sodium hydride were dissolved in 1 mL of tetrahydrofuran and stirred for 20 minutes, followed by 11.0 mg (10.6 μmоl) of tris. (Dibenzylideneacetone) dipalladium, 16.1 mg (52.8 μmоl) of tri (orthotrityl) phosphine, and 61.3 mg (0.21 mmоl) of compound 6 are dissolved in 2 mL of tetrahydrofuran under the conditions of 50 ° C. The compound 7 as an intermediate was synthesized by subjecting it to a Tsuji-Trost reaction for 6.5 hours. 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 mmоl) of the obtained compound 7 and 1 mL of 1N aqueous sodium hydroxide solution were added, and the mixture was 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 carried out for 20 hours under the condition of 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 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] ⁺ , requires m / z: 217.0685, found m / z: 217.0685.
[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 mmоl) of compound 9 (optical purity: 98% ee or higher) and 77.7 mg (0.32 mmоl) of meta-chloroperbenzoic acid (mCPBA) were dissolved in 2 mL of dichloromethane at 25 ° C. The compound 10 was obtained by reacting under the conditions of. Compound 10 and 2.5 μL (0.02 mmоl) boron trifluoride diethyl ether complex were dissolved in 1 mL of allyl alcohol and reacted at 60 ° C. for 24 hours to obtain compound 11. Compound 11 and 11.8 mg (12.8 μmоl) tris (triphenylphosphine) rhodium (I) chloride (RhCl (PPh ₃ ) ₃ ), 4.3 mg (38.4 μmоl) 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 solution 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 purified compound 12 (reaction yield: 57%, optical purity: 98%). ee).

The spectral data for compound 12 was as follows.
^{1 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 S).

<Evaluation of bioactivity>
The bioactivity of the compound 12 obtained above was evaluated in the same manner as in Example 1.
From the evaluation results, it was confirmed that the racemate of compound 12 has bioactivity against serotonin receptor proteins (standard ligand: 1.20 nM, " ^3H label", Lysergic acid diethylamide, inhibition rate: 44%). rice field. On the other hand, it showed no physiological activity against adrenaline receptor protein, noradrenaline receptor protein, sodium channel receptor protein, glutamate receptor protein, histamine receptor protein, opioid receptor protein, and sigma receptor protein.

Further, as the optical activity, compound 12 in which the stereochemistry on silicon is S-form and R-form was prepared. The concentration dependence of the bioactivity evaluation on the serotonin receptor protein was examined for each of the adjusted S-form and R-form. The concentration of the S-form and the R-form was adjusted to 100 μM, 10 μM, 1 μM, and 0.1 μM, and the concentration dependence of the physiological activity was examined to determine the 50% inhibitory concentration. As a result, the S-form IC ₅₀ of compound 12 is 6.4 μM, and its enantiomer R-form IC ₅₀ is 10.3 μM, which is 1.6 times higher in activity. It was confirmed that.

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

100.0 mg (0.43 mmоl) of compound 9 (optical purity: 98% ee or higher) and 154.6 mg (0.64 mmоl) of meta-chloroperbenzoic acid (mCPBA) were dissolved in 10 mL of dichloromethane at 25 ° C. The compound 10 was obtained by reacting under the conditions of. Compound 10, 88.0 mL (0.81 mmоl) of benzylamine, and 48.2 mg (80.5 μmоl) of europium (III) triflate were dissolved in 2 mL of toluene and reacted at 100 ° C. for 24 hours. The compound 13 was synthesized. The crude product was subjected to silica gel chromatography (using a mixed solvent of hexane: diethyl ether = 2: 1 to 1: 1 as an eluent) to obtain purified compound 13 (reaction yield: 49%, optical). Purity: 98% ee).

The spectral data for compound 13 was as follows.
^{1 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 above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group. ] An optically active substance having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

[In the above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group. ] A pharmaceutical composition containing a compound having a structure represented by the following general formula (1) or a pharmacologically acceptable salt thereof.

[In the above 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 different groups from each other, and FG represents an amino group or a carboxymethyl group. ] A step of subjecting an alicyclic alcohol having a structure represented by the following general formula (2) to a Mitsunobu reaction or a Tsuji-Trost reaction to obtain an intermediate represented by the following general formula (3), and the following general formula. A method for producing a compound, which comprises a step of obtaining a compound having a structure represented by the following general formula (1) from an intermediate represented by (3).

[In the above 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 different groups from each other. ]

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

[In the above 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 different groups from each other, 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 above 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 different groups from each other. ] An optically active substance having a structure represented by the following general formula (4) or a pharmacologically acceptable salt thereof.

[In the above 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 different groups from each other. ] A compound comprising a nucleophilic substitution reaction of a silacyclopentenol oxide having a structure represented by the following general formula (5) and an amine compound to obtain a compound having a structure represented by the following general formula (4). Production method.

[In the above 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 different groups from each other. ]

[In the above 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 different groups from each other. ]