WO2020032080A1

WO2020032080A1 - Compound, salt of compound, neuromodulation agent, method for evaluating neuromodulation agent, method for producing compound, and method for producing salt of compound

Info

Publication number: WO2020032080A1
Application number: PCT/JP2019/031022
Authority: WO
Inventors: 睦生塗谷; 洋祐芦刈; 正人安井; ゆかり藤本
Original assignee: 学校法人慶應義塾
Priority date: 2018-08-07
Filing date: 2019-08-07
Publication date: 2020-02-13
Also published as: JPWO2020032080A1; JP7456621B2

Abstract

Provided is a compound represented by general formula (I), or a salt thereof. (In the formula, X¹, X², X³ and X⁴ are a hydrogen atom, a C1-9 alkyl group, or a C3-9 unsaturated hydrocarbon group which has 1-4 triple bonds between carbon atoms and which may have a substituent (when the unsaturated hydrocarbon group has a methylene group at the end of the bond, the methylene group may be substituted with a carbonyl group); X⁵ is a C2-8 unsaturated hydrocarbon group which has 1-4 triple bonds between carbon atoms and which may have a substituent; X⁶ is a hydrogen atom, or a C3-9 unsaturated hydrocarbon group which has 1-4 triple bonds between carbon atoms and which may have a substituent; n₁ and n₃ are 0 or 1; and n₂ is an integer of 1-5.)

Description

Compound, salt of compound, neurological modulator, method for evaluating neurological modulator, method for producing compound, and method for producing salt of compound

The present invention relates to a compound, a salt of the compound, a neurological modulator, a method for evaluating a neurological modulator, a method for producing a compound, and a method for producing a salt of a compound.
Priority is claimed on Japanese Patent Application No. 2018-148873 filed on August 7, 2018, the content of which is incorporated herein by reference.

By understanding the action in the brain of a physiologically active substance involved in the regulation of nerve function (sometimes referred to as a “nerve function regulator” in the present specification) at the molecular level or the cellular level, medicine, biology, It is expected that pharmacy will greatly develop.

For example, at present, about 10% of the population is said to have a mental illness such as depression, and prevention and treatment thereof are one of the most important issues. Although the detailed mechanism of the onset of depression has not been elucidated yet, the effects of the drugs used may lead to changes in the qualitative or quantitative functions of neuronal function regulators such as noradrenaline and serotonin in the brain. , Is thought to be the cause.
However, practical methods have been developed to assess the state of uptake of neuromodulators into neurons, post-release kinetics in brain tissue, and the state of cellular responses resulting from uptake. Development of a therapeutic agent for such a mental illness is extremely difficult.

By the way, in order to observe the dynamics inside and outside a cell of a biological substance to be analyzed for the presence or absence of the biological activity and the details of the biological activity, a method for detecting the biological substance with high accuracy is required. 2. Description of the Related Art Conventionally, a method for detecting a biological substance is roughly divided into a label capable of emitting an electromagnetic wave such as a fluorescent substance and a radioisotope (in this specification, sometimes referred to as an “electromagnetic wave emission label”). There are two methods: a method of labeling a substance and detecting a biological substance by emitting electromagnetic waves from the label, and a method of detecting a biological substance without using such an electromagnetic wave emission label.

As a method for detecting a biological substance using an electromagnetic wave emission label, a method using a radioisotope and a method using a fluorescent substance are known.
Among them, the method using a radioisotope has the advantage that the biological activity of the biological substance is hardly lost and the specificity is high. However, this method has drawbacks that it is difficult to perform safety management due to the use of radioactive materials, is not suitable for observation in living tissue, and has low resolution and sensitivity. Low practicality. Therefore, it is also difficult to apply the method to the detection of a neurological modulator.
As a method using a fluorescent substance, a method using a fluorescent dye or a fluorescent protein has been put to practical use, but these fluorescent substances have a large molecular weight by themselves. Therefore, if a nerve function-modulating substance having a much smaller molecular weight than these fluorescent substances is labeled with a fluorescent substance, the behavior and properties of the nerve function-modulating substance will be greatly changed, and the nerve function-modulating substance cannot be accurately evaluated.

は As a fluorescent dye, a fluorescent green dye FFN511 which is itself taken into dopamine-containing neurons and is detectable in these cells is known (see Patent Document 1). Although the molecular weight of this fluorescent dye is relatively smaller than the molecular weight of the normal fluorescent dye or fluorescent protein, it is still about twice the molecular weight of dopamine. Therefore, the FFN 511 is significantly different from a normal observation target molecule in its behavior and properties. In fact, FFN 511 is considered to have no biological activity, and further absorbs short-wavelength light, which is not always common, and emits light in a wide wavelength band. Therefore, it is difficult to use with other dyes, and there is no alternative dye.

On the other hand, as a method of detecting biological substances without using an electromagnetic wave emission label, a method of detecting using a Raman microscope is known, focusing on the fact that a specific group in a molecule causes Raman scattering. I have. For example, a triple bond between carbon atoms (C≡C) can be detected by a Raman microscope, and a method for detecting an analog of a biomolecule into which such a triple bond is introduced has been disclosed (Non-Patent Document 1). reference).

U.S. Pat. No. 8,337,941

However, this molecule disclosed in Non-Patent Document 1 is irrelevant to a neurological function modulator, and no neuronal function modulator having a triple bond between carbon atoms has been reported so far. .

An object of the present invention is to provide a novel nerve function-regulating substance capable of practically evaluating the state of uptake into a nerve cell or the state of a cellular response caused by the uptake.

The present invention employs the following configuration.
[1]. A compound represented by the following general formula (I) or a salt thereof.

(In the general formula (I), X ¹ , X ² , X ³ and X ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms. When the unsaturated hydrocarbon group is an unsaturated hydrocarbon group having 3 to 9 carbon atoms which may have a substituent, and the unsaturated hydrocarbon group has a methylene group at a terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group is May be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the bonding end, one methylene group or two or more The methylene groups which are not adjacent to each other may be substituted with an oxygen atom, and when X ¹ and X ² are the alkyl groups, or when X ³ and X ⁴ are the alkyl groups The two alkyl groups are bonded to each other to form a ring Well;
X ⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X ⁶ is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₁ and n ₃ are each independently 0 or 1;
n ₂ is an integer from 1 to 5;
However, when n ₁ is 0 and n ₃ is 1, one or more of X ¹ , X ² , X ³ , X ^4, and X ⁶ are not the same A saturated hydrocarbon group,
When n ₁ is 1 and n ₃ is 0, one or more of X ¹ , X ² , X ³ , X ⁴ and X ⁵ are the unsaturated carbons. A hydrogen group,
When both n ₁ and n ₃ are 0, at least one of X ¹ , X ² , X ³ and X ⁴ is the unsaturated hydrocarbon group,
When both n ₁ and n ₃ are 1, one or more of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are the unsaturated hydrocarbons. Group. )

{[2]. The compound represented by the general formula (I) is a compound represented by the following general formula (I) -1, (I) -2, (I) -3 or (I) -4, [1] Or a salt thereof.

(In general formulas (I) -1, (I) -2, (I) -3 or (I) -4, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , n ₂ and n ₃ are The same as above;
X ^11, ^X ^{21, X 31} and ^{X 41} each independently represent a hydrogen atom or an alkyl group having 1-9 carbon ^atoms, when ^{X 11} and ^{X 21} are the alkyl group, ^{or, X 31} and X ^{When 41} is the above-mentioned alkyl group, these two alkyl groups may be mutually bonded to form a ring;
X ⁶¹ is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and optionally having 3 to 9 carbon atoms;
However, in the general formula (I) -1, one or both of X ¹ and X ² is the unsaturated hydrocarbon group,
In formula (I) -2, one or both of X ³ and X ⁴ are the unsaturated hydrocarbon groups. )

{[3]. Compounds represented by the general formulas (I) -1, (I) -2, (I) -3 or (I) -4 are represented by the following general formulas (I) -1-1 and (I) -1- 2, a compound represented by (I) -2-1, (I) -2-2, (I) -2-3, (I) -3-1 or (I) -4-1, 2] The compound according to [1] or a salt thereof.

(General formulas (I) -1-1, (I) -1-2, (I) -2-1, (I) -2-2, (I) -2-3, (I) -3-1) Or, in (I) -4-1, X ¹² , X ²² , X ³² and X ⁴² are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and X ¹² and X ²² are Or when X ³² and X ⁴² are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring;
G ¹ , G ² , G ³ , G ⁴ , G ⁵ and G ⁶ each independently represent a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a trialkyl group. Reelsilyl group, hydroxy group, halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group , A triarylsilylalkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group. R;
n ₃ are the same as above. )
[4]. A compound represented by the following general formula (II) or a salt thereof.

(In the general formula (II), X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms. When the unsaturated hydrocarbon group is an unsaturated hydrocarbon group having 3 to 9 carbon atoms which may have a substituent, and the unsaturated hydrocarbon group has a methylene group at a terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group is May be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the bonding end, one methylene group or two or more May be substituted with an oxygen atom, and when X ⁰¹ and X ⁰² are the alkyl groups, these two alkyl groups are bonded to each other to form a ring. May be formed;
X ⁰⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₀₁ is 0 or 1;
n ₀₂ is an integer of 1 to 5;
However, when n ₀₁ is 0, one or more of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ are the unsaturated hydrocarbon groups,
When n ₀₁ is 1, one or more of X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ and X ⁰⁵ are the unsaturated hydrocarbon groups. )

[5]. The compound or a salt thereof according to [4], wherein the compound represented by the general formula (II) is a compound represented by the following general formula (II) -1 or (II) -2.

(In the general formula (II) -1 or (II) -2, n ₀₂ is the same as described above;
X ⁰¹¹ , X ⁰²¹ and X ⁰³¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms. When X ⁰¹¹ and X ⁰²¹ are the above-mentioned alkyl groups, these two alkyl groups are May combine with each other to form a ring;
X ⁰⁴¹ is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent;
X ⁰¹⁰ , X ⁰²⁰ and X ⁰³⁰ each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms, and may have a substituent. When the unsaturated hydrocarbon group has 3 to 9 carbon atoms and the unsaturated hydrocarbon group has a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group; When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the bonding side, one methylene group or two or more methylene groups that are not adjacent to each other are may be substituted with an oxygen atom, if X ⁰¹⁰ and X ⁰²⁰ is the above alkyl group, these two alkyl groups may form a ring with each other, however, X ⁰¹⁰ , One of X ⁰²⁰ and X ⁰³⁰ Species or two or more are the aforementioned unsaturated hydrocarbon groups. )

[6]. Compounds represented by the general formula (II) -1 or (II) -2 are represented by the following general formulas (II) -1-1, (II) -2-1, (II) -2-2, and (II) ) The compound according to [5], which is a compound represented by 2-3, (II) -2-4 or (II) -2-5, or a salt thereof.

(General formulas (II) -1-1, (II) -2-1, (II) -2-2, (II) -2-3, (II) -2-4 or (II) -2-5) ^in, X ^{012, X 022} and ^{X 032} each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon ^atoms, when ^{X 012} and ^{X 022} is the above alkyl group, these two alkyl The groups may be linked to each other to form a ring;
G ⁰¹ , G ⁰² , G ⁰³ and G ⁰⁴ are each independently a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a triarylsilyl group, a hydroxy group , Halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group, triarylsilylalkyl group A hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group;
n ₀₂ is the same as described above. )

[7]. A neurological function modulator comprising the compound according to any one of [1] to [6] or a salt thereof.
[8]. A neurological function modulator comprising a group having a triple bond between carbon atoms.
[9]. The compound having a structure in which one or two or more hydrogen atoms in dopamine, noradrenaline, adrenaline or serotonin in the dopamine, noradrenaline, adrenaline or serotonin is replaced by a group having a triple bond between carbon atoms, or a salt thereof. The nerve function modulator according to [8].

[10]. Evaluation of a nerve function modulator, which evaluates a state of uptake of a nerve function modulator according to any one of [7] to [9] into a nerve cell or a state of a cellular response caused by the uptake. Method.
[11]. ^A method for producing a compound represented by the following general formula (IA) or a salt thereof, comprising reacting a compound represented by the following general formula (Ia) with a compound represented by the following general formula (Ic) And when one or more of the following Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a are the following protecting groups, after the step of reacting, removing the group, by performing, as a compound represented by the following general formula (I ^a), in the compounds represented by the following general formula (Ia), the following Z ^{1a, Z} ^2a, Z ^A method for producing a compound or a salt thereof, wherein a compound having a structure in which a hydrogen atom among ^3a , Z ^4a and Z ^6a is substituted with the following X ^0a or a salt thereof is obtained.

(In the general formula ^(I A), (Ia) or ^{^{(Ic), X 1, X}} 2, X 3 and ^{X 4} each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When it has a group, the methylene group may be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the bonding side, 1 Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X ¹ and X ² are the alkyl groups, or X ³ and X ⁴ Is a said alkyl group, these two alkyl groups It may bond to form a ring;
X ⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X ⁶ is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₁ and n ₃ are each independently 0 or 1;
n ₂ is an integer from 1 to 5;
However, one or more of X ¹ , X ² , X ³ and X ⁴ are the unsaturated hydrocarbon groups,
X ^0a is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, wherein the unsaturated hydrocarbon group is When having a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group, and the unsaturated hydrocarbon group may have one or more than two terminals other than the terminal on the bonding side. When it has a methylene group, one methylene group or two or more non-adjacent methylene groups may be substituted with an oxygen atom;
LG ¹ is a leaving group;
Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or a protecting group, and when Z ^1a and Z ^2a are the above-mentioned alkyl groups Or when Z ^3a and Z ^4a are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring, provided that Z ^1a , Z ^2a , Z ^3a , One or more of Z ^4a and Z ^6a are hydrogen atoms. )

[12]. A compound or a salt thereof represented by the following general formula (I ^B), reacting the compound represented by the following general formula (Ib), a compound represented by the following general formula (Id), the And when one or more of the following Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b are the following protecting groups, after the step of reacting, removing the group, by performing, as a compound represented by the following general formula (I ^B), in the compounds represented by the following general formula (Ib), the following LG ^2, following X ^0b A method for producing a compound or a salt thereof, wherein the compound or a salt thereof is obtained.

(In the general formula ^(I B), (Ib) or ^{^{(Id), X 1, X}} 2, X 3 and ^{X 4} each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X ¹ and X ² are the alkyl groups, or X ³ and X ⁴ Is a said alkyl group, these two alkyl groups It may bond to form a ring;
X ⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X ⁶ is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₃ is 0 or 1;
n ₂ is an integer from 1 to 5;
LG ² is a leaving group;
Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, 1 to 4 triple bonds between carbon atoms, and have a substituent. An optionally substituted unsaturated hydrocarbon group having 3 to 9 carbon atoms or a protecting group, wherein Z ^1b and Z ^2b are the aforementioned alkyl groups, or Z ^3b and Z ^4b are the aforementioned alkyl groups May have the two alkyl groups linked to each other to form a ring;
X ^0b is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent. )

[13]. ^A method for producing a compound represented by the following general formula (IIA) or a salt thereof, comprising reacting a compound represented by the following general formula (IIa) with a compound represented by the following general formula (Ic) a step of, following ^Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} when one or more are below protecting group, after the step of the reaction, further, removing the protecting group And a salt represented by the following general formula (II ^A ) or a salt thereof in a compound represented by the following general formula (IIa): Z ^01a , Z ^02a , Z ^03a and Z of ^04a, it is hydrogen atom, to obtain a compound or a salt structure substituted by the following X ^0a, compound or a salt thereof.

(Formula ^(II A), in (IIa) or ^{^{(Ic), X 01, X}} 02, X 03 and ^{X 04} each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X ⁰¹ and X ⁰² are the alkyl groups, these two alkyl groups Groups may be linked to each other to form a ring ;
X ⁰⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₀₁ is 0 or 1;
n ₀₂ is an integer of 1 to 5;
However, one or more of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ are the unsaturated hydrocarbon groups,
X ^0a is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, wherein the unsaturated hydrocarbon group is When having a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group, and the unsaturated hydrocarbon group may have one or more than two terminals other than the terminal on the bonding side. When it has a methylene group, one methylene group or two or more non-adjacent methylene groups may be substituted with an oxygen atom;
LG ¹ is a leaving group;
^{^Z ^01a,} Z 02a, Z ^03a and ^{Z 04a} each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, or a protecting ^group, if ^{Z 01a} and ^{Z 02a} is said alkyl group, these two alkyl groups may form a ring with each other, ^however, Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} 1 or 2 or more is a hydrogen atom. )

[14]. A compound or a salt thereof represented by the following general formula (II ^B), reacting the compound represented by the following general formula (IIb), a compound represented by the following general formula (Id), the ^And when one or more of the following Z ^01b , Z ^02b , Z ^03b and Z ^04b are the following protecting groups, after the step of reacting, further removing the protecting group a step of, by performing, as a compound represented by the following general formula (II ^B), in the compounds represented by the following general formula (IIb), is below LG ^3, is replaced by the following X ^0b A method for producing a compound or a salt thereof, wherein the compound or a salt thereof is obtained.

(In the general formulas (II ^B ), (IIb) or (Id), X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X ⁰¹ and X ⁰² are the alkyl groups, these two alkyl groups The groups may be linked to each other to form a ring ;
X ⁰⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n ₀₂ is an integer of 1 to 5;
LG ³ is a leaving group;
Z ^01b , Z ^02b , Z ^03b and Z ^04b each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, 1 to 4 triple bonds between carbon atoms, and have a substituent. When Z ^01b and Z ^02b are the above-mentioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. May be;
X ^0b is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent. )

The compound of the present embodiment or a salt thereof can be used as a nerve function regulating substance.
By using the nerve function-modulating substance of the present embodiment, or by applying the neurofunction-modulating substance evaluation method of the present embodiment, the state of uptake of the nerve function-modulating substance into nerve cells, or the state brought about by the uptake. The state of the cell response can be evaluated practically.
The compound represented by the general formula (I) or a salt thereof can be produced by the method for producing a compound or a salt thereof of the present embodiment.

FIG. 9 is imaging data of a test piece with a confocal microscope when the compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when the compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when the compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when another compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when another compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when another compound of the present invention is used in Example 6. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and another compound of the present invention are used in Example 7. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when the compound of the present invention is used in Example 8. FIG. FIG. 9 shows data on the time-dependent changes in the intensity of the fluorescent signal when the compound of the present invention is used in Example 8. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when another compound of the present invention is used in Example 8. FIG. FIG. 9 shows data on the change over time in the intensity of the fluorescence signal when another compound of the present invention was used in Example 8. FIG. FIG. 9 is imaging data of a test piece with a confocal microscope when a known compound is used in Example 8. FIG. FIG. 9 shows data on the change over time of the intensity of the fluorescent signal when a known compound is used in Example 8. FIG. FIG. 15 shows imaging data of nerve cells by a confocal microscope when a known fluorescent dye is used in Example 11. FIG. FIG. 14 shows imaging data of nerve cells by a confocal microscope when the compound of the present invention is used in Example 11. FIG. FIG. 14 shows imaging data of nerve cells by a confocal microscope when another compound of the present invention is used in Example 11. FIG. FIG. 11 shows imaging data of nerve cells by a confocal microscope when still another compound of the present invention is used in Example 11. FIG. FIG. 11 shows imaging data of nerve cells by a confocal microscope when still another compound of the present invention is used in Example 11. FIG. FIG. 11 shows imaging data of nerve cells by a confocal microscope when still another compound of the present invention is used in Example 11. FIG. FIG. 11 shows imaging data of nerve cells by a confocal microscope when still another compound of the present invention is used in Example 11. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and a compound of the present invention are used in Example 12. FIG. FIG. 14 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 15. FIG. FIG. 14 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 15. FIG. FIG. 14 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 15. FIG. FIG. 14 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 15. FIG. FIG. 14 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 16. FIG. Fig. 15 shows imaging data of a test piece with a confocal microscope when a known fluorescent protein is used in Example 16. FIG. 14 is imaging data of a test piece with a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 16. FIG. FIG. 14 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 17. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known antibody is used in Example 17. FIG. FIG. 14 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 17. FIG. FIG. 14 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 17. FIG. FIG. 14 is imaging data of a test piece obtained by a confocal microscope when a known antibody is used in Example 17. FIG. FIG. 14 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 17. FIG. FIG. 15 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 18. FIG. FIG. 15 shows imaging data of a test piece obtained by a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 18. FIG. FIG. 19 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 19. FIG. FIG. 19 is imaging data of a test piece obtained by using a confocal microscope when a known fluorescent dye and the compound of the present invention are used in Example 19. FIG.

<<< Compound (I) or a salt thereof >>>
The compound according to one embodiment of the present invention is represented by the following general formula (I), and the salt of the compound according to one embodiment of the present invention is a salt of the compound represented by the following general formula (I). In the present specification, the compound represented by the general formula (I) may be referred to as “compound (I)”. Further, the mere description of “compound (I)” means a compound that does not form a salt, and compound (I) that forms a salt is referred to as “salt of compound (I)”.

Compound (I) is useful as a nerve function regulator (that is, a physiologically active substance involved in the regulation of nerve function), as described later.
In addition, the compound (I) will be described later because at least one of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ is the unsaturated hydrocarbon group. As described above, detection can be performed with high accuracy, and its dynamics can be easily observed.
Hereinafter, first, the structure of compound (I) will be described in detail.

In the general formula (I), X ¹ , X ² , X ³ and X ⁴ (in the present specification, these may be abbreviated as “X ¹ to X ⁴ ”) are each independently: A hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent.
However, when the unsaturated hydrocarbon group in X ¹ to X ⁴ has a methylene group (—CH ₂ —) at the terminal on the bonding destination, the methylene group is a carbonyl group (—C (＝ O) —) May be substituted. In the case of X ¹ and X ^2, the methylene group at the terminal on the bonding destination side is a methylene group bonded to the nitrogen atom (N) in the general formula (I). In the case of X ³ and X ⁴ , the above-mentioned methylene group at the terminal on the bonding side is a methylene group bonded to an oxygen atom (O) bonded to a benzene ring skeleton in the general formula (I). .

The alkyl group in X ¹ to X ⁴ may have 1 to 9 carbon atoms, but is preferably linear or branched.

The number of carbon atoms of the alkyl group in X ¹ to X ⁴ may be any one of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, and 8 or more, and 9 or less, 8 or less , 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, and 2 or less.

Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. Tert-pentyl group, 1-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, n-heptyl group, -Methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, 2 , 2,3-trimethylbutyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, nonyl group and the like.

The unsaturated hydrocarbon group for X ¹ to X ⁴ is not particularly limited as long as it has 3 to 9 carbon atoms and has 1 to 4 triple bonds (C≡C) between carbon atoms. For example, the unsaturated hydrocarbon group may have both a triple bond (C≡C) and a double bond (C = C) as an unsaturated bond between carbon atoms, but has only a triple bond. Is preferred.

Examples of the unsaturated hydrocarbon group for X ¹ to X ⁴ include a structure in which a single bond (C—C) between carbon atoms in the alkyl group having 3 to 9 carbon atoms is substituted with an unsaturated bond. Ones having.
Preferred examples of the unsaturated hydrocarbon group include a structure in which, in the alkyl group having 3 to 9 carbon atoms, 1 to 4 single bonds (C—C) between carbon atoms are replaced by triple bonds. Things.

The carbon number of the unsaturated hydrocarbon group in X ¹ to X ⁴ may be any of 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, and 8 or more, and 9 or less, 8 or less, 7 or less. , 6 or less, 5 or less, and 4 or less.

In the unsaturated hydrocarbon group for X ¹ to X ^4, the number of triple bonds between carbon atoms may be any one or more, two or more, and three or more, or four or less, three or less. Any of the following and two or less may be used.

Compound (I) in which the number of triple bonds between carbon atoms in the unsaturated hydrocarbon group is one (that is, the unsaturated hydrocarbon group is an alkynyl group) is easy to produce. It is preferred in that respect.

In the unsaturated hydrocarbon groups for X ¹ to X ^4, the positions of triple bonds and double bonds between carbon atoms are not particularly limited.
However, it is preferable that the terminal carbon atom on the bonding destination side in X ¹ to X ⁴ does not form an unsaturated bond with an adjacent carbon atom. In the case of X ¹ and X ² , the above-mentioned carbon atom at the terminal on the bonding destination side is a carbon atom bonded to the nitrogen atom (N) in the general formula (I). In the case of X ³ and X ⁴ , the above-mentioned carbon atom at the terminal on the bonding side is a carbon atom bonded to an oxygen atom (O) bonded to a benzene ring skeleton in the general formula (I). .
In the case where there are two or more unsaturated bonds between carbon atoms in X ¹ to X ⁴ , one carbon atom does not form two unsaturated bonds (in other words, these unsaturated bonds Are not adjacent in X ¹ to X ⁴ ).

In the unsaturated hydrocarbon group for X ¹ to X ^4, the terminal carbon atom on the side opposite to the bond destination side preferably forms a triple bond with an adjacent carbon atom.
Examples of such an unsaturated hydrocarbon group which is an alkynyl group include a propargyl group (alias: 2-propynyl group, —CH ₂ —C≡CH), a 3-butynyl group, a 4-pentynyl group, and a 5-hexynyl group. , 6-heptynyl group, 7-octynyl group and 8-noninyl group.

When the unsaturated hydrocarbon group for X ¹ to X ⁴ has one or two or more methylene groups other than the terminal at the bonding destination, one methylene group is an oxygen atom (—O— ), Or two or more non-adjacent methylene groups may be substituted with an oxygen atom. Here, the terminus on the bonding destination side of the unsaturated hydrocarbon group is the same as that described above with reference to a methylene group as an example. That is, in the case of X ¹ and X ² , it is a group bonded to the nitrogen atom (N) in the general formula (I), and in the case of X ³ and X ⁴ , the benzene ring skeleton in the general formula (I) It is a group bonded to a bonded oxygen atom (O).

More specifically, when the unsaturated hydrocarbon group has one methylene group other than the terminal at the bonding destination, this one methylene group may be substituted with an oxygen atom.
When the unsaturated hydrocarbon group has two or more methylene groups in addition to the terminal on the bonding destination side, two or more non-adjacent methylene groups are substituted with an oxygen atom. It may be.
In the present specification, when the unsaturated hydrocarbon group has an alkylene group having 2 or more carbon atoms, the alkylene group is connected to a methylene group by the number of carbon atoms of the alkylene group. I reckon. Thus, some or all of the two or more non-adjacent methylene groups can be selected from such alkylene groups.

In the unsaturated hydrocarbon group, when the methylene group is substituted with an oxygen atom, the substitution position is not particularly limited as long as the above conditions are satisfied, and the carbon atom forming a triple bond between carbon atoms is not particularly limited. Preferably, it is a carbon atom that is not adjacent to an atom.

において In the unsaturated hydrocarbon group, the number of the methylene groups substituted with an oxygen atom is preferably one or two, and more preferably one.

The unsaturated hydrocarbon group in which the methylene group is substituted with an oxygen atom is preferable. For example, in the unsaturated hydrocarbon group having 5 to 9 carbon atoms, one methylene group is substituted with an oxygen atom. That have been included.

In the unsaturated hydrocarbon group for X ¹ to X ^4, the terminal methylene group on the bonding destination is substituted with a carbonyl group, and one or more methylene groups other than the terminal on the bonding destination are substituted. May be substituted with an oxygen atom.
Among such unsaturated hydrocarbon groups, preferred are, for example, the above-mentioned unsaturated hydrocarbon groups having 5 to 9 carbon atoms, wherein the terminal methylene group on the bonding side is substituted with a carbonyl group, and One in which one methylene group other than the terminal on the bonding side is substituted with an oxygen atom is exemplified.
Specific examples of such unsaturated hydrocarbon groups include groups represented by the formula CH 式 C—CH ₂ —O—CH ₂ CH ₂ —C (＝ O) —. However, this is an example of the unsaturated hydrocarbon group.

The unsaturated hydrocarbon group for X ¹ to X ⁴ may have a substituent.
Here, “the unsaturated hydrocarbon group may have a substituent” means that one or more hydrogen atoms in the unsaturated hydrocarbon group are substituted with a group other than a hydrogen atom. May be ". In this specification, the term “group” includes not only an atomic group formed by bonding a plurality of atoms but also one atom.

Examples of the substituent which X ¹ to X ⁴ may have include, for example, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a triarylsilyl group, a hydroxy group (—OH ), Halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group, triarylsilylalkyl Groups, hydroxyalkyl groups, halogenated alkyl groups, alkoxyalkyl groups, alkylcarbonyloxyalkyl groups, arylcarbonyloxyalkyl groups, aralkylcarbonyloxyalkyl groups, and the like.

The aryl group (aromatic hydrocarbon group) as the substituent may be monocyclic or polycyclic.
Examples of the aryl group include a phenyl group, 1-naphthyl group, 2-naphthyl group, o-tolyl group, m-tolyl group, p-tolyl group, xylyl group (dimethylphenyl group) and the like. Examples include groups in which one or more hydrogen atoms of the group are further substituted with an aryl group or an alkyl group similar to those in X ¹ to X ⁴ . The aryl group having such a substituent preferably has 6 to 20 carbon atoms including the substituent.
The aryl group preferably has 6 to 20 carbon atoms, and more preferably 6 to 10 carbon atoms. The aryl group having a substituent preferably has 7 to 20 carbon atoms including the substituent.

The trialkylsilyl group as the substituent is a monovalent group having a structure in which three hydrogen atoms of a silyl group (—SiH ₃ ) are substituted with the same alkyl groups as those in X ¹ to X ⁴ . No.
The three alkyl groups bonded to the silicon atom in the trialkylsilyl group may be all the same, may be different from each other, or only a part (more specifically, two) may be the same. It may be. The combination of different alkyl groups can be arbitrarily selected and is not particularly limited.
Examples of the trialkylsilyl group include, but are not limited to, a trimethylsilyl group, an ethyldimethylsilyl group, a diethylmethylsilyl group, a tert-butyldimethylsilyl group, and the like.
The trialkylsilyl group preferably has 3 to 20 carbon atoms.

In the dialkylmonoarylsilyl group as the substituent, two hydrogen atoms of a silyl group (—SiH ₃ ) are substituted with the same alkyl groups as those in X ¹ to X ⁴ , and one hydrogen atom is substituted. And a monovalent group having a structure substituted with the same aryl group as the above-mentioned substituent.
The two alkyl groups bonded to the silicon atom in the dialkylmonoarylsilyl group may be the same or different. The combination of different alkyl groups can be arbitrarily selected and is not particularly limited.
Examples of the dialkylmonoarylsilyl group include, but are not limited to, a dimethylphenylsilyl group and a diethylphenylsilyl group.
The dialkylmonoarylsilyl group preferably has 8 to 30 carbon atoms.

In the monoalkyldiarylsilyl group as the substituent, one hydrogen atom of the silyl group (—SiH ₃ ) is substituted with the same alkyl group as that in X ¹ to X ⁴ and two hydrogen atoms are And a monovalent group having a structure substituted with the same aryl group as the above-mentioned substituent.
The two aryl groups bonded to the silicon atom in the monoalkyldiarylsilyl group may be the same or different from each other. The combination of different aryl groups can be arbitrarily selected and is not particularly limited.
Examples of the monoalkyldiarylsilyl group include, but are not limited to, a methyldiphenylsilyl group, an ethyldiphenylsilyl group, and a tert-butyldiphenylsilyl group.
The monoalkyldiarylsilyl group preferably has 13 to 30 carbon atoms.

Examples of the triarylsilyl group as the substituent include a monovalent group having a structure in which three hydrogen atoms of a silyl group (—SiH ₃ ) are substituted with the same aryl group as the substituent. Can be
The three aryl groups bonded to the silicon atom in the triarylsilyl group may be all the same, may be different, or may be partially (more specifically, two) identical. It may be. The combination of different aryl groups can be arbitrarily selected and is not particularly limited.
Examples of the triarylsilyl group include, but are not limited to, a triphenylsilyl group.
The triarylsilyl group preferably has 18 to 30 carbon atoms.

ハロゲン Examples of the halogen atom as the substituent include a fluorine atom (—F), a chlorine atom (—Cl), a bromine atom (—Br), and an iodine atom (—I).

Examples of the alkoxy group as the substituent include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, nonyloxy, and the like. ^A monovalent group having a structure in which an alkyl group similar to that in ¹ to X ⁴ is bonded to an oxygen atom is exemplified.
The alkoxy group preferably has 1 to 9 carbon atoms.

Examples of the alkylcarbonyloxy group as the substituent include a methylcarbonyloxy group (also called an acetoxy group), an ethylcarbonyloxy group, an n-propylcarbonyloxy group, an isopropylcarbonyloxy group, an n-butylcarbonyloxy group, and isobutyl. Alkyl groups similar to those in X ¹ to X ⁴ such as carbonyloxy group, sec-butylcarbonyloxy group, tert-butylcarbonyloxy group, nonylcarbonyloxy group, etc. are substituted with carbonyloxy group (—C (＝ O) —O And-) a monovalent group having a structure bonded to the carbon atom in ()).
The alkylcarbonyloxy group preferably has 2 to 10 carbon atoms.

The arylcarbonyloxy group as the substituent includes, for example, phenylcarbonyloxy group, 1-naphthylcarbonyloxy group, 2-naphthylcarbonyloxy group, o-tolylcarbonyloxy group, m-tolylcarbonyloxy group, p-tolyl An aryl group similar to the above substituent such as a carbonyloxy group or a xylylcarbonyloxy group (dimethylphenylcarbonyloxy group) is added to a carbon atom in the carbonyloxy group (—C (＝ O) —O—). Examples include a monovalent group having a bonded structure.
The arylcarbonyloxy group preferably has 7 to 21 carbon atoms, and more preferably 7 to 11 carbon atoms.

Examples of the aralkyl group as the substituent include a benzyl group (alias: phenylmethyl group), a phenethyl group (alias: 2-phenylethyl group), a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 2- (1 In the same alkyl groups as those in X ¹ to X ⁴ such as —naphthyl) ethyl group, 2- (2-naphthyl) methyl group and phenylnonyl group, one hydrogen atom is the same as the above-mentioned substituent. And a monovalent group having a structure substituted with an aryl group.
The aralkyl group preferably has 7 to 29 carbon atoms, and more preferably 7 to 19 carbon atoms.

Examples of the aralkylcarbonyloxy group as the substituent include a benzylcarbonyloxy group (C ₆ H ₆ CH ₂ —C (＝ O) —O—) and a phenethylcarbonyloxy group (C ₆ H ₆ CH ₂ CH ₂ — C (＝ O) —O—), 1-naphthylmethylcarbonyloxy group (C ₁₀ H ₇ CH ₂ —C (＝ O) —O—), 2-naphthylmethylcarbonyloxy group (C ₁₀ H ₇ CH ₂ — C (＝ O) —O—), 2- (1-naphthyl) ethylcarbonyloxy group (C ₁₀ H ₇ CH ₂ CH ₂ —C (＝ O) —O—), 2- (2-naphthyl) ethylcarbonyl The above substituents such as an oxy group (C ₁₀ H ₇ CH ₂ CH ₂ —C (＝ O) —O—) and a phenylnonylcarbonyloxy group (C ₆ H ₅ C ₉ H ₁₈ —C (＝ O) —O—); Aralkyl, the base There include monovalent groups of the bound structure to a carbon atom in the carbonyl group (-C (= O) -O-).
The aralkylcarbonyloxy group preferably has 8 to 30 carbon atoms, and more preferably 8 to 20 carbon atoms.

In the trialkylsilylalkyl group as the substituent, one hydrogen atom in the same alkyl group as that in X ¹ to X ⁴ is substituted with the same trialkylsilyl group as the substituent. Monovalent groups of the structure are mentioned.
Examples of the trialkylsilylalkyl group as the substituent include, but are not limited to, a trimethylsilylmethyl group, an ethyldimethylsilylmethyl group, a diethylmethylsilylmethyl group, and a tert-butyldimethylsilylmethyl group.
The trialkylsilylalkyl group preferably has 4 to 25 carbon atoms.

Examples of the dialkyl monoaryl silylalkyl group is a substituent, one of the hydrogen atoms of the same alkyl group as in X 1 ^~ X ⁴ is substituted with the same dialkylamino monoaryl silyl group as being the substituent And a monovalent group having the following structure.
Examples of the dialkylmonoarylsilylalkyl group as the substituent include, but are not limited to, a dimethylphenylsilylmethyl group and a diethylphenylsilylmethyl group.
The dialkylmonoarylsilylalkyl group preferably has 9 to 35 carbon atoms.

Examples of the monoalkyl diaryl silylalkyl group is a substituent, one of the hydrogen atoms of the same alkyl group as in X 1 ^~ X ⁴ is substituted with the same mono alkyldiarylsilyl groups and those that are the substituent And a monovalent group having the following structure.
Examples of the dialkylmonoarylsilylalkyl group as the substituent include, but are not limited to, a methyldiphenylsilylmethyl group, an ethyldiphenylsilylmethyl group, and a tert-butyldiphenylsilylmethyl group.
The monoalkyldiarylsilylalkyl group preferably has 14 to 35 carbon atoms.

As the triarylsilylalkyl group as the substituent, one hydrogen atom of the same alkyl group as that in the above-described trialkylsilyl group is substituted with the same triarylsilyl group as the above-described substituent. And a monovalent group having the following structure.
Examples of the triarylsilylalkyl group as the substituent include, but are not limited to, a triphenylsilylmethyl group.
The triarylsilylalkyl group preferably has 19 to 35 carbon atoms.

Examples of the hydroxyalkyl group as the substituent include a monovalent group having a structure in which one hydrogen atom of the same alkyl group as in X ¹ to X ⁴ is substituted with a hydroxy group.
Examples of the hydroxyalkyl group as the substituent include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 3-hydroxy-n-propyl group, a 2-hydroxy-1-methylethyl group, Examples include, but are not limited to, a hydroxy-1-methylethyl group and a hydroxynonyl group.
The hydroxyalkyl group preferably has 1 to 9 carbon atoms.

Examples of the halogenated alkyl group as the substituent include a monovalent group having a structure in which one or more hydrogen atoms of the same alkyl group as those in X ¹ to X ⁴ are substituted with a halogen atom. For example, a perhaloalkyl group (a monovalent group having a structure in which all hydrogen atoms are substituted with halogen atoms) may be used.
Examples of the halogen atom that replaces the hydrogen atom include the same halogen atom as the substituent.
When the halogenated alkyl group has two or more halogen atoms, these two or more halogen atoms may be all the same, may be all different, or may be partially the same. Is also good. The combination of different halogen atoms can be arbitrarily selected and is not particularly limited.
Examples of the halogenated alkyl group as the substituent include, for example, a monochloromethyl group, a dichloromethyl group, a trichloromethyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monochlorononyl group, and the like. It is not limited to.
The halogenated alkyl group preferably has 1 to 9 carbon atoms.

The alkoxyalkyl group as the substituent is a monovalent structure having the same alkyl group as that in X ¹ to X ⁴ in which one hydrogen atom is substituted with the same alkoxy group as the substituent. The group of is mentioned.
Examples of the alkoxyalkyl group as the substituent include a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, an isopropoxymethyl group, a methoxyethyl group, an ethoxyethyl group, an n-propoxyethyl group, and an isopropoxyethyl group. , A nonyloxymethyl group, a nonyloxyethyl group, and the like, but are not limited thereto.
The alkoxyalkyl group preferably has 2 to 18 carbon atoms.

In the alkylcarbonyloxyalkyl group as the substituent, one hydrogen atom of the same alkyl group as that in X ¹ to X ⁴ is substituted with the same alkylcarbonyloxy group as the above substituent. Monovalent groups of the structure are mentioned.
Examples of the alkylcarbonyloxyalkyl group as the substituent include a methylcarbonyloxymethyl group (alias: acetoxymethyl group), an ethylcarbonyloxymethyl group, an n-propylcarbonyloxymethyl group, an isopropylcarbonyloxymethyl group, a nonylcarbonyl Oxymethyl group, methylcarbonyloxyethyl group (alias: acetoxyethyl group), ethylcarbonyloxyethyl group, n-propylcarbonyloxyethyl group, isopropylcarbonyloxyethyl group, nonylcarbonyloxyethyl group, methylcarbonyloxynonyl group (alias) : Acetoxynonyl group) and the like, but are not limited thereto.
The alkylcarbonyloxyalkyl group preferably has 3 to 19 carbon atoms.

In the arylcarbonyloxyalkyl group as the substituent, one hydrogen atom of the same alkyl group as that in X ¹ to X ⁴ is substituted with the same arylcarbonyloxy group as the above substituent. Monovalent groups of the structure are mentioned.
Examples of the arylcarbonyloxyalkyl group as the substituent include a phenylcarbonyloxymethyl group, a 1-naphthylcarbonyloxymethyl group, a 2-naphthylcarbonyloxymethyl group, a phenylcarbonyloxyethyl group, and a 1-naphthylcarbonyloxyethyl group. , 2-naphthylcarbonyloxyethyl group, phenylcarbonyloxynonyl, and the like, but are not limited thereto.
The arylcarbonyloxyalkyl group preferably has 8 to 30 carbon atoms, and more preferably 8 to 20 carbon atoms.

In the aralkylcarbonyloxyalkyl group as the substituent, one hydrogen atom of the same alkyl group as that in X ¹ to X ⁴ is substituted with the same aralkylcarbonyloxy group as the substituent. Monovalent groups of the structure are mentioned.
Examples of the aralkylcarbonyloxyalkyl group as the substituent include, for example, a benzylcarbonyloxymethyl group, a phenethylcarbonyloxymethyl group, a 1-naphthylmethylcarbonyloxymethyl group, a 2-naphthylmethylcarbonyloxymethyl group, a benzylcarbonyloxyethyl group Phenethylcarbonyloxyethyl group, 1-naphthylmethylcarbonyloxyethyl group, 2-naphthylmethylcarbonyloxyethyl group, benzylcarbonyloxynonyl group, and the like, but are not limited thereto.
The aralkylcarbonyloxyalkyl group preferably has 9 to 35 carbon atoms, and more preferably 9 to 26 carbon atoms.

When the unsaturated hydrocarbon group in X ¹ to X ⁴ has a substituent, the number of the substituent is not particularly limited, but is preferably one or two, and more preferably one.
When the unsaturated hydrocarbon group in X ¹ to X ⁴ has a substituent, the bonding position of the substituent is not particularly limited. It is preferable that a substituent is bonded to the cation.
As a preferable example of the unsaturated hydrocarbon group having a substituent in X ¹ to X ⁴ , the terminal carbon atom on the opposite side to the bonding destination side of the unsaturated hydrocarbon group is the same as that of the adjacent carbon atom. Among them, a triple bond is formed, and the above-mentioned substituent is bonded to the terminal carbon atom.

When X ¹ and X ² are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is a nitrogen-containing aliphatic ring containing one nitrogen atom as an atom constituting the ring skeleton.
The positions of the carbon atoms that are mutually bonded in the alkyl group are not particularly limited. For example, the carbon atoms bonded to each other may be terminal carbon atoms in the alkyl group or non-terminal carbon atoms.
The number of carbon atoms bonded to each other in the alkyl group is the same, and each may be only one, or may be two or more, but is preferably one or two. .
That is, the ring may be monocyclic or polycyclic.
The number of ring members of the ring (the total number of carbon atoms and nitrogen atoms constituting the ring skeleton) is not particularly limited, but is preferably 5 to 10, and more preferably 5 to 8.

The formation of the ring described above is the same in the case of X ³ and X ⁴ .
That is, when X ³ and X ⁴ are the aforementioned alkyl groups, these two alkyl groups have an oxygen atom to which each of these alkyl groups is bonded and a benzene ring skeleton to which these oxygen atoms are respectively bonded. Together with the constituent carbon atoms, they may be mutually bonded to form a ring. The ring is an oxygen-containing aliphatic ring containing two oxygen atoms as atoms constituting the ring skeleton.
The positions of the carbon atoms that are mutually bonded in the alkyl group are not particularly limited. For example, the carbon atoms bonded to each other may be terminal carbon atoms in the alkyl group or non-terminal carbon atoms.
The number of carbon atoms bonded to each other in the alkyl group is the same, and each may be only one, or may be two or more, but is preferably one or two. .
That is, the ring may be monocyclic or polycyclic.
The number of ring members of the ring (the total number of carbon atoms and oxygen atoms constituting the ring skeleton) is not particularly limited, but is preferably 5 to 10, and more preferably 5 to 8.

X ¹ , X ² , X ³ and X ⁴ each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms, and have a substituent. Is preferably an unsaturated hydrocarbon group having 3 to 9 carbon atoms, and when X ¹ and X ² are the aforementioned alkyl groups, or when X ³ and X ⁴ are the aforementioned alkyl groups, These two alkyl groups may be bonded to each other to form a ring. Here, the substituent, the unsaturated hydrocarbon group, and the ring are as described above.

In the general formula (I), n ₁ and n ₃ are each independently 0 or 1.
n ₁ defines the presence or absence of the bond of X ⁵ in the benzene ring skeleton where the group represented by the general formula —OX ³ and the group represented by the general formula —OX ⁴ are directly bonded. .
n ₃ defines the presence or absence of the group represented by the general formula —OX ⁶ in the alkylene skeleton directly bonded to the group represented by the general formula —NX ¹ X ² .

In the general formula (I), X ⁵ is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent.
X ⁵ is the same as the above-mentioned unsaturated hydrocarbon group for X ¹ to X ⁴ except that the number of carbon atoms is 2 to 8 instead of 3 to 9, that is, the number of carbon atoms is 1 .

For example, in the unsaturated hydrocarbon group for X ⁵ , the terminal carbon atom on the opposite side to the bond destination side preferably forms a triple bond with an adjacent carbon atom.
Examples of such an unsaturated hydrocarbon group which is an alkynyl group include an ethynyl group (—C≡CH), a propargyl group (alias: 2-propynyl group), a 3-butynyl group, a 4-pentynyl group, and a 5-hexynyl group. Group, 6-heptynyl group and 7-octynyl group.

For example, if the in X ⁵ is an unsaturated hydrocarbon group having a substituent, the number of substituents is not particularly limited, it is preferable that one or two, more preferably one.
For example, when the unsaturated hydrocarbon group for X ⁵ has a substituent, the bonding position of the substituent is not particularly limited. And a substituent is preferably bonded.
For example, in X ^5, as a preferred example of the unsaturated hydrocarbon group having a substituent, wherein the unsaturated terminal carbon atom of the side opposite to the coupling destination side of the hydrocarbon group, between adjacent carbon atoms Wherein a triple bond is formed, and the substituent is bonded to the terminal carbon atom.

When n ₁ is 1, in the general formula (I), a group represented by the general formula —OX ³ and a group represented by the general formula —OX ⁴ are directly bonded to each other, The bonding position of X ⁵ is not particularly limited. For example, a position having an ortho-position with respect to a group represented by the general formula —OX ³ (in other words, a group represented by the general formula —OX ³ is A carbon atom adjacent to the carbon atom to which it is bonded and to which the group represented by the general formula -OX ⁴ is not bonded), and a position having a meta-position (in other words, a carbon atom represented by the general formula -OX ⁴⁾ A carbon atom adjacent to the carbon atom to which the group is bonded and to which the group represented by the general formula -OX ³ is not bonded), or a position having a para-position relationship. .
Among them, the bonding position of X ⁵ in the benzene ring skeleton is a position having a meta-position or a position having a para-position with respect to the group represented by the general formula —OX ^3. It is preferable that

In the general formula (I), X ⁶ is a hydrogen atom or an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent. is there.
The unsaturated hydrocarbon group for X ⁶ is the same as the unsaturated hydrocarbon group for X ¹ to X ⁴ described above.
For example, in the unsaturated hydrocarbon group for X ⁶ , the terminal carbon atom on the opposite side to the bonding destination side preferably forms a triple bond with an adjacent carbon atom.
Examples of such an unsaturated hydrocarbon group which is an alkynyl group include a propargyl group (alias: 2-propynyl group), a 3-butynyl group, a 4-pentynyl group, a 5-hexynyl group, a 6-heptynyl group, and a 7-heptinyl group. Examples include an octynyl group and an 8-noninyl group.

For example, when the unsaturated hydrocarbon group for X ⁶ has a substituent, the number of substituents is not particularly limited, but is preferably one or two, and more preferably one.
For example, when the unsaturated hydrocarbon group in X ⁶ has a substituent, the bonding position of the substituent is not particularly limited, but the terminal carbon atom on the opposite side to the bonding destination side of the unsaturated hydrocarbon group is And a substituent is preferably bonded.
For example, as a preferable example of the unsaturated hydrocarbon group having a substituent in X ⁶ , the terminal carbon atom on the side opposite to the side to which the unsaturated hydrocarbon group is bonded may be located between an adjacent carbon atom and Wherein a triple bond is formed, and the substituent is bonded to the terminal carbon atom.

In the general formula (I), n ₂ is an integer of 1 to 5.
n ₂ defines the number of carbon atoms of the alkylene skeleton (in other words, a chain hydrocarbon skeleton) to which the group represented by the general formula —NX ¹ X ² is directly bonded. That is, the alkylene skeleton has 2 to 6 carbon atoms.
n ₂ may be, for example, any one of 1 or more, 2 or more, 3 or more, and 4 or more within a range of 5 or less. Further, n ₂ may be, for example, any one of 5 or less, 4 or less, 3 or less, and 2 or less within a range of 1 or more.
For example, the compound (I) or a salt thereof in which n ₂ is 1 has the same or similar chain skeleton having the same carbon number as dopamine, noradrenaline and adrenaline, which are important as naturally-occurring nerve function regulators. And its usefulness is high.
Further, the compound (I) or a salt thereof in which n ₂ is 2 to 5 may be able to regulate the level of its biological activity based on the compound (I) or a salt thereof in which n ₂ is 1; High usefulness.

However, in the general formula (I), when n ₁ is 0 and n ₃ is 1, one or two or more of X ¹ , X ² , X ³ , X ⁴ and X ⁶ Is an unsaturated hydrocarbon group (that is, an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and 3 to 9 carbon atoms which may have a substituent).
In the general formula (I), when n ₁ is 1 and n ₃ is 0, one or two of X ¹ , X ² , X ³ , X ⁴ and X ⁵ are used. The above description is based on the unsaturated hydrocarbon group (that is, an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and 3 to 9 or 2 to 8 carbon atoms which may have a substituent). ).
In the general formula (I), when n ₁ and n ₃ are both 0, one or more of X ¹ , X ² , X ³ and X ⁴ are the unsaturated hydrocarbons. (Ie, an unsaturated hydrocarbon group having 3 to 9 carbon atoms and having 1 to 4 triple bonds between carbon atoms and optionally having a substituent).
In the general formula (I), when n ₁ and n ₃ are both 1, one or more of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ are The unsaturated hydrocarbon group (that is, an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and 3 to 9 or 2 to 8 carbon atoms which may have a substituent); is there.
As described above, the compound (I) or a salt thereof has one or two or more unsaturated hydrocarbon groups having 3 to 9 or 2 to 8 carbon atoms in total. In other words, the compound (I) or a salt thereof always contains a group having a triple bond between carbon atoms. Therefore, compound (I) or a salt thereof can be detected by Raman scattering spectroscopy based on this triple bond, and a label can be introduced by reacting this triple bond with another reagent. Therefore, it can be detected by this label. Such a method for detecting compound (I) or a salt thereof will be described in detail later.

The salt of compound (I) is a compound in which the group capable of forming a salt in compound (I) forms a salt. Here, examples of the group capable of forming a salt include, but are not limited to, a group represented by the general formula -NX ¹ X ² in the general formula (I).

Examples of the salt of compound (I) include salts formed by reacting compound (I) with an acid or base.
When compound (I) has two or more groups capable of forming a salt in one molecule, examples of the salt of compound (I) include compounds having one or more salt formation sites. .
In a salt of compound (I) having two or more salt formation sites, these two or more salts may be all the same, may be all different, or may be partially identical. Good.

The valence of the anion forming the salt of compound (I) is not particularly limited, and may be 1 (monovalent) or 2 (divalent) or more.
Similarly, the valence of the cation forming the salt of the compound (I) is not particularly limited, and may be 1 (monovalent) or 2 (divalent) or more.
The number of cations and anions forming a salt of one molecule of compound (I) may be only one, or two or more, and when two or more, these cations or anions are used. All the anions may be the same, all may be different, or only some may be the same.
However, the salt of the compound (I) is electrically neutral as a whole molecule, that is, the total value of the valence of the cation and the total value of the valence of the anion in one molecule of the compound (I) are the same. Is preferred.

において In the salt of compound (I), the anion forming the salt may be any of an inorganic anion and an organic anion.

Examples of the inorganic anion include a hydroxide ion, a nitrate ion, a sulfate ion, a carbonate ion, a hydrogen carbonate ion, a halide ion, and an anion of an inorganic acid.
Examples of the halide ion include a fluoride ion, a chloride ion, a bromide ion, and an iodide ion.
Examples of the anion of the inorganic acid include an anion of phosphoric acid.

Examples of the organic anion include an anion of an organic acid.
Examples of the anion of the organic acid include a carboxylic acid anion, a halogenated carboxylic acid anion, a sulfonic acid anion, and a halogenated sulfonic acid anion.

The anion of the carboxylic acid may be an anion of a monocarboxylic acid (monovalent carboxylic acid) or an anion of a polyvalent carboxylic acid such as dicarboxylic acid or tricarboxylic acid.
Examples of the anion of the carboxylic acid include formate ion; acetate ion; propanoic acid (propionic acid) ion, butanoic acid (butyric acid) ion, pentanoic acid (valeric acid) ion, hexanoic acid (caproic acid) ion, and heptanoic acid ( Enanthate), octanoate (caprylate), nonanoate (pelargonate), decanoate (caprate), dodecanoate (laurate), tetradecanoate (myristate), pentadecanoate, hexadecane Acid (palmitic acid) ion, heptadecanoic acid ion, octadecanoic acid (stearic acid) ion, eicosanoic acid (arachidic acid) ion, cis-9-octadecenoic acid (oleic acid) ion, cis, cis-9,12-octadecadien Acid (linoleic acid) ion, cis, cis, is-9,12,15-octadecatrienoate (α-linolenate) ion, all-cis-6,9,12-octadecatrienoate (γ-linolenate) ion, (5Z, 8Z, 11Z, 14Z ) -Icosa-5,8,11,14-tetraenoic acid (arachidonic acid) ion or other anion of a saturated or unsaturated chain fatty acid having 3 or more carbon atoms; oxalate ion, malonate ion, succinate ion, glutaric acid Anion of a saturated or unsaturated dicarboxylic acid having 2 or more carbon atoms such as anion, adipate ion, fumarate ion and maleate ion; anion of hydroxy acid such as citrate ion and tartrate ion.
In this specification, “fatty acid” means a monocarboxylic acid having a chain structure, unless otherwise specified.

The anion of the halogenated carboxylic acid is preferably an anion of a fluorinated carboxylic acid or an anion of a chloride carboxylic acid.
Examples of the anion of the fluorinated carboxylic acid include, for example, anions having a structure in which one or two or more hydrogen atoms are substituted with a fluorine atom in the anion of the carboxylic acid, such as an anion of trifluoroacetic acid. May be replaced by a fluorine atom.
Similarly, examples of the anion of the carboxylic acid chloride include anions having a structure in which one or two or more hydrogen atoms are substituted with a chlorine atom in the anion of the carboxylic acid, such as an anion of trichloroacetic acid. All hydrogen atoms may be replaced by chlorine atoms.

The sulfonic acid anion may be a monosulfonic acid (monovalent sulfonic acid) anion or a polyvalent sulfonic acid anion.
Examples of the anion of the sulfonic acid include, for example, an anion of the carboxylic acid, such as methanesulfonic acid, in which a carboxy group anion (—COO ⁻ ) is substituted with a sulfo group anion (—SO ₃ ⁻ ). No.

The anion of the halogenated sulfonic acid is preferably an anion of fluorinated sulfonic acid.
Examples of the anion of the fluorinated sulfonic acid include, for example, an anion having a structure in which one or two or more hydrogen atoms are substituted with a fluorine atom in the anion of the sulfonic acid, such as trifluoromethanesulfonic acid and nonafluorobutanesulfonic acid. And all hydrogen atoms may be replaced by fluorine atoms.

において In the salt of compound (I), the cation forming the salt may be any of an inorganic cation and an organic cation.

Examples of the inorganic cation include sodium ions, potassium ions, calcium ions, magnesium ions, lithium ions, barium ions, aluminum ions, zinc ions, copper ions (Cu ⁺ , Cu ²⁺ ), and iron ions (Fe ²⁺ , Fe ^3+). ), Ammonium ion and the like.

Examples of the organic cation include a cation in which a hydrogen ion (H ⁺ ) is coordinated to a nitrogen atom of a group represented by the general formula —NX ¹ X ² in the general formula (I).

好ましい Preferred examples of the salt of the compound (I) include salts represented by the following general formula (Is).

(In the general formula (Is), X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , n ₁ , n ₂ and n ₃ are the same as described above; Q ⁻ is a monovalent anion. is there.)

In the general formula (Is), X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , n ₁ , n ₂ and n ₃ represent X ¹ , X ² , X ^{3 in the} general formula (I) , X ⁴ , X ⁵ , X ⁶ , n ₁ , n ₂ and n ₃ .

In the general formula (Is), Q 2 ^— is a monovalent anion, and examples thereof include monovalent inorganic anions; monocarboxylic acid anions, halogenated monocarboxylic acid anions, and monosulfones. Monovalent organic anions such as anions of acids and anions of halogenated monosulfonic acids are exemplified.

Compound (I) is a compound represented by the following general formula (I) -1 (hereinafter, may be abbreviated as “compound (I) -1” in the present specification), the following general formula (I) -2 (Herein, may be abbreviated as “compound (I) -2”), a compound represented by the following general formula (I) -3 (in the present specification, “compound (I) -2”). (Sometimes abbreviated as (I) -3)) or a compound represented by the following general formula (I) -4 (herein, sometimes abbreviated as “compound (I) -4”) It is preferable that
That is, compound (I) or a salt thereof is compound (I) -1 or a salt thereof, compound (I) -2 or a salt thereof, compound (I) -3 or a salt thereof, or compound (I) -4 or a salt thereof. And a salt.

<Compound (I) -1>
Compound (I) -1 is included in compound (I) when n ₁ is 0.
In the Formula ^{^{(I) -1, X 1,}} X 2, n 2 and _{n 3} are the same as general ^X 1 in formula ^{_{(I), X 2, n}} 2 and _{n 3.}
However, in the general formula (I) -1, one or both of X ¹ and X ² have 1 to 4 triple bonds between carbon atoms and may have 3 carbon atoms which may have a substituent. To 9 unsaturated hydrocarbon groups.

In the general formula (I) -1, X ³¹ and X ⁴¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms.
The alkyl group having 1 to 9 carbon atoms in X ³¹ and X ⁴¹ is the same as the alkyl group having 1 to 9 carbon atoms in X ¹ to X ⁴ .

When X ³¹ and X ⁴¹ are the above-mentioned alkyl groups, these two alkyl groups constitute an oxygen atom to which these alkyl groups are respectively bonded and a benzene ring skeleton to which these oxygen atoms are respectively bonded. And the carbon atoms may be mutually bonded to form a ring. The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ³ and X ⁴ are an alkyl group.

<Compound (I) -2>
Compound (I) -2 is included in compound (I) when n ₁ is 0.
In the Formula ^{^{(I) -2, X 3,}} X 4, n 2 and _{n 3} are the same as ^X ^3, ^X ^4, _{n 2} and _{n 3} in the general formula (I).
However, in the general formula (I) -2, one or both of X ³ and X ⁴ have 1 to 4 triple bonds between carbon atoms, and may have an optionally substituted carbon number. 3 to 9 unsaturated hydrocarbon groups.

In the general formula (I) -2, X ¹¹ and X ²¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms.
The alkyl group having 1 to 9 carbon atoms in X ¹¹ and X ²¹ is the same as the alkyl group having 1 to 9 carbon atoms in X ¹ to X ⁴ .

When X ¹¹ and X ²¹ are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ¹ and X ² are alkyl groups.

<Compound (I) -3>
Compound (I) -3 is included in compound (I) when n ₁ is 1.
In the Formula ^{(I) -3, X 5,} n 2 and _{n 3} are the same as ^X 5, _{n 2} and _{n 3} in the general formula (I).

In the general formula (I) -3, X ¹¹ , X ²¹ , X ³¹ and X ⁴¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms.
X ¹¹ , X ²¹ , X ³¹ and X ⁴¹ are the same as those described above.
For example, when X ¹¹ and X ²¹ are the aforementioned alkyl groups, or when X ³¹ and X ⁴¹ are the aforementioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. And when X ¹ and X ² are an alkyl group as described above, the ring may be formed by bonding these two alkyl groups to each other, or X ³ and When X ⁴ is an alkyl group, it is the same as the ring which these two alkyl groups may form by bonding to each other.

<Compound (I) -4>
Compound (I) -4 is included in compound (I) in which n ₁ is 0 and n ₃ is 1.
In the Formula (I) -4, _{n 2} is the same as _{n 2} in the general formula (I).

In the general formula (I) -4, X ¹¹ , X ²¹ , X ³¹ and X ⁴¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms.
X ¹¹ , X ²¹ , X ³¹ and X ⁴¹ are the same as those described above.
For example, when X ¹¹ and X ²¹ are the aforementioned alkyl groups, or when X ³¹ and X ⁴¹ are the aforementioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. And when X ¹ and X ² are an alkyl group as described above, the ring may be formed by bonding these two alkyl groups to each other, or X ³ and When X ⁴ is an alkyl group, it is the same as the ring which these two alkyl groups may form by bonding to each other.

In the general formula (I) -4, X ⁶¹ is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, X ¹ to X ⁴ are the same as the C 3 to C 9 unsaturated hydrocarbon group which has 1 to 4 triple bonds between carbon atoms and may have a substituent.

The compound (I) is a compound represented by the following general formula (I) -1-1 (in this specification, may be abbreviated as “compound (I) -1-1”); A compound represented by the following general formula (I) -2-1 (in some cases, abbreviated as "compound (I) -1-2") in the present specification. A compound (may be abbreviated as “compound (I) -2-1” in the present specification) and a compound represented by the following general formula (I) -2-2 (in the present specification, “compound (I) -2-1” (May be abbreviated as (I) -2-2)) or a compound represented by the following general formula (I) -2-3 (in this specification, abbreviated as "compound (I) -2-3"). A compound represented by the following general formula (I) -3-1 (hereinafter, abbreviated as “compound (I) -3-1”). There), or the following general formula (I) compound represented by -4-1 (herein, "compound (I) -4-1" It is preferable that a sometimes abbreviated as).
That is, compound (I) or a salt thereof is compound (I) -1-1 or a salt thereof, compound (I) -1-2 or a salt thereof, compound (I) -2-1 or a salt thereof, or a compound (I). ) -2-2 or a salt thereof, compound (I) -2-3 or a salt thereof, compound (I) -3-1 or a salt thereof, or compound (I) -4-1 or a salt thereof. preferable.
Compound (I) -1-1 or a salt thereof, and compound (I) -1-2 or a salt thereof are included in compound (I) -1 or a salt thereof.
Compound (I) -2-1 or a salt thereof, compound (I) -2-2 or a salt thereof, and compound (I) -2-3 or a salt thereof are included in compound (I) -2 or a salt thereof. Is done.
Compound (I) -3-1 or a salt thereof is included in compound (I) -3 or a salt thereof.
Compound (I) -4-1 or a salt thereof is included in compound (I) -4 or a salt thereof.

(General formulas (I) -1-1, (I) -1-2, (I) -2-1, (I) -2-2, (I) -2-3, (I) -3-1) Or, in (I) -4-1, X ¹² , X ²² , X ³² and X ⁴² are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and X ¹² and X ²² are Or when X ³² and X ⁴² are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring;
G ¹ , G ² , G ³ , G ⁴ , G ⁵ and G ⁶ each independently represent a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a trialkyl group. Reelsilyl group, hydroxy group, halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group , A triarylsilylalkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group. R;
n ₃ are the same as above. )

[Compound (I) -1-1]
In the Formula (I) -1-1, _{n 3} is the same as _{n 3} in the general formula (I).

In the general formula (I) -1-1, X ³² and X ⁴² are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
Among the alkyl groups having 1 to 5 carbon atoms in X ³² and X ^42, of the alkyl groups having 1 to 9 carbon atoms in X ¹ to X ⁴ (or X ³¹ and X ⁴¹ ), Same as the ones.

When X ³² and X ⁴² are the aforementioned alkyl groups, these two alkyl groups constitute an oxygen atom to which these alkyl groups are respectively bonded and a benzene ring skeleton to which these oxygen atoms are respectively bonded. And the carbon atoms may be mutually bonded to form a ring. The ring is an oxygen-containing aliphatic ring containing two oxygen atoms as atoms constituting the ring skeleton.
The positions of the carbon atoms that are mutually bonded in the alkyl group are not particularly limited. For example, the carbon atoms bonded to each other may be terminal carbon atoms in the alkyl group or non-terminal carbon atoms.
The number of carbon atoms bonded to each other in the alkyl group is the same, and each may be only one, or may be two or more, but is preferably one or two. .
That is, the ring may be monocyclic or polycyclic.
The number of ring members of the ring (the total number of carbon atoms and oxygen atoms constituting the ring skeleton) is not particularly limited, but is preferably 5 to 10, and more preferably 5 to 8.

In the general formula (I) -1-1, G ¹ represents a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a triarylsilyl group, a hydroxy group, a halogen Atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group, triarylsilylalkyl group, hydroxy An alkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group.
The groups other than the hydrogen atom and the alkyl group in G ¹ are the same as the above-described substituents which the unsaturated hydrocarbon group in X ¹ to X ⁴ may have.

Examples of the alkyl group for G ¹ include the same alkyl groups having 1 to 9 carbon atoms as those for X ¹ to X ⁴ , and are preferably linear or branched.

[Compound (I) -1-2]
In the Formula (I) -1-2, _{n 3} is the same as _{n 3} in the general formula (I).

In the general formula (I) -1-2, G ² is the same as G ¹ in the general formula (I) -1-1, and G ¹ and G ² are independently determined.

^{X 32} and ^{X 42} in the general formula (I) in -1-2 is the same as the ^{X 32} and ^{X 42} in the general formula (I) in -1-1.

[Compound (I) -2-1]
In the Formula (I) -2-1, _{n 3} is the same as _{n 3} in the general formula (I).

In the general formula (I) -2-1, X ¹² and X ²² are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
The alkyl group having 1 to 5 carbon atoms in X ¹² and X ²² includes the alkyl group having 1 to 5 carbon atoms among the alkyl groups having 1 to 9 carbon atoms in X ¹ to X ⁴ (or X ¹¹ and X ²¹ ). Same as the ones.

When X ¹² and X ²² are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is a nitrogen-containing aliphatic ring containing one nitrogen atom as an atom constituting the ring skeleton.
The positions of the carbon atoms that are mutually bonded in the alkyl group are not particularly limited. For example, the carbon atoms bonded to each other may be terminal carbon atoms in the alkyl group or non-terminal carbon atoms.
The number of carbon atoms bonded to each other in the alkyl group is the same, and each may be only one, or may be two or more, but is preferably one or two. .
That is, the ring may be monocyclic or polycyclic.
The number of ring members of the ring (the total number of carbon atoms and nitrogen atoms constituting the ring skeleton) is not particularly limited, but is preferably 5 to 10, and more preferably 5 to 8.

G ³ in the general formula (I) -2-1 is the same as G ¹ in the general formula (I) -1-1.

[Compound (I) -2-2]
In the Formula (I) -2-2, _{n 3} is the same as _{n 3} in the general formula (I).

In the general formula (I) -2-2, X ¹² and X ²² are the same as those described above.
For example, when X ¹² and X ²² are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring, and the aforementioned ring is the same as described above.

G ⁴ in the general formula (I) -2-2 is the same as G ¹ in the general formula (I) -1-1.

[Compound (I) -2-3]
In the Formula (I) -2-3, _{n 3} is the same as _{n 3} in the general formula (I).

In the general formula (I) -2-3, X ¹² and X ²² are the same as those described above.
For example, when X ¹² and X ²² are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring, and the aforementioned ring is the same as described above.

In the general formula (I) -2-3, G ³ and G ⁴ are the same as those described above.

[Compound (I) -3-1]
In formula (I) -3-1, n ₃ is the same as n ₃ in formula (I).

In the general formula (I) -3-1, X ¹² , X ²² , X ³² and X ⁴² are the same as those described above.
For example, when X ¹² and X ²² are the aforementioned alkyl groups, or when X ³² and X ⁴² are the aforementioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. Said ring may be the same as described above.

G ⁵ in the general formula (I) -3-1 is the same as G ¹ in the general formula (I) -1-1.

[Compound (I) -4-1]
In the general formula (I) -4-1, X ¹² , X ²² , X ³² and X ⁴² are the same as those described above.
For example, when X ¹² and X ²² are the aforementioned alkyl groups, or when X ³² and X ⁴² are the aforementioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. Said ring may be the same as described above.

G ⁶ in the general formula (I) -4-1 is the same as G ¹ in the general formula (I) -1-1.

The molecular weight of compound (I) is preferably 350 or less, more preferably 300 or less, and even more preferably 250 or less. The molecular weight of a naturally-occurring nerve function modulator having a physiological activity on nerve cells is usually relatively small. Therefore, by analyzing the behavior and properties of the compound (I) having a relatively small molecular weight as described above in a nerve cell, it is possible to consider the behavior and properties of a naturally-occurring nerve function regulator with high accuracy. It is possible, and the usefulness of compound (I) is higher.
On the other hand, the salt of the compound (I) may be referred to as “converted molecular weight” in the present specification when it is replaced with a salt-free state (that is, when considered as the compound (I)). Is preferably the same as the molecular weight of the compound (I) described above. Such a salt of compound (I) also usually has a relatively low molecular weight, and thus has higher utility similarly to the above-mentioned compound (I) having a small molecular weight.
However, such usefulness of the compound (I) and its salt is merely an example, and the upper limit of the molecular weight of the compound (I) and the converted molecular weight of the salt of the compound (I) are limited to those shown here. Not done.

下限 The lower limits of the molecular weight of compound (I) and the reduced molecular weight of the salt of compound (I) are not particularly limited. The molecular weight and the reduced molecular weight are preferably 177 or more from the viewpoint of easy production of the compound (I).

Preferred compounds (I) are exemplified below. Preferred compounds (I) also include, in addition to the above, compounds exemplified below and having the above substituent. Preferred salts of compound (I) include the salts of the compounds exemplified below and the salts of the compounds exemplified below having the substituent.
However, the compound (I) of the present embodiment or a salt thereof is not limited thereto.

Compound (I) can be regarded as a derivative of dopamine, noradrenaline (alias: norepinephrine) or adrenaline (alias: epinephrine), which are known neuronal function modulators. As used herein, the term “derivative” refers to a compound having a structure in which one or more hydrogen atoms of an original compound are substituted with a group other than a hydrogen atom.
Therefore, compound (I) and a salt thereof are useful for elucidating the role (in other words, biological activity) of dopamine, noradrenaline and adrenaline in nerve cells among known neuronal function regulators. .
The structural formulas of dopamine, noradrenaline and adrenaline are shown below.

<< Method for producing compound (I) or a salt thereof >>
The production method of compound (I) or a salt thereof varies depending on which of X ¹ , X ² , X ³ , X ⁴ , X ⁵ and X ⁶ is the above-mentioned unsaturated hydrocarbon group. Hereinafter, a method for producing such a compound (I) or a salt thereof will be sequentially described.

<Manufacturing method (1)>
When any of X ¹ , X ² , X ³ and X ⁴ is the above-mentioned unsaturated hydrocarbon group, the compound (I) or a salt thereof is, for example, a compound represented by the following general formula (Ia) ( In this specification, it may be referred to as “compound (Ia)” and a compound represented by the following general formula (Ic) (in this specification, it may be referred to as “compound (Ic)”). (In the present specification, it may be referred to as “unsaturated hydrocarbon group introduction step (1)”) and the following Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a When one or more of the protective groups are the following protective groups, after the step of reacting, a step of further removing the protective groups (in the present specification, a “deprotection step (1)” By the following formula (I ^A ) (As used herein, "compound ^{(I A)"} is sometimes referred to as) a compound represented as or a salt thereof, in the compound represented by the following general formula (Ia), the following ^Z ^{1a, Z} 2a, Z ^{Among the 3a} , Z ^4a and Z ^6a, a method for obtaining a compound having a structure in which a hydrogen atom is a hydrogen atom substituted with the following X ^0a or a salt thereof (hereinafter referred to as “production method (1)”) In some cases).
Compound ^{(I A)} can ^be any of X ^1, X 2, ^{X 3} and ^{X 4} is a compound where an unsaturated hydrocarbon group as described above (I).

[Unsaturated hydrocarbon group introduction step (1)]
In the unsaturated hydrocarbon group introduction step (1), the compound (Ia) is reacted with the compound (Ic).
In the general formula ^{_{(Ia), X 5, n}} 1, n 2 and _{n 3} are the same as ^X _5, _n _1, n ₂ and _{n 3} in the general formula (I).

In the general formula (Ia), Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or a protecting group.
The alkyl group having 1 to 9 carbon atoms in Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a is the same as the alkyl group having 1 to 9 carbon atoms in X ¹ to X ⁴ .

When Z ^1a and Z ^2a are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ¹ and X ² are alkyl groups.

When Z ^3a and Z ^4a are the above-mentioned alkyl groups, these two alkyl groups constitute an oxygen atom to which these alkyl groups are respectively bonded and a benzene ring skeleton to which these oxygen atoms are respectively bonded. May be mutually bonded to form a ring. The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ³ and X ⁴ are an alkyl group.

The protecting group in Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a may be a known one.
As the protecting group for Z ^1a and Z ^2a , for example, an amino group such as a tert-butoxycarbonyl group (may be abbreviated as “Boc group” in the present specification), a trifluoromethylcarbonyl group or the like is protected. Known protecting groups are mentioned.
^Examples of the protecting group for Z ^3a , Z ^4a and Z ^6a include known protecting groups for protecting a hydroxy group such as a Boc group. Examples of the protecting group for Z ^3a and Z ^4a include those in which they are mutually bonded to form a ring. As such a cyclic protecting group, an isopropylidene group (—C (CH ₃ ) _2- ) and the like.

However, one or more of Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a are hydrogen atoms.

In the general formula (Ic), X ^0a is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, and X ¹ wherein at ~ X ⁴ are the same as the unsaturated hydrocarbon group. For example, when the unsaturated hydrocarbon group for ^X0a has a methylene group at the terminal on the side of the bond, the methylene group may be substituted with a carbonyl group. For X ^0a, and the methylene group at the end of the coupling destination side, a methylene group bonded to the LG ¹ in the general formula (Ic).

In the general formula (Ic), LG ¹ is a leaving group, and may be a known group.
Examples of the leaving group include a halogen atom such as a bromine atom.

In the general formula ^{^{^{(I A), X 1,}}} X 2, X 3, X 4, X 5, X 6, n 1, n 2 and _{n 3,} ^X 1 in the general formula ^{(I), X 2, X} ³ , X ⁴ , X ⁵ , X ⁶ , n ₁ , n ₂ and n ₃ .
However, one or more of X ¹ , X ² , X ³ and X ⁴ are the unsaturated hydrocarbon groups.
Thus, except that the site with the unsaturated hydrocarbon group is limited, Compound (I ^A) is the same as compound (I).

In the compound (Ia), one or more of Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a are hydrogen atoms, and therefore, in the unsaturated hydrocarbon group introduction step (1), A compound having a structure in which this hydrogen atom is substituted by the above-mentioned ^X0a or a salt thereof is produced.

(4) In the unsaturated hydrocarbon group introduction step (1), there is a possibility that both a product that does not form a salt and a product that forms a salt are obtained. Which of these is obtained depends on the conditions of the unsaturated hydrocarbon group introduction step (1).

In the unsaturated hydrocarbon group introduction step (1), the amount (mol) of the compound (Ic) used is based on the amount (mol) of the hydrogen atom to be substituted with ^X0a in the compound (Ia). And preferably 1 to 2 times the molar amount.

In the step of introducing an unsaturated hydrocarbon group (1), it is preferable to react the compound (Ia) with the compound (Ic) using a base. By doing so, the reaction proceeds more smoothly.
Examples of the base include, but are not particularly limited to, sodium hydride (NaH), potassium carbonate (K ₂ CO ₃ ), N, N-diisopropylethylamine (((CH ₃ ) ₂ CH) ₂ NC ₂ H ₅ ), triethylamine ( (CH ₃ CH ₂ ) ₃ N), lithium diisopropylamide ([(CH ₃ ) ₂ CH] ₂ NLi) and the like.
In the unsaturated hydrocarbon group introduction step (1), the amount (mol) of the base used is 1 to the amount (mol) of the hydrogen atom to be substituted with ^X0a in the compound (Ia). It is preferable that the molar amount is up to 3 times.

In the unsaturated hydrocarbon group introduction step (1), a solvent may or may not be used during the reaction between the compound (Ia) and the compound (Ic).
The solvent may be appropriately selected depending on, for example, the types of the compound (Ia) and the compound (Ic), and is not particularly limited. Examples of the solvent include N, N-dimethylformamide (DMF), acetonitrile, methylene chloride, tetrahydrofuran (THF) and the like.
In the case where a solvent is used in the unsaturated hydrocarbon group introduction step (1), the amount of the solvent used (parts by mass) is not particularly limited, but the total amount (parts by mass) of all components other than the solvent is It is preferably 1 to 40 times by mass, and may be 1 to 30 times by mass.

In the unsaturated hydrocarbon group introduction step (1), the reaction temperature and the reaction time between the compound (Ia) and the compound (Ic) may be appropriately adjusted so as to improve the yield of the desired product. There is no particular limitation.
The reaction temperature may be, for example, any of 0 to 40 ° C and 10 to 40 ° C.
The reaction time may be, for example, 0.5 to 24 hours.

In the unsaturated hydrocarbon group introduction step (1), after the reaction is completed, post-treatment may be performed, if necessary, by a known method, and the product may be taken out. That is, if necessary, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed alone or in combination of two or more, and concentration, crystallization, reprecipitation, and column chromatography are performed. For example, the product may be taken out. Further, the product taken out may be further subjected to crystallization, reprecipitation, column chromatography, extraction, stirring and washing of crystals with a solvent, etc., either alone or in combination of two or more, as needed, once. Alternatively, purification may be performed by performing the purification twice or more.
In the case where another step such as the deprotection step (1) described later is continuously performed after the unsaturated hydrocarbon group introduction step (1), it is necessary to complete the reaction in the unsaturated hydrocarbon group introduction step (1). After the post-processing is performed accordingly, the above-mentioned other steps may be continuously performed without taking out the product.

In the unsaturated hydrocarbon group introduction step (1), the product of the reaction between the compound (Ia) and the compound (Ic) is one or two of Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a. When at least one species is a protecting group, the compound (I ^A ) is a compound in which the functional group at the corresponding site is protected by the protecting group. On the other ^hand, when ^{^{Z 1a, Z 2a, Z 3a}} , Z 4a and ^{Z 6a} are not both a protecting group, the product is a compound of the desired compound ^{(I A).}
^{^{^{Incidentally, Z 1a, Z 2a, Z}}} 3a, the alkyl group in ^{Z 4a} and ^{Z 6a} are those corresponding to the protecting group. For example, when Z ^3a and Z ^4a are the aforementioned alkyl groups, and these alkyl groups are bonded to each other to form a ring, this cyclic group is an isopropylidene group (—C (CH ₃ ) ₂ -) Is a protecting group as described above. In other ^{^{^{words, Z 1a, Z 2a, Z}}} 3a, among the ^{Z 4a} and ^{Z 6a,} the one or product when it is two or more protecting groups, equivalent to a compound of the desired product ^{(I A)} There is also. Whether the product obtained in this step is considered to have a protecting group or not to have a protecting group depends on what the target product is.

[Deprotection step (1)]
When the product in the unsaturated hydrocarbon group introduction step (1) is the compound (I ^A ) having a protective group, after the unsaturated hydrocarbon group introduction step (1), the protective group is further added. (Ie, the deprotection step (1)). By performing the deprotection step (1), the intended compound (I ^A) is obtained.
The deprotection conditions may be appropriately selected according to the type of the protecting group, and a known deprotection method can be appropriately used. For example, when the protecting group is a trifluoromethylcarbonyl group (also called a trifluoroacetyl group), the protecting group can be deprotected by a method using a base such as lithium hydroxide. When the protecting group is a Boc group, it can be deprotected by a method using an acid such as trifluoroacetic acid or hydrochloric acid. When the protecting group is an isopropylidene group, it can be deprotected by a method using an acid such as hydrochloric acid.

In the deprotection step (1) of the production method (1), the product may be handled after the reaction as in the case of the unsaturated hydrocarbon group introduction step (1).
That is, after the completion of the reaction in the deprotection step (1), post-treatment may be performed as necessary by a known method to remove the product. That is, if necessary, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed alone or in combination of two or more, and concentration, crystallization, reprecipitation, and column chromatography are performed. For example, the product may be taken out. Further, the product taken out may be further subjected to crystallization, reprecipitation, column chromatography, extraction, stirring and washing of crystals with a solvent, etc., either alone or in combination of two or more, as needed, once. Alternatively, purification may be performed by performing the purification twice or more.

Also in the deprotection step (1), as in the case of the unsaturated hydrocarbon group introduction step (1), as a product, any of a product that does not form a salt and a product that forms a salt can be used. May be obtained. Which of these is obtained depends on the conditions of the deprotection step (1).

In the unsaturated hydrocarbon group introduction step (1), for example, any one of Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^{6a in} the compound (Ia) is a hydrogen atom and a part thereof. Alternatively, a compound having a structure in which all hydrogen atoms are substituted with ^X0a or a salt thereof is produced. These ^{^{^{products, X 1, X 2, X}}} 3, out of the ^{X 4} and ^{X 6,} when that apply is an unsaturated hydrocarbon group, a compound ^{(I A)} or a salt thereof.
In the step (1) of introducing an unsaturated hydrocarbon group, Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^{6a in} the compound (Ia) are alkyl groups having 1 to 9 carbon atoms. Usually does not react as it is. As a ^{^{^{result, X 1, X 2, X}}} 3, out of the ^{X 4} and ^{X 6,} when that apply is an alkyl group having 1 to 9 carbon atoms, the compounds ^{(I A)} or a salt thereof to produce.
In the step (1) of introducing an unsaturated hydrocarbon group, of Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^{6a in} the compound (Ia), those which are protective groups are usually left as they are. Will not react. Thus, by performing the deprotection step (1), a compound having a structure in which the protective group is substituted with a hydrogen atom or a salt thereof is generated. These ^{^{^{products, X 1, X 2, X}}} 3, out of the ^{X 4} and ^{X 6,} when that apply is a hydrogen atom, a compound ^{(I A)} or a salt thereof.

[Salt production process (1)]
It performs an unsaturated hydrocarbon group-introducing step (1), if necessary, by performing the deprotection step (1), and finally, the compound does not form a salt when (I ^A) is obtained , after the unsaturated hydrocarbon group-introducing step (1) or deprotection step (1), further, in the step (herein that the obtained compound (I ^a) and its salt, "salt formation step (1) by carrying out the is) called "can be prepared salts of the compounds (I ^a).

The salt formation step (1) is, for example, is reacted with an acid or a base of compound (I ^A), it can be carried out by known methods, depending on the type of salt of interest, by appropriately selecting the process conditions I just need.
For example those cations which form salts, general formula to the nitrogen atom of the group represented by (I ^A) formula -NX ¹ X ² in the hydrogen ion (H ⁺⁾ is coordinated, when producing a salt of compound (I ^a), the compound (I ^a) may be reacted with an acid.
For example, when producing the salt represented by the general formula (Is), the compound (I ^A ) is converted to a compound of the general formula HQ (HQ is a hydrogen ion (H ⁺ ) of Q ⁻ ) , Q ^- are the same as described above).

In the salt formation step (1) of the production method (1), after the reaction is completed, the product is subjected to post-treatment, removal, purification, and the like in the same manner as in the unsaturated hydrocarbon group introduction step (1). Operations can be performed.

[Optional step (1)]
In the production method (1), an optional step (1) that does not correspond to any of the unsaturated hydrocarbon group introduction step (1), the deprotection step (1), and the salt formation step (1) is performed. One or two or more kinds may be performed.

The optional step (1) can be appropriately selected depending on the purpose, and is not particularly limited.
For example, when a commercially available product does not exist as the compound (Ia) used in the unsaturated hydrocarbon group introduction step (1), a known method is used alone or in combination of two or more using a commercially available raw material. Thus, compound (Ia) may be produced.

When n ₁ is 1, the compound (Ia) is represented by X ⁵ (that is, an unsaturated unsaturated group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent). (Hydrocarbon group). Such a compound (Ia) can be produced, for example, by utilizing the production method (2) described below. That is, in the compound (Ib), “an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and 3 to 9 carbon atoms which may have a substituent” is represented by Z ^1b , Z 1 ^2b , Z ^3b , Z ^4b, and Z ^6b , except that the compound excluded from the options is used in place of compound (Ib) in the same manner as in production method (2) described below, when n ₁ is 1. Compound (Ia) can be produced. However, this is an example of a method for producing such a compound (Ia).

<Production method (2)>
When n ₁ is 1, the compound (I) or a salt thereof is, for example, a compound represented by the following general formula (Ib) (in this specification, sometimes referred to as “compound (Ib)”). A step of reacting a compound represented by the following general formula (Id) (herein, sometimes referred to as “compound (Id)”) (in the present specification, “an unsaturated hydrocarbon group”). Introduction step (2) "), and when one or more of the following Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b are the following protecting groups, the reaction after the step of, further, (herein sometimes referred to as "deprotection step (2)") removing the protecting group and, by performing the following general formula (I ^B) compound represented by (herein, "compound (I ^B)" Or a salt thereof, a method for obtaining a compound of the structure represented by the following formula (Ib) in which the following LG ² is substituted by the following X ^0b or a salt thereof (the present specification). , May be referred to as “manufacturing method (2)”).
Compound ^{(I B)} is a compound where _{n 1} is 1 (I).

[Unsaturated hydrocarbon group introduction step (2)]
In the unsaturated hydrocarbon group introduction step (2), the compound (Ib) is reacted with the compound (Id).
In the general formula (Ib), _{n 2} and _{n 3} are the same as _{n 2} and _{n 3} in the general formula (I).

In the general formula (Ib), Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b each independently represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, and 1 to 4 triple bonds between carbon atoms. And an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which may have a substituent, or a protecting group.
The alkyl group and the unsaturated hydrocarbon group in Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b are the same as the alkyl group and the unsaturated hydrocarbon group in X ¹ to X ⁴ .

When Z ^1b and Z ^2b are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ¹ and X ² are alkyl groups.

When Z ^3b and Z ^4b are the above-mentioned alkyl groups, these two alkyl groups constitute an oxygen atom to which these alkyl groups are respectively bonded and a benzene ring skeleton to which these oxygen atoms are respectively bonded. May be mutually bonded to form a ring. The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ³ and X ⁴ are an alkyl group.

The protective group in Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b is the same as the protective group in Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a in the general formula (Ia).

In the general formula (Ib), LG ² is a leaving group, and may be a known group.
Examples of the leaving group include an iodine atom, a bromine atom, a chlorine atom, a p-toluenesulfonyl group, a trifluoromethylsulfonyl group, and the like.

In the general formula (Id), X ^0b is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 2 to 8 carbon atoms which may have a substituent, and X ⁵ And the same as the above-mentioned unsaturated hydrocarbon group.

In the general formula ^{^{^{(I B), X 1,}}} X 2, X 3, X 4, X 5, X 6, n 2 and _{n 3,} ^X 1 in the general formula ^{^{(I), X 2, X}} 3, X ⁴ , X ⁵ , X ⁶ , n ₂ and n ₃ .
However, the compound ^{(I B)} has been identified to have ^{X 5.}
Thus, except that n ₁ is limited to 1, the compound (I ^B) is the same as compound (I).

By compound (Ib) has a LG ^2, in the unsaturated hydrocarbon group-introducing step (2) is a compound or a salt thereof, having the structure The LG ² is substituted with the X ^0b generated.

(4) In the unsaturated hydrocarbon group introduction step (2), there is a possibility that both a product that does not form a salt and a product that forms a salt are obtained. Which of these is obtained depends on the conditions of the unsaturated hydrocarbon group introduction step (2).

In the unsaturated hydrocarbon group introduction step (2), the amount (mol) of the compound (Id) used is 1.0 to 2.0 times the molar amount of the compound (Ib) used. Is preferred.

In the unsaturated hydrocarbon group introduction step (2), the reaction of the compound (Ib) with the compound (Id) is preferably performed using a palladium catalyst, a copper catalyst, and a base. By doing so, the reaction proceeds more smoothly. This reaction is a Sonogashira-Hagihara cross-coupling reaction. In particular, X ^0b has a carbon atom at the terminal on the bonding side, that is, at a site bonded to a hydrogen atom, and this carbon atom is adjacent to the carbon atom. This is particularly preferred when a triple bond is formed with the carbon atom to be formed.

Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) palladium (II).
In the unsaturated hydrocarbon group introduction step (2), the amount (mol) of the palladium catalyst used may be 0.05 to 0.20 times the molar amount of the compound (Ib). preferable.

Examples of the copper catalyst include copper (I) iodide (CuI) and the like.
In the unsaturated hydrocarbon group introduction step (2), the used amount (mol) of the copper catalyst may be 0.05 to 0.40 times the molar amount of the compound (Ib). preferable.

Examples of the base include diethylamine, triethylamine, diisopropylamine and the like.
In the unsaturated hydrocarbon group introduction step (2), the amount (mol) of the base used is preferably an excess with respect to the amount (mol) of the compound (Ib), for example, 1 to 100-fold molar. Preferably, it is an amount. In this step, a base may be used also as a solvent.

In the unsaturated hydrocarbon group introduction step (2), a solvent may or may not be used during the reaction between the compound (Ib) and the compound (Id).
The solvent may be appropriately selected depending on, for example, the types of the compound (Ia) and the compound (Ic), and is not particularly limited.
In the case where a solvent is used in the unsaturated hydrocarbon group introduction step (2), the amount of the solvent used (parts by mass) is 1 to 20 times the total amount (parts by mass) of all components other than the solvent. It is preferred that

In the unsaturated hydrocarbon group introduction step (2), the reaction temperature and reaction time between the compound (Ib) and the compound (Id) may be appropriately adjusted so as to improve the yield of the target product. There is no particular limitation.
The reaction temperature may be, for example, from 10 to 80 ° C.
The reaction time may be, for example, from 10 to 48 hours.

In the unsaturated hydrocarbon group introduction step (2), after the reaction is completed, post-treatment may be performed, if necessary, by a known method, and the product may be taken out. That is, if necessary, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed alone or in combination of two or more, and concentration, crystallization, reprecipitation, and column chromatography are performed. For example, the product may be taken out. Further, the product taken out may be further subjected to crystallization, reprecipitation, column chromatography, extraction, stirring and washing of crystals with a solvent, etc., either alone or in combination of two or more, as needed, once. Alternatively, purification may be performed by performing the purification twice or more.
In the case where another step such as the deprotection step (2) described later is continuously performed after the unsaturated hydrocarbon group introduction step (2), it is necessary to complete the reaction in the unsaturated hydrocarbon group introduction step (2). After the post-processing is performed accordingly, the above-mentioned other steps may be continuously performed without taking out the product.

In the unsaturated hydrocarbon group introduction step (2), the product of the reaction between the compound (Ib) and the compound (Id) is one or two of Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b. When at least one species is a protecting group, the compound (I ^B ) is a compound in which the functional group at the corresponding site is protected by the protecting group. On the other ^hand, when ^{^{Z 1b, Z 2b, Z 3b}} , Z 4b and ^{Z 6b} is neither a protecting group, the product is a compound of the desired compound ^{(I B).}
The above alkyl groups in Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b include those corresponding to protective groups. For example, when Z ^3b and Z ^4b are the aforementioned alkyl groups, and these alkyl groups are bonded to each other to form a ring, this cyclic group, an isopropylidene group (—C (CH ₃ ) ₂ -) Is a protecting group as described above. In other ^words, Z ^1b, ^{Z 2b,} among Z ^{3b, Z 4b} and ^{Z 6b,} the one or in the case of two or more is a protecting group product, equivalent to a compound of the desired product ^{(I B)} There is also. Whether the product obtained in this step is considered to have a protecting group or not to have a protecting group depends on what the target product is.

[Deprotection step (2)]
Products in unsaturated hydrocarbon group introducing step (2) is, when a compound having a protecting group (I ^B), after the unsaturated hydrocarbon group-introducing step of (2), further, the protective group (That is, the deprotection step (2)). By performing the deprotection step (2), the intended compound (I ^B) is obtained.
The deprotection conditions may be appropriately selected according to the type of the protecting group, and a known deprotection method can be appropriately used. For example, the conditions for deprotection in the deprotection step (2) may be the same as the conditions for deprotection in the above deprotection step (1).

In the deprotection step (2) of the production method (2), the product may be handled after the reaction, as in the case of the unsaturated hydrocarbon group introduction step (2).
That is, after completion of the reaction in the deprotection step (2), post-treatment may be carried out by a known method, if necessary, to remove the product. That is, if necessary, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed alone or in combination of two or more, and concentration, crystallization, reprecipitation, and column chromatography are performed. For example, the product may be taken out. Further, the product taken out may be further subjected to crystallization, reprecipitation, column chromatography, extraction, stirring and washing of crystals with a solvent, etc., either alone or in combination of two or more, as needed, once. Alternatively, purification may be performed by performing the purification twice or more.

In the deprotection step (2) as well, as in the case of the unsaturated hydrocarbon group introduction step (2), both of a product that does not form a salt and a product that forms a salt are obtained. May be obtained. Which of these is obtained depends on the conditions of the deprotection step (2).

In the unsaturated hydrocarbon group introduction step (2), a compound having a structure in which LG ² in compound (Ib) is substituted with X ^0b or a salt thereof is produced. These products are compound (I ^B) or a salt thereof.
In the step (2) of introducing an unsaturated hydrocarbon group, any of Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^{6b in} the compound (Ib) is an alkyl group having 1 to 9 carbon atoms. Usually does not react as it is. As a result, a compound (I ^B ) or a salt thereof is produced when the corresponding one of X ¹ , X ² , X ³ , X ⁴ and X ⁶ is an alkyl group having 1 to 9 carbon atoms.
In the step (2) of introducing an unsaturated hydrocarbon group, of Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^{6b in} the compound (Ib), those which are protective groups are usually left as they are. Will not react. Then, by performing the deprotection step (2), a compound having a structure in which the protective group is substituted with a hydrogen atom or a salt thereof is generated. These ^{^{^{products, X 1, X 2, X}}} 3, out of the ^{X 4} and ^{X 6,} when that apply is a hydrogen atom, a compound ^{(I B)} or a salt thereof.

[Salt-forming step (2)]
Performs an unsaturated hydrocarbon group-introducing step (2), if necessary, by performing the deprotection step (2), and finally, if the compound does not form a salt (I ^B) is obtained , after the unsaturated hydrocarbon group-introducing step (2) or deprotection step (2), furthermore, in the step (herein that the obtained compound (I ^B) and its salt, "salt formation step by performing the (2) "and that there is referred), it can be prepared salts of the compounds (I ^B).

The salt-forming step (1) is the same as the salt-forming step (1) except that, for example, the compound (I ^B ) that does not form a salt is used in place of the compound (I ^A ) that does not form a salt. ) Can be performed in the same manner as in the case of).

In the salt formation step (2) of the production method (2), after the reaction is completed, the product is subjected to post-treatment, removal, purification, and the like in the same manner as in the unsaturated hydrocarbon group introduction step (2). Operations can be performed.

[Optional step (2)]
In the production method (2), an optional step (2) that does not correspond to any of the unsaturated hydrocarbon group introduction step (2), the deprotection step (2), and the salt formation step (2) is performed. One or two or more kinds may be performed.

The optional step (2) can be appropriately selected depending on the purpose, and is not particularly limited.
For example, when a commercially available product does not exist as the compound (Ib) used in the unsaturated hydrocarbon group introduction step (2), a known method is used alone or in combination of two or more using a commercially available raw material. Thus, compound (Ib) may be produced.

Any of Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^6b has 1 to 4 triple bonds between carbon atoms and may have 3 to 9 carbon atoms which may have a substituent. Compound (Ib) having a hydrocarbon group can be produced, for example, by utilizing the above-mentioned production method (1). That is, in the compound (Ia), except that a compound in which X ⁵ is LG ² and n ₁ is 1 is used instead of the compound (Ia), the same method as the above-mentioned production method (1) is used. Compound (Ib) in the case where any one of Z ^1b , Z ^2b , Z ^3b , Z ^4b and Z ^{6b is} the unsaturated hydrocarbon group can be produced. However, this is an example of a method for producing such a compound (Ib).

<< Method for producing salt of compound (I) >>
So far, as a method salt of Compound (I), wherein the manufacturing method (1) or (2), without performing the salt formation step (1) or (2), the salts of the compounds (I ^A) or a method for producing a salt of a compound (I ^B), by performing a salt formation step (1) or (2) a process for producing a salt of a compound salt or compounds of (I ^a) (I ^B), description did. However, the method of forming a salt in the salt formation step (1) or (2) is not limited to the application to the compound (I) produced by the production method (1) or (2), but may be produced by another method. May be applied to the compound (I).

The structures of compound (I) and salts thereof include, for example, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), infrared spectroscopy (IR), ultraviolet / visible spectroscopy (UV-VIS absorption spectrum), It can be confirmed by a known method such as elemental analysis.

<< Compound (II) or a salt thereof >>
The compound according to one embodiment of the present invention is represented by the following general formula (II), and the salt of the compound according to one embodiment of the present invention is a salt of the compound represented by the following general formula (II). In the present specification, the compound represented by the general formula (II) may be referred to as “compound (II)”. Further, the mere description of “compound (II)” means a compound that does not form a salt, and the compound (II) that forms a salt is referred to as “salt of compound (II)”.

Compound (II) is useful as a nerve function regulator (that is, a physiologically active substance involved in regulation of nerve function), as described later.
In addition, the compound (II) has a structure in which one or more of X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ and X ⁰⁵ is the unsaturated hydrocarbon group, as described below. It can be detected with high accuracy and its dynamics can be easily observed.
Hereinafter, the structure of compound (II) will be described in detail.

In the general formula (II), X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ (in this specification, these may be abbreviated as “X ⁰¹ to X ⁰⁴ ”) are each independently: A hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an unsaturated hydrocarbon group having 3 to 9 carbon atoms and having 1 to 4 triple bonds between carbon atoms and which may have a substituent;
X ⁰¹ and X ⁰² are the same as X ¹ and X ² in the general formula (I). For example, when X ⁰¹ and X ⁰² are the aforementioned alkyl groups, these two alkyl groups are mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring. You may.
X ⁰⁴ is the same as X ¹ or X ² in the general formula (I).
X ⁰³ is the same as X ³ or X ^{4 in} formula (I).

In the general formula (II), X ⁰⁵ is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 2 to 8 carbon atoms which may have a substituent.
X ⁰⁵ is the same as X ⁵ in formula (I).

When the unsaturated hydrocarbon group for X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ has a methylene group at the terminal on the bonding destination, the methylene group may be substituted with a carbonyl group, When the unsaturated hydrocarbon group represented by X ¹ , X ² , X ³ and X ⁴ in the general formula (I) has a methylene group at the terminal on the bonding destination, the methylene group is substituted with a carbonyl group. Means the same content.
Similarly, when the unsaturated hydrocarbon group for X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ has one or two or more methylene groups other than the terminal on the bonding side, one methylene group The group or the two or more methylene groups which are not adjacent to each other may be substituted with an oxygen atom, which is defined as X ¹ , X ² , X ³ and X ⁴ in the general formula (I). When the saturated hydrocarbon group has one or two or more methylene groups other than the terminal on the bonding side, one methylene group or two or more methylene groups that are not adjacent to each other are oxygen It means the same content that it may be substituted by an atom.

X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms, and have a substituent. Is preferably an unsaturated hydrocarbon group having 3 to 9 carbon atoms, and when X ⁰¹ and X ⁰² are the aforementioned alkyl groups, these two alkyl groups are mutually bonded to form a ring It may be. Here, the substituent, the unsaturated hydrocarbon group, and the ring are as described above.

In the general formula (II), n ₀₁ is 0 or 1.
n ₀₁ is in the benzene ring structure group represented by the general formula ^{-OX 03} is directly ^attached, defines whether the binding of ^{X 05.}

When n ₀₁ is 1, the bonding position of X ⁰⁵ in the benzene ring skeleton to which the group represented by the general formula —OX ⁰³ is directly bonded in the general formula (II) is not particularly limited. against group represented by the general formula -OX ^03, in other words the relationship ortho position (, of the two adjacent carbon atoms of the groups represented by the general formula -OX ⁰³ is attached , Any one of carbon atoms) and a position having a meta-position.

In the general formula (II), n ₀₂ is an integer of 1 to 5.
n ₀₂ specifies the number of carbon atoms of the alkylene skeleton (in other words, a chain hydrocarbon skeleton) to which the group represented by the general formula —NX ⁰¹ X ⁰² is directly bonded. That is, the alkylene skeleton has 2 to 6 carbon atoms.
n ₀₂ may be any one of 1 or more, 2 or more, 3 or more, and 4 or more, for example, within a range of 5 or less. Further, n ₀₂ may be any one of 5 or less, 4 or less, 3 or less, and 2 or less within a range of 1 or more.
For example, the compound (II) or a salt thereof in which n ₀₂ is 1 has the same or similar chain skeleton having the same carbon number as serotonin which is important as a naturally-occurring neuronal function regulator, High usefulness.
Further, the compound (II) or a salt thereof in which n ₀₂ is 2 to 5 may be able to regulate the level of its biological activity based on the compound (II) or a salt thereof in which n ₀₂ is 1; High usefulness.

However, when n ₀₁ is 0 in the general formula (II), one or more of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ are the unsaturated hydrocarbon groups (ie, An unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and optionally having 3 to 9 carbon atoms).
When n ₀₁ is 1, one or more of X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ and X ⁰⁵ are the unsaturated hydrocarbon groups (that is, carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and optionally having 3 to 9 or 2 to 8 carbon atoms).
As described above, the compound (II) or a salt thereof has one or two or more unsaturated hydrocarbon groups having 3 to 9 or 2 to 8 carbon atoms in total. In other words, the compound (II) or a salt thereof always contains a group having a triple bond between carbon atoms. Therefore, compound (II) or a salt thereof can be detected by Raman scattering spectroscopy based on this triple bond, and a label can be introduced by reacting this triple bond with another reagent. Therefore, it can be detected by this label. Such a method for detecting compound (II) or a salt thereof will be described in detail later.

The salt of the compound (II) is a compound in which the group capable of forming a salt in the compound (II) forms a salt. Here, examples of the group capable of forming a salt include, but are not limited to, a group represented by the general formula —NX ⁰¹ X ⁰² in the general formula (II).

Examples of the salt of compound (II) include salts formed by reacting compound (II) with an acid or base.
When the compound (II) has two or more groups capable of forming a salt in one molecule, examples of the salt of the compound (II) include compounds having one or two or more salt formation sites. .
In a salt of compound (II) having two or more salt formation sites, these two or more salts may be all the same, may be all different, or may be partially identical. Good.

Examples of the cation and anion that form the salt of compound (II) include the same cations and anions that form the salt of compound (I).
The number of cations and anions forming a salt of one molecule of compound (II) may be only one, or two or more, and when two or more, these cations or anions may be used. All the anions may be the same, all may be different, or only some may be the same.
However, the salt of the compound (II) is electrically neutral as a whole molecule, that is, the total value of the valence of the cation and the total value of the valence of the anion in one molecule of the compound (II) are the same. Is preferred.

好ましい Preferred examples of the salt of compound (II) include salts represented by the following general formula (IIs) -1, (IIs) -2, or (IIs) -3.

(In the general formula (IIs) -1, (IIs) -2, or (IIs) -3, X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ , X ⁰⁵ , n ₀₁ and n ₀₂ are the same as described above.) Q ₁ ^- and Q ₂ ^- are each independently a monovalent anion.)

In the general formula (IIs), X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ , X ⁰⁵ , n ₀₁ and n ₀₂ represent X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ , X ^{05 in the} general formula (II) , N ₀₁ and n ₀₂ .
In the general formula (IIs), _{Q 1} ^- and _{Q 2} ^- are each independently a monovalent anionic, Q in the general formula (Is) ^- it is the same as. Q ₁ ^- and Q ₂ ^- may be the same or may be different from one another.

The compound (II) is a compound represented by the following general formula (II) -1 (in this specification, sometimes abbreviated as “compound (II) -1”) or the following general formula (II)- It is preferably a compound represented by Formula 2 (in this specification, may be abbreviated as “compound (II) -2”).
That is, compound (II) or a salt thereof is preferably compound (II) -1 or a salt thereof, or compound (II) -2 or a salt thereof.

<Compound (II) -1>
Compound (II) -1 is included in compound (I) when n ₀₁ is 0.
In the Formula (II) _{-1, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -1, X ⁰¹¹ , X ⁰²¹ and X ⁰³¹ are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms.
The alkyl group having 1 to 9 carbon atoms in X ⁰¹¹ , X ⁰²¹ and X ⁰³¹ is the same as the alkyl group having 1 to 9 carbon atoms in X ⁰¹ , X ⁰² and X ⁰³ .

When X ⁰¹¹ and X ⁰²¹ are the aforementioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring . The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ⁰¹ and X ⁰² are alkyl groups.

In the general formula (II) -1, X ⁰⁴¹ is an unsaturated hydrocarbon group having 3 to 9 carbon atoms and having 1 to 4 triple bonds and optionally having a substituent.
The unsaturated hydrocarbon group for X ⁰⁴¹ is the same as the unsaturated hydrocarbon group for X ⁰⁴ .

<Compound (II) -2>
Compound (II) -2 is also included in compound (I) when n ₀₁ is 0.
In the Formula (II) _{-2, n 02} is the same as _{n 02} in the general formula (II).
X ⁰⁴¹ is the same as X ⁰⁴¹ in formula (II) -1.

In the general formula (II) -2, the alkyl group and the unsaturated hydrocarbon group in X ⁰¹⁰ , X ⁰²⁰ and X ⁰³⁰ are the alkyl groups in X ⁰¹ , X ⁰² and X ⁰³ in the general formula (II) And unsaturated hydrocarbon groups. For example, when ^X010 and ^X020 are the above-mentioned alkyl groups, these two alkyl groups are mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring. You may.
However, one or more of X ⁰¹⁰ , X ⁰²⁰ and X ⁰³⁰ are the aforementioned unsaturated hydrocarbon groups. That is, X ⁰¹⁰ , X ⁰²⁰ and X ⁰³⁰ are X ⁰¹ , X ⁰² and X ^{03 in the} general formula (II) except that one or two or more of them are the unsaturated hydrocarbon groups. Is the same as

The compound (II) is a compound represented by the following general formula (II) -1-1 (in this specification, may be abbreviated as “compound (II) -1-1”), II) -2-1 (hereinafter, may be abbreviated as “compound (II) -2-1”), represented by the following general formula (II) -2-2 A compound (may be abbreviated as “compound (II) -2-2” in the present specification), a compound represented by the following general formula (II) -2-3 (in the present specification, “compound (II) -2-2”) (II) -2-3), and a compound represented by the following formula (II) -2-4 (herein, abbreviated as “compound (II) -2-4”). Or a compound represented by the following general formula (II) -2-5 (in the present specification, “compound ( It is preferred that it is there) abbreviated as I) -2-5 '.
That is, compound (I) or a salt thereof is compound (II) -1-1 or a salt thereof, compound (II) -2-1 or a salt thereof, compound (II) -2-2 or a salt thereof, or a compound (II). ) -2-3 or a salt thereof, compound (II) -2-4 or a salt thereof, or compound (II) -2-5 or a salt thereof.
Compound (II) -1-1 or a salt thereof is included in compound (II) -1 or a salt thereof.
Compound (II) -2-1 or a salt thereof, Compound (II) -2-2 or a salt thereof, Compound (II) -2-3 or a salt thereof, Compound (II) -2-4 or a salt thereof, and Compound (II) -2-5 or a salt thereof is included in compound (II) -2 or a salt thereof.

[Compound (II) -1-1]
In the Formula (II) _{-1-1, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -1-1, X ⁰¹² , X ⁰²² and X ⁰³² are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
The alkyl group having 1 to 5 carbon atoms in X ⁰¹² , X ⁰²² and X ⁰³² is the alkyl group having 1 to 9 carbon atoms in X ⁰¹ to X ⁰⁴ (or X ⁰¹¹ , X ⁰²¹ and X ⁰³¹ ) It is the same as that having 1 to 5 carbon atoms.

When ^X012 and ^X022 are the above-mentioned alkyl groups, these two alkyl groups may be mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring. . The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ⁰¹ and X ⁰² are alkyl groups.

In the general formula (II) -1-1, G ⁰⁴ represents a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a triarylsilyl group, a hydroxy group, a halogen Atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group, triarylsilylalkyl group, hydroxy An alkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group.
G ⁰⁴ is the same as G ¹ in formula (I) -1-1.

[Compound (II) -2-1]
In the Formula (II) _{-2-1, n 02} is the same as _{n 02} in the general formula (II).

In the Formula (II) ^{-2-1, G 04} is the same as described above.
In the general formula (II) -2-1, G ⁰¹ and G ⁰³ are the same as G ¹ in the general formula (I) -1-1.
In the general formula (II) -2-1, G ⁰¹ , G ⁰³ and G ⁰⁴ are each independently determined.

[Compound (II) -2-2]
In the Formula (II) _{-2-2, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -2-2, G ⁰¹ , G ⁰³ and G ⁰⁴ are the same as those described above.
In the general formula (II) -2-2, G ⁰² is the same as G ¹ in the general formula (I) -1-1.
In the general formula (II) -2-2, G ⁰¹ , G ⁰² , G ⁰³ and G ⁰⁴ are each independently determined.

[Compound (II) -2-3]
In the Formula (II) _{-2-3, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -2-3, X ⁰¹² , X ⁰²² , G ⁰³ and G ⁰⁴ are the same as those described above.
For example, when ^X012 and ^X022 are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring, and the aforementioned ring is the same as that described above.
In the general formula (II) -2-3, G ⁰³ and G ⁰⁴ are each independently determined.

[Compound (II) -2-4]
In the Formula (II) _{-2-4, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -2-4, X ⁰³² , G ⁰¹ and G ⁰⁴ are the same as those described above.
In the general formula (II) -2-4, G ⁰¹ and G ⁰⁴ are each independently determined.

[Compound (II) -2-5]
In the Formula (II) _{-2-5, n 02} is the same as _{n 02} in the general formula (II).

In the general formula (II) -2-5, X ⁰³² , G ⁰¹ , G ⁰² and G ⁰⁴ are the same as those described above.
In the general formula (II) -2-5, G ⁰¹ , G ⁰² and G ⁰⁴ are each independently determined.

The molecular weight of the compound (II) is preferably 350 or less, more preferably 300 or less, for example, 250 or less. The molecular weight of a naturally-occurring nerve function modulator having a physiological activity on nerve cells is usually relatively small. Therefore, by analyzing the behavior and properties of the compound (II) having a relatively small molecular weight as described above in a nerve cell, it is possible to consider the behavior and properties of a naturally-occurring nerve function regulator with high accuracy. It is possible and compound (II) is more useful.
On the other hand, when the salt of compound (II) is replaced with a state in which no salt is formed (that is, when considered as compound (II)), the molecular weight (converted molecular weight) is the same as the molecular weight of compound (II) described above. The same is preferred. Such a salt of compound (II) usually has a relatively small molecular weight, and thus has higher utility as in the case of the above-mentioned compound (II) having a small molecular weight.
However, such usefulness of the compound (II) and its salt is merely an example, and the upper limit of the molecular weight of the compound (II) and the converted molecular weight of the salt of the compound (II) are limited to those shown here. Not done.

下限 The lower limits of the molecular weight of compound (II) and the reduced molecular weight of the salt of compound (II) are not particularly limited. From the viewpoint of easy production of the compound (II), the molecular weight and reduced molecular weight are preferably 177 or more.

Preferred compounds (II) are exemplified below. Preferred compounds (II) also include, in addition to the above, compounds exemplified below and having the above substituent. Preferred salts of the compound (II) include the salts of the compounds exemplified below and the salts of the compounds exemplified below having the substituent.
However, the compound (II) of the present embodiment or a salt thereof is not limited thereto.

Compound (II) can be regarded as a derivative of serotonin (also known as 5-hydroxytryptamine, 3- (2-aminoethyl) indol-5-ol), which is a known neuronal function regulator.
Therefore, compound (II) and salts thereof are useful for elucidating the role of serotonin in nerve cells (in other words, physiological activity) among known neuronal function regulators.
The structural formula of serotonin is shown below.

<< Method for producing compound (II) or a salt thereof >>
The production method of compound (II) or a salt thereof differs depending on which of X ⁰¹ , X ⁰² , X ⁰³ , X ⁰⁴ and X ⁰⁵ is the above-mentioned unsaturated hydrocarbon group. Hereinafter, a method for producing such a compound (II) or a salt thereof will be sequentially described.

<Production method (1 ')>
When any of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ is the aforementioned unsaturated hydrocarbon group, the compound (II) or a salt thereof is, for example, a compound represented by the following general formula (IIa) ( In the present specification, a step of reacting a compound (may be referred to as “compound (IIa)”) with a compound represented by the following general formula (Ic) (compound (Ic)) (in the present specification, and may be referred to as "unsaturated hydrocarbon group-introducing step (1 ')"), the following ^Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} when one or more are below protecting group After the step of reacting, a step of removing the protecting group (hereinafter, may be referred to as a “deprotection step (1 ′)” in the present specification) is further performed, whereby ^A compound represented by the formula (II ^A ) Oite as is) or a salt thereof may be referred to as "compound (II ^A)" in the compound represented by the following general formula (IIa), following ^Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} A method for producing a compound or a salt thereof, which obtains a compound or a salt thereof having a structure in which a hydrogen atom is substituted by the following X ^0a (in the present specification, this may be referred to as “production method (1 ′)”). ).
The compound (II ^A ) is the compound (II) in which any of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ is the above-mentioned unsaturated hydrocarbon group.

[Unsaturated hydrocarbon group introduction step (1 ')]
In the unsaturated hydrocarbon group introduction step (1 ′), the compound (IIa) is reacted with the compound (Ic).
In the general formula ^{_{(IIa), X 05, n}} 01 and _{n 02} are the same as ^X _{05, n 01} and _{n 02} in the general formula (II).

In the general formula ^{^{(IIa), Z 01a, Z}} 02a, Z 03a and ^{Z 04a} each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or a protecting group.
Z ^01a, ^Z ^02a, the ^{Z 03a} and ^{Z 04a,} alkyl group having 1-9 carbon atoms, and protecting groups, ^Z 1a in the general formula ^{^{(Ia), Z 2a, Z}} 3a, in ^{Z 4a} and ^{Z 6a,} It is the same as an alkyl group having 1 to 9 carbon atoms and a protecting group.
For example, when Z ^01a and Z ^02a are the aforementioned alkyl groups, these two alkyl groups are mutually bonded together with the nitrogen atom to which the two alkyl groups are bonded to form a ring. Is also good. The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ⁰¹ and X ⁰² are alkyl groups.

^However, Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} 1 or 2 or more is a hydrogen atom.

Compound (Ic) is the same as compound (Ic) used in production method (1), which is the production method of compound (I) described above.

The reaction between compound (IIa) and compound (Ic) proceeds in the same manner as the reaction between compound (Ia) and compound (Ic) in production method (1) described above.
For example, in the compound ^(IIa), Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} 1 or 2 or more are the hydrogen atom, the unsaturated hydrocarbon group-introducing step (1 ') is A compound having a structure in which this hydrogen atom is substituted by the above-mentioned ^X0a or a salt thereof is produced.
In addition, in the unsaturated hydrocarbon group introduction step (1 ′), there is a possibility that both a product that does not form a salt and a product that forms a salt are obtained. Which of these is obtained depends on the conditions of the unsaturated hydrocarbon group introduction step (1 ′).

The reaction between the compound (IIa) and the compound (Ic) is carried out by using the compound (Ia) and the compound (I) in the production method (1) described above except that the compound (IIa) is used instead of the compound (Ia). The reaction with Ic) can be carried out in a similar manner.
For example, the amount (mol) of the compound (Ic) to be used is 1 to 2 times the molar amount (mol) of the hydrogen atom to be substituted with ^X0a in the compound (IIa). Is preferred.
The reaction between compound (IIa) and compound (Ic) is preferably carried out using a base. In this case, the amount (mol) of the base used is the same as that for substitution of X ^0a in compound (IIa). The molar amount is preferably 1 to 3 times the molar amount (mol) of the target hydrogen atom.
In the reaction of the compound (IIa) with the compound (Ic), a solvent may be used. In such a case, the amount (parts by mass) of the solvent is not particularly limited, but the total amount of all components other than the solvent is used. The amount is preferably 1 to 40 times by mass, and more preferably 1 to 30 times by mass based on the amount (parts by mass).
In the reaction between the compound (IIa) and the compound (Ic), the reaction temperature may be, for example, any of 0 to 40 ° C. and 10 to 40 ° C., and the reaction time may be, for example, 0.5. It may be up to 24 hours.
In addition, in the unsaturated hydrocarbon group introduction step (1 ′), after the reaction is completed, post-treatment may be carried out by a known method, if necessary, and the product may be taken out. May be purified according to When another step such as a deprotection step (1 ') described later is continuously performed after the unsaturated hydrocarbon group introduction step (1'), after the completion of the reaction in the unsaturated hydrocarbon group introduction step (1 '). After the post-treatment is performed as necessary, the other steps may be continuously performed without taking out the product.

In the unsaturated hydrocarbon group-introducing step (1 '), the product from the reaction between the compound (IIa) with the compound (Ic) ^can, Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} 1 or 2 or more Is a compound (II ^A ) in which the functional group at the corresponding site is protected by this protecting group. On the other ^hand, when ^{Z ^01a,} Z ^02a, Z ^03a and ^{Z 04a} is not any protecting groups, the product is a compound of the desired compound (II ^A).

[Deprotection step (1 ')]
When the product in the unsaturated hydrocarbon group introduction step (1 ′) is the compound (II ^A ) having a protecting group, the compound is further added after the unsaturated hydrocarbon group introduction step (1 ′). The step of removing the protecting group (ie, the deprotection step (1 ′)) is performed. The target compound (II ^A ) is obtained by performing the deprotection step (1 ′).

The deprotection step (1 ′) is the same as the production method described above except that the compound (II ^A ) having a protecting group is used instead of the compound (I ^A ) having a protecting group as an object of deprotection. It can be carried out in the same manner as in the deprotection step (1) in the method (1).
For example, the conditions for deprotection may be appropriately selected according to the type of the protecting group.
In addition, in the deprotection step (1 ′), after the reaction is completed, post-treatment may be carried out by a known method, if necessary, and the product may be taken out. It may be purified.

In the deprotection step (1 ′), as in the case of the unsaturated hydrocarbon group introduction step (1 ′), as a product, a product having no salt and a product having a salt are formed. Either can be obtained. Which of these is obtained depends on the conditions of the deprotection step (1 ').

In the unsaturated hydrocarbon group-introducing step (1 '), for example, in the compound ^(IIa), Z ^01a, Z ^02a, either of ^{Z 03a} and ^{Z 04a,} a hydrogen atom, a part or all of A compound having a structure in which a hydrogen atom of the above is substituted with ^X0a or a salt thereof is produced. These products ^are of ^{X ^01,} X 02, X ⁰³ and ^{X 04,} in the case that apply is an unsaturated hydrocarbon group, a compound (II ^A) or a salt thereof.
Also, in the unsaturated hydrocarbon group-introducing step (1 '), in the compound ^(IIa), Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} as an alkyl group having 1-9 carbon atoms, Usually, it does not react as it is. As a result, when the corresponding one of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ is an alkyl group having 1 to 9 carbon atoms, compound (II ^A ) or a salt thereof is formed.
Also, in the unsaturated hydrocarbon group-introducing step (1 '), in the compound ^(IIa), Z ^01a, Z ^02a, among the ^{Z 03a} and ^{Z 04a,} what is a protecting group, typically, reacts in situ Never. Then, by performing the deprotection step (1 ′), a compound having a structure in which the protective group is substituted with a hydrogen atom or a salt thereof is generated. These products ^are of ^{X ^01,} X 02, X ⁰³ and ^{X 04,} in the case that apply is a hydrogen atom, a compound (II ^A) or a salt thereof.

[Salt-forming step (1 ')]
By performing the unsaturated hydrocarbon group introduction step (1 ′) and, if necessary, the deprotection step (1 ′), the compound (II ^A ) which did not form a salt was finally obtained. In some cases, after the unsaturated hydrocarbon group introduction step (1 ′) or the deprotection step (1 ′), the obtained compound (II ^A ) is further converted into a salt thereof (in the present specification, by performing it may be referred to as "salt forming step (1 ')") can be prepared salts of the compounds (II ^a).

The salt formation step (1 ′) can be performed by a known method, for example, by reacting the compound (II ^A ) with an acid or a base, and the process conditions are appropriately selected according to the kind of the target salt. do it.
For example, the cations forming the salt are the same as those in the general formula (II ^A ) except that the nitrogen atom of the group represented by the general formula —NX ⁰¹ X ⁰² and the nitrogen atom of the group represented by the general formula —NX ⁰⁴ — and atoms, in either or both of the hydrogen ions (H ⁺⁾ in which is coordinated, in the case of producing the salt of compound (II ^a) is reacted compound (II ^a) with an acid I just need.
For example, when producing a salt represented by the general formula (IIs) -1, (IIs) -2, or (IIs) -3, the compound (II ^A ) is converted to a compound represented by the general formula HQ ₁ (HQ ₁ is , Q ₁ ^{− and} a hydrogen ion (H ⁺ ), wherein Q ₁ ⁻ is the same as described above) and an acid represented by the general formula HQ ₂ (HQ ₂ is a hydrogen ion of Q ₂ ⁻ (H ⁺ ), and Q ₂ ^- is the same as described above).

In the salt formation step (1 ′) of the production method (1 ′), after the reaction is completed, as in the case of the unsaturated hydrocarbon group introduction step (1 ′), the product is subjected to post-treatment, removal, Operations such as purification can be performed.

[Optional step (1 ')]
In the production method (1 ′), any step that does not correspond to any of the unsaturated hydrocarbon group introduction step (1 ′), the deprotection step (1 ′), and the salt formation step (1 ′) (1 ′) may be performed alone or in combination of two or more.

The optional step (1 ′) can be appropriately selected depending on the purpose, and is not particularly limited.
For example, when a commercially available product does not exist as the compound (IIa) used in the unsaturated hydrocarbon group introduction step (1 ′), a commercially available raw material is used, and a known method is used alone or in combination of two or more. By performing the reaction, compound (IIa) may be produced.

When n ₀₁ is 1, the compound (IIa) is represented by X ⁰⁵ (ie, an unsaturated C 2-8 unsaturated carbon atom having 1-4 carbon-carbon triple bonds and optionally having a substituent) (Hydrocarbon group). Such a compound (IIa) can be produced, for example, by utilizing the production method (2 ′) described below. That is, in the compound (IIb), “an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and 3 to 9 carbon atoms which may have a substituent” is represented by Z ^01b , Z ^01b Compounds in the case where n ₀₁ is 1 by the same method as the production method (2 ′) described below except that compounds excluded from the options of ^02b , Z ^03b and Z ^04b are used in place of compound (IIb) ( IIa) can be prepared. However, this is an example of a method for producing such a compound (IIa).

<Production method (2 ')>
When n ₀₁ is 1, the compound (II) or a salt thereof is, for example, a compound represented by the following general formula (IIb) (in this specification, sometimes referred to as “compound (IIb)”). With a compound represented by the following general formula (Id) (compound (Id)) (in the present specification, this may be referred to as “unsaturated hydrocarbon group introduction step (2 ′)”). And when one or more of the following Z ^01b , Z ^02b , Z ^03b and Z ^04b are the following protecting groups, after the step of reacting, further removing the protecting group (In this specification, it may be referred to as “deprotection step (2 ′)”) to obtain a compound represented by the following general formula (II ^B ) (in this specification, “compound” (II ^B) "and that there is referred) or a salt thereof In a compound represented by the following general formula (IIb), the following LG ³ is substituted by X ^0b to obtain a compound having a structure or a salt thereof (in the present specification, “the production method (2 ′ ))).
Compound (II ^B ) is the compound (II) when n ₀₁ is 1.

[Unsaturated hydrocarbon group introduction step (2 ')]
In the unsaturated hydrocarbon group introduction step (2 ′), the compound (IIb) is reacted with the compound (Id).
In the general formula _{(IIb), n 02} is the same as _{n 02} in the general formula (II).

In the general formula (IIb), Z ^01b , Z ^02b , Z ^03b and Z ^04b each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, and 1 to 4 triple bonds between carbon atoms, An unsaturated hydrocarbon group having 3 to 9 carbon atoms which may have a substituent, or a protecting group.
The alkyl group and the unsaturated hydrocarbon group in Z ^01b , Z ^02b , Z ^03b and Z ^04b are the same as the alkyl group and the unsaturated hydrocarbon group in X ⁰¹ to X ⁰⁴ .
For example, when Z ^01b and Z ^02b are the aforementioned alkyl groups, these two alkyl groups are mutually bonded together with the nitrogen atom to which these two alkyl groups are bonded to form a ring. Is also good. The ring is the same as the above-described ring which may be formed by bonding these two alkyl groups to each other when X ⁰¹ and X ⁰² are alkyl groups.

The protective groups in Z ^01b , Z ^02b , Z ^03b and Z ^04b are the same as the protective groups in Z ^1a , Z ^2a , Z ^3a , Z ^4a and Z ^6a in the general formula (Ia).

In the general formula (IIb), LG ³ is a leaving group, and is the same as LG ² (leaving group) in the general formula (Ib).

The compound (Id) is the same as the compound (Id) used in the production method (2) which is the production method of the compound (I) described above.

In the general formula ^{^{^{(II B), X 01,}}} X 02, X 03, X 04 and ^{X 05} are the same as general ^X 01 in formula ^{^{(II), X 02, X}} 03, X 04 and ^{X 05.}
However, the compound (II ^B) ^has been identified to have ^{X 05.}
Thus, compound (II ^B ) is the same as compound (II) except that n ₀₁ is limited to 1.

The reaction between compound (IIb) and compound (Id) proceeds in the same manner as the reaction between compound (Ib) and compound (Id) in production method (2) described above.
For example, the compound (IIb) has the LG ^3, in the unsaturated hydrocarbon group-introducing step (2 ') The compound or a salt of the LG ³ is substituted with the X ^0b structure generated I do.
In addition, in the unsaturated hydrocarbon group introduction step (2 ′), there is a possibility that both a product that does not form a salt and a product that forms a salt are obtained. Which of these is obtained depends on the conditions of the unsaturated hydrocarbon group introduction step (2 ′).

The reaction between the compound (IIb) and the compound (Id) is carried out in the same manner as in the production method (2) described above except that the compound (IIb) is used instead of the compound (Ib). The reaction with Id) can be carried out in a similar manner.
For example, the amount (mol) of the compound (Id) used may be 1.0 to 2.0 times the amount (mol) of the compound (IIb) used.
The reaction between compound (IIb) and compound (Id) may be performed using a palladium catalyst, a copper catalyst, and a base (Sonogashira-Hagihara cross-coupling reaction). In this case, the amount (mol) of the palladium catalyst used may be 0.05 to 0.20 times the molar amount (mol) of the compound (IIb), and the amount (mol) of the copper catalyst may be used. ) May be 0.05 to 0.40 times the molar amount of the compound (IIb), and the amount (mol) of the base is the amount (mol) of the compound (IIb). Mol), may be in excess, for example, 1 to 100 times the molar amount, or a base may be used also as a solvent.
In the reaction between compound (IIb) and compound (Id), a solvent may be used. In this case, the amount of the solvent used (parts by mass) is determined by the total amount of all components other than the solvent (parts by mass). May be 1 to 20 times by mass.
In the reaction between compound (IIb) and compound (Id), the reaction temperature may be, for example, 10 to 80 ° C., and the reaction time may be, for example, 10 to 48 hours.
In addition, in the unsaturated hydrocarbon group introduction step (2 ′), after the reaction is completed, post-treatment may be carried out by a known method, if necessary, and a product may be taken out. May be purified according to When performing other steps such as the deprotection step (2 ') described later after the unsaturated hydrocarbon group introduction step (2'), the reaction in the unsaturated hydrocarbon group introduction step (2 ') is completed. After the post-treatment is performed as necessary, the other steps may be continuously performed without taking out the product.

In the unsaturated hydrocarbon group introduction step (2 ′), the product of the reaction between the compound (IIb) and the compound (Id) is one or more of Z ^01b , Z ^02b , Z ^03b and Z ^04b. There when a protecting group is a compound of the state where the functional group of the corresponding portion is protected by the protecting group (II ^B). On the other hand, when none of Z ^01b , Z ^02b , Z ^03b and Z ^04b is a protecting group, the product is the target compound (II ^B ).

[Deprotection step (2 ')]
When the product in the unsaturated hydrocarbon group introduction step (2 ′) is the compound (II ^B ) having a protecting group, the compound is further added after the unsaturated hydrocarbon group introduction step (2 ′). The step of removing the protecting group (ie, the deprotection step (2 ′)) is performed. By performing the deprotection step (2 ′), the target compound (II ^B ) is obtained.

Deprotection step (2 ') as an object of deprotection, in place of the compound having a protecting group (I ^B), except using a compound having a protecting group (II ^B), prepared as described above It can be performed in the same manner as in the deprotection step (2) in the method (2).
For example, the conditions for deprotection may be appropriately selected according to the type of the protecting group.
In addition, in the deprotection step (2 ′), after the reaction is completed, post-treatment may be carried out by a known method, if necessary, and the product may be taken out. It may be purified.

In the deprotection step (2 ′), as in the case of the unsaturated hydrocarbon group introduction step (2 ′), there are two types of products, one having no salt and the other having a salt. Either can be obtained. Which of these is obtained depends on the conditions of the deprotection step (2 ').

In the unsaturated hydrocarbon group introduction step (2 ′), for example, among Z ^01b , Z ^02b , Z ^03b and Z ^{04b in} the compound (IIb), those which are alkyl groups having 1 to 9 carbon atoms are Usually, it does not react as it is. As a result, when the corresponding one of X ⁰¹ , X ⁰² , X ⁰³ and X ⁰⁴ is an alkyl group having 1 to 9 carbon atoms, compound (II ^B ) or a salt thereof is produced.
In addition, in the unsaturated hydrocarbon group introduction step (2 ′), of Z ^01b , Z ^02b , Z ^03b and Z ^{04b in} the compound (IIb), those which are protective groups usually react as they are. Never. Thus, by performing the deprotection step (2 ′), a compound having a structure in which the protective group is substituted with a hydrogen atom or a salt thereof is generated. These products ^are of ^{X ^01,} X 02, X ⁰³ and ^{X 04,} in the case that apply is a hydrogen atom, a compound (II ^B) or a salt thereof.

[Salt-forming step (2 ')]
By performing the unsaturated hydrocarbon group introduction step (2 ′) and, if necessary, the deprotection step (2 ′), a compound (II ^B ) that did not form a salt was finally obtained. In some cases, after the unsaturated hydrocarbon group introduction step (2 ′) or the deprotection step (2 ′), the obtained compound (II ^B ) is further converted into a salt thereof (in the present specification, by performing it may be referred to as "salt forming step (2 ')") can be prepared salts of the compounds (II ^B).

The salt-forming step (2 ′) is, for example, the above-mentioned salt-forming step (2A) except that the compound (II ^B ) that does not form a salt is used instead of the compound (II ^A ) that does not form a salt. This can be done in the same manner as in 1 ').

In the salt formation step (2 ′) of the production method (2 ′), after the reaction is completed, the product is post-treated, taken out, and treated in the same manner as in the unsaturated hydrocarbon group introduction step (2 ′). Operations such as purification can be performed.

[Optional step (2 ')]
In the production method (2 ′), any step that does not correspond to any of the unsaturated hydrocarbon group introduction step (2 ′), the deprotection step (2 ′), and the salt formation step (2 ′) (2 ′) may be performed alone or in combination of two or more.

The optional step (2 ′) can be appropriately selected depending on the purpose, and is not particularly limited.
For example, when there is no commercial product as the compound (IIb) used in the unsaturated hydrocarbon group introduction step (2 ′), a commercially available raw material is used, and a known method is used alone or in combination of two or more. By performing the reaction, compound (IIb) may be produced.

Any one of Z ^01b , Z ^02b , Z ^03b and Z ^04b has 1 to 4 triple bonds between carbon atoms, and may have a substituent, and may have 3 to 9 carbon atoms. Compound (IIb) can be produced, for example, by utilizing the above-mentioned production method (1 ′). That is, in the compound (IIa), except that a compound in which X ⁰⁵ is LG ³ and n ₀₁ is 1 is used in place of the compound (IIa), the same method as the above-mentioned production method (1 ′) is used. , Z ^01b , Z ^02b , Z ^03b and Z ^04b can be used to produce the compound (IIb) in the case where the compound is the unsaturated hydrocarbon group. However, this is an example of a method for producing such a compound (IIb).

<< Method for producing salt of compound (II) >>
So far, as a method for producing a salt of compound (II), wherein in the production process (1 ') or (2'), a salt formation step (1 ') or (2') without performing, Compound (II ^A ) Or a salt of compound (II ^B ) and the salt-forming step (1 ′) or (2 ′) to obtain a salt of compound (II ^A ) or a salt of compound (II ^B ). The manufacturing method has been described. However, the method of forming a salt in the salt formation step (1 ′) or (2 ′) is not limited to the application to the compound (II) produced by the production method (1 ′) or (2 ′). May be applied to compound (II) produced by the method of (1).

The structures of the compound (II) and its salt include, for example, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), infrared spectroscopy (IR), ultraviolet / visible spectroscopy (UV-VIS absorption spectrum), It can be confirmed by a known method such as elemental analysis.

<<<< neuronal function regulator >>
A neurological function modulating substance according to an embodiment of the present invention includes a group having a triple bond (C 炭素 C) between carbon atoms.
It is known that a group having a triple bond between carbon atoms causes specific Raman scattering in a wave number region where a living body does not generate a signal, and can be detected by Raman scattering spectroscopy using a Raman microscope. That is, since the nerve function regulating substance of the present embodiment contains a group having a triple bond between carbon atoms, it can be detected by Raman scattering spectroscopy.

On the other hand, when a compound having a triple bond between carbon atoms (C≡C) at the terminal and a compound having an azide group (—N = N ⁺ = N ⁻ ) are reacted, these triple bond and azide group By this [3 + 2] dipolar cycloaddition reaction, a 1,2,3-triazole ring with high selectivity and high reaction rate and high stability is formed. This reaction is one type of technique for achieving click chemistry, and is also referred to as click reaction.
Among the nerve function regulating substances of the present embodiment, those having a triple bond between carbon atoms at the terminal can be click-reacted with a compound having an azide group. Therefore, by using a dye (for example, a fluorescent label) as the compound having an azide group, the nerve function regulating substance can be labeled so as to emit light. Since the click reaction is highly selective and has a high reaction rate, the nerve function-regulating substance can react with various kinds of dyes having an azide group, and can be labeled in various ways.

The dye to be click-reacted is not particularly limited as long as it has an azide group. The non-commercially available dye can be produced, for example, by azido-forming a commercially available known dye having no azido group by a known method. The azidation can be performed by a known method using an azidating agent such as sodium azide and trimethylsilyl azide.

As described above, the neurological function-modulating substance of the present embodiment includes detection by Raman scattering spectroscopy and detection by fluorescence emission (which is a kind of the above-described electromagnetic wave emission) after labeling using a click reaction. Two types of detection are possible, and various detection methods can be applied.

Here, although a dye is described as a compound having an azide group, a click reaction can be performed by using a compound having an azide group other than the dye depending on the purpose.

神経 The nerve function regulating substance of the present embodiment has a physiological activity related to regulation of nerve function. Therefore, the nerve function-modulating substance of the present embodiment is taken up into nerve cells, and after being taken up, can be directly detected by Raman scattering spectroscopy, or after labeling using a click reaction. It can also be detected by fluorescence emission, and the state of uptake into nerve cells can be easily and practically evaluated.

As a dye incorporated into nerve cells, a fluorescent green dye FFN511 represented by the following formula, which is incorporated into dopamine-containing nerve cells and is detectable in these cells, is known (see Patent Document 1). Although the molecular weight of this dye is relatively small as compared with the molecular weights of other fluorescent dyes, it is about twice as high as the molecular weight of dopamine and is still larger than the molecular weight of the target molecule. In addition, this dye is considered to have no biological activity, and further absorbs light of a short wavelength, which is not always common, and emits light in a wide wavelength range, so that it is difficult to use it in combination with other dyes. And has many undesirable properties, such as the absence of alternative dyes.
On the other hand, as described above, the nerve function regulating substance of the present embodiment has a physiological activity and can be detected by various means, and thus has extremely high utility.

The neurological function-modulating substance of the present embodiment is a compound having a structure in which one or two or more hydrogen atoms in dopamine, noradrenaline, adrenaline or serotonin are substituted with a group having a triple bond between carbon atoms or It is preferably a salt thereof (these may be collectively referred to as "analog substance" in this specification). Dopamine, noradrenaline, adrenaline, and serotonin are important as naturally-occurring nerve function regulators that act in the brain.Moreover, the dynamics after uptake into nerve cells are unknown, and mental disorders and other diseases are unknown. It is also unknown how they are involved in the onset of various diseases. Therefore, the above-mentioned compounds or salts thereof, which are analogs thereof, provide a means for solving these unknown points, and have extremely high utility.
The analog substance of the present embodiment includes those contained in the compound (I) or a salt thereof described above, and those contained in the compound (II) or a salt thereof described above.

In the analog substance of the present embodiment, the position of the hydrogen atom substituted with a group having a triple bond between carbon atoms is not particularly limited.
In the analog substance of the present embodiment, the number of hydrogen atoms replaced with a group having a triple bond between carbon atoms is not particularly limited, but is preferably 1 to 6, for example, 1 to 5, Any of 1 to 4, 1 to 3, 1 or 2, and 1 may be used.

Among the analog substances of the present embodiment, as dopamine analog substances, for example, in dopamine, one or two hydrogen atoms in a terminal amino group are substituted with a group having a triple bond between carbon atoms. Or a salt thereof having a structure in which a hydrogen atom in one or two hydroxy groups is replaced by a group having a triple bond between carbon atoms (the number of substitutions and the substitution position at this time are not particularly limited) Or a salt thereof, among the carbon atoms constituting the benzene ring skeleton, which are located between the carbon atom to which the 2-aminoethyl group is bonded and the carbon atom at the para position thereof, A structure in which a hydrogen atom bonded to one or both of two adjacent carbon atoms is substituted with a group having a triple bond between carbon atoms (the number of substitutions and substitution positions are not particularly limited.) Or a salt thereof; in any of the compounds or salts thereof in any of these three groups, a hydrogen atom which is not substituted with a group having a triple bond between carbon atoms in the amino group or the hydroxy group, A compound having a structure substituted with an alkyl group (preferably an alkyl group having 1 to 9 carbon atoms) (the number and position of substitution at this time are not particularly limited), a salt thereof, and the like.

Among the analog substances of the present embodiment, examples of the analog substance of noradrenaline include, for example, a structure in which one or two hydrogen atoms in a terminal amino group are substituted with a group having a triple bond between carbon atoms. Compound or salt thereof; a structure in which a hydrogen atom in one, two or three hydroxy groups is substituted with a group having a triple bond between carbon atoms (the number and position of substitution are not particularly limited) Or a salt thereof, which is located between the carbon atom to which the 2-amino-1-hydroxyethyl group is bonded and the para-position carbon atom among the carbon atoms constituting the benzene ring skeleton. A structure in which a hydrogen atom bonded to one or both of two carbon atoms adjacent to each other is replaced with a group having a triple bond between carbon atoms (the number of substitutions and the substitution position at this time are Or a salt thereof; in any of these three groups or a salt thereof, a hydrogen atom which is not substituted with a group having a triple bond between carbon atoms in the amino group or the hydroxy group And a compound having a structure substituted with an alkyl group (preferably an alkyl group having 1 to 9 carbon atoms) (the number and position of substitution are not particularly limited) or a salt thereof.

Among the analog substances of the present embodiment, examples of the adrenaline analog substance include a compound having a structure in which one hydrogen atom in a terminal methylamino group is substituted with a group having a triple bond between carbon atoms or A salt thereof; a compound having a structure in which a hydrogen atom in one, two or three hydroxy groups is substituted with a group having a triple bond between carbon atoms (the number and position of substitution are not particularly limited) Or a salt thereof, among carbon atoms constituting the benzene ring skeleton, a position between the carbon atom to which the (1-hydroxy-2-methylamino) ethyl group is bonded and the carbon atom at the para position. A structure in which a hydrogen atom bonded to one or both of two carbon atoms adjacent to each other is substituted with a group having a triple bond between carbon atoms (the number of substitutions and the substitution positions at this time) Is Or a salt thereof; a hydrogen atom which is not substituted with a methylamino group or a hydroxy group having a triple bond between carbon atoms in any of the compounds or salts thereof in the above three groups. Is substituted with an alkyl group (preferably an alkyl group having 1 to 9 carbon atoms), and a compound having a structure (the number and position of substitution at this time are not particularly limited) or a salt thereof.

Among the analog substances of the present embodiment, as the analog substance of serotonin, for example, one having one or two hydrogen atoms in a terminal amino group substituted with a group having a triple bond between carbon atoms is used. Compound or salt thereof; Compound having a structure in which a hydrogen atom in a hydroxy group is substituted with a group having a triple bond between carbon atoms or a salt thereof; Hydrogen atom bonded to a nitrogen atom constituting a nitrogen-containing ring Is a compound having a structure substituted with a group having a triple bond between carbon atoms or a salt thereof; of the carbon atoms constituting the benzene ring skeleton, the carbon atom to which the hydroxy group is bonded is ortho-positioned Or a salt thereof, in which a hydrogen atom bonded to one or both of the two carbon atoms is replaced by a group having a triple bond between carbon atoms; or a carbon having a benzene ring skeleton. A compound having a structure in which a hydrogen atom bonded to a carbon atom at a meta position with respect to a carbon atom bonded to a hydroxy group is replaced by a group having a triple bond between carbon atoms, or a salt thereof. And the like.

神経 The neurological function regulating substance of the present embodiment includes, for example, those comprising the above-mentioned compound (I) or a salt thereof, and those comprising the above-mentioned compound (II) or a salt thereof. The compound (I) or a salt thereof, and the compound (II) or a salt thereof have a high degree of retention of a molecular structure required for recognition by a nerve cell, similarly to a naturally-occurring nerve function regulator. Therefore, it is presumed to function as a nerve function regulator.

<< Evaluation method for neurological function modulator >>
The method for evaluating a nerve function-modulating substance according to one embodiment of the present invention is a method for evaluating the state of uptake of the nerve function-modulating substance into nerve cells or the state of a cellular response caused by the uptake.
As described above, the nerve function regulating substance of the present embodiment has a physiological activity, and is taken into a nerve cell by coexisting with the nerve cell. Then, as described above, the nerve function regulating substance in the nerve cell can be detected by, for example, Raman scattering spectroscopy or fluorescence emission after labeling using a click reaction.
Therefore, when evaluating the nerve function regulating substance, the nerve function regulating substance may be allowed to coexist with a nerve cell, and then the nerve function regulating substance taken into the nerve cell may be detected.

In the present embodiment, to evaluate the state of uptake of a nerve function regulating substance into a nerve cell means, for example, the place (in other words, distribution) of the nerve function regulating substance uptake in a nerve cell, This means that the amount of the function-modulating substance, the place of incorporation of the substance or the change over time of the amount, and the like are specified.
According to this embodiment, the role (in other words, physiological activity) of the nerve function modulator in the nerve cell and the degree thereof can be evaluated by evaluating the state of uptake of the nerve function modulator into the nerve cell. is there. For example, nerve cells may have a specific effect depending on the area. Therefore, by specifying a detection site (in other words, an uptake site) in the nerve cell of the nerve function modulator incorporated in the nerve cell, the role of the nerve function modulator in the nerve cell may be specified. In some cases, by specifying the amount of the nerve function-regulating substance at the location of the uptake, the strength of the physiological activity of the nerve function-modulating substance in the nerve cell can be specified.
However, these are one mode of evaluation, and the evaluation is not limited to these.

In the present embodiment, to evaluate the state of a cellular response brought about by the uptake of a nerve function modulator into a nerve cell means, for example, in a nerve cell or outside a nerve cell, other than the nerve function modulator. This means specifying changes in the concentration of a substance.
According to the present embodiment, the role (in other words, physiological activity) of a nerve function regulator in a nerve cell may be evaluated by evaluating the state of the cell response. For example, certain neurological modulators such as dopamine and noradrenaline bind to specific receptors on the surface of nerve cells and activate these nerve cells to cause various cellular responses. One such cell response that is relatively well known is intracellular signaling with increasing or decreasing concentrations of second messengers such as cyclic AMP (cAMP). Therefore, for example, when the function of a nerve function modulator in a nerve cell can be specified by specifying the change in the concentration of another substance caused by incorporating the nerve function modulator into a nerve cell and then causing the change in the concentration of another substance caused thereby. There is.
However, this is one mode of evaluation, and the evaluation is not limited to these.

According to the present embodiment, it is possible to evaluate the state of uptake of the nerve function regulating substance into the nerve cell, so that the presence or absence of the release of the nerve function regulating substance from the nerve cell can be evaluated at the same time. In addition, by evaluating the state of uptake of the nerve function-modulating substance and the state of the cellular response caused by the uptake, the dynamics of the nerve function-modulating substance in the brain tissue after the uptake can be evaluated.

According to the evaluation method of the present embodiment, the state of the uptake of such a nerve function regulating substance into a nerve cell, or the state of a cellular response brought about by the uptake, can be evaluated practically. For example, it is suitable for use in the development of a therapeutic drug for a mental disorder, and is useful in the fields of psychiatry and pharmacy.

The neurological function regulating substance used at one time in the evaluation method of the present embodiment may be only one kind, or two or more kinds, and when two or more kinds, the combination and the ratio thereof are optional. You can choose.
For example, by using two or more types of neurological modulators having different detection methods in combination and simultaneously detecting these two or more types of neurological modulators, the role of these neurological modulators in nerve cells can be efficiently determined. In some cases.

As a method for simultaneously detecting two or more types of neurological modulators having different detection methods, for example, one or two or more of these neuronal functional modulators are detected by Raman scattering spectroscopy, and the other A method of detecting two or more kinds of the neuronal function regulating substances by labeling using a click reaction with a dye and then using fluorescence emission after labeling the two or more kinds of these nerve function modulators using a click reaction with a dye having a different detection wavelength. Then, after labeling each, a method of detecting by fluorescence emission of different wavelengths, and the like can be mentioned.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the examples described below.

The abbreviations described in the following examples have the following meanings.
Me: methyl group Et: ethyl group ⁱ Pr: isopropyl group (alias: 1-methylethyl group)
Ac: acetyl group Ts: p-toluenesulfonyl group Boc: tert-butoxycarbonyl group DMF: N, N-dimethylformamide THF: tetrahydrofuran TFA: 2,2,2-trifluoroacetic acid DMAP: N, N-dimethyl-4- Aminopyridine LDA: lithium diisopropylamide

<< Production of Compound (I) >>
[Example 1]
A compound represented by the following formula (I) -1-101 (which may be abbreviated as “compound (I) -1-101” in the present specification) by the following route, and a compound represented by the following formula (I) A compound represented by formula (I) -1-102 (hereinafter, may be abbreviated as “compound (I) -1-102”) and a compound represented by the following formula (I) -1-103 ( In this specification, the compound may be abbreviated as “compound (I) -1-103”.

<Production of Compound (I) -1-101>
(Production of N-trifluoroacetyldopamine)
In a round bottom flask having a capacity of 100 mL, dopamine hydrochloride (2.20 g, 11.6 mmol) and methanol (12 mL) were mixed, and nitrogen gas was allowed to flow for 30 minutes to degas the resulting mixture.
Next, ethyl trifluoroacetate (2.0 mL, 16.8 mmol) and N, N-diisopropylethylamine (2.0 mL, 11.6 mmol) were added to the degassed mixture, and the mixture was stirred at room temperature for 30 hours. And reacted.
Next, 1N hydrochloric acid was added to the obtained reaction solution to stop the reaction. Then, extraction was performed with ethyl acetate, the collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain N-trifluoroacetyldopamine as a white solid.

(Production of N-trifluoroacetyl-O, O'-isopropylidendopamine)
The whole amount of N-trifluoroacetyldopamine obtained above was added to a 300 mL round bottom flask without purification, and further, 2,2-dimethoxypropane (5.69 mL, 46.4 mmol), p -Toluenesulfonic acid monohydrate (0.23 g, 1.2 mmol) and benzene (120 mL) were added.
Next, the round bottom flask in this state was connected to a dropping funnel filled with the molecular sieve 4A, and further connected to a condenser from which water was sufficiently removed.
Next, in this state, the mixture in the round bottom flask was stirred at 105 ° C. for 39 hours, and the solvent was distilled off under reduced pressure at room temperature.
Next, the obtained crude product was dissolved in methylene chloride, and the obtained solution was used to pass through a tube (3 cm in length) filled with silica gel.
Next, the solvent was removed, and the deposited yellowish solid was filtered off, washed with hexane, and dried to obtain N-trifluoroacetyl-O, O'-isopropylidendopamine as a target substance ( Yield 2.50 g (8.64 mmol), total yield of two steps 75%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.56. .
The NMR data of the obtained N-trifluoroacetyl-O, O'-isopropylidendopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.67 (s, 6 H), 2.77-2.80 (m, 2 H), 3.54-3.59 (m, 2 H), 6.35 (br, 1 H), 6.58- 6.59 (m, 2 H), 6.67-6.69 (m, 1 H).

(Production of N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine)
Sodium hydride (concentration: 60% by mass, 55 mg (33 mg as sodium hydride), 1.38 mmol) was added to a 50 mL round bottom flask. This sodium hydride was washed three times with hexane (10 mL). Then, the remaining hexane was distilled off under reduced pressure, DMF (5 mL) was added, and the resulting suspension was stirred at 0 ° C.
Then, a DMF solution (5 mL) of the N-trifluoroacetyl-O, O'-isopropylidendopamine (289 mg, 1.00 mmol) obtained above was added thereto, and the resulting mixture was added at 0 ° C for 4 hours. Stirred for hours.
Next, propargyl bromide (88 μL, 1.1 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 14 hours to be reacted.
Next, the obtained reaction solution was cooled to 0 ° C., and water was added thereto to stop the reaction. Then, the obtained mixture was extracted with diethyl ether (30 mL), and the organic layer was washed with water and dried over anhydrous sodium sulfate.
Then, the solvent was distilled off under reduced pressure, and the obtained mixture was passed through a tube filled with silica gel, and eluted with a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume). The product was obtained.
Then, the obtained crude product was purified by flash chromatography. At this time, using a mixed solvent of ethyl acetate and hexane as the mobile phase, increasing the concentration of ethyl acetate from 10% by volume to 20% by volume, separating and eluting the target substance, and removing the solvent from the eluate The solvent was distilled off under reduced pressure.
Thus, N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine, which was the target substance, was obtained as a pale yellow oil (yield 300 mg (0.917 mmol), yield 92%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.67. .
The NMR data and HRMS (ESI) data of the obtained N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.67 (s, 6 H), 2.35-2.37 (m, 1 H), 2.86 (t, J = 7.6 Hz, 2 H), 3.68-3.73 (m, 2 H), 4.04 and 4.28 (rotameric d, J = 2.0 Hz, 2 H), 6.60-6.68 (m, 3 H).
¹³ C NMR (100 MHz, CDCl ₃ , mixture of two rotamers) δ25.70 and 25.73 (two methyl carbons of the isopropylidene moiety were overlapping), 32.6 and 34.8, 36.0 and 37.8 (q for δ37.8 peak, J = 3.7 Hz), 48.8 and 49.2 (q for δ48.8 peak, J = 2.8 Hz), 73.4 and 73.6, 76.7 and 76.8, 108.2 and 108.3, 108.7 and 108.8, 116.1 and 116.3 (q, J = 292 Hz), 117.9 and 118.0, 120.98 and 121.00, 129.9 and 130.8, 146.2 and 146.4, 147.6 and 147.7, 156.2 and 156.6 (q, J = 37.0 Hz).
HRMS (ESI) calcd for C ₁₆ H ₁₇ F ₃ NO ₃ [M + H] ⁺ : 328.1155, found: 328.1168.

(Production of Compound (I) -1-101)
In a 50 mL round bottom flask, N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine (350 mg, 1.07 mmol) and THF (7 mL) were mixed.
Next, an aqueous solution of lithium hydroxide (concentration 1M, 2.1 mL) was added to the obtained mixture, and the obtained mixture was stirred at room temperature for 15 hours to be reacted.
Next, the obtained reaction solution was cooled to 0 ° C., and 1N hydrochloric acid was added thereto to stop the reaction. Methylene chloride was further added, and the obtained mixture was extracted with water, and the aqueous layer was washed with methylene chloride. Further, the aqueous layer was made basic with a saturated aqueous solution of sodium hydrogencarbonate, the aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a light yellow color. N-propargyl-O, O'-isopropylidendopamine (ie, compound (I) -1-101) was obtained as an oil (yield 220 mg (0.951 mmol), 89%).
The NMR data and HRMS (ESI) data of the obtained compound (I) -1-101 are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.67 (s, 6 H), 2.21 (t, J = 2.4 Hz, 1 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.92 (t, J = 7.2 Hz, 2 H), 3.44 (d, J = 2.8 Hz, 2 H), 6.60-6.66 (m, 3 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ25.9 (two methyl carbons of the isopropylidene moiety were overlapping), 35.8, 38.1, 50.0, 71.3, 82.1, 108.0, 108.8, 117.7, 120.9, 132.8, 145.8, 147.5.
HRMS (ESI) calcd for C ₁₄ H ₁₈ NO ₂ [M + H] ⁺ : 232.1332, found: 232.1332.

<Production of Compound (I) -1-102>
In a sample vial having a capacity of 10 mL, compound (I) -1-101 obtained above (that is, N-propargyl-O, O′-isopropylidendopamine) (20 mg, 0.086 mmol), and diethyl ether (1 mL) Was added and the resulting mixture was stirred to obtain a solution free of unnecessary substances.
Then, a diethyl ether solution containing hydrogen chloride at a concentration of 1 M (10 drops) was added to the solution at room temperature, and a white precipitate was immediately formed. After washing and drying, N-propargyl-O, O'-isopropylidendopamine hydrochloride (ie, compound (I) -1-102) was obtained as a white solid (yield 22 mg (0.0822 mmol), Yield 96%).
The NMR data and HRMS (ESI) data of the obtained compound (I) -1-102 are shown below.

¹ H NMR (400 MHz, D ₂ O) δ 1.66 (s, 6 H), 2.91-2.95 (m, 3 H), 3.36 (t, J = 7.2 Hz, 2 H), 3.88 (d, J = 2.0 Hz, 2 H), 6.75-6.80 (m, 3 H).
¹³ C NMR (100 MHz, D ₂ O) δ25.3 (two methyl groups of isopropylidene moiety were overlapping), 32.1, 37.1, 48.5, 73.8, 78.5, 109.5, 109.8, 119.7, 122.4, 130.4, 146.5, 147.8.
HRMS (ESI) calcd for C ₁₄ H ₁₈ NO ₂ [M-Cl] ⁺ : 232.1332, found: 232.1334.

<Production of Compound (I) -1-103>
Compound (I) -1-101 (ie, N-propargyl-O, O′-isopropylidendopamine) (100 mg, 0.432 mmol) obtained above and dioxane (5 mL) were placed in a 30 mL round bottom flask. )) Was added and the resulting mixture was stirred at room temperature until the unwanted material disappeared.
Then, a dioxane solution (0.5 mL) containing hydrogen chloride at a concentration of 4N was added to the resulting solution, and a white precipitate was formed. Methanol was added until the precipitate was completely dissolved. Further, hydrochloric acid (concentration: 12N, 1 mL) was added, and the mixture was stirred at room temperature for 16 hours. Here, it was confirmed that the reaction was completed by analyzing the reaction solution by NMR.
Next, the solvent was distilled off under reduced pressure from the obtained reaction solution, the obtained oily crude product was dissolved in a small amount of methanol, and the obtained methanol solution was dropped into diethyl ether to give a white solution. A precipitate was formed. The precipitate was separated by filtration, washed with diethyl ether, and dried to obtain N-propargyl dopamine hydrochloride (ie, compound (I) -1-103) as a white solid (yield: 80 mg ( 0.416 mmol), 96% yield).
The NMR data and HRMS (ESI) data of the obtained compound (I) -1-103 are shown below.

¹ H NMR (400 MHz, D ₂ O) δ 2.88 (t, J = 7.2 Hz, 2 H), 2.93 (t, J = 2.8 Hz, 1 H), 3.35 (t, J = 7.2 Hz, 2 H ), 3.86 (d, J = 2.4 Hz, 2 H), 6.72 (dd, J = 2.0, 8.4 Hz, 1 H), 6.81 (d, J = 2.0 Hz, 1 H), 6.86 (d, J = 8.4) Hz, 1 H).
¹³ C NMR (100 MHz, D ₂ O) δ31.5, 37.1, 48.5, 73.6, 78.7, 117.1, 117.2, 121.8, 129.4, 143.8, 144.9.
HRMS (ESI) calcd for C ₁₁ H ₁₄ NO ₂ [M-Cl] ⁺ : 192.1019, found: 192.1025.

[Example 2]
<Production of compound (I) -2-301>
A compound represented by the following formula (I) -2-301 (which may be abbreviated as “compound (I) -2-301” in the present specification) was produced by the following route.

(Production of dopamine hydrobromide)
In a round bottom flask having a capacity of 100 mL, homoveratrylamine (also known as 2- (3,4-dimethoxyphenyl) ethylamine, 931 mg, 5.14 mmol) and methylene chloride (50 mL) were mixed, and the resulting solution was mixed. Cooled to -78 ° C.
Next, a solution of boron tribromide in methylene chloride (concentration: about 1 M, 11.3 mL) was slowly added to the cooled solution, and the resulting mixture was stirred at room temperature for 3 hours.
Next, methanol was added to the obtained reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure. The precipitated solid was washed with diethyl ether and dried to obtain dopamine hydrobromide (830 mg (3.55 mmol), 69% yield).
The NMR data of the obtained dopamine hydrobromide are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ2.79 (t, J = 7.6 Hz, 2 H), 3.09 (t, J = 7.6 Hz, 2 H),
6.58 (dd, J = 2.4, 8.0 Hz, 1 H), 6.69-6.74 (m, 2 H).

(Production of N-Boc-dopamine)
In a 100 mL round bottom flask, dopamine hydrobromide obtained above (468 mg, 2.00 mmol), di-tert-butyl dicarbonate (alias: Boc ₂ O, 468 mg, 2.00 mmol), N, N-diisopropylethylamine (1.0 mL, 5.73 mmol) and DMF (5 mL) were mixed and reacted at room temperature for 3 hours with stirring.
Next, water was added to the obtained reaction solution, and the obtained mixture was extracted three times with a mixed solvent of ethyl acetate (50% by volume) / hexane (50% by volume) (30 mL), and collected. The obtained organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Then, the obtained crude product was purified by flash chromatography. At this time, a mixed solvent of methanol and methylene chloride was used as a mobile phase, and the concentration of methanol was increased from 5% by volume to 10% by volume to separate and elute the target substance. Distilled off.
As described above, tert-butyl (3,4-dihydroxyphenethyl) carbamate (abbreviated as “N-Boc-dopamine” in this specification) was obtained (yield 380 mg (1.22 mmol), yield 61). %).
Using a mixed solvent of methanol (10% by volume) / methylene chloride (90% by volume) as a developing solvent, the obtained N-Boc-dopamine was developed by thin layer chromatography (TLC) to find that the Rf value was 0.57. Met.
The NMR data of the obtained N-Boc-dopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.44 (s, 9 H), 2.65 (br, 2 H), 3.32 (br, 2 H), 6.57-6.80 (m, 3 H).

(Production of tert-butyl (3,4-di-2-propynyloxyphenethyl) carbamate)
In a 30 mL round bottom flask, N-Boc-dopamine obtained above (300 mg, 1.07 mmol), potassium carbonate (443 mg, 3.21 mmol), and DMF (5 mL) were added, and further added thereto. , Propargyl bromide (0.18 mL, 2.45 mmol) was added, and the resulting mixture was stirred and reacted at room temperature for 12 hours.
Next, water was added to the obtained reaction solution to stop the reaction. The obtained mixture is extracted three times with a mixed solvent (20 mL) of ethyl acetate (50% by volume) / hexane (50% by volume), and the collected organic layer is washed with water (20 mL). It was washed three times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Then, the obtained crude product was purified by flash chromatography. At this time, the target substance was separated and eluted using a mixed solvent of ethyl acetate (25% by volume) / hexane (75% by volume) as a mobile phase, and the solvent was distilled off from the eluted substance under reduced pressure.
As a result, tert-butyl (3,4-di-2-propynyloxyphenethyl) carbamate was obtained as the target product (350 mg (1.06 mmol), 99% yield).
Using a mixed solvent of methanol (30% by volume) / methylene chloride (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.37. .
The NMR data of the obtained target product is shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.44 (s, 9 H), 2.53 (m, 2 H), 2.75 (br, 2 H), 3.37 (br, 2 H), 4.74 (dd, J = 2.0, 6.8 Hz, 4 H), 6.79-6.81 (m, 1 H), 6.89 (br, 1 H), 7.00 (d, J = 8.4 Hz, 1 H).

(Production of Compound (I) -2-301)
In a 50 mL round bottom flask, tert-butyl (3,4-di-2-propynyloxyphenethyl) carbamate (296 mg, 0.90 mmol) obtained above, TFA (0.5 mL) and methylene chloride (5 mL) ) Was added and the resulting mixture was stirred at room temperature for 14 hours to react. Here, by analyzing the reaction solution by NMR, it was confirmed that deprotection for removing the Boc group was completed.
Next, an aqueous solution of sodium hydrogen carbonate was added to the obtained reaction solution to stop the reaction. The obtained mixture was extracted three times with methylene chloride (20 mL), and the collected organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow oily crude product. Was obtained (yield 97 mg).
Next, in a round bottom flask having a capacity of 50 mL, the whole amount of the crude product obtained above, diethyl ether (1 mL), and a diethyl ether solution (1 mL) containing hydrogen chloride at a concentration of 1 M were added, The resulting mixture was stirred at room temperature for 4 hours.
Then, the solid is filtered off using a filter, and the solid is washed with diethyl ether and dried to obtain O, O'-dipropargyldopamine hydrochloride (that is, compound (I) -2-301). (87 mg (0.33 mmol), 37% yield).
The NMR data and HRMS (ESI) data of the obtained compound (I) -2-301 are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ2.92 (t, J = 8.0 Hz, 2 H), 2.96 (dt, J = 10.8, 2.4 Hz, 2 H), 3.16 (dd, J = 6.8, 8.4 Hz, 2 H), 4.74 (t, J = 2.0 Hz, 2 H), 4.78 (t, J = 2.0 Hz, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 7.02 (m, 1 H), 7.06-7.08 (m, 1 H).
¹³ C NMR (100 MHz, CD ₃ OD) δ 34.0, 42.0, 57.9 (two peaks overlapping), 77.0, 77.1, 79.71, 79.74, 117.0, 117.1, 123.3, 131.8, 148.3, 149.3.
HRMS (ESI) calcd for C ₁₄ H ₁₆ NO ₂ [M-Cl] ⁺ : 230.1176, found: 230.1173.

[Example 3]
<Production of Compound (I) -2-302>
A compound represented by the following formula (I) -2-302 (which may be abbreviated as “compound (I) -2-302” in the present specification) was produced by the following route.

(Production of (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-dihydroxyphenyl) ethyl carbamate)
In a 30 mL round bottom flask, DL-norepinephrine hydrochloride (103 mg, 0.5 mmol), di-tert-butyl dicarbonate (also called Boc ₂ O, 240 mg, 1.10 mmol), DMAP (24 mg, 0.2 mmol) ), N, N-diisopropylethylamine (1 mL, 5.76 mmol) and DMF (10 mL) were mixed and reacted at room temperature for 18 hours.
Next, water was added to the obtained reaction solution to stop the reaction. The obtained mixture is extracted three times with a mixed solvent (20 mL) of ethyl acetate (50% by volume) / hexane (50% by volume), and the collected organic layer is dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a crude product.
Then, the obtained crude product was purified by flash chromatography. At this time, a mixed solvent of ethyl acetate and hexane was used as the mobile phase, and the concentration of ethyl acetate was increased from 25% by volume to 50% by volume to separate and elute the target substance. The solvent was distilled off under reduced pressure.
As a result, (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-dihydroxyphenyl) ethylcarbamate was obtained as the desired product (yield 74 mg (0.20 mmol). Rate 40%).
Using a mixed solvent of methanol (10% by volume) / methylene chloride (90% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.58. . When the obtained target product was developed by thin layer chromatography (TLC) using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the Rf value was 0.07. there were.
The NMR data of the obtained (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-dihydroxyphenyl) ethyl carbamate are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.29 (s, 2 H), 2.61-2.69 (m, 2 H), 2.76-2.80 (m, 2 H), 3.495 (s, 2 H), 3.500 ( s, 2 H), 5.63 (br, 2 H), 6.56 (d, J = 8.0 Hz, 1 H), 6.69 (s, 1 H), 6.75 (d, J = 2 H).

(Production of (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethyl carbamate)
In a 50 mL round bottom flask, (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-dihydroxyphenyl) ethylcarbamate (74 mg, 0.200 mmol) obtained above ), Potassium carbonate (110 mg, 0.8 mmol) and DMF (5 mL) were added, and propargyl bromide (40 μL, 60 mg, 0.5 mmol) was further added thereto. And reacted for 3 hours. Here, analysis by thin layer chromatography (TLC) confirmed the disappearance of the raw materials.
Next, water was added to the obtained reaction solution to stop the reaction. The obtained mixture is extracted with a mixed solvent of ethyl acetate (50% by volume) / hexane (50% by volume), and the collected organic layers are washed with saturated saline and dried over anhydrous sodium sulfate. And the solvent was distilled off under reduced pressure to obtain a crude product.
Then, the obtained crude product was purified by flash chromatography. At this time, a mixed solvent of ethyl acetate and hexane was used as the mobile phase, and the concentration of ethyl acetate was increased from 25% by volume to 50% by volume to separate and elute the target substance. The solvent was distilled off under reduced pressure.
As a result, (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethylcarbamate was obtained as the desired product (yield 77 mg (0%)). .19 mmol), yield 95%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.13. .
The NMR data of the obtained (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethyl carbamate are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.44 (d, J = 2.0 Hz, 9 H), 1.55 (d, J = 1.2 Hz, 9 H), 2.52 (q, J = 2.4 Hz, 1 H) , 3.14-3.22 (m, 1 H), 3.39-3.47 (m, 2 H), 3.58 (br, 1 H), 4.71 (dd, J = 2.4, 4.4 Hz, 2 H), 4.70-4.78 (br, 1 H), 5.03 (br, 1 H), 6.93-7.18 (m, 3 H).

(Production of Compound (I) -2-302)
In a 50 mL round bottom flask, (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethyl carbamate ( 77 mg, 0.19 mmol), and diethyl ether (0.5 mL), and a diethyl ether solution (2 mL) containing hydrogen chloride at a concentration of 1 M was added to the obtained solution. The mixture was stirred and reacted at room temperature for 48 hours. Here, a chewing gum-like solid precipitated, which was filtered off, washed with diethyl ether, and dried to give (RS) -1- (2-amino-1-hydroxyethyl) -3,4-. Bis (2-propynyloxy) benzene hydrochloride (that is, compound (I) -2-302) was obtained (10 mg (0.035 mmol), 19% yield).
The NMR data of the obtained compound (I) -2-302 are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ 2.93-2.97 (m, 2 H), 2.99-3.11 (m, 2 H), 4.79 (dd, J = 2.4, 8.0 Hz, 4 H), 4.87 ( s, 1 H), 6.82-6.93 (m, 3 H).

[Example 4]
<Production of Compound (I) -2-303>
A compound represented by the following formula (I) -2-303 (in this specification, sometimes abbreviated as “compound (I) -2-303”) was produced by the following route.

（(RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethyl carbamate was produced in the same manner as in Example 3.

In a 100 mL round bottom flask, (RS) -tert-butyl-2- (tert-butoxycarbonyloxy) -2- (3,4-di-2-propynyloxyphenyl) ethylcarbamate ( 61 mg, 0.15 mmol) and methylene chloride (5 mL), further TFA (0.1 mL, 0.13 mmol) was added to the resulting solution, and the resulting mixture was stirred at room temperature for 20 hours. And reacted. Here, when the reaction solution was analyzed by NMR, it was confirmed that 20 mol% of the Boc group based on the initial amount was not removed and remained in the raw material. Therefore, TFA (0.1 mL, 0.13 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 19 hours to be reacted. Here, by analyzing the reaction solution by NMR, it was confirmed that deprotection for removing the Boc group was completed.
Then, the solvent was distilled off under reduced pressure. As a result, a chewing gum-like solid was precipitated. Ethyl) -3,4-bis (2-propynyloxy) benzenetrifluoroacetate (namely, compound (I) -2-303) was obtained (20 mg (0.056 mmol), 37% yield).
The NMR data of the obtained compound (I) -2-303 are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ 2.86 (t, J = 2.4 Hz, 1 H), 2.88 (t, J = 2.4 Hz, 1 H), 2.90-3.03 (m, 2 H), 4.79 (dd, J = 2.4, 8.0 Hz, 4 H), 4.87 (s, 1 H), 6.73-6.78 (m, 2 H), 6.81-6.84 (m, 1 H).

[Example 5]
<Production of Compound (I) -1-201>
A compound represented by the following formula (I) -1-201 (which may be abbreviated as “compound (I) -1-201” in the present specification) was produced by the following route.

ドー Dopamine hydrobromide was produced in the same manner as in Example 2.

In a 100 mL round bottom flask, the dopamine hydrobromide obtained above (936 mg, 4.00 mmol), N, N-diisopropylethylamine (2.4 mL, 14 mmol), and acetonitrile (20 mL) were added. The resulting suspension was stirred at room temperature.
Next, propargyl bromide (0.64 mL, 8.0 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour to be reacted.
Then, the obtained reaction solution was concentrated, and ethyl acetate and water were added thereto. Then, the mixture obtained by the reaction was extracted with ethyl acetate, the collected organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
Then, the obtained crude product was purified by flash chromatography. At this time, the target substance was separated and eluted using a mixed solvent of methanol (10% by volume) / methylene chloride (90% by volume) as a mobile phase, and the solvent was distilled off from the eluted substance under reduced pressure.
As described above, N, N-dipropargyldopamine (that is, compound (I) -1-201) was obtained (20 mg (0.087 mmol), 2% yield).
The NMR data of the obtained compound (I) -1-201 are shown below.

<< Evaluation of neurological modulator >>
Using Compound (I) -1-102 and Compound (I) -1-103 obtained as described above, the following test was performed to evaluate whether or not the compound was taken up into nerve cells. The present invention is not limited to this example, but at the time of evaluation of each compound shown below, for convenience, each compound is specified in the initial state subjected to this evaluation, and each compound under evaluation is identified in the initial state. It is uncertain whether it will remain. For example, the description regarding each evaluation does not necessarily mean that the compound that was initially in a salt state during the evaluation was a salt during the evaluation. A compound that was not a salt does not necessarily mean that it is not a salt during the evaluation.

[Example 6]
Compound (I) -1-102 obtained above was dissolved in artificial cerebrospinal fluid to prepare a solution of compound (I) -1-102. Here, the artificial cerebrospinal fluid contains sodium chloride (NaCl) at a concentration of 126 mmol / L, contains sodium bicarbonate (NaHCO ₃ ) at a concentration of 26 mmol / L, and has a concentration of 1 mmol / L. It contains sodium dihydrogen phosphate (NaH ₂ PO ₄ ), contains dextrose at a concentration of 10 mmol / L, contains potassium chloride (KCl) at a concentration of 3 mmol / L, and contains 1 mmol / L. PH 7.3 aqueous solution containing magnesium chloride (MgCl ₂ ) and containing calcium chloride (CaCl ₂ ) at a concentration of 3 mmol / L. The concentration of compound (I) -1-102 in this solution was 10 μmol / L.
In addition, a solution having a concentration of 10 μmol / L was similarly prepared for the compound (I) -1-103 obtained above.
Two acute brain slices (thickness: 300 μm) were prepared from mouse cerebral cortex and used as test specimens.
One test piece was immersed in a solution of compound (I) -1-102 at 37 ° C. for 30 minutes. Similarly, the remaining one test piece was immersed in a solution of compound (I) -1-103 at 37 ° C. for 30 minutes.
Next, the test pieces were removed from these solutions, and the test pieces were chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using Triton X-100 solution.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). The results are shown in FIGS. 1A to 1C and FIGS. 2A to 2C. FIGS. 1A to 1C are imaging data of a test piece when compound (I) -1-102 is used, and show data at three different magnifications. FIGS. 2A to 2C are imaging data of a test piece when Compound (I) -1-103 is used, and show data at three different magnifications.

FIGS. 1A to 1C and FIGS. 2A to 2C show that even when Compound (I) -1-102 or Compound (I) -1-103 is used, the regulation of neuronal function running in the cerebral cortex Axon-like structures of neurons containing the substance were seen. This is because compound (I) -1-102 and compound (I) -1-103 having physicochemical properties similar to endogenous dopamine are taken up in dopamine-containing neurons and stored in vesicles. In this state, a click reaction was performed to react with the fluorescent dye to which the azide group was added, labeling was performed, and the label was detected by a confocal microscope.

[Example 7]
The compound (I) -1-102 obtained above and the FFN511 fluorescent dye were dissolved in the same artificial cerebrospinal fluid as used in Example 6, and the concentration of compound (I) -1-102 was 10 μmol / L and a solution having a concentration of the FFN511 fluorescent dye of 10 μmol / L was prepared. Further, the compound (I) -1-103 obtained above and the FFN511 fluorescent dye are similarly dissolved in artificial cerebrospinal fluid, and the concentration of the compound (I) -1-103 is 10 μmol / L, and And a solution having a concentration of FFN511 fluorescent dye of 10 μmol / L was prepared.
Next, a solubilized test piece was prepared in the same manner as in Example 6.
Then, Alexa Fluor® 594 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
These two types of test pieces were observed using an 840 nm femtosecond ultrashort pulse laser (Maitai HP manufactured by Newport) and a microscope (“FV1000MPE” manufactured by Olympus). The results are shown in FIGS. 3A to 3F and FIGS. 4A to 4F.
FIG. 3A is imaging data of a test piece when only the FFN511 fluorescent dye is detected, and FIG. 3B is a test piece when only the compound (I) -1-102 is detected in the same region as in FIG. 3A. FIG. 3C shows the imaging data of the test piece when the FFN511 fluorescent dye and the compound (I) -1-102 were simultaneously detected in the same region as in FIG. 3A. 3D, 3E, and 3F are imaging data obtained by magnifying the data of FIGS. 3A, 3B, and 3C five times, respectively.
FIG. 4A is imaging data of a test piece when only the FFN511 fluorescent dye is detected, and FIG. 4B is a test piece when only compound (I) -1-103 is detected in the same region as in FIG. 4A. FIG. 4C shows the imaging data of the test piece when the FFN511 fluorescent dye and the compound (I) -1-103 were simultaneously detected in the same region as in FIG. 4A. 4D, 4E, and 4F are imaging data obtained by magnifying the data of FIGS. 4A, 4B, and 4C five times, respectively.

3A and 3D, light emission by the FFN511 fluorescent dye was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 3A and FIG. 3D, there were other light-emitting regions by the FFN511 fluorescent dye. 3A and 3D, it was confirmed that the FFN511 fluorescent dye was incorporated into dopamine-containing neurons, as disclosed in the known literature.
In FIGS. 3B and 3E, light emission by the labeled compound (I) -1-102 was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 3B and FIG. 3E, another light emitting region by the labeled compound (I) -1-102 was present. From FIG. 3B and FIG. 3E, compound (I) -1-102 was incorporated into dopamine-containing nerve cells, and in this state, the compound was labeled by a click reaction by reacting with the fluorescent dye to which an azide group was added. I was able to confirm that.
3C and 3F, the FFN511 fluorescent dye and the labeled compound (I) -1-102 can be simultaneously detected, and in the dopamine-containing neurons, the compound (I) -1-102 is It was confirmed that it was selectively taken up in the same region as the FFN511 fluorescent dye or in a region closer to the nerve ending.

Compound (I) -1-103 also showed the same results as compound (I) -1-102.
That is, in FIGS. 4A and 4D, light emission by the FFN511 fluorescent dye was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 4A and FIG. 4D, other light-emitting regions due to the FFN511 fluorescent dye were present. 4A and 4D, it was confirmed that the FFN511 fluorescent dye was incorporated into the dopamine-containing neurons, as disclosed in the known literature.
In FIGS. 4B and 4E, light emission by the labeled compound (I) -1-103 was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 4B and FIG. 4E, another light emitting region by the labeled compound (I) -1-103 was present. From FIG. 4B and FIG. 4E, compound (I) -1-103 was taken up into dopamine-containing neurons, and in this state, it was labeled by reacting with the azido group-added fluorescent dye by a click reaction. I was able to confirm that.
4C and 4F, the FFN511 fluorescent dye and the labeled compound (I) -1-103 can be simultaneously detected, and in the dopamine-containing neurons, the compound (I) -1-103 is It was confirmed that it was selectively taken up in the same region as the FFN511 fluorescent dye or in a region closer to the nerve ending.

The results of Examples 6 and 7 show that both Compound (I) -1-102 and Compound (I) -1-103 were taken up into nerve cells in the same manner as in the case of a naturally-occurring nerve function regulator. Furthermore, it has been shown that the compound can react with various azide group-added compounds in nerve cells, and that such compounds can be clearly detected in nerve cells by using a fluorescent dye.

In Examples 6 and 7, Compound (I) -1-102 and Compound (I) -1-103 were detected after reacting with a fluorescent dye by a click reaction. It has a triple bond between atoms. Therefore, these compounds can be directly detected using a Raman microscope without using a luminescent label.

Example 8
Using a kit for detecting the concentration of intracellular cAMP (cyclic AMP) (a cAMPis kit manufactured by Montana Molecular), the compound (I) -1-102 obtained above at a concentration of 5 μM was used as an extracellular solution. , A compound containing the compound (I) -1-103 obtained above at a concentration of 5 μM, and a compound containing dopamine at a concentration of 5 μM were separately prepared.
Next, cultured brain cells (primary cultured astrocytes) were added as test pieces to these three extracellular fluids, and the brain cells were observed using the same confocal microscope as in Example 6, Further, a fluorescent signal indicating the presence of cAMP was detected. The results at this time are shown in FIGS. 5A to 5B, FIGS. 6A to 6B, and FIGS. 7A to 7B. FIGS. 5A and 5B show the results when compound (I) -1-102 was used, and FIGS. 6A and 6B show the results when compound (I) -1-103 was used. FIG. 7 to FIG. 7B show the results when dopamine was used.

More specifically, FIG. 5A shows the imaging data of the brain cell and its surroundings acquired at this time, and 1, 2 and 3 in FIG. 5A all indicate the brain cell. FIG. 5B is a graph showing the time-dependent change in the intensity of the fluorescent signal derived from one to three brain cells.
6A and 6B are the same. FIG. 6A shows the acquired imaging data of the brain cell and its surroundings, and 1, 2 and 3 in FIG. 6A all indicate the brain cell. FIG. 6B is a graph showing the time-dependent change in the intensity of the fluorescent signal derived from one to three brain cells.
7A and 7B are the same. FIG. 7A shows the acquired imaging data of the brain cell and its surroundings, and both 1 and 2 in FIG. 7A show the brain cell. FIG. 7B is a graph showing the time-dependent change in the intensity of the fluorescent signal derived from these 1 and 2 brain cells.
5B, 6B, and 7B, the vertical axis represents “normalized fluorescence intensity”, and the horizontal axis represents “time (seconds)”.

From FIGS. 5A to 5B, FIGS. 6A to 6B, and FIGS. 7A to 7B, in each of the case using compound (I) -1-102 and the case using compound (I) -1-103 Also, as in the case of using dopamine, a change in the fluorescence intensity was observed. That is, similarly to dopamine, both compound (I) -1-102 and compound (I) -1-103 bind to the G protein-coupled receptor on the cell surface, and change the concentration of cAMP which is a second messenger. It was confirmed that it had the same physiological activity as that of naturally occurring dopamine.

<< Production of Compound (I) >>
[Example 9]
<Production of compound (I) -3-101>
A compound represented by the following formula (I) -3-101 (which may be abbreviated as “compound (I) -3-101” in the present specification) was produced by the following route.

(Production of 3-bromo-4,5-dimethoxybenzaldehyde)
5-bromovanillin (10.0 g, 43.3 mmol), potassium carbonate (8.97 g, 64.9 mmol) and DMF (40 mL) were added to a 100-mL round bottom flask whose atmosphere was replaced with nitrogen gas. And stirred at room temperature.
Next, iodomethane (4.04 mL, 9.22 g, 64.9 mmol) was added to the obtained suspension, and the obtained mixture was stirred at room temperature for 19 hours to be reacted.
Next, water was added to the obtained reaction solution to stop the reaction. Then, the obtained mixture is extracted three times with a mixed solvent (30 mL) of ethyl acetate (50% by volume) / hexane (50% by volume), and the collected organic layer is washed with water (30 mL). It was washed three times, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a precipitate.
Next, the obtained precipitate was washed with hexane and dried under reduced pressure.
As a result, 3-bromo-4,5-dimethoxybenzaldehyde was obtained as the desired product (9.72 g (39.7 mmol), 92% yield).
The NMR data and HRMS (ESI) data of the obtained 3-bromo-4,5-dimethoxybenzaldehyde are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.89 (s, 3 H), 3.24 (s, 3 H), 7.29 (d, J = 1.6 Hz, 1 H), 7.55 (d, J = 1.6 Hz, 1 H), 9.75 (s, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) 56.1, 60.7, 110.0, 117.7, 128.5, 132.9, 151.6, 154.0, 189.7.
HRMS (ESI) calcd for C ₉ H ₁₀ BrO ₃ [M + H] ⁺ : 244.9808, 246.9787, found: 244.9885, 246.9775; calcd for C ₉ H ₉ BrO ₃ Na [M + Na] +: 266.9627, 268.9607, found : 266.9612, 268.9594.

(Production of (E) -3-bromo-4,5-dimethoxy-β-nitrostyrene)
The atmosphere obtained was replaced with nitrogen gas, and the obtained 3-bromo-4,5-dimethoxybenzaldehyde (12.0 g, 49.0 mmol) and ammonium acetate (200 g) were placed in a 200-mL round bottom flask equipped with a Dimroth. 3.80 g, 49.3 mmol), molecular sieve 3A (6.0 g), nitromethane (12 mL) and acetic acid (36 mL) were added.
Then, the resulting mixture was heated at 100 ° C. for 2 hours and cooled to room temperature.
Next, the molecular sieve 3A was removed by filtration using a filter paper, and the residue was washed with ethyl acetate.
Then, the solvent is removed, and the obtained solid is washed with a small amount of ethyl acetate, filtered, and dried under reduced pressure to obtain the target compound (E) -3-bromo-4,5 as a bright yellow solid. -Dimethoxy-β-nitrostyrene was obtained (yield 10.2 g (35.5 mmol), yield 72%).
The NMR data of the obtained (E) -3-bromo-4,5-dimethoxy-β-nitrostyrene are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ3.92 (s, 3 H), 3.93 (s, 3 H), 6.98 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H), 7.51 (d, J = 13.6 Hz, 1 H), 7.89 (d, j = 13.6 Hz, 1 H).

(Production of 3-bromo-4,5-dimethoxyphenethylamine)
In a 100 mL round bottom flask, (E) -3-bromo-4,5-dimethoxy-β-nitrostyrene (2.10 g, 7.29 mmol) obtained above and zinc powder (5.7 g, 87 .5 mmol) and methanol (15 mL) were added and stirred at -10.degree.
Next, hydrochloric acid (concentration: 12N, 15 mL) was added dropwise to the obtained mixture, and the mixture was stirred at -10 ° C for 6 hours to be reacted.
Another one of the same reaction mixture obtained by the above-mentioned operations was further prepared, and these two reaction mixtures were mixed.
The obtained mixture was filtered with filter paper, and the residue was washed with methanol.
Then, the resulting solution was stirred again at −10 ° C., and a saturated aqueous sodium hydroxide solution was added until the pH reached 11.
Next, water was added to the obtained reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
As a result, the target substance, 3-bromo-4,5-dimethoxyphenethylamine, was obtained as a reddish oil in a quantitative yield (3.82 g, 14.7 mmol).
The NMR data and HRMS (ESI) data of the obtained 3-bromo-4,5-dimethoxyphenethylamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.67 (t, J = 6.8 Hz, 2 H), 2.95 (t, J = 6.8 Hz, 2 H), 3.84 8s, 3 H), 3.86 (s, 3 H), 6.70 (d, J = 1.6 Hz, 1 H), 6.98 (d, J = 2.0 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ) 38.8, 42.9, 55.9, 60.4, 112.2, 117.3, 124.5, 136.7, 144.6, 153.4.
HRMS (ESI) calcd for C ₁₀ H ₁₅ BrNO ₂ [M + H] ⁺ : 260.0281, 262.0260, found: 260.0249, 262.0228.

(Production of N-trifluoroacetyl-3-bromo-4,5-dimethoxyphenethylamine)
In a 50 mL round bottom flask, 3-bromo-4,5-dimethoxyphenethylamine obtained above (530 mg, 2.04 mmol), ethyl trifluoroacetate (0.27 mL, 2.24 mmol), N, N- Diisopropylethylamine (0.36 mL, 2.04 mmol) and methanol (5 mL) were added, and the mixture was stirred at room temperature for 21 hours.
Next, the solvent was distilled off from the obtained reaction solution under reduced pressure to obtain a crude product. The crude product was added to a tube (3 cm in length) filled with silica gel, and eluted with a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume). Then, the solvent was removed from the eluate, and the obtained crude product was purified by flash chromatography.
As described above, N-trifluoroacetyl-3-bromo-4,5-dimethoxyphenethylamine, which was the target substance, was obtained as a white solid (360 mg (1.01 mmol), 50% yield).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.39. .
The NMR data and HRMS (ESI) data of the obtained N-trifluoroacetyl-3-bromo-4,5-dimethoxyphenethylamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.80 (t, J = 7.2 Hz, 2 H), 3.56 (dd, J = 6.8, 13.6 Hz, 2 H), 3.81 (s, 3 H), 3.84 ( s, 3 H), 6.67 (d, J = 1.6 Hz, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 7.10 (br, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ34.2, 40.8, 55.8, 60.4, 112.1, 115.8 (q, J = 287 Hz), 117.6, 124.5, 135.1, 145.0, 153.7, 157.4 (J = 36.9 Hz).
HRMS (ESI) calcd for C ₁₂ H ₁₃ BrF ₃ NO ₃ Na [M + Na] ⁺ : 377.9923, 379.9903, found: 377.9864, 379.9845.

(Production of N-trifluoroacetyl-5-bromodopamine)
In a 100 mL round bottom flask, N-trifluoroacetyl-3-bromo-4,5-dimethoxyphenethylamine (1.46 g, 4.10 mmol) obtained above and dry methylene chloride (30 mL) were added, Stirred at -10 ° C.
Next, a methylene chloride solution of boron tribromide having a concentration of 1 M (90 mL) was added dropwise to the obtained solution, and the obtained mixture was stirred at room temperature for 2 hours to be reacted.
Next, methanol was added to the obtained reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure to obtain a crude product.
Next, the obtained crude product was dissolved in ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. The washed organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain N-trifluoroacetyl-5-bromodopamine as a brown oily substance (yield 1.16 g). .
The NMR data and HRMS (ESI) data of the obtained N-trifluoroacetyl-5-bromodopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ2.67 (t, J = 7.2 Hz, 2 H), 3.48 (dd, J = 6.8, 13.6 Hz, 2 H), 6.64 (d, J = 2.0 Hz, 1 H), 6.77 (d, J = 2.0 Hz, 1 H), 7.31 (br, 1 H).
_{HRMS (ESI) calcd for C 10} H 9 BrF 3 NO 3 Na [M + Na] +: 349.9610, 351.9610, found: 349.9566, 351.9555.

(Production of N-trifluoroacetyl-O, O'-isopropylidene-5-bromodopamine)
In a 100 mL round bottom flask, the N-trifluoroacetyl-5-bromodopamine obtained above (1.16 g, total amount), 2,2-dimethoxypropane (2.0 mL, 16.4 mmol), p- Toluenesulfonic acid monohydrate (39 mg, 0.21 mmol) and benzene (40 mL) were added.
Then, the round bottom flask in this state was connected to a dropping funnel filled with molecular sieve 4A, the dropping funnel was connected to a Dimroth, and the Dimroth was connected to a tube filled with calcium chloride.
Next, in this state, the mixture in the round bottom flask was stirred at 100 ° C. for 20 hours, during which the solvent vaporized in the molecular sieve 4A was allowed to pass.
Next, the solvent was distilled off from the obtained reaction solution under reduced pressure, the obtained reaction mixture was dissolved in ethyl acetate, and this solution was washed with a saturated aqueous solution of sodium hydrogen carbonate. The washed organic layer was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a crude product.
This crude product was purified by flash chromatography. At this time, using a mixed solvent of ethyl acetate (20% by volume) / hexane (80% by volume) as a mobile phase, the target product was separated and eluted, and the solvent was removed from the eluate.
As a result, N-trifluoroacetyl-O, O'-isopropylidene-5-bromodopamine was obtained as the desired product (yield 1.31 g (3.56 mmol), total yield of two steps 87%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.71. .
The NMR data and HRMS (ESI) data of the obtained N-trifluoroacetyl-O, O'-isopropylidene-5-bromodopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.71 (s, 6 H), 2.77 (t, J = 7.2 Hz, 2 H), 3.54 (dd, J = 6.8, 13.6 Hz, 2 H), 6.52 ( d, J = 1.6 Hz, 1 H), 6.75 (d, J = 1.6 Hz, 2 H).
HRMS (ESI) calcd for C ₁₃ H ₁₄ BrF ₃ NO ₃ [M + H] ⁺ : 368.0104, found: 368.0438.

(Production of N-trifluoroacetyl-O, O'-isopropylidene-5- (2-trimethylsilylethynyl) dopamine)
Bis (triphenylphosphine) palladium (II) dichloride (190 mg, 0.27 mmol), copper iodide (104 mg, 0.55 mmol) in a 50 mL two-necked round bottom flask equipped with a Dimroth and heat-dried And triphenylphosphine (69 mg, 0.26 mmol) were added. Then, the operation of sucking the atmosphere inside the flask and then flowing argon gas into the flask was repeated, thereby replacing the atmosphere inside the flask with argon gas.
Separately, N-trifluoroacetyl-O, O'-isopropylidene-5-bromodopamine (1.00 g, 2.72 mmol) obtained above was placed in a 50-mL round-bottomed flask having a capacity of 50 mL, which had been dried by heat. Was added and dissolved in diisopropylamine (20 mL). This diisopropylamine was distilled in the presence of sodium hydroxide and then stored in the presence of molecular sieve 4A.
The entire amount of the obtained diisopropylamine solution was transferred into a two-necked round-bottomed flask after the replacement with the above argon gas, and the obtained mixture was stirred at room temperature for 30 minutes.
Then, to the resulting mixture was added trimethylsilylacetylene (0.5 mL, 3.53 mmol) and the resulting mixture was stirred at 75 ° C. for 36 hours.
Next, the reaction solution was cooled to room temperature and concentrated to obtain a crude product. This crude product was added inside a tube filled with silica gel and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, and the obtained mixture was added again to the inside of a tube filled with silica gel, and eluted with a mixed solvent of ethyl acetate (50% by volume) / hexane (50% by volume). Then, the eluate was purified by flash chromatography.
As a result, N-trifluoroacetyl-O, O'-isopropylidene-5- (2-trimethylsilylethynyl) dopamine as a target substance was obtained as a brown oil (yield 779 mg (2.02 mmol), yield 74). %).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.56. .
The NMR data and HRMS (ESI) data of the obtained N-trifluoroacetyl-O, O'-isopropylidene-5- (2-trimethylsilylethynyl) dopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.26 (s, 9 H), 1.70 (s, 6 H), 2.74 (t, J = 7.2 Hz, 2 H), 3.55 (dd, J = 6.8, 13.2 Hz, 2 H), 6.40 (br, 1 H), 6.52 (d, J = 1.6 Hz, 1 H), 6.68 (d, J = 1.2 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ-0.2 (three trimethylsilyl carbons), 25.9 (two isopropyliden methyl carbons), 34.4, 40.9, 98.7, 98.8, 104.3, 109.0, 115.8 (q, J = 286 Hz), 119.3 , 124.7, 130.3, 147.9, 148.0, 157.3 (q, J = 36.4 Hz).
HRMS (ESI) calcd for C ₁₈ H ₂₃ F ₃ NO ₃ Si [M + H] ⁺ : 386.1394, found: 386.1353; calcd for C ₁₈ H ₂₂ F ₃ NO ₃ SiNa [M + Na] ⁺ : 408.1213, found: 408.1164.

(Production of N-trifluoroacetyl-O, O'-isopropylidene-5-ethynyldopamine)
In a 50 mL round bottom flask, N-trifluoroacetyl-O, O'-isopropylidene-5- (2-trimethylsilylethynyl) dopamine (136 mg, 0.353 mmol) obtained above, potassium carbonate (10 mg, 0.071 mmol) and methanol (2 mL) were added.
Next, the resulting mixture was stirred at room temperature for 22 hours to react.
Next, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction solution to stop the reaction. Then, the obtained reaction solution was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
This crude product was purified by flash chromatography. At this time, using a mixed solvent of ethyl acetate (15% by volume) / hexane (85% by volume) as a mobile phase, the target substance was separated and eluted, and the solvent was removed from the eluted substance.
As a result, N-trifluoroacetyl-O, O'-isopropylidene-5-ethynyldopamine as a target substance was obtained as a brown oil (yield: 65.0 mg (0.207 mmol), yield: 59%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.48. .
The NMR data and HRMS (ESI) data of the obtained N-trifluoroacetyl-O, O'-isopropylidene-5-ethynyldopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ1.71 (s, 6 H), 2.76 (t, J = 7.2 Hz, 2 H), 3.28 (s, 1 H), 3.56 (dd, J = 6.8, 13.6 Hz, 2 H), 6.57 (d, J = 1.2 Hz, 2 H), 6.70 (d, J = 1.2 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ25.8 (two isopropyliden methyl carbons), 34.4, 40.9, 77.8, 81.2, 103.0, 109.4, 115.8 (q, J = 286 Hz), 119.5, 124.3, 130.7, 148.0, 148.4, 157.3 (q, J = 36.6 Hz).
HRMS (ESI) calcd for C ₁₅ H ₁₄ F ₃ NO ₃ Na [M + Na] ⁺ : 336.0818, found: 336.0721.

(Production of Compound (I) -3-101)
N-trifluoroacetyl-O, O'-isopropylidene-5-ethynyldopamine (65.0 mg, 0.207 mmol) obtained above in a round bottom flask having a capacity of 30 mL, lithium hydroxide having a concentration of 1 M An aqueous solution (0.4 mL) and tetrahydrofuran (0.9 mL) were added.
Next, the obtained mixture was stirred at room temperature for 7 hours to be reacted.
Next, water was added to the obtained reaction solution, the obtained mixture was extracted with diethyl ether, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
As a result, O, O'-isopropylidene-5-ethynyldopamine (namely, compound (I) -3-101) was obtained as a yellow oil (yield: 40.2 mg (0.184 mmol); 89%).
The NMR data and HRMS (ESI) data of the obtained compound (I) -3-101 are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 (br, 2 H), 1.71 (s, 6 H), 2.62 (t, J = 6.8 Hz, 2 H), 2.91 (t, J = 6.8 Hz, 2 H), 3.27 (s, 1 H), 6.59 (d, J = 1.2 Hz, 1 H), 6.72 (d, J = 1.2 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ25.8 (two isopropyliden methyl carbons), 39.4, 43.3, 78.2, 80.8, 102.6, 109.7, 119.1, 124.4, 132.9, 147.6, 147.7.
HRMS (ESI) calcd for C ₁₃ H ₁₆ NO ₂ [M + H] ⁺ : 218.1176, found 218.1179.

[Example 10]
A compound represented by the following formula (I) -1-104 (hereinafter sometimes abbreviated as “compound (I) -1-104”) was produced by the following route.

<Production of Compound (I) -1-104>
(Production of N-propargyl-N-trifluoroacetyl-O, O'-dimethyldopamine)
In a 50 mL round bottom flask, N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine (220 mg, 0.672 mmol), trifluoroacetic acid (26 μL, 0.336 mmol) and methylene chloride (3 mL) ) Was added. N-propargyl-N-trifluoroacetyl-O, O'-isopropylidendopamine was prepared in the same manner as in Example 1.
Next, the obtained mixture was stirred at room temperature for 43 hours to be reacted.
Next, water was added to the obtained reaction solution to stop the reaction. Then, the obtained reaction solution was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a crude product.
This crude product was dissolved in DMF (3 mL), to which iodomethane (0.13 mL, 2.02 mmol) and potassium carbonate (280 mg, 2.02 mmol) were added, and the resulting mixture was allowed to stand at room temperature for 24 hours. Stir and react.
Next, water was added to the obtained reaction solution to stop the reaction. The obtained reaction solution is extracted with a mixed solvent of ethyl acetate (50% by volume) / hexane (50% by volume), the organic layer is dried over anhydrous sodium sulfate, and the solvent is removed. A crude product was obtained. This crude product was added into a tube filled with silica gel, and eluted with a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume). Then, the eluate was dried under reduced pressure.
As a result, N-propargyl-N-trifluoroacetyl-O, O'-dimethyldopamine was obtained as the desired product (yield 190 mg (0.603 mmol), yield 90%).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.31. .
The NMR data and HRMS (ESI) data of the obtained N-propargyl-N-trifluoroacetyl-O, O'-dimethyldopamine are shown below.

¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ2.28-2.29 (m, 1 H), 2.82 (t, J = 7.6 Hz, 2 H), 3.63-3.68 (m, 2 H), 3.77 -3.79 (m, 6 H), 3.89 and 4.17 (rotameric d, J = 2.0 Hz, 2 H), 6.63-6.69 (m, 2 H), 6.72-6.75 (m, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ , mixture of two rotamers) δ32.4 and 32.5, 35.9 and 37.7 (q for δ37.7 peak, J = 4.1 Hz), 48.6 and 48.9 (q for δ48.6 peak, J = 2.1 Hz), 55.60 and 55.65 (two methoxy carbon peaks are overlapping), 73.31 and 73.35, 76.6 and 76.8, 111.2 and 111.3, 111.6 and 111.7, 116.0 and 116.2 (q, J = 292 Hz), 120.5, 129.4 and 130.2, 147.7 and 147.9, 148.9 and 149.0, 156.1 and 156.4 (q, J = 37.0 Hz).
HRMS (ESI) calcd for C ₁₅ H ₁₇ F ₃ NO ₃ [M + H] ⁺ : 316.1155, found: 316.1140; calcd for C ₁₅ H ₁₆ F ₃ NO ₃ Na [M + Na] ⁺ : 338.0974, found: 338.0960 .

(Production of Compound (I) -1-104)
The N-propargyl-N-trifluoroacetyl-O, O'-dimethyldopamine (190 mg, 0.603 mmol) obtained above in a round-bottomed flask having a capacity of 100 mL and a 1 M aqueous lithium hydroxide solution (1 .3 mL) and THF (4 mL).
Next, the obtained mixture was stirred at room temperature for 12 days to be reacted.
Next, the obtained reaction solution was cooled to 0 ° C., and 1N hydrochloric acid was added thereto to stop the reaction. Then, methylene chloride was added to the obtained reaction solution, extraction was performed with water, and the aqueous layer was washed with methylene chloride. An aqueous sodium hydrogen carbonate solution was added to the aqueous layer until the pH of the washed aqueous layer reached 11, and the obtained mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. By removing the solvent, a crude product was obtained.
The crude product was dissolved in diethyl ether (1 mL) in a 10 mL round bottom flask, to which was added a 1 M solution of hydrogen chloride in diethyl ether (1 mL). Then, the resulting solid was separated by filtration, washed with diethyl ether, and dried under reduced pressure.
Thus, O, O'-dimethyl-N-propargyldopamine hydrochloride (namely, compound (I) -1-104) was obtained as a light brown solid (yield 98 mg (0.383 mmol). Rate 64%).
The NMR data and HRMS (ESI) data of the obtained compound (I) -1-104 are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ2.92 (t, J = 8.0 Hz, 2 H), 3.22 (t, J = 2.8 Hz, 1 H), 3.26-3.28 (m, 2 H), 3.917 (s, 3 H), 3.294 (s, 3 H), 3.92 (d, J = 2.8 Hz, 2 H), 6.79 (dd, J = 2.0, 8.4 Hz, 1 H), 6.87-6.90 (m, 2 H).
¹³ C NMR (100 MHz, CD ₃ OD) δ 32.7, 37.4, 49.8, 56.5 (two MeO carbons were overlapping), 74.5, 79.3, 113.4, 113.6, 122.2, 130.1, 149.9, 150.9.
HRMS (ESI) calcd for C ₁₃ H ₁₈ NO ₂ [M + H] ⁺ : 220.1332, found: 220.1303.

<< Evaluation of neurological modulator >>
[Example 11]
Using the following seven compounds, the following tests were performed to evaluate whether or not the compounds were taken up into nerve cells.
・ FFN511
-Compound (I) -1-102 obtained in Example 1
-Compound (I) -1-103 obtained in Example 1
-Compound (I) -1-104 obtained in Example 10
-Compound (I) -1-201 obtained in Example 5
-Compound (I) -2-301 obtained in Example 2
-Compound (I) -3-101 obtained in Example 9

That is, PC-12 cells, which are rat adrenal pheochromocytoma, are maintained in a normal medium, and then seeded on a cover glass coated with type I collagen. Differentiated into cells. Here, the normal medium contains fetal bovine serum (Fetal Bovine Serum) at a concentration of 10% by mass, horse serum (Horse Serum) at a concentration of 10% by mass, and contains penicillin and streptomycin. It is Dulbecco's modified Eagle's medium.
Next, an extracellular solution containing each of the seven compounds was prepared. Here, the extracellular fluid contains sodium chloride (NaCl) at a concentration of 125 mM, potassium chloride (KCl) at a concentration of 5 mM, dextrose at a concentration of 10 mM, and It contains HEPES (2- [4- (2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid) at a concentration of 10 mM, contains magnesium chloride (MgCl ₂ ) at a concentration of 1 mM, and contains 2 mM Is an aqueous solution containing calcium chloride (CaCl ₂ ) at a concentration of pH 7.3. Then, the differentiated nerve cells obtained above were immersed in this extracellular solution at 37 ° C. for 30 minutes. Then, the immersed nerve cells were chemically fixed.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the immobilized nerve cells using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst. The fixed nerve cells subjected to this reaction were immersed in an extracellular solution containing six compounds other than FFN511 among the seven compounds.
Next, the nerve cells after the reaction and the nerve cells fixed by immersion in an extracellular solution containing FFN511 (that is, unreacted nerve cells) are confocal microscope (Olympus “FV1000”). Observation was performed with a 10 × or 60 × objective lens. The results are shown in FIGS. 8A to 8G. FIG. 8A is imaging data of a nerve cell using FFN511, FIG. 8B is imaging data of a nerve cell using Compound (I) -2-301, and FIG. ) -1-201 shows the imaging data of nerve cells using FIG. 8D, FIG. 8D shows the imaging data of nerve cells using compound (I) -1-103, and FIG. FIG. 8F is image data of a nerve cell when compound (I) -1-104 is used, and FIG. 8G is image data of a nerve cell when compound (I) -1-104 is used. 2) Imaging data of a nerve cell when -3-101 is used.

From FIGS. 8A to 8G, all the six compounds other than FFN511 were taken into neurons differentiated from PC-12 cells in the same manner as FFN511, and in this state, the azide group was added by a click reaction. It was confirmed that the label was reacted with the fluorescent dye and detected by a confocal microscope.
These six compounds of the present invention can be evaluated for their localization in nerve cells. In particular, compound (I) -1-102, compound (I) -1-103, and compound (I) -1- 104 and Compound (I) -3-101 could be confirmed to exhibit similar intracellular distribution to that of FFN511.

[Example 12]
The compound (I) -3-101 obtained above and the FFN511 fluorescent dye were dissolved in the same artificial cerebrospinal fluid as used in Example 6, and the concentration of the compound (I) -3-101 was 10 μmol / ml. L and a solution having a concentration of the FFN511 fluorescent dye of 10 μmol / L was prepared.
Next, a solubilized test piece was prepared in the same manner as in Example 6.
Then, Alexa Fluor® 594 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
The test piece was observed using an 840 nm femtosecond ultrashort pulse laser (Maitai HP manufactured by Newport) and a microscope (“FV1000MPE” manufactured by Olympus). The results are shown in FIGS. 9A to 9F.
FIG. 9A is imaging data of a test piece when only the FFN511 fluorescent dye is detected, and FIG. 9B is a test piece when only the compound (I) -3-101 is detected in the same region as in FIG. 9A. FIG. 9C shows the imaging data of the test piece when the FFN511 fluorescent dye and the compound (I) -3-101 were simultaneously detected in the same region as in FIG. 9A. 9D, 9E, and 9F are image data obtained by enlarging the data of FIGS. 9A, 9B, and 9C by 2.5 times, respectively.

9A and 9D, light emission by the FFN511 fluorescent dye was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 9A and FIG. 9D, other light emitting regions by the FFN511 fluorescent dye were present. 9A and 9D, it was confirmed that the FFN511 fluorescent dye was incorporated into the dopamine-containing neurons, as disclosed in the known literature.
9B and 9E, light emission by the labeled compound (I) -3-101 was confirmed. A part of the light emitting region is indicated by a circle. In FIG. 9B and FIG. 9E, another light emitting region by the labeled compound (I) -3-101 was present. From FIG. 9B and FIG. 9E, compound (I) -3-101 was incorporated into dopamine-containing neurons, and in this state, it was labeled by reacting with the azido group-added fluorescent dye by a click reaction. I was able to confirm that.
9C and 9F, the FFN511 fluorescent dye and the labeled compound (I) -3-101 can be simultaneously detected, and in the dopamine-containing neurons, the compound (I) -3-101 is It could be confirmed that the FFN511 was selectively incorporated into the same region as the fluorescent dye.

As is clear from the comparison between this example and Example 7, compound (I) -3-101 was prepared in the same manner as compound (I) -1-101 and compound (I) -1-103, and As in the case of a naturally-occurring nerve function-modulating substance, it can be taken up into nerve cells and further react with various azide-group-added compounds in the nerve cells. It was shown that the use of a dye allowed clear detection in nerve cells.

In this example, compound (I) -3-101 was also detected after reacting with a fluorescent dye by a click reaction, but this compound has a triple bond between carbon atoms. Therefore, this compound can also be directly detected using a Raman microscope without using a luminescent label.

<< Production of Compound (II) >>
Example 13
A compound represented by the following formula (II) -1-101 (which may be abbreviated as “compound (II) -1-101” in the present specification) was produced by the following route.

<Production of Compound (II) -1-101>
(Production of 2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethylamine)
In a 100 mL round bottom flask, serotonin hydrochloride (2.12 g, 10 mmol), imidazole (2.24 g, 33 mmol), tert-butyldimethylchlorosilane (3.32 g, 22 mmol), and THF (50 mL) were added. .
Next, these mixtures were stirred at room temperature for 24 hours to react.
Next, the precipitate was separated by filtration, washed with methylene chloride (20 mL) three times, and dissolved in 0.5 M sodium hydroxide (100 mL).
Next, the obtained aqueous solution was extracted three times with diethyl ether (30 mL), and the collected organic layers were washed three times with water (30 mL) and dried over anhydrous sodium sulfate.
Then, the solvent was removed to obtain 2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethylamine as a white solid.
The NMR data of the obtained 2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethylamine are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ 0.18 (s, 6 H), 1.01 (s, 9 H), 2.82-2.92 (m, 4 H), 6.67 (dd, J = 2.0, 8.8 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1 H), 7.04 (s, 1 H), 7.19 (d, J = 8.8 Hz, 1 H).

(Production of N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide)
In a 100 mL round bottom flask, the total amount of N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide obtained above, Ethyl trifluoroacetate (1.55 mL, 1.85 g, 13 mmol), N, N-diisopropylethylamine (1.75 mL, 1.29 g, 10 mmol) and methanol were added.
Next, these mixtures were stirred at room temperature for 48 hours to be reacted.
Next, water was added to the obtained reaction solution to stop the reaction. Then, the reaction mixture was extracted three times with ethyl acetate (30 mL), and the collected organic layers were washed with water and dried over anhydrous sodium sulfate.
Next, after removing the solvent, the precipitated solid was washed with hexane and dried under reduced pressure to give N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl as a white solid. -2,2,2-trifluoroacetamide was obtained (3 g (7.76 mmol), 78% yield).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.4. .
The NMR data and HRMS (ESI) data of the obtained N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.21 (s, 6 H), 1.02 (s, 9 H), 2.98 (t, J = 6.8 Hz, 2 H), 3.66 (dd, J = 6.8 , 12.8 Hz, 2 H), 6.38 (br, 1 H), 6.79 (dd, J = 2.0, 8.8 Hz, 1 H), 6.98 (dt, J = 2.4, 0.4 Hz, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 8.00 (br, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ-4.45, 18.2, 24.7, 25.8, 39.9, 107.9, 111.2, 111.4, 111.7, 115.8 (q, J = 292 Hz), 117.3, 123.0, 127.6, 132.0, 149.4, 157.1 (q, J = 37.8 Hz).
HRMS (ESI) calcd for C ₁₈ H ₂₆ F ₃ N ₂ O ₂ Si [M + H] ⁺ : 387.1710, found: 387.1724.

(Production of N-2- (5-tert-butyldimethylsilyloxy-1-propargyl-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide)
In a 100 mL round bottom flask, N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide (800 mg, 2.07 mmol), and dry THF (20 mL).
Then, the obtained solution was stirred at 0 ° C, and a THF solution of lithium diisopropylamide (concentration: 1.5 M, 1.5 mL, 2.25 mmol as lithium diisopropylamide) was added thereto, and the resulting mixture was cooled to 0 ° C. For 1 hour. To this, propargyl bromide (0.17 mL, 253 mmg, 2.13 mmol) was added, and the resulting mixture was stirred at 0 ° C. and further stirred at room temperature for 18 hours to react.
Next, a saturated ammonium chloride aqueous solution was added to the obtained reaction solution to stop the reaction. Then, the obtained reaction solution was extracted with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate to obtain a crude product.
Next, the crude product was added into a tube filled with silica gel, and eluted with a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume). Then, the eluate was purified by flash chromatography. At this time, a mixed solvent of ethyl acetate and hexane was used as a mobile phase, and the concentration of ethyl acetate was increased from 10% by volume to 30% by volume to separate and elute the target substance. Removed.
As described above, N-2- (5-tert-butyldimethylsilyloxy-1-propargyl-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide as a target substance was obtained as a pale white solid. Was obtained (180 mg (0.424 mmol), 20% yield).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.52. .
The NMR data and HRMS (ESI) data of the obtained compound (II) -1-101 are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ0.20 (s, 6 H), 1.01 (s, 9 H), 2.39 (dt, J = 0.4, 2.4 Hz, 1 H), 2.96 (t, J = 6.8 Hz, 2 H), 3.63 (dd, J = 6.8, 13.2 Hz, 2 H), 4.77 (d, J = 2.8 Hz, 2 H), 6.50 (br, 1 H), 6.83 (dd, J = 2.0, 8.8 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H), 7.00 (s, 1 H), 7.22 (d, J = 9.2 Hz, 1 H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ-4.45, 18.1, 24.5, 25.7, 35.7, 39.9, 73.5, 77.6, 108.3, 109.9, 110.6, 115.8 (q, J = 292 Hz), 116.5, 125.8, 128.5, 131.9, 149.5, 157.1 (q, J = 37.3 Hz).
HRMS (ESI) calcd for C ₂₁ H ₂₇ F ₃ N ₂ O ₂ SiNa [M + Na] ⁺ : 447.1686, found: 447.1656.

(Production of Compound (II) -1-101)
The above obtained N-2- (5-tert-butyldimethylsilyloxy-1-propargyl-1H-indol-3-yl) ethyl-2,2,2-trifluoro was placed in a 50 mL round bottom flask. Acetamide (180 mg, 0.424 mmol), aqueous lithium hydroxide solution (concentration 1 M, 0.85 mL) and THF (2.8 mL) were added.
Then, the obtained mixture was stirred at room temperature for 12 hours, and water (20 mL) was added thereto.
Next, the obtained reaction mixture was extracted three times with chloroform (20 mL), the collected organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. (1 mL). Then, the methanol solution obtained above was dropped into a diethyl ether solution (10 mL) at 0 ° C. containing hydrogen chloride at a concentration of 1 M, and after removing the solvent, the obtained residual mixture was again added to methanol (1 mL). ). Then, the methanol solution obtained above was dropped into diethyl ether (50 mL) at 0 ° C., and the precipitated crystals were separated by filtration, washed with diethyl ether, and dried under reduced pressure to obtain brown crystals. Thus, 1-propargyl serotonin hydrochloride (the compound (II) -1-101), which was the target product, was obtained (30 mg (0.12 mmol), 28% yield).
The NMR data and HRMS (ESI) data of the obtained compound (II) -1-101 are shown below.

¹ H NMR (400 MHz, CD ₃ OD) δ2.76 (dt, J = 1.2, 2.4 Hz, 1 H), 2.80-2.83 (m, 2 H), 2.89-2.93 (m, 2 H), 4.85- 4.86 (br, 2 H), 6.74 (dd, J = 2.0, 8.8 Hz, 1 H), 6.93 (d, J = 2.0 Hz, 1 H), 7.04 (s, 1 H), 7.24 (d, J = (8.8 Hz, 1 H).
¹³ C NMR (100 MHz, CD ₃ OD) δ 29.4, 36.2, 42.8, 74.0, 79.7, 104.1, 111.2, 112.7, 113.0, 127.3, 130.5, 132.9, 151.8.
HRMS (ESI) calcd for C ₁₃ H ₁₅ N ₂ O [M + H] +: 215.1179, found: 215.1165.

[Example 14]
A compound represented by the following formula (II) -2-101 (which may be abbreviated as “compound (II) -2-101” in the present specification) by the following route, and a compound represented by the following formula (II) ) -2-102 (in this specification, may be abbreviated as “compound (II) -2-102”).

<Production of compound (II) -2-101>
(Production of N-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethyl-N-propargyl-2,2,2-trifluoroacetamide)
In a 100 mL round bottom flask was added 52 mg of sodium hydride (2.17 mmol) immersed in 78 mg of oil. This sodium hydride was washed three times with hexane (10 mL). Then, the remaining hexane was distilled off under reduced pressure, the atmosphere in the round bottom flask was replaced with nitrogen gas, and dry DMF (30 mL) was further added to the round bottom flask. And stirred.
N-2- (5-tert-butyldimethylsilyloxy-1H-indol-3-yl) ethyl-2,2,2-trifluoroacetamide (800 mg, 2.07 mmol) obtained in the previous example was added to DMF. (10 mL) to prepare a DMF solution. This DMF solution is added dropwise to the 0 ° C. suspension obtained above, and the resulting solution is stirred at 0 ° C. for 30 minutes. Was added, and the resulting mixture was stirred at 0 ° C. and further stirred at room temperature for 6 hours to react.
Next, a saturated ammonium chloride aqueous solution was added to the obtained reaction solution to stop the reaction. Then, the obtained reaction solution was extracted three times with methylene chloride (20 mL), and the obtained organic layer was dried over anhydrous sodium sulfate.
Next, the solvent was removed from the dried organic layer, water was added, and the obtained mixture was extracted three times with diethyl ether (30 mL), and the obtained organic layer was dried over anhydrous sodium sulfate. By drying, a crude product was obtained.
Next, the crude product was added into a tube filled with silica gel, and eluted with a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume). Then, the eluate was purified by flash chromatography. At this time, a mixed solvent of ethyl acetate and hexane was used as a mobile phase, and the concentration of ethyl acetate was increased from 5% by volume to 20% by volume to separate and elute the target substance. Removed.
Thus, N-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethyl-N-propargyl-2,2,2-trifluoroacetamide was obtained (yield 70 mg (0.181 mmol). ), 9% yield).
Using a mixed solvent of ethyl acetate (30% by volume) / hexane (70% by volume) as a developing solvent, the obtained target product was developed by thin-layer chromatography (TLC) to find that the Rf value was 0.46. .
NMR data and HRMS (ESI) data of the obtained N-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethyl-N-propargyl-2,2,2-trifluoroacetamide were obtained. It is shown below.

¹ H NMR (400 MHz, CDCl ₃ mixture of rotamers) δ 2.35 and 2.37 (rotameric t, J = 2.4 Hz, 1 H), 2.39 and 2.41 (rotameric t, J = 2.4 Hz, 1 H), 2.53 (t , J = 2.4 Hz, 1 H), 3.08 (t, J = 8.0 Hz, 2 H), 3.80 (q, J = 8.0 Hz, 2), 4.06 and 4.32 (rotameric d, J = 2.0 Hz for δ4.07 peak and J = 2.8 Hz for δ4.32 Hz, 2 H), 4.74 (t, J = 2.4 Hz, 2 H), 4.78 and 4.80 (rotameric d, J = 6.8 Hz, 2 H), 6.98 (dt, J = 9.2, 2.8 Hz, 1 H), 7.04 (d, J = 6.8 Hz, 1 H), 7.14 and 7.22 (rotameric d, J = 2.4 Hz, 1 H), 7.28 and 7.30 (rotameric d, J = 9.2 Hz , 1H).
¹³ C NMR (100 MHz, CDCl ₃ mixture of rotamers) δ22.6 and 24.7, 35.8 and 35.9, 36.2 and 37.9 (q for δ37.9 peak, J = 4.3 Hz), 47.8 and 48.2 (q for δ47.8 peak , J = 3.1 Hz), 56.8 and 56.9, 73.4 and 73.6, 73.6 and 73.7, 75.27 and 75.35, 77.0, 77.6 and 77.7, 79.0 and 79.2, 102.8 and 103.1, 110.4 and 110.5, 110.6 and 111.3, 113.0 and 113.1, 116.2 and 116.4 (q, J = 292 Hz), 126.2, 128.2 and 128.4, 131.9 and 132.0, 152.2 and 152.3, 156.3 and 156.7 (q, J = 37.0 Hz).
HRMS (ESI) calcd for C ₂₁ H ₁₈ F ₃ N ₂ O ₃ [M + H] ⁺ : 387.1315, found: 387.1320.

(Production of Compound (II) -2-101)
In a 50 mL round bottom flask, the N-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethyl-N-propargyl-2,2,2-trifluoro obtained above was added. Acetamide (70 mg, 0.181 mmol), aqueous lithium hydroxide solution (concentration 1 M, 0.3 mL) and THF (1 mL) were added.
Then, the obtained mixture was stirred at room temperature for 12 hours, and water (20 mL) was added thereto.
Next, the obtained reaction mixture is extracted three times with chloroform (20 mL), the collected organic layers are dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain the desired N- compound. Propargyl-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethylamine (that is, compound (II) -2-101) was obtained (yield 30 mg (0.103 mmol), yield 57). %).
The NMR data and HRMS (ESI) data of the obtained compound (II) -2-101 are shown below.

¹ H NMR of neutral compound (400 MHz, CDCl ₃ ) δ 1.16 (br, 1 H), 2.20 (t, J = 2.4 Hz, 1 H), 2.38 (dd, J = 2.4, 2.8 Hz, 1 H) , 2.51 (t, J = 2.4 Hz, 1 H), 2.93 (t, J = 6.8 Hz, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 3.50 (d, J = 2.4 Hz, 2 H), 4.73 (d, J = 2.4 Hz, 2 H), 4.79 (d, J = 2.4 Hz, 2 H), 6.97 (dd, J = 2.4, 9.2 Hz, 1 H), 7.04 (s, 1 H) ), 7.17 (d, J = 2.4 Hz, 1 H), 7.28 (d, J = 9.2 Hz, 1 H).
¹³ C NMR of neutral compound (100 MHz, CDCl ₃ ) δ25.5, 35.8, 38.1, 48.6, 56.9, 71.3, 73.4, 75.1, 77.8, 79.2, 82.1, 103.4, 110.1, 112.7, 113.0, 126.0, 128.6, 132.0 , 151.9.
HRMS (ESI) calcd for C ₁₉ H ₁₈ N ₂ ONa [M + Na] ⁺ : 313.1311, found: 313.1322.

<Production of compound (II) -2-102>
The compound (II) -2-101 obtained above is dissolved in methanol, the methanol solution is cooled to 0 ° C., and a diethyl ether solution (20 mL) containing hydrogen chloride at a concentration of 1 M is added dropwise thereto. did.
Next, the precipitated solid is separated by filtration and dried under reduced pressure to obtain N-propargyl-2- (1-propargyl-5-propargyloxy-1H-indol-3-yl) ethylamine hydrochloride (namely, the target substance) Compound (II) -2-102) was obtained (yield 20 mg).
The NMR data of the obtained compound (II) -2-102 are shown below.

¹ H NMR of HCl salt (400 MHz, CD ₃ OD) δ 2.84 (t, J = 2.8 Hz, 1 H), 2.92 (t, J = 3.2 Hz, 1 H), 3.13 (t, J = 8.0 Hz , 2 H), 3.23-3.26 (m, 1 H), 3.41 (t, J = 8.0 Hz, 2 H), 3.96 (t, J = 2.4 Hz, 2 H), 4.75-4.76 (m, 2 H) , 4.93-4.94 (m, 2 H), 6.95 (dd, J = 2.4, 9.2 Hz, 1 H), 7.19 (d, J = 2.4 Hz, 1 H), 7.23 (s, 1 H), 7.40 (d , J = 9.2 Hz, 1 H).

[Example 15]
Compound (I) -1-103 was dissolved in a culture solution of N27 cells (N27 rat dopaminergic neurons, Merck Millipore) to prepare a solution of compound (I) -1-103. Here, the N27 cell culture solution is obtained by adding 10% FBS (Fetal Bovine Serum) and an antibiotic (penicillin-streptomycin) to a PRMI1640 basal medium. The concentration of compound (I) -1-103 in this solution was 50 μmol / L. N27 cells cultured on a cover glass were immersed in a solution of compound (I) -1-103 at 37 ° C. for 30 minutes together with the cover glass.
Next, a test piece (cover glass) was taken out of these solutions, and the test piece was chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using 0.5% Triton X-100 solution.
Alexa Fluor® 488, 555, 594 and 647 fluorescent dyes with added azide groups were then solubilized using Thermo Fisher's Click-iT reagent in the presence of a copper catalyst as described above. Reacted with pieces.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). The results are shown in FIG.
FIG. 10 shows imaging data of N27 cells in which Compound (I) -1-103 was detected using the above four types of fluorescent dyes. FIG. 10A shows imaging data of N27 cells when using compound (I) -1-103 labeled with Alexa Fluor 488, and FIG. 10B shows compound (I)-labeled with Alexa Fluor 555. FIG. 10C is imaging data of N27 cells using 1-1103, and FIG. 10C is imaging data of N27 cells using compound (I) -1-103 labeled with Alexa Fluor 594. 10D is imaging data of N27 cells using compound (I) -1-103 labeled with Alexa Fluor 647.

結果 The results of Example 15 showed that compound (I) -1-103 was taken up by N27 cells and could be detected by the fluorescent dye. From these results, it is considered that compound (I) -1-103 can be labeled with an arbitrary fluorescent dye and can be detected.

[Example 16]
N27 cells were cultured on a cover glass, and one day after seeding, the gene was transfected using CellLight RFP-Actin (ThermoFisher). The cells were further cultured at 37 ° C. for 2 days. Thereafter, Compound (I) -1-103 was dissolved in a culture solution of N27 cells to prepare a solution of Compound (I) -1-103. The concentration of compound (I) -1-103 in this solution was 10 μmol / L. RFP-Actin-introduced N27 cells cultured on a cover glass were immersed in the solution of compound (I) -1-103 at 37 ° C. for 30 minutes together with the cover glass.
Next, a test piece (cover glass) was taken out from these solutions, and the test piece was chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using 0.5% Triton X-100 solution.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). The results are shown in FIG. FIG. 11A shows fluorescence image data of labeled compound (I) -1-103 in RFP-Actin-transduced N27 cells, and FIG. 11B shows fluorescence image data of RFP-Actin in the same region as FIG. 11A. FIG. 11C shows image data obtained by superimposing the image data of FIG. 11A and the image data of FIG. 11B.

From the results of Example 16, it can be seen that the localization of these compounds can be analyzed using a combination of the labeled compound (I) -1-103 and a cell morphological marker labeled with a fluorescent protein or the like. Indicated.

[Example 17]
Compound (I) -1-103 was dissolved in artificial cerebrospinal fluid to prepare a solution of compound (I) -1-103. Here, the artificial cerebrospinal fluid contains sodium chloride (NaCl) at a concentration of 126 mmol / L, contains sodium bicarbonate (NaHCO ₃ ) at a concentration of 26 mmol / L, and has a concentration of 1 mmol / L. It contains sodium dihydrogen phosphate (NaH ₂ PO ₄ ), contains dextrose at a concentration of 10 mmol / L, contains potassium chloride (KCl) at a concentration of 3 mmol / L, and contains 1 mmol / L. PH 7.3 aqueous solution containing magnesium chloride (MgCl ₂ ) and containing calcium chloride (CaCl ₂ ) at a concentration of 3 mmol / L. The concentration of compound (I) -1-103 in this solution was 10 μmol / L.
An acute brain slice (thickness: 300 μm) was prepared from the midbrain of the mouse and used as a test piece.
The test piece was immersed in a solution of compound (I) -1-103 at 37 ° C. for 30 minutes. Thereafter, the plate was immersed in artificial cerebrospinal fluid at 37 ° C. containing no compound (I) -1-103 for 30 minutes.
Next, the test pieces were removed from these solutions, and the test pieces were chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using Triton X-100 solution.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
Next, this is reacted with an antibody solution in which an antibody (anti-Tyrosine Hydroxylase antibody, Merck Millipore) that specifically recognizes Tyrosine Hydroxylase (tyrosine hydroxylase), which is specifically possessed by cells that produce and release dopamine, is dissolved. Further, this test piece was reacted with an antibody solution to which Alexa Fluor (registered trademark) 555 fluorescent dye was added and which recognizes an anti-Tyrosine Hydroxylase antibody, and Tyrosine Hydroxylase expressed by cells was fluorescently labeled.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). The result is shown in FIG. FIG. 12A shows the imaging data of the labeled compound (I) -1-103 of the test strip, and FIG. 12B shows the imaging data of the labeled anti-Tyrosine Hydroxylase antibody of the test strip in the same region as FIG. 12A. FIG. 12C shows image data obtained by superimposing the image data of FIG. 12A and the image data of FIG. 12B. 12D, 12E, and 12F are imaging data obtained by enlarging the data of FIGS. 12A, 12B, and 12C three times, respectively.

The results of Example 17 indicate that there is a site where the signal of Tyrosine @ Hydroxylase in the neurons of the midbrain that produces and releases dopamine in brain tissue coincides with the signal of compound (I) -1-103. . The results revealed that dopaminergic neurons in the midbrain take up compound (I) -1-103. That is, it was revealed that compound (I) -1-103 was recognized as an analog of dopamine in these cells and living tissues. It also shows that the labeled compound (I) -1-103 can be used as a probe for specifically detecting dopaminergic neurons.

[Example 18]
Rat primary cultured cerebral cortical astrocytes (Lonza) were cultured on coverslips and analyzed 6 days later.
Compound (I) -1-103 was dissolved in an astrocyte culture solution (Astrocyte Growth Medium, Lonza) to prepare a solution containing compound (I) -1-103 at a concentration of 100 μmol / L. Compound (I) -1-103 and JHW007 (Tocris), a drug that inhibits a dopamine transporter that takes up dopamine from outside the cell, are dissolved in astrocyte culture solution to give compound (I) -1-103. A solution containing 103 at a concentration of 100 μmol / L and JHW007 at a concentration of 10 μmol / L was prepared. Next, the rat primary cultured astrocytes cultured on the cover glass were immersed together with the cover glass in these solutions for 30 minutes.
Next, a test piece (cover glass) was taken out from these solutions, and the test piece was chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using 0.5% Triton X-100 solution.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). FIG. 13 shows the results. FIG. 13A is imaging data of labeled compound (I) -1-103 in astrocyte cells immersed in a solution containing only labeled compound (I) -1-103, and FIG. 10 is data obtained by imaging the labeled compound (I) -1-103 in astrocyte cells, which was immersed in a solution containing the labeled compound (I) -1-103 and the dopamine uptake inhibitor JHW007. .

The results of Example 18 show that, first, compound (I) -1-103 is incorporated into astrocytes, glial cells of the cerebral cortex, as an analog of dopamine, and second, compound (I) This shows that uptake of -1-103 is performed via the dopamine transporter. In addition, since the effects of dopamine uptake inhibitors on neurons could be visualized in this way, dopamine and other neuromodulators important for the treatment of various psychiatric disorders including Parkinson's disease and depression. The present invention has been shown to be useful in the assessment of group uptake inhibitors.

[Example 19]
Rat primary cultured striatal neurons and cerebral cortical astrocytes (Lonza) were cultured on cover glass and analyzed 28 days and 3 days after culture, respectively.
Compound II-1-101 was dissolved in a nerve cell culture solution (Primary Neuron Growth Medium, Lonza) and an astrocyte culture solution (Astrocyte Growth Medium, Lonza), and compound II-1-101 was dissolved at a concentration of 100 μmol / L. A solution containing was prepared. Next, the rat primary cultured striatal neurons and astrocytes cultured on a cover glass were immersed together with the cover glass in these solutions for 30 minutes.
Next, a test piece (cover glass) was taken out from these solutions, and the test piece was chemically fixed using a phosphate buffered saline of paraformaldehyde having a concentration of 4% by mass (Phosphate Buffered Saline, PBS). The test piece was solubilized using 0.5% Triton X-100 solution.
Then, Alexa Fluor® 488 fluorescent dye to which an azide group was added was reacted with the solubilized test piece using a Click-iT reaction reagent manufactured by Thermo Fisher in the presence of a copper catalyst.
Next, the test piece after the reaction was observed using a confocal microscope (“FV1000” manufactured by Olympus Corporation). FIG. 14 shows the results. FIG. 14A is imaging data of labeled compound II-1-101 in primary cultured striatal neurons, and FIG. 14B is imaging data of labeled compound II-1-101 in primary cultured astrocytes. It is.

結果 The results of Example 19 show that compound II-1-101 is taken up by striatal neurons and astrocytes. It is considered that the compound II-1-101 can be used to evaluate serotonin uptake inhibitory function, which is an action of many antidepressants.

The present invention can be used for analyzing the action of a nerve function regulating substance in the brain.

Claims

The following general formula (I):

(In the general formula (I), X 1 , X 2 , X 3 and X 4 each independently represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms. When the unsaturated hydrocarbon group is an unsaturated hydrocarbon group having 3 to 9 carbon atoms which may have a substituent, and the unsaturated hydrocarbon group has a methylene group at a terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group is May be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the bonding end, one methylene group or two or more The methylene groups which are not adjacent to each other may be substituted with an oxygen atom, and when X 1 and X 2 are the alkyl groups, or when X 3 and X 4 are the alkyl groups The two alkyl groups are bonded to each other to form a ring Well;
X 5 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X 6 is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 1 and n 3 are each independently 0 or 1;
n 2 is an integer from 1 to 5;
However, when n 1 is 0 and n 3 is 1, one or more of X 1 , X 2 , X 3 , X 4, and X 6 are not the same A saturated hydrocarbon group,
When n 1 is 1 and n 3 is 0, one or more of X 1 , X 2 , X 3 , X 4 and X 5 are the unsaturated carbons. A hydrogen group,
When both n 1 and n 3 are 0, at least one of X 1 , X 2 , X 3 and X 4 is the unsaturated hydrocarbon group,
When both n 1 and n 3 are 1, one or more of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are the unsaturated hydrocarbons. Group. )
Or a salt thereof.
The compound represented by the general formula (I) is represented by the following general formula (I) -1, (I) -2, (I) -3 or (I) -4:

(In general formulas (I) -1, (I) -2, (I) -3 or (I) -4, X 1 , X 2 , X 3 , X 4 , X 5 , n 2 and n 3 are The same as above;
X 11, X 21, X 31 and X 41 each independently represent a hydrogen atom or an alkyl group having 1-9 carbon atoms, when X 11 and X 21 are the alkyl group, or, X 31 and X When 41 is the above-mentioned alkyl group, these two alkyl groups may be mutually bonded to form a ring;
X 61 is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and optionally having 3 to 9 carbon atoms;
However, in the general formula (I) -1, one or both of X 1 and X 2 is the unsaturated hydrocarbon group,
In formula (I) -2, one or both of X 3 and X 4 are the unsaturated hydrocarbon groups. )
The compound according to claim 1, which is a compound represented by the formula: or a salt thereof.
Compounds represented by the general formulas (I) -1, (I) -2, (I) -3 or (I) -4 are represented by the following general formulas (I) -1-1 and (I) -1- 2, (I) -2-1, (I) -2-2, (I) -2-3, (I) -3-1 or (I) -4-1:

(General formulas (I) -1-1, (I) -1-2, (I) -2-1, (I) -2-2, (I) -2-3, (I) -3-1) Or, in (I) -4-1, X 12 , X 22 , X 32 and X 42 are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and X 12 and X 22 are Or when X 32 and X 42 are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring;
G 1 , G 2 , G 3 , G 4 , G 5 and G 6 each independently represent a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a trialkyl group. Reelsilyl group, hydroxy group, halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group , A triarylsilylalkyl group, a hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group. R;
n 3 are the same as above. )
The compound according to claim 2, which is a compound represented by the formula: or a salt thereof.
The following general formula (II):

(In the general formula (II), X 01 , X 02 , X 03 and X 04 each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms. When the unsaturated hydrocarbon group is an unsaturated hydrocarbon group having 3 to 9 carbon atoms which may have a substituent, and the unsaturated hydrocarbon group has a methylene group at a terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group is May be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the bonding end, one methylene group or two or more May be substituted with an oxygen atom, and when X 01 and X 02 are the alkyl groups, these two alkyl groups are bonded to each other to form a ring. May be formed;
X 05 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 01 is 0 or 1;
n 02 is an integer of 1 to 5;
However, when n 01 is 0, one or more of X 01 , X 02 , X 03 and X 04 are the unsaturated hydrocarbon groups,
When n 01 is 1, one or more of X 01 , X 02 , X 03 , X 04 and X 05 are the unsaturated hydrocarbon groups. )
Or a salt thereof.
The compound represented by the general formula (II) is represented by the following general formula (II) -1 or (II) -2:

(In the general formula (II) -1 or (II) -2, n 02 is the same as described above;
X 011 , X 021 and X 031 are each independently a hydrogen atom or an alkyl group having 1 to 9 carbon atoms. When X 011 and X 021 are the above-mentioned alkyl groups, these two alkyl groups are May combine with each other to form a ring;
X 041 is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent;
X 010 , X 020 and X 030 each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or 1 to 4 triple bonds between carbon atoms, and may have a substituent. When the unsaturated hydrocarbon group has 3 to 9 carbon atoms and the unsaturated hydrocarbon group has a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group; When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the bonding side, one methylene group or two or more methylene groups that are not adjacent to each other are may be substituted with an oxygen atom, if X 010 and X 020 is the above alkyl group, these two alkyl groups may form a ring with each other, however, X 010 , One of X 020 and X 030 Species or two or more are the aforementioned unsaturated hydrocarbon groups. )
The compound according to claim 4, which is a compound represented by the formula: or a salt thereof.
Compounds represented by the general formula (II) -1 or (II) -2 are represented by the following general formulas (II) -1-1, (II) -2-1, (II) -2-2, and (II) ) -2-3, (II) -2-4 or (II) -2-5:

(General formulas (II) -1-1, (II) -2-1, (II) -2-2, (II) -2-3, (II) -2-4 or (II) -2-5) in, X 012, X 022 and X 032 each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, when X 012 and X 022 is the above alkyl group, these two alkyl The groups may be linked to each other to form a ring;
G 01 , G 02 , G 03 and G 04 are each independently a hydrogen atom, an alkyl group, an aryl group, a trialkylsilyl group, a dialkylmonoarylsilyl group, a monoalkyldiarylsilyl group, a triarylsilyl group, a hydroxy group , Halogen atom, alkoxy group, alkylcarbonyloxy group, arylcarbonyloxy group, aralkylcarbonyloxy group, aralkyl group, trialkylsilylalkyl group, dialkylmonoarylsilylalkyl group, monoalkyldiarylsilylalkyl group, triarylsilylalkyl group A hydroxyalkyl group, a halogenated alkyl group, an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an arylcarbonyloxyalkyl group or an aralkylcarbonyloxyalkyl group;
n 02 is the same as described above. )
The compound according to claim 5, which is a compound represented by the formula: or a salt thereof.
神経 A neurological function regulating substance comprising the compound according to any one of claims 1 to 6 or a salt thereof.
(4) A nerve function regulating substance containing a group having a triple bond between carbon atoms.
The compound having a structure in which one or more hydrogen atoms in dopamine, noradrenaline, adrenaline or serotonin are substituted with a group having a triple bond between carbon atoms, or a salt thereof, The nerve function modulator according to claim 8, which is present.
A method for evaluating a nerve function-regulating substance, comprising evaluating the state of uptake of a nerve function-modulating substance according to any one of claims 7 to 9 into a nerve cell, or the state of a cellular response caused by the uptake.
A method for producing a compound represented by the following general formula (IA) or a salt thereof,
Reacting a compound represented by the following general formula (Ia) with a compound represented by the following general formula (Ic);
When one or more of the following Z 1a , Z 2a , Z 3a , Z 4a and Z 6a are the following protecting groups, the protecting group is further removed after the step of reacting. Process and
By performing, as a compound represented by the following general formula (I A), in the compound represented by the following general formula (Ia), the following Z 1a, Z 2a, Z 3a , Z 4a and Z 6a Among them, a method for producing a compound or a salt thereof, wherein a compound having a structure in which a hydrogen atom is substituted by the following X 0a or a salt thereof is obtained.

(In the general formula (I A), (Ia) or (Ic), X 1, X 2, X 3 and X 4 each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When it has a group, the methylene group may be substituted with a carbonyl group, and when the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the bonding side, 1 Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X 1 and X 2 are the alkyl groups, or X 3 and X 4 Is a said alkyl group, these two alkyl groups It may bond to form a ring;
X 5 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X 6 is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 1 and n 3 are each independently 0 or 1;
n 2 is an integer from 1 to 5;
However, one or more of X 1 , X 2 , X 3 and X 4 are the unsaturated hydrocarbon groups,
X 0a is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, wherein the unsaturated hydrocarbon group is When having a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group, and the unsaturated hydrocarbon group may have one or more than two terminals other than the terminal on the bonding side. When it has a methylene group, one methylene group or two or more non-adjacent methylene groups may be substituted with an oxygen atom;
LG 1 is a leaving group;
Z 1a , Z 2a , Z 3a , Z 4a and Z 6a are each independently a hydrogen atom, an alkyl group having 1 to 9 carbon atoms or a protecting group, and when Z 1a and Z 2a are the above-mentioned alkyl groups Or when Z 3a and Z 4a are the aforementioned alkyl groups, these two alkyl groups may be bonded to each other to form a ring, provided that Z 1a , Z 2a , Z 3a , One or more of Z 4a and Z 6a are hydrogen atoms. )
A compound or a salt thereof represented by the following general formula (I B),
Reacting a compound represented by the following general formula (Ib) with a compound represented by the following general formula (Id);
When one or more of the following Z 1b , Z 2b , Z 3b , Z 4b and Z 6b are the following protecting groups, the protecting group is further removed after the step of reacting. Process and
By performing, as a compound represented by the following general formula (I B), in the compound represented by the following general formula (Ib), the following LG 2 is a compound of structure substituted by the following X 0b Or a method for producing a compound or a salt thereof to obtain a salt thereof.

(In the general formula (I B), (Ib) or (Id), X 1, X 2, X 3 and X 4 each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X 1 and X 2 are the alkyl groups, or X 3 and X 4 Is a said alkyl group, these two alkyl groups It may bond to form a ring;
X 5 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
X 6 is a hydrogen atom or an unsaturated hydrocarbon group having 3 to 9 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 3 is 0 or 1;
n 2 is an integer from 1 to 5;
LG 2 is a leaving group;
Z 1b , Z 2b , Z 3b , Z 4b and Z 6b each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, 1 to 4 triple bonds between carbon atoms, and have a substituent. An optionally substituted unsaturated hydrocarbon group having 3 to 9 carbon atoms or a protecting group, wherein Z 1b and Z 2b are the aforementioned alkyl groups, or Z 3b and Z 4b are the aforementioned alkyl groups May have the two alkyl groups linked to each other to form a ring;
X 0b is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent. )
A method for producing a compound represented by the following general formula (II A ) or a salt thereof,
Reacting a compound represented by the following general formula (IIa) with a compound represented by the following general formula (Ic);
Below Z 01a, Z 02a, among the Z 03a and Z 04a, when one or more are below protecting group, after the step of the reaction, further, removing the protecting group,
By performing, as a compound represented by the following general formula (II A), in the compounds represented by the following general formula (IIa), following Z 01a, Z 02a, among the Z 03a and Z 04a, A method for producing a compound or a salt thereof, wherein a compound or a salt thereof having a structure in which a hydrogen atom is substituted by the following X0a is obtained.

(Formula (II A), in (IIa) or (Ic), X 01, X 02, X 03 and X 04 each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms or between carbon atoms Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X 01 and X 02 are the alkyl groups, these two alkyl groups Groups may be linked to each other to form a ring ;
X 05 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 01 is 0 or 1;
n 02 is an integer of 1 to 5;
However, one or more of X 01 , X 02 , X 03 and X 04 are the unsaturated hydrocarbon groups,
X 0a is an unsaturated hydrocarbon group having 1 to 4 triple bonds between carbon atoms and having 3 to 9 carbon atoms which may have a substituent, wherein the unsaturated hydrocarbon group is When having a methylene group at the terminal on the bonding side, the methylene group may be substituted with a carbonyl group, and the unsaturated hydrocarbon group may have one or more than two terminals other than the terminal on the bonding side. When it has a methylene group, one methylene group or two or more non-adjacent methylene groups may be substituted with an oxygen atom;
LG 1 is a leaving group;
Z 01a, Z 02a, Z 03a and Z 04a each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, or a protecting group, if Z 01a and Z 02a is said alkyl group, these two alkyl groups may form a ring with each other, however, Z 01a, Z 02a, among the Z 03a and Z 04a, 1 or 2 or more is a hydrogen atom. )
A method for producing a compound represented by the following general formula (II B ) or a salt thereof,
Reacting a compound represented by the following general formula (IIb) with a compound represented by the following general formula (Id);
When one or more of the following Z 01b , Z 02b , Z 03b and Z 04b are the following protective groups, after the step of reacting, further removing the protective groups;
By carrying out, as a compound represented by the following general formula (II B ) or a salt thereof, a compound having a structure in which the following LG 3 in the compound represented by the following general formula (IIb) is substituted by the following X 0b Or a method for producing a compound or a salt thereof to obtain a salt thereof.

(In the general formulas (II B ), (IIb) or (Id), X 01 , X 02 , X 03 and X 04 each independently represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or Is an unsaturated hydrocarbon group having 1 to 4 triple bonds and having 3 to 9 carbon atoms, which may have a substituent, wherein the unsaturated hydrocarbon group has methylene When the unsaturated hydrocarbon group has one or two or more methylene groups other than the terminal on the side to which the unsaturated hydrocarbon group is bonded, the methylene group may be substituted with a carbonyl group. Two methylene groups or two or more non-adjacent methylene groups may be substituted with an oxygen atom, and when X 01 and X 02 are the alkyl groups, these two alkyl groups The groups may be linked to each other to form a ring ;
X 05 is an unsaturated hydrocarbon group having 2 to 8 carbon atoms, which has 1 to 4 triple bonds between carbon atoms and may have a substituent;
n 02 is an integer of 1 to 5;
LG 3 is a leaving group;
Z 01b , Z 02b , Z 03b and Z 04b each independently have a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, 1 to 4 triple bonds between carbon atoms, and have a substituent. When Z 01b and Z 02b are the above-mentioned alkyl groups, these two alkyl groups are mutually bonded to form a ring. May be;
X 0b is an unsaturated hydrocarbon group having 2 to 8 carbon atoms which has 1 to 4 triple bonds between carbon atoms and may have a substituent. )