WO2016084870A1

WO2016084870A1 - Compound having acylaminophenyl group, and use thereof

Info

Publication number: WO2016084870A1
Application number: PCT/JP2015/083139
Authority: WO
Inventors: 望月　秀樹; 佐々木　勉; 其静鐘; 新一上里
Original assignee: 国立大学法人大阪大学; 学校法人関西大学
Priority date: 2014-11-25
Filing date: 2015-11-25
Publication date: 2016-06-02
Also published as: JPWO2016084870A1

Abstract

Provided is an acylaminophenyl-group-containing compound having a neuroprotective effect. Also provided is a neuroprotective agent including an acylaminophenyl-group-containing compound. A novel acylaminophenyl-group-containing compound, and neural cells are protected and cell death of neural cells is minimized by using an acylaminophenyl-group-containing compound.

Description

Compound having acylaminophenyl group and use thereof

The present invention relates to an acylaminophenyl group-containing compound and a neuroprotective agent containing the compound or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof.

In recent years, with the increase in the number of elderly people, shortening the healthy life expectancy due to neurological diseases such as neurodegenerative diseases and cerebrovascular disorders has become a social issue, and research on various drugs has been conducted in order to seek therapeutic agents for these neurological diseases. Has been made from many directions. As part of this research, research has been conducted on drugs that prevent damage and death of nerve cells caused by nervous system diseases, but no drugs that effectively protect nerve cells have been found.

For neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), there is no radical treatment, DMT (Disease modifying therapies), and the development of new therapies is extremely important. Based on the above, development of therapeutic drugs is desired. On the other hand, there is almost no clinical effect including neuroprotective drugs in cerebral ischemia or cognitive function decline due to acute cerebral ischemia or chronic cerebral ischemia. As described above, since the QOL is often significantly inhibited or a serious aftereffect is left behind due to a neurodegenerative disease or cerebrovascular disorder, it is important to prevent the death of nerve cells.

In Parkinson's disease, drugs that control motor symptoms have been used clinically, but there is no therapeutic agent that suppresses neuronal cell death in the substantia nigra and striatum itself.

Currently, a thrombolytic agent for restoring blood flow at an early stage is approved as a drug administered when cerebrovascular disorder occurs. However, since the thrombolytic agent is indicated only for patients delivered in the hyperacute phase, only a few percent of all cerebrovascular disorder cases are applicable to the thrombolytic agent. In addition, the thrombolytic agent is not effective when the degree of ischemia is strong, and there are many cases in which a serious disorder is caused and a sequela remains.

On the other hand, free radical scavengers that damage nerve cells have been developed as drugs for protecting nerve cells, but the effect is extremely weak at present. Conventionally, in cerebral ischemic pathology, therapeutic agents targeting NMDA type receptors such as MK-801 have been actively tried under the glutamate-Ca hypothesis, but clinically useful ones have not been obtained. I couldn't. NMDA receptors are known to have a variety of subtypes and have opposite effects depending on the subtype, and NMDA-type receptor inhibitors are clinically able to eliminate even the good effects of NMDA receptors. It is also assumed that this is one of the causes of ineffectiveness. Thus, in neurological diseases, there is a limit in drug discovery targeting conventional G protein-coupled receptors and the like, and it is considered that drug discovery based on a completely new concept is necessary.

On the other hand, some of the compounds having an acylaminophenyl group (Patent Documents 1 and 2 and Non-Patent Document 1) are known to inhibit binding between proteins in cells (Patent Documents 1 and 2). . In particular, it is known to inhibit the binding between p53, which is a tumor suppressor gene, and Mdm2, which is a ubiquitin ligase (Patent Document 2).

JP 2010-053060 A JP 2011-178704 A

An object of the present invention is to provide an acylaminophenyl group-containing compound having a neuroprotective action. Furthermore, it is providing the neuroprotective agent containing an acylaminophenyl group containing compound.

As a result of extensive research, the present inventor has found that an acylaminophenyl group-containing compound having the structure described below has a neuroprotective action. Moreover, the novel acylaminophenyl group containing compound was discovered.

This invention is completed based on the said knowledge, and contains the following aspects.
Item 1. A neuroprotective agent comprising a compound represented by the following general formula (A), or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof:

{X represents a sulfur atom, a methylene group or an oxygen atom:
R ^a is a pyridyl group, an aryl group, a piperidyl group, a piperazyl group, a pyrrolidyl group, an alkyl group having 1 to 7 carbon atoms, a group represented by the following general formula (A-1), or the following general formula (A-2) The group shown by is shown. The pyridyl group, aryl group, piperidyl group, piperazyl group, and pyrrolidyl group may be substituted with at least one selected from the group consisting of a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 7 carbon atoms may be substituted with halogen;

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or a halogen)

(Y ¹ represents a carbon atom;
R ³ , R ⁴ and R ⁵ are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or a halogen):
R ^b represents a group represented by the following general formula (A-3), a group represented by the following general formula (A-4), or a hydrogen atom;

(R ^c represents an alkyl group having 1 to 6 carbon atoms)

(X and ^Ra are the same as above)}.
Item 2. Item 2. The neuroprotective agent according to Item 1, wherein X is a sulfur atom or a methylene group.
Item 3. Item 3. The neuroprotective agent according to Item 1 or 2, which is used for prevention or treatment of nervous system diseases.
Item 4. Item 4. The neuroprotective agent according to Item 3, wherein the nervous system disease is a neurodegenerative disease or an ischemic brain disease.
Item 5. Neurodegenerative disease is Parkinson's disease, amyotrophic lateral sclerosis, dementia, cerebrovascular dementia, polyglutamine disease, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuritis, or multiple Item 5. The neuroprotective agent according to Item 4, which is focal motor neuropathy.
Item 6. A compound represented by the following general formula (A), or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof:

(R ^c represents an alkyl group having 1 to 6 carbon atoms)

(X and R ^a are the same as above),
However, S- (2-isobutylamidophenyl) 2-methylpropanethioate, N, N '-(disulfanediylbis (2,1-phenylene)) bis (2-methylpropanamide), 2-isobutyramidophenyl Isobutyrate, N- (2-hydroxyphenyl) isobutyramide, S- (2-benzamidophenyl) 2-methylpropanethioate, N, N '-(disulfanediylbis (2,1-phenylene)) di Benzamide, N, N '-(disulfanediylbis (2,1-phenylene)) dioctanamide, N, N'-(disulfanediylbis (2,1-phenylene)) bis (pyrrolidine-1- Carboxamide), N, N '-(disulfanediylbis (2,1-phenylene)) bis (piperidine-1-carboxamide), 1,1'-(disulfanediylbis (2,1-phenylene)) Bis (3,3-diethyl Element), and N, N '- (2,2'-di sulfanediyl bis (2,1-phenylene)) except bis (2,2-dimethylpropanamide)}.
Item 7. Item 2. The compound according to Item 1, wherein X is a sulfur atom or a methylene group, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof.
Item 8. Item 8. The compound according to Item 6 or 7, wherein R ^b is a group represented by the general formula (A-2) or a group represented by the general formula (A-3), or a pharmaceutically acceptable salt thereof or a salt thereof Pharmaceutically acceptable hydrate.
Item 9. Item 9. The compound according to any one of Items 6 to 8, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof, wherein R ^c is an isopropyl group.
Item 10. R ^a represents a pyridyl group, a phenyl group, a piperidyl group, a piperazyl group, a pyrrolidyl group, or a group represented by the following general formula (A-1). The pyridyl group, the phenyl group, the piperidyl group, the piperazyl group, and the pyrrolidyl group The group according to any one of Items 6 to 9, wherein the group may be substituted with at least one selected from the group consisting of a chlorine atom, an oxygen atom, a methyl group, and an ethyl group, or a pharmaceutical product thereof Or a pharmaceutically acceptable hydrate thereof:

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or a chlorine atom).

According to the present invention, a neuroprotective agent containing an acylaminophenyl group-containing compound can be provided. Moreover, it is possible to prevent and / or treat nervous system diseases with the neuroprotective agent. Furthermore, a novel acylaminophenyl group-containing compound is provided.

The experimental result which confirmed the nerve cell protective effect with respect to cerebral ischemia of the acylaminophenyl group containing compound is shown. A: The results are shown 24 hours after adding K-202, K-205, K-880 or K-890 at a final concentration of 10 μM. B: shows the results when K-670 was added at a final concentration of 10 μM. C: shows the results when K-640 or K-890 was added at a final concentration of 10 μM. D: The results are shown 24 hours after the addition of K-210 or K-630 at a final concentration of 10 μM. E: KS-151, KS-152, and K-154 show the results 48 hours after adding 1 μM, K-181, or K-630 at final concentrations of 10 μM, respectively. F: KS-151 (final concentration 1 μM), KS-152 (final concentration 1 μM), K-154 (final concentration 1 μM), K-181 (final concentration 10 μM), K-630 (final concentration 10 μM), K-670 The results 24 hours after the addition of (final concentration 10 μM), K-680 (final concentration 10 μM) or K-710 (final concentration 10 μM) are shown. The star in the graph indicates p <0.05. G: shows the results 48 hours after the addition of K-154, K-202, K-640 or K-680 at a final concentration of 10 μM. The star in the graph indicates p <0.05. H: 結果 K-154, K-180 (final concentration 1 μM), K-740 or K-760 are each added at a final concentration of 10 μM, and the results after 48 hours are shown. The star in the graph indicates p <0.05. The experimental result which confirmed the neuroprotective effect of the test compound in the in-vitro Parkinson's disease experimental model is shown. A: The results when K-152, K-153, or K-154 were added at a final concentration of 1 μM, respectively. B: shows the results when K-178, K-202 or K-630 was added at a final concentration of 1 μM. C: The results when K-680, K-880, and KS-153 were added at final concentrations of 1 μM are shown. The experimental result which confirmed the neuroprotective effect of K-640 (final concentration of 10 micromol) or K-890 (final concentration of 5 micromol) in the in-vitro Parkinson disease experimental model is shown. The experimental result which confirmed the concentration-dependent neuroprotective effect of K-202 or K-880 in an in-vitro Parkinson's disease experimental model is shown. The result of having confirmed the neuroprotective effect of K-178 and K-880 in an in vivo Parkinson's disease experimental model is shown. In the figure, ** indicates p <0.01 in comparison with the Vehicle + MPTP group, and # indicates p <0.05.

1. Neuroprotective agent The neuroprotective agent of the present invention is a compound represented by the following general formula (A) or general formula (A '), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydration thereof. Including things.
1-1. Compound represented by general formula (A) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrate thereof
1-1-1. Compound Represented by General Formula (A) The acylaminophenyl group-containing compound of the present invention is a compound represented by the following general formula (A):

(R ^c represents an alkyl group having 1 to 6 carbon atoms or —N (CH ₂ CH ₃ ) ₂ )

(X and ^Ra are the same as above)}.

X is preferably a sulfur atom or a methylene group, more preferably a sulfur atom.

In general formula (A) and general formula (A-4), the group represented by R ^a —CO—NH— is more preferably bonded to the ortho, meta or para position of the group to which X is bonded. Binds to the ortho position. When the group represented by R ^a —CO—NH— in the general formula (A) is bonded to the ortho position, it is represented by the following general formula (AI);

(X, R ^a and R ^b are the same as above).

The bonding positions of the groups represented by R ^a —CO—NH— in the general formula (A) and the general formula (A-4) may be the same or different. The same position is preferred, and the ortho position is more preferred.

When R ^a is ^a pyridyl group which may be substituted with at least one selected from the group consisting of halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, the substituent for the pyridyl group is preferably halogen and It is at least one selected from the group consisting of alkyl groups having 1 to 3 carbon atoms, more preferably at least one selected from the group consisting of a chlorine atom, a methyl group and an ethyl group.

When R ^a is an aryl group optionally substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, the aryl group is a monocyclic aromatic group It is a hydrocarbon or a polycyclic hydrocarbon, preferably having 6 to 10 carbon atoms, more preferably a phenyl group, a naphthyl group or the like, and further preferably a phenyl group. The substituent for the aryl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a is ^a piperidyl group optionally substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, a piperidyl group preferably not substituted as a piperidyl group It is. The substituent of the piperidyl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a is ^a piperazyl group optionally substituted with at least one selected from the group consisting of halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, the substituent of the piperazyl group is preferably halogen, It is at least one selected from the group consisting of an oxygen atom and an alkyl group having 1 to 3 carbon atoms, more preferably at least one selected from the group consisting of an oxygen atom, a methyl group and an ethyl group. Further, the piperazyl group is preferably a dioxopiperazyl group, and a dioxopiperazyl group in which any one hydrogen atom bonded to any one nitrogen atom of the piperazyl group is substituted with a methyl group or an ethyl group. preferable.

When R ^a is ^a pyrrolidyl group which may be substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, a pyrrolidyl group which is preferably not substituted as a pyrrolidyl group It is. The substituent of the pyrrolidyl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a is an alkyl group having 1 to 7 carbon atoms which may be substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, 1 to 7 carbon atoms The alkyl group is preferably an unsubstituted alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. The alkyl group having 1 to 7 carbon atoms is preferably an alkyl group having 5, 6, or 7 carbon atoms, and more preferably an alkyl group having 7 carbon atoms. The substituent for the alkyl group having 1 to 7 carbon atoms is preferably at least one selected from the group consisting of halogen, more preferably a chlorine atom.

R ^a is a group represented by the following general formula (A-1):

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or a halogen)
In this case, both R ¹ and R ² are preferably an alkyl group having 1 to 3 carbon atoms or a halogen, and more preferably R ¹ and R ² are both a methyl group, an ethyl group, or a chlorine atom.

R ^a is a group represented by the following general formula (A-3):

(Y ¹ represents a carbon atom;
R ³ , R ⁴ and R ⁵ are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or halogen)
In this case, R ³ , R ⁴ and R ⁵ are all preferably alkyl groups having 1 to 3 carbon atoms or halogen, more preferably R ³ , R ⁴ and R ⁵ are both methyl, ethyl or chlorine. Is an atom.

Particularly preferred groups as R ^a are any groups represented by the following formulas (R ^a -1) to (R ^a -12).

R ^b is a group represented by the following general formula (A-3):

(R ^c represents an alkyl group having 1 to 6 carbon atoms),
R ^c is preferably an alkyl group having 1 to 4 carbon atoms. The alkyl group may be linear or branched, but is more preferably branched. R ^c is preferably an isopropyl group, a normal propyl group, an isobutyl group, an ethyl group, or a methyl group, and more preferably an isopropyl group, an ethyl group, or a methyl group. More preferably, it is an isopropyl group.

R ^b is a group represented by the following general formula (A-4):

(X and R ^a are the same as above),
In this case, the group represented by the general formula (A-4) may be the same as or different from the portion other than R ^{b of the} group represented by the general formula (A), but more preferably the same It is.

R ^b is preferably a group represented by the general formula (A-3) or the general formula (A-4).

1-1-1 ′. Compound Represented by General Formula (A ′) As another embodiment of the present invention, an acylaminophenyl group-containing compound is a compound represented by the following general formula (A ′):

{X is the same as X described in the description of the general formula (A) (X is preferably a sulfur atom or a methylene group, more preferably a sulfur atom):
R ^a ′ is a cycloalkyl group having 3 to 7 carbon atoms, a pyridyl group, an aryl group, a piperidyl group, a piperazyl group, a pyrrolidyl group, an alkyl group having 1 to 7 carbon atoms, represented by the following general formula (A′-1) Or a group represented by the following general formula (A′-2). The cycloalkyl group pyridyl group, aryl group, piperidyl group, piperazyl group, and pyrrolidyl group may be substituted with at least one selected from the group consisting of halogen, oxygen atom, and alkyl group having 1 to 6 carbon atoms. The cycloalkyl group and the alkyl group having 1 to 7 carbon atoms may be substituted with a halogen;

(Y, ^{R 1} and ^{R 2} are as described in the description of the general formula (A) Y, the same :) in ^{R 1} and ^{R 2}

(Y ¹ , R ³ , R ⁴ and R ⁵ are the same as Y ¹ , R ³ , R ⁴ and R ⁵ described in the description of the general formula (A)):
R ^b ′ represents a group represented by the following general formula (A′-3), a group represented by the following general formula (A′-4), or a hydrogen atom;

(R ^c is the same as R ^c in the description of the general formula (A))

(X and R ^a ′ are the same as X and R ^a ′ described in the description of the general formula (A ′))}.

In general formula (A ′) and general formula (A′-4), the group represented by R ^a —CO—NH— is bonded to the ortho, meta or para position of the group to which X is bonded, More preferably, it is bonded to the ortho position. When the group represented by R ^a —CO—NH— in the general formula (A ′) is bonded to the ortho position, the group is represented by the following general formula (A′-I);

(X, R ^a ′ and R ^b ′ are the same as X, R ^a ′ and R ^b ′ described in the description of the general formula (A ′)).

The bonding positions of the groups represented by R ^a —CO—NH— in the general formula (A ′) and the general formula (A′-4) may be the same or different. The same position is preferred, and the ortho position is more preferred.

When R ^a ′ is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, The ˜7 cycloalkyl group is preferably an unsubstituted alkyl group having 3, 4, 5, 6, or 7 carbon atoms. The cycloalkyl group having 3 to 7 carbon atoms is preferably an alkyl group having 5, 6, or 7 carbon atoms, and more preferably a cycloalkyl group having 5 carbon atoms. The substituent for the cycloalkyl group having 3 to 7 carbon atoms is preferably at least one selected from the group consisting of halogens, and more preferably a chlorine atom.

When R ^a ′ is ^a pyridyl group which may be substituted with at least one selected from the group consisting of halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, And at least one selected from the group consisting of alkyl groups having 1 to 3 carbon atoms, more preferably at least one selected from the group consisting of a chlorine atom, a methyl group and an ethyl group.

When R ^a ′ is an aryl group optionally substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, the aryl group is a monocyclic ring having aromaticity Or a polycyclic hydrocarbon, preferably having 6 to 10 carbon atoms, more preferably a phenyl group, a naphthyl group, or the like, and still more preferably a phenyl group. The substituent for the aryl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a ′ is ^a piperidyl group which may be substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, preferably piperidyl group which is preferably not substituted as a piperidyl group It is a group. The substituent of the piperidyl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a ′ is ^a piperazyl group which may be substituted with at least one selected from the group consisting of halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, , At least one selected from the group consisting of an oxygen atom and an alkyl group having 1 to 3 carbon atoms, more preferably at least one selected from the group consisting of an oxygen atom, a methyl group and an ethyl group. Further, the piperazyl group is preferably a dioxopiperazyl group, and a dioxopiperazyl group in which any one hydrogen atom bonded to any one nitrogen atom of the piperazyl group is substituted with a methyl group or an ethyl group. preferable.

When R ^a ′ is ^a pyrrolidyl group which may be substituted with at least one selected from the group consisting of halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, pyrrolidyl which is preferably not substituted as a pyrrolidyl group It is a group. The substituent of the pyrrolidyl group is preferably at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. Is at least one kind.

When R ^a ′ is an alkyl group having 1 to 7 carbon atoms which may be substituted with at least one selected from the group consisting of ^a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms, The alkyl group having 7 carbon atoms is preferably an unsubstituted alkyl group having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. The alkyl group having 1 to 7 carbon atoms is preferably an alkyl group having 5, 6, or 7 carbon atoms, and more preferably an alkyl group having 7 carbon atoms. The substituent for the alkyl group having 1 to 7 carbon atoms is preferably at least one selected from the group consisting of halogen, more preferably a chlorine atom.

R ^a ′ is a group represented by the following general formula (A′-1):

If it is, Y, ^{R 1} and ^{R 2,} Y according to the description of the general formula (A), are the same for ^{R 1} and ^{R 2,} Y in the description of the general formula (A), ^{R 1} And descriptions of preferred groups for R ² are incorporated herein.

R ^a 'is a group represented by the following general formula (A'-3):

If it is, ^{Y 1} ^is R 3, ^{R 4} and ^{R 5,} ^{Y 1} according to the description of the general formula (A) ^is the same as R 3, ^{R 4} and ^{R 5,} the general formula ( Y ^{1 in} the description of A) is incorporated herein by reference for the preferred groups of R ³ , R ⁴ and R ⁵ .

A particularly preferable group as R ^a ′ is a cycloalkyl group having 5 carbon atoms, or any group represented by the following formulas (R ^a -1) to (R ^a -12).

R ^b ′ is a group represented by the following general formula (A′-3):

, R ^c is the same as R ^c described in the description of the general formula (A), and description of preferred groups of R ^{c in} the description of the general formula (A) is incorporated herein.

R ^b ′ is a group represented by the following general formula (A′-4):

(X and R ^a ′ are the same as X and R ^a ′ described in the description of the general formula (A ′)),
In this case, the group represented by the general formula (A′-4) may be the same as or different from the portion other than R ^b ′ of the group represented by the general formula (A ′). Preferably they are the same.

R ^b ′ is preferably a group represented by the general formula (A′-3) or the general formula (A′-4).

The synthesis of the compound represented by the general formula (A ′) can be performed according to the method described in JP 2010-053060 A, for example.

1-1-2. Preferred groups as R ^a in formula is a compound represented by a compound represented by (A) compounds wherein X is sulfur atom general formula (A) X is a sulfur atom compounds, the following is there.

A pyridyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group A pyridyl group optionally substituted by at least one species;
A phenyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group; A phenyl group optionally substituted with at least one species;
A piperidyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. A piperidyl group optionally substituted by at least one species;
A piperazil group optionally substituted with at least one selected from the group consisting of an oxygen atom, a methyl group and an ethyl group, more preferably at least one selected from the group consisting of a methyl group and an ethyl group A good dioxopiperazyl group, more preferably a dioxopiperazyl group in which any one hydrogen atom bonded to any one nitrogen atom of the piperazyl group is substituted with a methyl group or an ethyl group;
A pyrrolidyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group A pyrrolidyl group optionally substituted with at least one;
An unsubstituted alkyl group having 5, 6 or 7 carbon atoms;
Groups represented by the following general formula (A-1):

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are preferably both an alkyl group having 1 to 3 carbon atoms or a halogen, more preferably R ¹ and R ² are both a methyl group, an ethyl group or a chlorine atom); Group represented by (A-2):

(Y ¹ represents a carbon atom;
R ³ , R ⁴ and R ⁵ are preferably both an alkyl group having 1 to 3 carbon atoms or a halogen, and more preferably R ³ , R ⁴ and R ⁵ are a methyl group, an ethyl group or a chlorine atom. )
A particularly preferred group as R ^a of the compound represented by the general formula (A), wherein X is a sulfur atom, is any of the following formulas (R ^a -1) to (R ^a -8): It is a group.

In general formula (A), the group represented by R ^a —CO—NH— is preferably bonded to the ortho position of the group to which X is bonded.

As R ^b of the compound represented by the general formula (A) in which X is a sulfur atom, a group represented by the following general formula (A-3) is preferable:

(R ^c represents an isopropyl group, an ethyl group, or a methyl group, more preferably an isopropyl group); or R ^b is a group represented by the following general formula (A-4):

(X and R ^a are the same as above),
And the group represented by formula (A-4) is the same as the moiety other than R ^{b of the} group represented by formula (A).

As the compounds represented by the general formula (A) or the general formula (A ′) and X being a sulfur atom, particularly preferred compounds are compounds shown in the following Tables 1-1 to 1-4. .

1-1-2. The compound represented by the general formula (A), wherein X is a methylene group. The compound represented by the general formula (A), wherein X is a methylene group, is preferably the following groups as R ^a It is.

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are preferably both an alkyl group having 1 to 3 carbon atoms or a halogen, and more preferably R ¹ and R ² are both a methyl group, an ethyl group or a chlorine atom); Group represented by (A-2):

(Y ¹ represents a carbon atom;
R ³ , R ⁴ and R ⁵ are preferably both an alkyl group having 1 to 3 carbon atoms or a halogen, and more preferably R ³ , R ⁴ and R ⁵ are a methyl group, an ethyl group or a chlorine atom. )
A particularly preferred group as R ^a of the compound represented by the general formula (A), wherein X is a methylene group, is any of the following formulas (R ^a -1) to (R ^a -12): The group is:

As R ^b of the compound represented by the general formula (A), wherein X is a methylene group, a group represented by the following general formula (A-3) is preferable:

(X and R ^a are the same as above),
And the group represented by formula (A-4) is the same as the moiety other than R ^{b of the} group represented by formula (A).
As the compound represented by the general formula (A) and X being a methylene group, particularly preferable compounds are those shown in Table 2 below.

1-1-3. R ^a of the compound represented by the general formula (A) wherein X is an oxygen atom and the compound represented by the general formula (A) and X is an oxygen atom is preferably represented by the following general formula Group represented by (A-1):

(Y represents a nitrogen atom or a carbon atom,
R ¹ and R ² are preferably both an alkyl group having 1 to 3 carbon atoms or a halogen, more preferably R ¹ and R ² are both a methyl group, an ethyl group or a chlorine atom.

As R ^b of the compound represented by the general formula (A) in which X is an oxygen atom, a group represented by the following general formula (A-3) is preferable:

As the compound represented by the general formula (A), in which X is an oxygen atom, particularly preferred compounds are those shown in Table 3 below.

1-1-4. Pharmaceutically acceptable salt of compound represented by general formula (A) or general formula (A ′) or pharmaceutically acceptable hydrate thereof In the above general formula (A) or general formula (A ′) Pharmaceutically acceptable hydrates of the represented compounds are not particularly limited, but include 1/2 hydrate, 3/2 hydrate, 1 hydrate, 2 hydrate, 3 hydrate, Tetrahydrate can be raised. Preferred are 1/2 hydrate, 3/2 hydrate, monohydrate and dihydrate.

The pharmaceutically acceptable salt of the compound represented by the general formula (A) or the general formula (A ′) is not particularly limited, but hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphorus Inorganic acids such as acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid Acid addition salts with organic acids such as sulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid; inorganic salts such as sodium, potassium, magnesium, calcium, aluminum; methylamine, ethylamine, ethanolamine, lysine, ornithine, etc. And salts with organic bases; and ammonium salts. Preferred are organic acid addition salts with sulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid.

1-2. Method for synthesizing compound represented by general formula (A) The method for synthesizing the compound represented by general formula (A) used in the present invention is not particularly limited. For example, the method described in JP-A-2011-178704, Or the method shown to a "synthesis scheme" can be illustrated. X and R ^a described in “Synthesis Scheme” are the same as those in 1-1. Is the same as
(I) Step (1): Synthesis of Compound (Ic) from Compound (Ia) (Synthesis Scheme)
Compound (Ia) is dissolved in dichloromethane (CH ₂ Cl ₂ ) or dimethylformamide (DMF) or the like, and pyridine (Py) or N, N-dimethyl-4-aminopyridine (DMAP) or the like is added, for example, 20 to 35 Stir for 1 to 3 hours at ° C. Compound (Ib) dissolved in water, dichloromethane or the like is added, for example, at room temperature or under ice cooling, and stirred at, for example, 20 to 35 ° C. for 12 to 48 hours. The reaction solution is diluted with dichloromethane, chloroform or the like, washed with, for example, 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, brine, etc., dried over sodium sulfate, and concentrated under reduced pressure. Alternatively, it is purified by silica gel chromatography using a mixed solution of ethyl acetate and toluene to obtain compound (Ic).

(Ii) Step (2): Synthesis of Compound (Id) from Compound (Ic) (Synthesis Scheme)
Compound (Ic) is dissolved in, for example, a mixed solution of tetrahydrofuran (THF) and ethanol (EtOH), and sodium borohydride (NaBH ₄ ) is added to the solution, for example, under ice cooling. This is stirred, for example, at 4-25 ° C. for 2-5 hours. Acetic acid or the like is added to the reaction solution to adjust the pH to about 3, and the reaction solution is concentrated under reduced pressure and dissolved in ethanol. After washing with water or the like, the solution is concentrated under reduced pressure to obtain a crude product of compound (Id). Since this compound (Id) is subjected to stability, this crude product is used in the next reaction.

(Iii) Step (2): Synthesis of Compound (If) from Compound (Id) (Synthesis Scheme)
The crude product of compound (Id) is dissolved in dichloromethane or the like, and a base such as pyridine is added and stirred. To this, for example, compound (Ie) is slowly added under ice cooling, and the mixture is stirred, for example, at 20 to 35 ° C. for 1 to 3 hours. The reaction solution is diluted with dichloromethane, chloroform or the like, washed with, for example, 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, brine, etc., dried over sodium sulfate, and concentrated under reduced pressure. Alternatively, it is purified by silica gel chromatography using a mixed solution of ethyl acetate and toluene to obtain compound (If).

1-3. A neuroprotective agent comprising a pharmaceutically acceptable salt of a compound represented by the general formula (A) or the general formula (A ′) or a pharmaceutically acceptable hydrate thereof is the above general formula ( In addition to the compound represented by A) or the general formula (A ′), or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof, it can be prepared in combination with a pharmaceutical carrier. . As the carrier used in the preparation of the neuroprotective agent, various commonly used ones such as excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants, etc. Can be illustrated.

The dosage form when the above-mentioned neuroprotective agent is orally administered is not particularly limited, and examples thereof include tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions and the like. . Moreover, when the said neuroprotective agent is administered parenterally, an injection, a liquid formulation, an infusion, etc. can be illustrated.

When the neuroprotective agent is a solid neuroprotective agent for oral use such as tablets, powders, granules, etc., as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystals Cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, gum arabic, etc. , Water, ethanol, binders such as potassium phosphate, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauric Disintegrants such as sodium sulfate, monostearate monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, starch Adsorbents such as lactose, kaolin, bentonite, colloidal silicic acid, etc., lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol and the like can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.

When the neuroprotective agent is an oral solid neuroprotective agent for pills, carriers such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic Binders such as powder, tragacanth powder and gelatin, and disintegrants such as laminaran and agar can be used.

If the neuroprotective agent is a tablet or pill, sucrose, hydroxypropylcellulose (HPC), shellac, gelatin, glycerin, sorbitol, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinylpyrrolidone (PVP), if necessary , Hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), or a methyl methacrylate-methacrylic acid copolymer.

When the above-mentioned neuroprotective agent is an oral solid neuroprotective agent for capsules, the capsules are mixed with various carriers exemplified above and filled into hard gelatin capsules, soft capsules, etc. Prepared.

When the neuroprotective agent is a liquid, it may be an aqueous or oily suspension, solution, syrup, or elixir, and is prepared according to a conventional method using ordinary additives.

In preparation when the neuroprotective agent is an injection, the carrier is diluted with water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Agent, pH adjuster such as sodium citrate, sodium acetate, sodium phosphate, buffer such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate, sodium pyrosulfite, EDTA, thioglycolic acid For example, saccharides such as mannitol, inositol, maltose, sucrose, and lactose can be used as stabilizers such as thiolactic acid and molding agents when lyophilized. In this case, a sufficient amount of glucose or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, soothing agent, local anesthetic, etc. may be added. Also good. By adding these carriers, subcutaneous, intramuscular and intravenous injections can be produced by conventional methods.

When the above-mentioned neuroprotective agent is an infusion, it can be prepared by dissolving the administered compound in an isotonic electrolyte infusion preparation based on physiological saline, Ringer's solution or the like.

The dose of the neuroprotective agent of the present invention is not particularly limited as long as the effect of the present invention is exhibited, and can be appropriately set depending on the dosage form, patient age, sex, degree of disease, etc. Converted to the amount of the compound represented by the formula (A) or the general formula (A ′), adult (over 15 years old) (calculated as a body weight of about 60 kg), about 0.1 to 1,000 mg / kg per day, preferably It is about 0.5-500 mg / kg. When the neuroprotective agent is administered by a method other than oral administration, the effective blood concentration is 0.2 in terms of the amount of the compound represented by the general formula (A) or the general formula (A ′). It can be administered at a dose of ˜100 μg / ml, more preferably 0.5 to 50 μg / ml. In addition, the neuroprotective agent of the present invention is administered continuously for 1 week or longer, preferably 3 months or longer, more preferably 1 year or longer, in order to prevent the death of nervous system cells or to suppress the progression of diseases described later. be able to.

In the present invention, a “neuroprotective agent” refers to a drug that exhibits an action of suppressing cell death of nervous system cells. “Cell death” means that a cell is killed, and its mechanism includes all mechanisms such as apoptosis, necrosis, autophagy pathway, etc., and is not particularly limited. Furthermore, “suppression of cell death” refers to decreasing the number or ratio of cells that die.

In the present invention, neural cells include nerve cells, glial cells, astrocytes, microglia, oligodendrocytes, Schwann cells and the like.

The neuroprotective agent of the present invention has an action of suppressing cell death of nervous system cells. Specifically, the neuroprotective agent of the present invention suppresses cell death of neural cells such as nerve cells, glial cells, astrocytes, microglia, oligodendrocytes, and Schwann cells, and preferably It suppresses cell death of nerve cells, glial cells, and oligodendrocytes, and more preferably suppresses nerve cell death.

The neuroprotective agent of the present invention can be used for prevention and / or treatment of nervous system diseases. The “prevention and / or treatment” of the present invention includes so-called Disease Modifying Therapy (DMT) that prevents the recurrence of a disease and the progression of the disease.

In the present invention, “neurological diseases” include neurodegenerative diseases, ischemic brain diseases, traumatic brain disorders and the like.

In the present invention, "neurodegenerative disease" means a disease in which nervous system cells are killed due to causes other than ischemia. The neuroprotective agent of the present invention is a patient who has been diagnosed with a neurodegenerative disease, or even if there is no symptom of a nervous system disease, it is likely to develop a future nervous system disease from family history or other clinical laboratory data. Can be administered to subjects suspected of being. The neurodegenerative disease includes, for example, Parkinson's disease; amyotrophic lateral sclerosis; mild cognitive impairment (MCI); at least one dementia selected from the group consisting of Alzheimer type, cerebrovascular type, and mixed type (one In embodiments, it does not include those caused by cerebral infarction); polyglutamine disease; prion disease; multiple sclerosis; myasthenia gravis; Guillain-Barre syndrome; Fisher syndrome; chronic inflammatory demyelinating polyneuritis; Examples include multifocal motor neuropathy; Crow-Fukase syndrome; HTLV-1-related myelopathy (HAM); Preferably, the neurodegenerative disease is Parkinson's disease; amyotrophic lateral sclerosis; mild cognitive dysfunction; dementia; polyglutamine disease multiple sclerosis; Guillain-Barre syndrome; chronic inflammatory demyelinating polyneuritis; or Multifocal motor neuropathy, more preferably Parkinson's disease; amyotrophic lateral sclerosis; or dementia, and further preferably Parkinson's disease; amyotrophic lateral sclerosis.

The criteria and methods used in clinical practice can be applied to the diagnosis of these diseases and the method for determining that these diseases are likely to develop.

When the neuroprotective agent of the present invention is administered to a subject diagnosed with mild cognitive dysfunction or suspected of having mild cognitive dysfunction, progression from mild cognitive dysfunction to dementia can be prevented. In addition, when the neuroprotective agent of the present invention is administered to a patient with cerebrovascular dementia, it is preferable to administer the neuroprotective agent at an early stage where symptoms are mild after dementia is suspected.

Alzheimer-type dementia is classified into stages 1 to 3 according to symptoms. When the neuroprotective agent of the present invention is used to treat Alzheimer's dementia, it can be used in patients of any stage, but in one embodiment, family history, genetic analysis, amyloid β in cerebrospinal fluid or plasma Subjects who are suspected of developing Alzheimer-type dementia from the concentration of protein Aβ42 or phosphorylated tau protein, and other clinical symptoms, or subjects suspected of developing Alzheimer-type dementia in the future, or whose stage is the first stage and / or It is preferably used for patients with Alzheimer-type dementia in the second stage, more preferably subjects who are suspected of developing Alzheimer-type dementia or those who are suspected of developing Alzheimer-type dementia in the future, or whose stage is the first stage I have Alzheimer's disease.

In the present invention, “ischemic brain disease” means a disease that develops due to cerebral ischemia, for example, non-cardiogenic cerebral infarction such as cardiogenic cerebral infarction, atherothrombotic cerebral infarction or lacunar infarction. Dementia due to cerebral infarction, etc., preferably non-cardiogenic cerebral infarction.

In the acute phase of cerebral infarction, nerve cells are killed by disruption of blood flow, but at present, there are many cases in which death of nerve cells cannot be suppressed after several hours from the onset.

The neuroprotective agent of the present invention can be administered immediately after the onset of cerebral infarction, preferably in the acute phase. More specifically, it can be administered within 2 weeks, within 1 week, within 72 hours, within 48 hours, within 24 hours, or within 6 hours from onset. Whether or not cerebral infarction has developed can be determined by conventional methods such as CT examination, MRI examination, MRA examination, and cerebral angiography.

2. Agent for prevention and / or treatment of nervous system diseases As one embodiment of the present invention, a compound represented by the above general formula (A) or general formula (A ′), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof Agents for the prevention and / or treatment of nervous system diseases including acceptable hydrates are included.

The preventive and / or therapeutic agent of the present invention can be prepared in combination with a pharmaceutical carrier in addition to the compound represented by the above general formula (A) or general formula (A ') or a salt thereof. The carrier, dosage form, and preparation method thereof used in the preparation of the prophylactic and / or therapeutic agent are the same as those of the “neuroprotective agent”. The dosage of the preventive and / or therapeutic agent of the present invention and the disease to be administered are the same as those of the above-mentioned “neuroprotective agent”.

3. Pharmaceutical Composition As one embodiment of the present invention, there is provided a compound represented by the above general formula (A) or general formula (A ′), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrate thereof. A pharmaceutical composition for the prevention and / or treatment of nervous system diseases is included.

The pharmaceutical composition of the present invention can be prepared in combination with a pharmaceutical carrier in addition to the compound represented by the general formula (A) or the general formula (A ') or a salt thereof. Carriers used in the preparation of the pharmaceutical composition include excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like described in the above “neuroprotective agent”. It can be illustrated.

Examples of the dosage form when the pharmaceutical composition is orally administered include tablets, coated tablets, powders, granules, capsules, liquids, pills, suspensions, emulsions and the like. Moreover, when the said pharmaceutical composition is administered parenterally, an injection, a liquid formulation, an instillation etc. can be illustrated. The preparation method of each dosage form can be performed according to the preparation method of the above-mentioned “neuroprotective agent”.

In addition, the dosage of the pharmaceutical composition of the present invention and the disease to be administered are the same as those of the “neuroprotective agent”.

4). Method for preventing and / or treating nervous system disease As one embodiment of the present invention, the above-mentioned “compound represented by the above general formula (A) or general formula (A ′), or a pharmaceutically acceptable salt thereof, or a method thereof Methods for the prevention and / or treatment of nervous system diseases using “pharmaceutically acceptable hydrates” are included. Specific examples of nervous system diseases and the method of administering neuroprotective agents are as described above.

5). Compound having acylaminophenyl group The compound having an acylaminophenyl group of the present invention is the above-described 1-1. It is a compound represented by general formula (A) or general formula (A ') described in the above. However, in some embodiments, the following compounds are excluded:
・ S- (2-Isobutylamidophenyl) -2-methylpropanethioate: K-178

・ N, N '-(Disulfanediylbis (2,1-phenylene)) bis (2-methylpropanamide): K-152

・ 2-Isobutyramide phenylisobutyrate: K-205

・ N- (2-Hydroxyphenyl) isobutyramide: K-204

S- (2-benzamidophenyl) 2-methylpropanethioate: K-181

・ N, N '-(Disulfanediylbis (2,1-phenylene)) dibenzamide: K-202

・ N, N '-(Disulfanediylbis (2,1-phenylene)) dioctanamide: K154

N, N '-(disulfanediylbis (2,1-phenylene)) bis (pyrrolidine-1-carboxamide): K-700

N, N '-(disulfanediylbis (2,1-phenylene)) bis (piperidine-1-carboxamide): K-680

・ 1,1 '-(Disulfanediylbis (2,1-phenylene)) bis (3,3-diethylurea): K-640

・ N, N '-(2,2'-Disulfanediylbis (2,1-phenylene)) bis (2,2-dimethylpropanamide): K-153

In the compound of the present invention represented by the general formula (A), X is preferably a sulfur atom or a methylene group, and more preferably a sulfur atom.

In the compound of the present invention represented by the general formula (A), when X is a sulfur atom, preferred R ^a is a pyridyl group, piperazyl group, piperidyl group, pyrrolidyl group, or the following general formula (A-5) Group. The pyridyl group, piperazyl group, piperidyl group, and pyrrolidyl group may be substituted with at least one selected from the group consisting of a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms.

(Y represents a nitrogen atom,
R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 3 carbon atoms)
In the compound of the present invention represented by the general formula (A), when X is a sulfur atom, R ^b is preferably a group represented by the following general formula (A-3) or a general formula (A-4) ). When X is a sulfur atom and R ^a is a piperidyl group, a pyrrolidyl group, or a group represented by the above general formula (A-5), preferably R ^b is represented by the following general formula (A-3): The group shown is:

(R ^c represents an alkyl group having 1 to 6 carbon atoms)

(X and ^Ra are the same as above)}.

In the compounds of the present invention represented by Formula (A), when X is a sulfur atom, a more preferred R ^a, include the following groups.

A pyridyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group A pyridyl group optionally substituted by at least one species;
A piperidyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group. A piperidyl group optionally substituted by at least one species;
A piperazil group optionally substituted with at least one selected from the group consisting of an oxygen atom, a methyl group and an ethyl group, more preferably at least one selected from the group consisting of a methyl group and an ethyl group A good dioxopiperazyl group, more preferably a dioxopiperazyl group in which any one hydrogen atom bonded to any one nitrogen atom of the piperazyl group is substituted with a methyl group or an ethyl group;
A pyrrolidyl group optionally substituted with at least one selected from the group consisting of halogen and an alkyl group having 1 to 3 carbon atoms, more preferably selected from the group consisting of a chlorine atom, a methyl group and an ethyl group A pyrrolidyl group optionally substituted by at least one type; or a group represented by the following general formula (A-5):

(Y represents a nitrogen atom,
R ¹ and R ² are preferably both alkyl groups having 1 to 3 carbon atoms, and more preferably R ¹ and R ² are both methyl groups or ethyl groups. )
Particularly preferred groups as R ^a of the compound represented by the general formula (A), wherein X is a sulfur atom, are represented by the following formulas (R ^a -1) and (R ^a -3) to (R ^a- 6) any of the groups shown:

In the compound of the present invention represented by the general formula (A), when X is a sulfur atom, more preferable R ^b is a group represented by the following general formula (A-3):

(R ^c represents an isopropyl group, an ethyl group, or a methyl group, more preferably an isopropyl group); or a group represented by the following general formula (A-4):

As the compound of the present invention represented by the general formula (A), wherein X is a sulfur atom, particularly preferred compounds are the compounds 7, 9 and 11 shown in Tables 1-1 to 1-3. Compound 14 and Compound 18.

In the compound of the present invention represented by the general formula (A), when X is a methylene group, a preferred compound is the compound described in 1-1-2 above.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the embodiments.

The animal experiments shown below were carried out at the Animal Experiment Facility attached to the Osaka University School of Medicine with the approval of the Animal Experiment Committee of the Osaka University Graduate School of Medicine based on the Osaka University Animal Experiment Regulations. The use and disposal of 1-methyl-4-ridphenylpyridinium (MPP +) was performed according to the safety data sheet (MSDS).

Synthesis Example 1: 1,1 '-(Disulfanediylbis (2,1-phenylene)) bis (3,3-diethylurea) (K-640)

2,2-dithiodianiline (0.50 g, 2.01 mmol) was dissolved in dichloromethane (2 ml), and pyridine (810 μl, 10.05 mmol) was added and stirred. Under ice cooling, diethylcarbamoyl chloride (565 μl, 6.03 mmol) was slowly added and stirred at room temperature for 16 hours. This reaction was performed under anhydrous conditions. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine in that order, and then dried over sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by silica gel chromatography (ethyl acetate: toluene = 1: 9) to obtain pale yellow crystals (150 mg, 0.35 mmol, yield 17.2%).
mp 131.7-134.5 ° C.
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.19 (12H, t, J = 7.1 Hz, NCH ₂ C H ₃ × 4), 3.22 (8H, q, J = 7.3 Hz, NCH ₂ CH ₃ × 4) , 6.85 (2H, brt, J = 7.3 Hz, Ar-H ₂ ), 7.16-7.28 (4H, m, Ar-H ₄ ), 7.35 (2H, brt, J = 8.6 Hz, Ar-H ₂ ), 7.57 (2H, s, NHCO × 2), 8.29 (2H, d, J = 8.3 Hz, Ar-H ₂ ).
ESI-MS m / z: 447.1 (M + H) ⁺ .HR-LC-TOF-MS m / z: (M + H) ⁺ calcd for C ₂₂ H ₃₀ N ₄ O ₂ S ₂ , 447.1883; found, 447.1897 .

Synthesis Example 2: S-2- (3, 3-diethylureido) phenyl 2-methylpropanethioate (K-630)

K-640 (0.15 g, 0.35 mmol) was dissolved in tetrahydrofuran (2 ml) and ethanol (2 ml), and sodium borohydride (26.1 mg, 0.69 mmol) was added under ice cooling. The reaction was stirred at room temperature for 4 hours. Acetic acid was added and the mixture was stirred at pH 3, and the reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. After washing with water, the solution was concentrated under reduced pressure to obtain a pale yellow oily compound (96 mg) as a crude product. Since this compound was unstable and difficult to purify, it was directly used in the next reaction. The total amount of this compound (96 mg) was dissolved in dichloromethane (1 ml), and pyridine (172.4 μl, 2.14 mmol) was added and stirred. Isobutyryl chloride (135.4 μl, 1.29 mmol) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. This reaction was performed under anhydrous conditions. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine in that order, and then dried over sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3), and the resulting white crystals (56 mg, 0.19 mmol, yield 44.4%) Got.
mp 113.2-113.7 ° C.
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.17 (3H, brs, NCH ₂ C H ₃ ), 1.26 (6H, d, J = 6.8 Hz, CH (C H ₃ ) ₂ ), 1.33 (3H, brs , NCH ₂ C H ₃ ), 2.50-2.60 (1H, m, C H (CH ₃ ) ₂ ), 3.43-3.52 (4H, m, NC H ₂ CH ₃ × 2), 7.10 (1H, brt, J = 7.6 Hz, Ar-H), 7.42-7.49 (2H, m, Ar-H ₂ ), 8.22 (1H, d, J = 8.3 Hz, Ar-H), 8.34 (1H, brs, NHCO).
ESI-MS m / z: 295.1 (M + H) ⁺ .HR-LC-TOF-MS m / z: (M + H) ⁺ calcd for C ₁₅ H ₂₂ N ₂ O ₂ S, 295.1475; found, 295.1474.

Synthesis Example 3: N, N ′-(2,2′-disulfanediylbis (2,1-phenylene)) dipiperidine-1-carboxamide (K-680)

2,2-dithiodianiline (1.00 g, 4.03 mmol) in dichloromethane (5 ml), pyridine (1.95 ml, 24.18 mmol) was added and stirred. Under ice cooling, 1-piperidinecarbonyl chloride (1.5 ml, 12.09 mmol) was added, and the reaction station was stirred overnight at room temperature. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate: toluene = 1: 1) to obtain a pale yellow powdery compound (1.40 g, 2.97 mmol, yield 73.7%).
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.54-1.62 (12H, m, -CH ₂ CH ₂ CH _2- × 2), 3.23-3.26 (8H, m, -N-CH _2- × 4), 6.89 (2H, td, J = 7.2, 1.2 Hz, Ar-H ₂ ), 7.33-7.38 (4H, m, Ar-H ₄ ), 7.50 (2H, brs, NHCO × 2), 8.18 (2H, dd, J = 8.8, 1.2 Hz, Ar-H ₂ ).
. ESI-MS m / z: 471.2 (M + H) + HR-LC-TOF-MS m / z: (M + H) + calcd for C 24 H 30 N 4 O 2 S 2, 471.1883; found, 471.1896 .

Synthesis Example 4: S-2- (piperidine-1-carboxamido) phenyl 2-methylpropanethioate (K-670)

K-680 (1.4 g, 2.97 mmol) was dissolved in tetrahydrofuran (5 ml) and ethanol (5 ml), sodium borohydride (0.11 g, 2.97 mmol) was added under ice-cooling, and the reaction solution was stirred at room temperature. Stir for hours. Acetic acid was added to the reaction mixture to adjust the pH to 3, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and concentrated under reduced pressure to obtain 2.00 g of a pale yellow oily reduced product as a crude product. Since this substance was unstable and difficult to purify, it was directly used in the next reaction. 2.00 g of the crude product was dissolved in dichloromethane (20 ml), and pyridine (4.09 ml, 50.76 mmol) was added and stirred. Under ice cooling, isobutyryl chloride (2.68 ml, 25.38 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: toluene = 1: 1) to obtain a pale yellow powdery compound (263 mg, 0.86 mmol, yield 9.06%).
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz, (CH ₃ ) ₂ ), 1.60-1.68 (6H, m, -CH ₂ CH ₂ CH _2- × 2), 2.56 (1H, m, C H (CH ₃ ) ₂ ), 3.56-3.59 (4H, m, -N-CH _2- × 2), 7.10 (1H, td, J = 7.6, 1.2 Hz, Ar-H) , 7.43 (1H, td, J = 8.3, 1.7 Hz, Ar-H), 7.47 (1H, dd, J = 7.8, 1.7 Hz, Ar-H), 8.23 (1H, d, J = 8.0 Hz, Ar- H), 8.29 (1H, brs, NHCO).
ESI-MS m / z: 307.1 (M + H) ⁺ .HR-LC-TOF-MS m / z: (M + H) ⁺ calcd for C ₁₆ H ₂₂ N ₂ O ₂ S, 307.1475; found, 307.1472.

Synthesis Example 5: N, N ′-(disulfanediylbis (2,1-phenylene)) bis (pyrrolidine-1-carboxamide) (K-700)

2,2-dithiodianiline (0.50 g, 2.02 mmol) in dichloromethane Dissolved in (2 ml), pyridine (0.81 ml, 10.10 mmol) was added and stirred. Under ice-cooling, 1-pyrrolidinecarbamoyl chloride (0.67 ml, 6.06 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: toluene = 1: 2) to give pale-yellow crystals (65.2 mg, yield 7.28%).
mp 137.5-140.0 ° C.
¹ H-NMR (399.65 MHz, CDCl ₃ ) δ: 1.89 (8H, t, J = 6.8 Hz, -CH ₂ CH _2- × 2), 3.22 (8H, brs, -NCH _2- × 4), 6.88 ( 2H, dt, J = 7.6, 1.2 Hz, Ar-H ₂ ), 7.33-7.40 (6H, m, Ar-H ₄ , NHCO × 2), 8.31 (2H, dd, J = 8.3, 1.2 Hz, Ar- H ₂ ).
. ESI-MS m / z: 444.3 (M + H) + HR-LC-TOF-MS m / z: (M + H) + calcd for C 22 H 26 N 4 O 2 S 2, 443.1570; found, 443.1563 .

Synthesis Example 6: S-2- (pyrrolidine-1carboxamido) phenyl 2-methylpropanethioate (K-690)

K-700 (1.02 g, 2.30 mmol) was dissolved in tetrahydrofuran (5 ml) and ethanol (5 ml), and sodium borohydride (87 mg, 2.30 mmol) was added under ice cooling. The reaction was stirred at room temperature for 4 hours. Acetic acid was added to the reaction solution to adjust the pH to 3, and then the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and the solution was concentrated under reduced pressure to give a pale yellow oil (0.28 g) as a crude product. Since this compound was unstable, it was used in the next reaction without purification. Total amount of this compound (0.28 g, 0.95 mmol) was dichloromethane In (2 ml), pyridine (0.39 ml, 4.75 mmol) was added and stirred. Isobutyryl chloride (0.30 ml, 2.85 mmol) was slowly added under ice cooling, and the mixture was stirred at room temperature for 2 hours. This reaction was performed under anhydrous conditions. The reaction solution was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. After concentrating this solution under reduced pressure, the obtained residue was subjected to silica gel column chromatography (ethyl acetate: toluene = 2: 3) to obtain pale yellow crystals (100 mg, 0.35 mmol, yield 8.7%).
mp 62.0-63.0 ° C. ¹ H NMR (399.65 MHz, CDCl ₃ ) δ1.25 (6H, d, J = 6.8 Hz, CH (C H ₃ ) ₂ ), 1.90-2.05 (4H, m, -CH ₂ CH _2- ), 2.56 (1H, m, C H (CH ₃ ) ₂ ), 7.09 (1H, td, J = 7.8, 1.2 Hz, Ar-H), 7.42 (1H, td, J = 7.8, 1.7 Hz , Ar-H), 7.47 (1H, dd, J = 7.6, 1.5 Hz, Ar-H), 8.20 (1H, d, J = 8.0 Hz, Ar-H), 8.42 (1H, brs, NHCO).
ESI-MS m / z: 293.7 (M + H) ⁺ .HR-LC-TOF-MS m / z: (M + H) ⁺ calcd for C ₁₅ H ₂₀ N ₂ O ₂ S, 293.1318; found, 393.1311.

Synthesis Example 7: 1,1 ′-(2,2 ′-(ethane-1,2-diyl) bis (2,1-phenylene)) bis (3,3-diethylurea) (K-860)

2,2'-ethylenedianiline (1.0 g, 4.71 mmol) in dichloromethane Dissolved in (10 ml), pyridine (1.1 ml, 14.1 mmol) was added and stirred. Under ice-cooling, diethylcarbamyl chloride (1.8 ml, 14.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 days. The generated crystals were collected by filtration and purified by silica gel chromatography (ethyl acetate: hexane = 1: 2) to obtain pale brown crystals (29 mg, 0.07 mmol, yield 1.5%).
mp 171.6-174.9 ° C. ¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.11 (12H, t, J = 7.2 Hz, -NCH ₂ C H ₃ × 4), 2.90 (4H, s, -CH ₂ CH _2- ), 3.18 (8H, q, J = 7.2 Hz, -NC H ₂ CH ₃ × 4), 5.83 (2H, brs, NH × 2), 7.06 (2H, td, J = 7.4, 1.2 Hz, Ar -H ₂ ), 7.15-7.21 (4H, m, Ar-H ₄ ), 7.50 (2H, dd, J = 8.0, 1.2 Hz, Ar-H ₂ ).
. ESI-MS m / z: 411.5 (M + H) + HR-ESI-MS m / z: (M + H) + calcd for C 24 H 35 N 4 O 2, 411.2761; found, 411.2736.

Synthesis Example 8: N, N ′-(2,2′-disulfanediylbis (2,1-phenylene)) bis (4-chlorobenzamide) (KS-151)

2,2'-dithiodianiline (1 g, 4.02 mmol) in dichloromethane (50 ml), pyridine (0.96 ml, 12.0 mmol) was added and stirred. 4-chlorobenzoyl chloride (1.53 ml, 12.0 mmol) was added dropwise at room temperature, and the mixture was stirred for 5 hours. The reaction solution was diluted with dichloromethane, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, and dried over NaSO ₄ . The solution was concentrated under reduced pressure and then subjected to silica gel chromatography (ethyl acetate: hexane = 1: 9) to obtain white crystals (480 mg, 0.915 mmol, yield 22.8%).
mp 178.0-178.8 ° C.
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 6.97 (2H, td, J = 7.6, 1.2 Hz, Ar-H ₂ ), 7.30 (2H, td, J = 8.6, 1.0 Hz, Ar-H ₂ ), 7.41, 7.57 (4H, A ₂ B ₂ , J = 8.4 Hz, Ar-H ₄ ), 7.46 (2H, dd, J = 7.8, 1.8 Hz, Ar-H ₂ ), 8.43 (2H, dd, J = 8.0 , 1.0 Hz, -NH-).
ESI-MS m / z: 524.4 (M-H) ^- .

Synthesis Example 9 N, N '-(2,2'-disulfanediylbis (2,1-phenylene)) bis (2,2-dichloroacetamide) (KS-152)

2,2'-dithiodianiline (1 g, 4.02 mmol) in dichloromethane (10 ml), pyridine (0.96 ml, 12.0 mmol) was added and stirred. Dichloroacetyl chloride (1.15 ml, 12.0 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with dichloromethane, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain white crystals (870 mg, 1.85 mmol, yield 45.96%).
mp 187.1 -188.9 ° C.
¹ H NMR (399.65 MHz, DMSO) δ: 6.74 (2H, s, -CHCl ₂ ), 7.31-7.39 (6H, m, Ar-H ₆ ), 7.590 (2H, d, J = 7.6 Hz, Ar-H ₂ ), 10.50 (2H, s, -NH-).
ESI-MS m / z: 469.2 (M-H) ^- . HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₁₆ H ₁₃ Cl ₄ N ₂ O ₂ S ₂ , 470.9144 .; found, 470.9138.

Synthesis Example 10: S-2- (4-Chlorobenzamido) phenyl 2-methylpropanethioate (KS-153)

KS-151 (0.5 g, 0.95 mmol) was dissolved in tetrahydrofuran (20 ml) and ethanol (20 ml), sodium borohydride (0.036 g, 0.95 mmol) was added under ice-cooling, and the reaction solution was stirred at room temperature. Stir for hours. Acetic acid was added to the reaction mixture to adjust the pH to 3, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and concentrated under reduced pressure to obtain 2.00 g of a pale yellow oily reduced product as a crude product. Since this substance was unstable and difficult to purify, it was directly used in the next reaction. 0.51 g of crude product in dichloromethane (10 ml), pyridine (0.187 ml, 2.32 mmol) was added and stirred. Under ice-cooling, isobutyryl chloride (0.245 ml, 2.32 mmol) was added dropwise, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 19) to give white crystals (154 mg, 0.46 mmol, yield 48.5%).
mp 107.4 -110.1 ° C.
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.26 (6H, d, J = 7.2 Hz, CH (C H ₃ ) ₂ ), 2.93 (1H, m, C H (CH ₃ ) ₂ ), 7.18 (1H , brt, J = 7.6 Hz, Ar-H), 7.40-7.46 (4H, m, Ar-H ₄ ), 7.77 (2H, d, J = 8.8 Hz, Ar-H ₂ ), 8.40 (1H, d, J = 8.4 Hz, Ar-H)), 8.47 (1H, brs, NHCO).
HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₁₇ H ₁₇ ClNO ₂ S, 334.0669; found, 334.0663.

Synthesis Example 11: N, N '-(2,2'-disulfanediylbis (2,1-phenylene)) bis (4-methylbenzamide) (K-870)

2,2-dithiodianiline (0.50 g, 2.01 mmol) in dichloromethane (20 ml), pyridine (0.39 ml, 4.83 mmol) was added and stirred. Under ice cooling, p-toluoyl chloride (0.64 ml, 4.83 mmol) was slowly added and stirred at room temperature for 16 hours. This reaction was performed under anhydrous conditions. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine in that order, and then dried over sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by flash column chromatography (ethyl acetate: n-hexane = 1: 7). Thereafter, pale yellow crystals (33.3 mg, 0.07 mmol, yield 3.4%) were obtained by recrystallization.
mp 165.8-166.3 ° C.
¹ H NMR (399.65 MHz CDCl ₃ ) δ: 2.44 (6H, s, -CH ₃ ), 6.95 (2H, t, J = 7.6 Hz, Ar-H ₂ ), 7.25,7.59 (8H, A ₂ B ₂ , J = 7.8 Hz, Ar-H ₈ ), 7.33 (2H, t, J = 8.0 Hz, Ar-H ₂ ), 7.41 (2H, d, J = 8.0 Hz, Ar-H ₂ ), 8.92 (2H, s , CONH). ESI-MS m / z: 485.3 (M + H) ⁺ .

Synthesis Example 12: N, N ′-(2,2′-disulfanediylbis (2,1-phenylene)) bis (6-chloronicotinamide) (K-880)

2,2′-dithiodianiline (0.5 g, 2.01 mmol) was dissolved in dimethylfuran (10 ml), and N, N-dimethyl-4-aminopyridine (0.59 ml, 4.82 mmol) was added and stirred. 6-chloronicotinoyl chloride (0.85 g, 4.82 mmol) was added dropwise at room temperature, and the mixture was stirred for 9 hours. Dimethylfuran was removed by lyophilization to obtain yellowish white crystals. The crystals were washed successively with water and ethanol, dissolved in chloroform, and recrystallized to obtain white crystals (600 mg, 1.14 mmol, yield 56.7%).
mp: 216.1 -218.0 ° C.
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 7.01 (2H, td, J = 7.7, 1.6 Hz, Ar-H ₂ ), 7.27 (2H, td, J = 8.0, 1.4 Hz, Ar-H ₂ ), 7.44 (2H, dd, J = 8.4, 0.8 Hz, Ar-H ₂ ), 7.53 (2H, dd, J = 7.8, 1.4 Hz, Ar-H ₂ ), 7.90 (2H, dd, J = 8.4, 2.4 Hz , Ar-H ₂ ), 8.34 (2H, dd, J = 8.4, 1.2 Hz, Ar-H ₂ ), 8.63 (2H, brd, J = 2.4 Hz, Ar-H ₂ ), 8.77 (2H, brs, NHCO ).
HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₂₄ H ₁₇ Cl ₂ N ₄ O ₂ S ₂ , 527.0171; found, 527.0169.

Synthesis Example 13: N, N ′-(2,2′-disulfanediylbis (2,1-phenylene)) bis (4-ethyl-2,3-dioxopiperazine-1-carboxamide) (K-890 )

2,2-dithiodianiline (1.00 g, 4.02 mmol) was dissolved in dichloromethane (20 ml), and pyridine (2.33 ml, 28.94 mmol) was added and stirred. To this solution, 4-ethyl-2,3-dioxo-1-piperazinecarbonylchloride (1.97 g, 9.65 mmol) dissolved in dichloromethane (20 ml) was added dropwise little by little under an argon atmosphere and stirred for 24 hours. Then, it concentrated under reduced pressure. Ice water was added to the obtained crystals, and suction filtration was performed to obtain pale yellow crystals (1.07 g, 1.83 mmol, yield 45.5%).
mp 172.8-175.5
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.27-1.31 (6H, m, NCH ₂ C H ₃ × 2), 3.62 (4H, q, J = 7.6 Hz, NC H ₂ CH ₃ × 2), 3.70 -3.71 (4H, m, NCH ₂ C H ₂ × 2), 4.04-4.13 (4H, m, NC H ₂ CH ₂ × 2), 6.97-7.07 (2H, m, Ar- H ₂ × 2), 7.27 -7.32 (2H, m, Ar- H ₂ × 2), 7.38 (2H, dd, J = 7.8 Hz, 1.4 Hz Ar-H ₂ × 2), 8.12 (2H, dd, J = 8.0 Hz, 1.2 Hz Ar -H ₂ × 2), 11.68 (2H, s, N H CO × 2)

Synthesis Example 14: S-4- (3,3-Diethylureido) phenyldiethylcarbamothioate (K-730)

p-Aminothiophenol (0.50 g, 3.99 mmol) was dissolved in dichloromethane (5 ml), and pyridine (1.93 ml, 23.94 mmol) was added and stirred. Under ice cooling, diethylcarbamoyl chloride (1.52 ml, 11.97 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with CHCl ₃ , washed successively with 1N HCl, water, saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethanol :: hexane = 1: 1) to obtain a pale yellow powdery compound (0.99 g, 3.07 mmol, yield 75.0%).
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 1.19 (12H, t, J = 7.1 Hz, -NCH ₂ C H ₃ × 4), 3.34 (4H, q, J = 7.1 Hz, -NC H ₂ CH ₃ × 2), 3.43 (4H, brq, J = 6.8 Hz, -NC H ₂ CH ₃ × 2), 7.34, 7.39 (4H, A ₂ B ₂ , J = 9.0 Hz, Ar-H ₄ ).
ESI-MS m / z: 324.2 (M + H) ⁺ .HR-LC-TOF-MS m / z: (M + H) ⁺ calcd for C ₁₆ H ₂₅ N ₃ O ₂ S, 324.1740; found, 324.1737.

Synthesis Example 15 S-4- (3,3-diethylureido) phenyl 2-methylpropanethioate (K-740)

K-730 (3.58 g, 11.1 mmol) was dissolved in methanol (20 ml), 5N potassium hydroxide (8.88 ml, 44.4 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust the pH to 6, and the mixture was concentrated under reduced pressure. Dissolve the residue in chloroform and wash sequentially with saturated sodium bicarbonate solution and brine. After drying, concentration under reduced pressure gave a pale yellow oily compound (3.66 g, 16.3 mmol) as a crude product. Since this compound was unstable and difficult to purify, it was directly used in the next reaction. The total amount of this substance (3.66 g, 16.3 mmol) was dissolved in dichloromethane (10 ml), and pyridine (3.9 ml, 49.0 mmol) was added and stirred. Isobutyryl chloride (5.2 ml, 49.0 mmol) was added and stirred at room temperature for 6 hours. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethanol :: hexane = 1: 2) to obtain pale yellow crystals (0.22 g, 0.075 mmol, yield 0.460%).
mp: 82.4 -84.5 ° C
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 0.90 (3H rs, -NCH ₂ C H ₃ ), 1.17-1.24 (9H, m, CH (C H ₃ ) ₂ , -NCH ₂ C H ₃ ), 2.77 (1H, m, C H (CH ₃ ) ₂ ), 3.27-3.46 (4H, m, -NC H ₂ CH ₃ × 2), 7.25, 7.50 (4H, A ₂ B ₂ , J = 8.8 Hz, Ar- H ₄ ).
ESI-MS m / z: 293.5 (M-H) ^- . HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₁₅ H ₂₃ N ₂ O ₂ S, 295.4203; found, 295.4203.

Synthesis Example 16: S-3- (3,3-Diethylureido) phenyl 2-methylpropanethioate (K-760)

K-730 (3.45 g, 10.7 mmol) was dissolved in methanol (20 ml), 5N potassium hydroxide (8.56 ml, 42.8 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust the pH to 6, and the mixture was concentrated under reduced pressure. Dissolve the residue in chloroform and wash sequentially with saturated sodium bicarbonate solution and brine. After drying, the filtrate was concentrated under reduced pressure to give a pale yellow oily compound (3.01 g, 13.4 mmol) as a crude product. Since this compound was unstable and difficult to purify, it was directly used in the next reaction. The total amount of this substance (3.01 g, 13.4 mmol) was dissolved in dichloromethane (10 ml), and pyridine (3.3 ml, 40.3 mmol) was added and stirred. Isobutyryl chloride (4.3 ml, 40.3 mmol) was added and stirred at room temperature for 6 hours. The reaction mixture was diluted with CHCl ₃ , washed successively with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethanol :: hexane = 1: 2) to obtain a white powdery compound (0.10 g, 0.034 mmol, yield 0.254%).
¹ H NMR (399.65 MHz, CDCl ₃ ) δ: 0.75-0.98 (3H, m, -NCH ₂ C H ₃ ), 1.14-1.21 (9H, m, -NCH ₂ C H ₃ and CH (C H ₃ ) ₂ ), 2.76 (1H, m, C H (CH ₃ ) ₂ ), 3.17-3.50 (4H, m, -NC H ₂ CH ₃ × 2), 7.16-7.41 (3H, m, Ar-H ₃ ), 7.46 (1H, brs, Ar-H) ..
ESI-MS m / z: 293.5 (M-H) ^- . HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₁₅ H ₂₃ N ₂ O ₂ S, 295.1481; found, 295.1475.

Example 1: Neuroprotective action of acylaminophenyl group-containing compound against hypoxia and low glucose In order to examine whether an acylaminophenyl group-containing compound has an action of protecting nerve cells from cell death due to ischemia, The following experiment was conducted.
(1) Method According to a conventional method, a primary neuronal cell culture system was established from the rat cerebral cortex on embryonic day 16 (E16), and cells on days 10 to 12 after the culture were subjected to the experiment. As a medium, Neurobasal (registered trademark) medium (Life Technologies) to which B-27 (registered trademark) Supplement (Life Technologies) and antibiotics (penicillin-streptomycin-ampicillin) were added (hereinafter, Neurobasal + B27 + P / S) / Amp medium) was used. As an in vitro ischemia, 3.5 hours of Oxygen Glucose Deprivation (OGD) was performed. Specifically, test compounds K-202 (final concentration 10 μM), K-880 (final concentration 10 μM), K-670 (final concentration 10 μM), K-640 (so that the medium becomes 30 minutes before OGD is performed. Final concentration 10 μM), K-890 (final concentration 10 μM), K-205 (final concentration 10 μM), K-210 (final concentration 10 μM), K-630 (final concentration 10 μM), KS-151 (final concentration 1 μM), KS-152 (final concentration 1 μM), K-154 (final concentration 1 μM), K-181 (final concentration 10 μM), K-680 (final concentration 10 μM), K-710 (final concentration 10 μM), K-180 (final concentration) Concentration 1 μM), K-740 (final concentration 10 μM), K-760 (final concentration 10 μM) or DMSO are added, and the medium of the primary neuron culture system is replaced with a glucose-free medium (also referred to as OGD medium), The cells were incubated for 3.5 hours in a 95% N ₂ , 5% CO _2, 1% O ₂ environment. After completion of the incubation, the OGD medium was replaced with Neurobasal + B27 + P / S / Amp medium containing the test compound at the above final concentration, and cultured under normal conditions. Culture supernatant was collected 24 hours, 48 hours, or 72 hours after OGD loading, and LDH assay (Roche Cytotoxicity Detection Kit) was performed according to the conventional method to measure the ratio of dead cells. As a control showing 100% cell death, a sample containing N-methyl-D-aspartic acid (NMDA) with a final concentration of 2 mM was used, and the amount of cells to which each test compound was added was compared to the absorbance of the control (LDH activity). The ratio of dead cells was determined from the relative value of absorbance (LDH activity).

Here, K-210 (2- (4- (nitrooxymethyl) benzamido) phenyl 4- (nitrooxymethyl) benzoate) is a compound having no acylaminophenyl group.
(2) Results FIGS. 1A to 1H show graphs comparing the proportion of dead cells under hypoxic and low glucose conditions in cells added with each test substance. Addition of test compounds other than K-210 reduced the proportion of dead cells compared to cells to which DMSO, a negative control, was added. In addition, K-210 having no acylaminophenyl group did not show the effect of suppressing cell death. In particular, K-181, K-630 and K-760 significantly reduced the proportion of dead cells compared to cells 24 hours after addition of DMSO. Among them, K-154, K-202, K640, and K-680 significantly decreased the proportion of dead cells as compared to cells 48 hours after addition of DMSO.

From this, it was shown that the acylaminophenyl group-containing compound shows a protective action against cerebral ischemia.

Example 2: Neuroprotective action of K-152, K-153, K-154, K-178, K-202, K-630, K-680, K-880, KS-153 in an experimental model of Parkinson's disease in vitro Next, the following experiment was conducted in order to confirm the protective effect of the acylaminophenyl group-containing compound on neuronal cells in a Parkinson's disease experimental model.
(1) Method SH-SY5Y cells, which are cultured human neuroblastoma cells, were cultured in DMEM medium supplemented with 10% FBS and penicillin / streptomycin. Prior to treatment with 1-methyl-4-phenylpyridinium (MPP +), the medium was replaced with 10 μM retinoic acid and 3% FBS-added DMEM, and cultured for 8 days to differentiate SH-SY5Y cells.

MPP + was added to the differentiated SH-SY5Y cells to a final concentration of 3 mM. Simultaneously with the addition of MPP +, K-152, K-153, K-154, K-178, K-202, K-630, K-680, K-880 and KS-153 were added at a final concentration of 1 μM. Cells were collected 48 hours after the addition of MPP +, and the percentage of dead cells was determined by LDH assay. DMSO represents a negative control. In the MPP + non-added group (MPP−), the culture supernatant was collected 48 hours after adding the test compound in the same manner as the MPP + added cells, and LDH assay was performed.
(2) Results As shown in FIGS. 2A to 2C, when the test compound was added, the ratio of dead cells was decreased as compared with the negative control.

From this, K-152, K-153, K-154, K-178, K-202, K-630, K-680, K-880, KS-153 are expressed in neurons in Parkinson's disease experimental models. It was confirmed to show a protective effect.

Example 3: Neuroprotective effect of K-640 and K-890 in Parkinson's disease experimental model in vitro Next, the same experiment as in Example 2 was performed for K-640 and K-890.
(1) Method MPP + was added to SH-SY5Y cells differentiated in the same manner as in Example 2 (1) to a final concentration of 3 mM. Simultaneously with the addition of MPP +, K-640 was added at a final concentration of 10 μM and K-890 at 5 μM. Cells were collected 48 hours after the addition of MPP +, and the percentage of dead cells was determined by LDH assay. DMSO represents a negative control. In the MPP + non-added group (MPP−), the culture supernatant was collected 48 hours after adding the test compound in the same manner as the MPP + added cells, and LDH assay was performed.
(2) Results As shown in FIG. 3, when K-640 and K-890 were added, the ratio of dead cells was reduced compared to the negative control.

From this, it was confirmed that K-640 and K-890 show a protective effect on nerve cells in Parkinson's disease experimental model.

Example 4: Concentration-dependent neuroprotective action of K-202 and K-880 in an in vitro Parkinson's disease experimental model Next, for K-202 and K-880, the same experiment as in Example 2 was carried out by changing the addition concentration. went.
(1) Method MPP + was added to SH-SY5Y cells differentiated in the same manner as in Example 2 (1) to a final concentration of 3 mM. Simultaneously with the addition of MPP +, K-202 or K-880 was added at a final concentration of 1, 5, or 10 μM. Test compound was added. Cells were collected 48 hours after the addition of MPP +, and the percentage of dead cells was determined by LDH assay. DMSO represents a negative control.
(2) Results As shown in FIG. 4, the proportion of dead cells in K-202 and K-880 decreased depending on the concentration.

From the results of Examples 2 to 4, it was confirmed that the acylaminophenyl group-containing compound exhibits a protective effect on neurons in a Parkinson's disease experimental model.

From this result, it was considered that the acylaminophenyl group-containing compound has an action of protecting nerve cells from cell death in various nervous system diseases.

Example 5: In vivo neuroprotective action of K-178 and K-880 in an experimental model of Parkinson's disease In order to confirm the in vivo neuroprotective action of a compound having an acylaminophenyl group, 1-methyl-4-phenyl-1 , 2,3,6-tetrahydropyridine (MPTP) -administered Parkinson's disease animal mouse model was prepared, and the effects of K-178 or K-880 administration were confirmed.
(1) Method C57BL6 / J mice were divided into the following 4 groups, and physiological saline, MPTP, or a test compound was administered.

Control: Administration of physiological saline only (n = 4)
vehicle + MPTP group: MPTP and physiological saline administered (n = 4)
K178 + MPTP group: administered MPTP and K-178 (n = 4)
K880 + MPTP group :: MPTP and K-880 administered (n = 2)
In the MPTP administration group, MPTP (Fluka Biochem) was intraperitoneally administered 5 times every 24 hours at a dose of 30 mg / kg.

K-178 was orally administered at 45 mg / kg once / day for 7 days, and K-880 was administered intraperitoneally at 45 mg / kg once / day for 7 days. Administration of K-178 or K-880 started 2 days before MPTP administration.
(2) Results FIG. 5 shows a graph in which substantia nigra TH-positive cells were counted 21 days after MPTP administration. The vertical axis represents the percentage (%) of TH staining positive cells. In the K-178 administration group, cell death in the substantia nigra after MPTP was significantly suppressed. As for K-880, although the number of n was small, it similarly tended to suppress neuronal cell death. In the K-880 administration group, no neurological symptoms were observed.

Here, statistical analysis was performed with One-WAY ANOVA; post hoc LSD. In the figure, ** was p <0.01 in comparison with the Vehicle + MPTP group, and # was p <0.05. Indicates.

Claims

A neuroprotective agent comprising a compound represented by the following general formula (A), or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof:

{X represents a sulfur atom, a methylene group or an oxygen atom:
R a is a pyridyl group, a group represented by the following general formula (A-1), a piperazyl group, a piperidyl group, a pyrrolidyl group, an aryl group, an alkyl group having 1 to 7 carbon atoms, or the following general formula (A-2) The group shown by is shown. The pyridyl group, aryl group, piperidyl group, piperazyl group, and pyrrolidyl group may be substituted with at least one selected from the group consisting of a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 7 carbon atoms may be substituted with halogen;

(Y represents a nitrogen atom or a carbon atom,
R 1 and R 2 are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or halogen)

(Y 1 represents a carbon atom;
R 3 , R 4 and R 5 are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or halogen):
R b represents a group represented by the following general formula (A-4), a group represented by the following general formula (A-3), or a hydrogen atom;

(R c represents an alkyl group having 1 to 6 carbon atoms)

(X and Ra are the same as above)}.
The neuroprotective agent according to claim 1, wherein X is a sulfur atom or a methylene group.
The neuroprotective agent according to claim 1 or 2, which is used for prevention or treatment of nervous system diseases.
The neuroprotective agent according to claim 3, wherein the nervous system disease is a neurodegenerative disease or an ischemic brain disease.
Neurodegenerative disease is Parkinson's disease, amyotrophic lateral sclerosis, dementia, cerebrovascular dementia, polyglutamine disease, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuritis, or multiple The neuroprotective agent according to claim 4, which is a focal motor neuropathy.
A compound represented by the following general formula (A), or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof:

{X represents a sulfur atom, a methylene group or an oxygen atom:
R a is a pyridyl group, a group represented by the following general formula (A-1), a piperazyl group, a piperidyl group, a pyrrolidyl group, an aryl group, an alkyl group having 1 to 7 carbon atoms, or the following general formula (A-2) The group shown by is shown. The pyridyl group, aryl group, piperidyl group, piperazyl group, and pyrrolidyl group may be substituted with at least one selected from the group consisting of a halogen, an oxygen atom, and an alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 7 carbon atoms may be substituted with halogen;

(Y represents a nitrogen atom or a carbon atom,
R 1 and R 2 are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or halogen)

(Y 1 represents a carbon atom;
R 3 , R 4 and R 5 are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or halogen):
R b represents a group represented by the following general formula (A-4), a group represented by the following general formula (A-3), or a hydrogen atom;

(R c represents an alkyl group having 1 to 6 carbon atoms)

(X and R a are the same as above),
However, S- (2-isobutylamidophenyl) 2-methylpropanethioate, N, N '-(disulfanediylbis (2,1-phenylene)) bis (2-methylpropanamide), 2-isobutyramidophenyl Isobutyrate, N- (2-hydroxyphenyl) isobutyramide, S- (2-benzamidophenyl) 2-methylpropanethioate, N, N '-(disulfanediylbis (2,1-phenylene)) di Benzamide, N, N '-(disulfanediylbis (2,1-phenylene)) dioctanamide, N, N'-(disulfanediylbis (2,1-phenylene)) bis (pyrrolidine-1- Carboxamide), N, N '-(disulfanediylbis (2,1-phenylene)) bis (piperidine-1-carboxamide), 1,1'-(disulfanediylbis (2,1-phenylene)) Bis (3,3-diethyl Element), and N, N '- (2,2'-di sulfanediyl bis (2,1-phenylene)) except bis (2,2-dimethylpropanamide)}.
The compound according to claim 1, wherein X is a sulfur atom or a methylene group, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof.
The compound according to claim 6 or 7, or a pharmaceutically acceptable salt thereof, wherein R b is a group represented by the general formula (A-3) or a group represented by the general formula (A-4) Its pharmaceutically acceptable hydrate.
The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof, wherein R c is an isopropyl group.
R a represents a pyridyl group, the following general formula (A-1), a piperazyl group, a piperidyl group, a pyrrolidyl group, or a group represented by a phenyl group. The compound according to any one of claims 6 to 9, wherein the group may be substituted with at least one selected from the group consisting of a chlorine atom, an oxygen atom, a methyl group, and an ethyl group, or a pharmaceutical product thereof Pharmaceutically acceptable salt or pharmaceutically acceptable hydrate thereof:

(Y represents a nitrogen atom or a carbon atom,
R 1 and R 2 are the same or different and each represents an alkyl group having 1 to 3 carbon atoms or a chlorine atom).