JPH09118660A - Aromatic hydroxamic acid derivative, production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful for treating and preventing a neurodegeneration disease such as Alzheimer's disease, etc., a cerebral function disorder such as cerebral infarction, etc., or improving convalescence due to possession of excellent suppressing action on neurodegeneration and low toxicity. SOLUTION: This compound is shown by formula I [Ar is a (substituted) aromatic group; Q is a bifunctional aliphatic hydrocarbon group; R<1> is H, CN, a (substituted) hydrocarbon group (X) or a group of formula II (R<3> and R<4> are each H, an acyl or X and R<3> and R<4> may form a ring with an adjoining N); R<2> is an acyl; (m) is 1 or 2; a wavy line part is a single bond or a double bond] or its salt such as O-acetyl-6-(4-methoxyphenyl)-6-(3-methyl-1,4- naphthoquinon-2-yl)hexanohydroxamic acid. The compound of formula I is obtained by reacting a compound of formula III with a compound of the formula Y-R<2> (Y is an eliminable group).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel aromatic hydroxamic acid derivative and a neurodegeneration inhibitor. More specifically, brain disorders such as Alzheimer's disease, neurodegenerative diseases such as Down's syndrome, viral meningitis caused by viral infection, and multiple sclerosis (multiple sclerosis)
Aromatic hydroxamic acid derivatives and agents having a therapeutic / preventive action such as sclerosis).

[0002]

2. Description of the Related Art Cranial nerve tissue represented by the cerebral cortex is composed of neurons that control sensory and sensory functions and glial cells (astrocytes, oligodendrocytes, microglia) that support them, and among them, glial cells account for 90% of the total. Occupy Conventionally, the central nervous system is maintained in a static state, and the immune system in the center is generally considered to be in a special environment (so-called immune privilege). However, recent advances in molecular biological analysis have revealed that various cytokines are produced and secreted in the brain, and the cellular or humoral immune system is important for maintaining homeostasis in the brain. It turned out to play a role. At the same time, it has been suggested that excessive or abnormal activation of the immune system in the brain leads to the onset, progression, and exacerbation of various central diseases, like peripheral immune diseases. On the other hand, Alzheimer's disease (AD) has been attracting attention in recent years as a dementia accompanied by degeneration and loss of nerve cells, which is mainly seen in old age. With the increase in the number of patients, prevention of the disease
Research and development of drugs for treatment are being actively pursued, but at the present stage, it remains at a symptomatic level,
The development of a fundamental therapeutic drug has not been reached. Brain tissue of patients with Alzheimer's disease has neuritic plaques and neurofibrillary tangles (neuropathy).
Accumulation such as ofibrillary tangle (NFT) has been observed, and these are listed as the causes of the onset and progression of AD. Β-amyloid prot
Since the deposition of ein; β-AP) is observed, it is believed that Alzheimer's disease is mainly caused by β-AP deposition and aggregation and senile plaque formation. In addition, accumulation of microglia has been observed around the senile plaque in the brain of AD patients,
Since they are in an activated state, there is a theory that aggregation is promoted in the process of removing dietary deprived microglia such as β-AP and the like, resulting in the promotion of senile plaque formation. Deposition of complement has also been observed in senile plaques, and one of the causes of the progression of AD pathology and accompanying neuronal degeneration / loss is the promotion of the immune system. With the recognition of commonality, AD came to be regarded as an autoimmune disease of the brain. Epidemiologic AD in patients with rheumatoid arthritis taking long-term anti-inflammatory drugs
Focusing on the low disease incidence, it was reported that the continuous administration of an anti-inflammatory agent (indomethacin) to AD patients can suppress the progress of AD (WO 93/24115). Also, W
O 93/08819 describes that lycoportin, which is known as an endogenous antagonist of IL-1, is useful for neuronal degenerative diseases such as AD. However, lycoportin is a high molecular weight protein and thus stable. It is easily conceivable that there is a problem with sex, oral absorbability, and brain transferability.

[0003] The glial cells, which are the main constituent cells of the central nervous system, constantly and actively interact with neurons, thereby causing differentiation of the brain, synapse formation, and its pla.
Known to be involved in maintaining sticy. on the other hand,
Among glial cells, it has become known that microglia release various immune-related factors by external stimulation such as brain tissue destruction due to infection, trauma, etc. (for example, V.
Trends by H. Perry, PB. Andersson, S. Gordon
In Neuro Chemical Research Volume 16, 268-273
P., 1993). Microglia belonging to resident macrophages are activated by IL-1, IL-6 and TNF.
It is known to produce and release cytokines such as α. It is known that these cytokines play an important role as messengers between immunocompetent cells (for example, lymphocytes, macrophages, etc.). However, it has been found that activation of immunocompetent cells caused by excessive production of these cytokines causes an acute or chronic inflammatory disease in the central or peripheral areas. For example, IL-1β and IL-in cerebrospinal fluid of patients with acute bacterial or viral meningitis.
It is known that 6 levels show high prices. There are also reports that interferon (IFNγ) and TNFα levels rise. Furthermore, the involvement of the above-mentioned cytokines has been suggested in multiple sclerosis (MS), which is known as a delayed cerebral inflammatory disease caused by immune abnormality or viral infection. In Alzheimer's disease and Parkinson's disease, which are defined as neurodegenerative and deciduous diseases, activated macrophages and microglia are also observed in the brains of these patients, especially accumulation in the nerve injury site and around senile plaques. Is becoming clear. Also, in acute cerebral insufficiency diseases such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and trauma, it has become known that exacerbation of disorders occurs due to abnormal activation of microglia, macrophages, neutrophils, etc. . For example, it suppresses neuronal degeneration caused by activated microglia, and abnormal IL-1β and TN
Drugs that suppress the production of Fα or the neuronal degeneration caused by β-amyloid are used for neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Down's syndrome, Pick's disease, multiple sclerosis, Borna's disease, etc.). It is suggested to be useful for the treatment / prevention of membranitis, post-vaccination encephalitis, AIDS encephalopathy, etc.) and cerebral dysfunction (eg, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, trauma, etc.) or improvement of prognosis [ Torrens in Neuroscience (TINS), Vol. 16, No. 7, p. 268 (1993)]. In addition, nitric oxide plays an important role in the blood circulation system, immune system, and central nervous system, and it is known that when its production level increases, it acts as a powerful cytotoxic factor on the biological system. Furthermore, it has been suggested that abnormal release of nitric oxide due to enhancement of the immune system causes septic shock, arteriosclerosis, etc. [Annual Reports in Medicinal Chemistry, 29, 83 (1994)].

The following compounds are known as hydroxamic acid derivatives. 1) JP-A-63-264442 and US Pat. No. 4,
No. 731,382 has the general formula

Embedded image [Wherein n is an integer of 6 to 11, M is hydrogen or a pharmaceutically acceptable cation, and Xa, Xb and Xc are each,
Hydrogen, (lower) alkyl, (lower) alkenyl, C ₁ -
C ₄ alkoxy, halo, nitro, hydroxy, amino,
Cyano, thio, optionally substituted aryl, optionally substituted aryl (lower) alkyl, (lower) alkylthio, acyl, acyloxy, acylamino, 3
Represents cycloalkyl having 6 to 6 carbon atoms, cycloalkyloxy represents cycloalkyloxy having 3 to 6 carbon atoms, (lower) alkylamino or di (lower) alkylamino, but Xa, Xb and Xc Are not all hydrogen], have a 5-lipoxygenase inhibitory action, and are useful for the prevention or treatment of inflammation in mammals. 2) JP-A-59-46244 discloses a compound of the general formula AB (CH ₂ ) _n CONHOH [wherein A represents RXm (wherein R represents a phenyl group, a pyrrolyl group, a thienyl group, an imidazolyl group and a thiazolyl group). X represents a halogen atom, a lower alkyl group, a lower acyloxy group, and a nitro group, m represents 0, 1 or 2, and m Xs can be the same or different.), B is —CHOH—. , —CH ₂ —, —O— and —CO—, and n represents an integer of 2-10. ] It is described that the hydroxamic acid derivative represented by the formula is valuable as an antiprotozoal agent or an intermediate of the antiprotozoal agent.

3) US Pat. No. 4,564,476
General formula

Embedded image [In the formula, R ₁ , R ₂ and R ₃ are hydrogen, X is CH═CH
Etc., Y represents -CONHR ⁴ (R ⁴ represents alkyl or hydroxyl group) and the like] are described as having a lipoxygenase inhibitory action. 4) JP-A-53-84938 and US Pat. No. 4,1.
88,338, the general formula

Embedded image [Wherein R is C _1-6 alkoxy, etc., R ₁ and R ₂ are hydrogen, C _1-6 alkoxy, etc., R ₃ and R ₄ are hydrogen or C
_1-6 alkyl, R ₅ represents hydrogen or methylene together with R ₃ or R ₄ , and n is 0 or 1] is described as being useful for inhibiting platelet aggregation. 5) JP-A-61-251640 and U.S. Pat. No. 4,
No. 608,390 has the formula

Embedded image [ _Wherein , X is hydrogen, C _1-22 alkyl, alkenyl or electron withdrawing group, n is 0 or 1, m is 0, 1, 2 or 3
Where n and m are not 0 at the same time, and R
₁ and R ₂ are each hydrogen, C _1-6 alkyl, an electron withdrawing group or R ₄ , R ₃ is hydrogen, C _1-6 alkyl, cycloalkyl or R ₄ , R ₄ is a formula

Embedded image (Wherein Y represents hydrogen or an electron-withdrawing group) and M represents a pharmaceutically acceptable cation] are described as lipoxygenase inhibitors.

6) EP-199,151A2 describes the formula

Embedded image (R ₁ is a tricyclic aromatic or biaryl group, R ₂ is hydrogen,
It is described that the compound represented by C _1-6 alkyl or cycloalkyl, n is 0 or 1, and M is a pharmaceutically acceptable cation) has lipoxygenase inhibitory activity. 7) Japanese Patent Application Laid-Open Nos. 1-104033 and 1-110
No. 624 has the general formula

Embedded image [Wherein R ¹ and R ² are the same or different and each represent a methyl group or a methoxy group, or R ¹ and R ² are bonded to each other to represent —CH═CH—CH═CH— in R ¹ and R ^2. . R ³ represents an optionally substituted aromatic group or heterocyclic group, and n is 2
Is an integer from 8 to 10 (JP-A-1-110624), and n is 5 or 6 (JP-A-1-104033). ] The compound represented by and its cell growth inhibitory action, angiogenesis inhibitory action,
The effect of improving autoimmune diseases is described. 8) Japanese Patent Laid-Open No. 61-44840 discloses a general formula

Embedded image ^{Wherein, R 1, R 2, R} 3 is a hydrogen atom, a methyl group, R ⁴
Is an optionally substituted aliphatic group, aromatic group or heterocyclic group, R ⁵ is an optionally esterified or amidated carboxyl group, Z is —CH═CH— or the like, n
Is an integer of 0 to 10, m is an integer of 0 to 3, and k is 0 to 5.
Indicates an integer. ] It is described that the compound represented by the formula [5] has a 5-lipoxygenase inhibitory action and is useful as an anti-asthma agent, an anti-allergic agent or a cerebral circulatory system improving agent.

Further, as a compound having thromboxane synthase inhibitory activity, JP-A-58-92677 discloses N.
As one of the -substituted-2-pyridylindole compounds, 1- (7-hydroxycarbamoyl-heptyl)-
3-Methyl-2- (3-pyridyl) indole hydrochloride is disclosed in Japanese Unexamined Patent Publication No. 59-118784 as a typical example of a substituted imidazo [1,5-a] pyridine derivative.
[5- (Hydroxycarbamoyl) pentyl] -imidazo [1,5-a] pyridine is exemplified and mentions the therapeutic effect of thromboembolism. However, in any of the compounds, the OH group on hydroxamic acid is not substituted with an acyl group. The O-carbamoyl derivative of phenylacetohydroxamic acid is described in Journal of Organic Chemistry (J. Org. Chem.,) Vol. 26, p. 782 (1961), but its medicinal effect is not described.

[0008]

It has been known that there is no known drug that significantly inhibits neurodegeneration by inhibiting activation of immunocompetent cells (eg, microglia, astrocytes, etc.) in the brain. Has the effect of suppressing neurodegeneration,
There is a strong demand for the development of new compounds useful for the prevention and treatment of brain disorders.

[0009]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that aromatic hydroxamic acid derivatives have a formula having an acyl group on the oxygen atom of hydroxamic acid.

Embedded image [In the formula, Ar represents an aromatic group which may have a substituent,
Q is a divalent aliphatic hydrocarbon group, R ¹ is a hydrogen atom, a cyano group, an optionally substituted hydrocarbon group, a formula

Embedded image A compound represented by or a salt thereof (hereinafter abbreviated as compound (I)) was synthesized for the first time, and a compound containing the synthesized compound

Embedded image [Wherein R ² 'is a hydrogen atom or an acyl group, and other symbols have the same meanings as described above] or a salt thereof (hereinafter abbreviated as compound (II)) is unexpectedly excellent. It was found through various medicinal and pharmacological experiments that the therapeutic / preventive effects on brain disorders can be expected due to its neurodegenerative inhibitory effect and low toxicity, and the present invention was completed based on these. That is, the present invention provides (1) compound (I),
(2) R ¹ is a hydrogen atom, a cyano group, an optionally substituted hydrocarbon group or a formula

Embedded image [Wherein R ³ and R ⁴ each represent a hydrogen atom, an acyl group or a hydrocarbon group which may have a substituent, or R ³ and R ⁴ form a ring with an adjacent nitrogen atom. May be. ] The compound according to (1) above, which is a group represented by:

(3) Ar is a halogen atom, a C _1-3 alkylenedioxy group, a nitro group, a cyano group, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _{3- 6} cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group,
Mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group,
C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, A C _6-10 aryl group,
1 to 5 substituents selected from a C _6-10 aryloxy group, an _optionally halogenated C _1-6 alkylsulfonylamino group and an optionally substituted C _6-10 arylsulfonylamino group. I) C which may have one
_6-14 aryl group, ii) 5- to 11-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom, or iii)
Quinone ring group, Q is a divalent C _2-8 aliphatic hydrocarbon group, R ¹ is i) hydrogen atom, ii) cyano group, iii) halogen atom, C
_1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group,
Amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _{1- 6} alkylcarbamoyl group, di-C _1-6
Substitution selected from alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group A) C _1-6 alkyl group, b) C _2-6 alkenyl group, c) C _2-6 alkynyl group, d) C _3-6 cycloalkyl group or e, which may have 1 to 5 groups. ) C _6-14 aryl group, iv) formula

Embedded image[Wherein, R^ThreeAnd R^FourAre a) hydrogen atom and b) formula, respectively.
 -CO-R, -SO_Two-R, -SO-R, -CONH
-R, -CO-OR, -CS-NH-R or-
CS-OR (in the formula, R is a hydrogen atom or a halogen atom)
Child, C_1-3Alkylenedioxy group, nitro group, cyano
Group, optionally halogenated C_1-6Alkyl group, ha
C which may be formed into a log_3-6Cycloalkyl group, ha
C which may be formed into a log_1-6Alkoxy group, halogen
C which may be_1-6Alkylthio group, hydroxy
Syl group, amino group, mono-C_1-6Alkylamino group, di
-C_1-6Alkylamino group, C_1-6Alkylcarbonyl
Group, carboxyl group, C_1-6An alkoxycarbonyl group,
Carbamoyl group, mono-C_1-6Alkyl carbamoyl
Group, di-C_1-6Alkylcarbamoyl group, C_6-10Ally
Lucarbamoyl group, sulfo group, C_1-6Alkylsulfoni
Group, C_6-10Aryl group, C_6-10Aryloxy group and
And 1 or less substituents selected from 5- or 6-membered heterocyclic groups
A) C) _1-6Alkyl group, b) C
_2-6Alkenyl group, c) C_2-6Alkynyl group, d) C_3-6
Cycloalkyl group or e) C_6-14Aryl group or
Halogen atom, C_1-3Alkylenedioxy group, nitro
Group, cyano group, optionally halogenated C_1-6Al
Kill group, optionally halogenated C_3-6Cycloal
Kill group, optionally halogenated C_1-6Alkoxy
Group, optionally halogenated C_1-6Alkylthio
Group, hydroxyl group, amino group, mono-C_1-6Alkyl
Amino group, di-C_1-6Alkylamino group, C_1-6Alkyl
Carbonyl group, carboxyl group, C_1-6Alkoxycal
Bonyl group, carbamoyl group, mono-C_1-6Alkyl cal
Vamoyl group, di-C_1-6Alkylcarbamoyl group, C
_6-10Arylcarbamoyl group, sulfo group, C_1-6Archi
Rusulfonyl group, C_6-10Aryl group, C_6-10Arlio
Substitutions selected from xy groups and 5- or 6-membered heterocyclic groups
Nitrogen in addition to the carbon atoms which may have 1 to 5 groups
1 to 3 selected from atom, oxygen atom and sulfur atom
5 to 10 membered heterocyclic group containing 3 heteroatoms
You. ) Acyl group, c) halogen atom, C_1-3
Alkylenedioxy group, nitro group, cyano group, halogen
C which may be converted_1-6Alkyl group, halogenated
May be C_3-6Cycloalkyl group, halogenated
May be C_1-6Alkoxy group, halogenated
May be C_1-6Alkylthio group, hydroxyl group, ami
No group, mono-C_1-6Alkylamino group, di-C_1-6Archi
Luamino group, C_1-6Alkylcarbonyl group, carboxy
Group, C_1-6Alkoxycarbonyl group, carbamoyl
Group, mono-C_1-6Alkylcarbamoyl group, di-C_1-6A
Rucylcarbamoyl group, C_6-10Aryl carbamoyl
Group, sulfo group, C_1-6Alkylsulfonyl group, C_6-10A
Reel base, C_6-10Aryloxy group and 5- or 6-membered
Having 1 to 5 substituents selected from the heterocyclic groups of
May be C_1-6Alkyl group, C_2-6Alkenyl group,
C_2-6Alkynyl group, C_3-6A cycloalkyl group or
C_6-14An aryl group or R^ThreeAnd R^FourAre adjacent
At least one nitrogen in addition to carbon atoms
1 containing an atom and selected from oxygen atom or sulfur atom
5-7 member which may contain 3 hetero atoms
It may form a nitrogen-containing heterocycle. ] A group represented by
Or v) formula -CO-R, -SO_Two-R, -SO-
R, -CONH-R, -CO-OR, -CS-NH-
R or -CS-OR (wherein R is a hydrogen atom,
Halogen atom, C_1-3Alkylenedioxy group, nitro
Group, cyano group, optionally halogenated C_1-6Al
Kill group, optionally halogenated C_3-6Cycloal
Kill group, optionally halogenated C_1-6Alkoxy
Group, optionally halogenated C_1-6Alkylthio
Group, hydroxyl group, amino group, mono-C_1-6Alkyl
Amino group, di-C_1-6Alkylamino group, C_1-6Alkyl
Carbonyl group, carboxyl group, C_1-6Alkoxycal
Bonyl group, carbamoyl group, mono-C_1-6Alkyl cal
Vamoyl group, di-C_1-6Alkylcarbamoyl group, C
_6-10Arylcarbamoyl group, sulfo group, C_1-6Archi
Rusulfonyl group, C_6-10Aryl group, C_6-10Arlio
Substitutions selected from xy groups and 5- or 6-membered heterocyclic groups
A) C which may have 1 to 5 groups_1-6Alkyl
Group, b) C_2-6Alkenyl group, c) C_2-6An alkynyl group,
D) C_3-6Cycloalkyl group or e) C_6-14Aryl
Group or halogen atom, C_1-3Alkylenedioxy
Group, nitro group, cyano group, optionally halogenated
C_1-6Alkyl group, optionally halogenated C_3-6Shi
Chloroalkyl group, optionally halogenated C_1-6A
Lucoxy group, optionally halogenated C_1-6Archi
Ruthio group, hydroxyl group, amino group, mono-C_1-6A
Alkylamino group, di-C_1-6Alkylamino group, C_1-6A
Rukylcarbonyl group, carboxyl group, C_1-6Alkoki
Sicarbonyl group, carbamoyl group, mono-C_1-6Archi
Lucarbamoyl group, di-C_1-6Alkyl carbamoyl
Group, C_6-10Arylcarbamoyl group, sulfo group, C_1-6
Alkylsulfonyl group, C_6-10Aryl group, C_6-10Ants
Selected from aryloxy groups and 5- or 6-membered heterocyclic groups
Other than a carbon atom which may have 1 to 5 substituents
1 selected from nitrogen atom, oxygen atom and sulfur atom
5 to 10 membered heterocyclic group containing 3 heteroatoms
Is shown. ) An acyl group represented by^TwoIs the formula −C
OR, -SO_Two-R, -SO-R, -CONH-R,
-CO-OR, -CS-NH-R or -CS-
OR (wherein R is i) hydrogen atom, ii) halogen atom,
C_1-3Alkylenedioxy group, nitro group, cyano group, ha
C which may be formed into a log_1-6Alkyl group, halogen
C which may be converted_3-6Cycloalkyl group, halogen
C which may be converted_1-6Alkoxy group, halogenated
May be C_1-6Alkylthio group, hydroxyl
Group, amino group, mono-C_1-6Alkylamino group, di-C
_1-6Alkylamino group, C_1-6Alkylcarbonyl group,
Ruboxyl group, C_1-6Alkoxycarbonyl group, carba
Moyl group, Mono-C_1-6Alkylcarbamoyl group, di-
C_1-6Alkylcarbamoyl group, C_6-10Aryl carba
Moyl group, sulfo group, C_1-6Alkylsulfonyl group, C
_6-10Aryl group, C_6-10Aryloxy groups and 5 or
Has 1 to 5 substituents selected from 6-membered heterocyclic groups
C that may be_1-6Alkyl group, C_2-6Alkenyl
Group, C_2-6Alkynyl group, C_3-6Cycloalkyl group
Or C_6-14Aryl group or iii) halogen atom, C
_1-3Alkylenedioxy group, nitro group, cyano group, halo
C which may be genated_1-6Alkyl group, halogenated
C that may be_3-6Cycloalkyl group, halogenated
C that may be_1-6Alkoxy group, halogenated
May be C_1-6Alkylthio group, hydroxyl group,
Amino group, mono-C_1-6Alkylamino group, di-C_1-6A
Rukylamino group, C_1-6Alkylcarbonyl group, carbo
Xyl group, C_1-6Alkoxycarbonyl group, carbamoy
Group, mono-C_1-6Alkylcarbamoyl group, di-C_1-6
Alkylcarbamoyl group, C_6-10Aryl carbamoyl
Group, sulfo group, C_1-6Alkylsulfonyl group, C_6-10A
Reel base, C_6-10Aryloxy group and 5- or 6-membered
Having 1 to 5 substituents selected from the heterocyclic groups of
In addition to carbon atom, nitrogen atom, oxygen atom and sulfur
5 containing 1 to 3 heteroatoms selected from atoms
A 10-membered heterocyclic group is shown. ) With an acyl group
A certain compound according to the above (1),

(4) Ar is a halogen atom, a C _1-3 alkylenedioxy group, a nitro group, a cyano group, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _{3- 6} cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group,
Mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group,
C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, A C _6-10 aryl group,
1 to 5 substituents selected from a C _6-10 aryloxy group, an _optionally halogenated C _1-6 alkylsulfonylamino group and an optionally substituted C _6-10 arylsulfonylamino group. I) p-
Benzoquinonyl group, ii) 1,4-naphthoquinone-2-yl group, iii) anthraquinonyl group, iv) 5,6-chrysenequinonyl group or v) 5,8-dioxo-5,8-dihydroquinolin-6-yl group, R ¹ is a halogen atom, C
_1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group,
Amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _{1- 6} alkylcarbamoyl group, di-C _1-6
Substitution selected from alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group I) a phenyl group which may have 1 to 5 groups or ii) a naphthyl group, and R ² is of the formula —CO—R or —CONH—R (wherein
R has the same meaning as described in (3) above. (5) R ¹ is a cyano group and R ² is a formula —CO—R or —CONH—.
The compound according to (3) above, which is an acyl group represented by R (wherein R has the same meaning as described in (3) above),

(6) Ar is i) a halogen atom, ii) a nitro group, iii) an optionally halogenated C _1-6 alkyl group, iv) an optionally halogenated C _1-6 alkoxy group, v) hydroxyl group, vi) amino group, vii) mono-C
_1-6 alkylamino group, viii) di-C _1-6 alkylamino group, ix) optionally halogenated C _1-6 alkylsulfonylamino group, and x) 1 to 3 halogen atoms or halogenated _Optionally substituted C _1-6 alkyl group, optionally substituted C _6-10 arylsulfonylamino group, which may have 1 to 4 substituents selected from phenyl, 1-naphthyl, 2-naphthyl , 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,
4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl, p-benzoquinone-2-yl, 1,4-naphthoquinone-2-yl or 5,8-dioxo -5,8
-Dihydroquinolin-6-yl group, Q is a divalent C _2-5 alkylene group, R ¹ is i) hydrogen atom, ii) cyano group, iii)
A phenyl group which may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group and an optionally halogenated C _1-6 alkoxy group, iv )formula

Embedded image [In the formula, R ³ is a hydrogen atom and R ⁴ is a formula —CO—R ′ or —SO ₂ —R ′ (in the formula, R ′ is a halogen atom or C
_{It represents a} C _1-6 alkyl group or a C _6-14 aryl group, each of which may be substituted with 1 to 3 _1-6 alkyl groups. ) Represents an acyl group. Or a) an acyl group represented by the formula: —CO—O—R ″ (in the formula, R ″ represents a C _1-6 alkyl group), and R ² represents a formula —CO.
—R ′ ″ or —CO—NH—R ′ ″ (wherein R ′ ″ is i) hydrogen atom or ii) a) halogen atom, b) optionally halogenated C _1-6 alkyl A group, c) an optionally halogenated C _1-6 alkoxy group, d) a C _1-6 alkylcarbonyloxy group and e) a C _1-6 alkyl group or a C _1-6 alkoxy group, with 1 to 3 substituents _{Represents a} C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _6-14 aryl group which may have 1 to 3 substituents selected from the optionally substituted C _6-14 aryl group. . ),

Embedded image

(7) Ar is a substituent selected from i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group and iii) an optionally halogenated C _1-6 alkoxy group. 1 to 4 a) p-benzoquinone-2-yl group or b) 1,4-naphthoquinone-2-yl group, R ¹ is i) halogen atom, ii) may be halogenated A good C _1-6 alkyl group and iii) a phenyl group which may have 1 to 3 substituents selected from an optionally halogenated C _1-6 alkoxy group,
And R ² is of the formula —CO—R ″ ″, where R ″ ″ is a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms, C _3-6 cyclo The compound according to (6) above, which is an acyl group represented by an alkyl group or a phenyl group), (8) the compound according to (3) above, wherein Q is a trimethylene group or a tetramethylene group, (9) O- Acetyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-propionyl-6- (4-methoxyphenyl) -6- (3 -Methyl-1,4-naphthoquinone-
2-yl) hexanohydroxamic acid, O-isobutyryl-6- (4-methoxyphenyl) -6- (3-methyl-
1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-benzoyl-6- (4-methoxyphenyl)
-6- (3-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-propionyl-7-
(4-Methoxyphenyl) -7- (3-methyl-1,4
-Naphthoquinone-2-yl) heptanohydroxamic acid,
O-propionyl-7- (4-fluorophenyl) -7
-(3-Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid or a salt thereof, the compound according to (1) above,

Equation (10)

Embedded image [The symbols in the formula are as defined above. ] The compound or its salt represented by these, and a formula Y-R < ² > [In formula, Y is a leaving group and R < ² > shows a said meaning. ] The compound or its salt represented by these are made to react, The manufacturing method of the compound of the said (1) description, (1
1) A neurodegeneration inhibitor containing compound (II), (1
2) A neurodegeneration inhibitor comprising the compound described in (1) or a salt thereof, (13) O-propionyl-6-
(4-Methoxyphenyl) -6- (3-methyl-1,4
-Naphthoquinone-2-yl) hexanohydroxamic acid,
O-propionyl-7- (4-methoxyphenyl) -7
-(3-Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, 7- (4-methoxyphenyl)
-7- (3-Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, 6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2
-Yl) Hexanohydroxamic acid or a salt thereof, the neurodegeneration inhibitor according to the above (11), (1
4) The neurodegeneration inhibitor described in (11) above, which is a therapeutic / preventive agent for neurodegenerative diseases, (15) the neurodegeneration inhibitor described in (14) above, which is a therapeutic / preventive agent for Alzheimer's disease or multiple sclerosis, and ( 16) A pharmaceutical composition comprising the compound according to (1) above or a salt thereof.

[0015]

Embedded image

In the above formulas (I) and (II), the "aromatic group" of the "aromatic group which may have a substituent" represented by Ar is, for example, an aromatic hydrocarbon group or an aromatic group. Examples of the heterocyclic group include a quinone ring group. The "aromatic hydrocarbon group" has, for example, 6 carbon atoms.
To 14 monocyclic or condensed polycyclic aromatic hydrocarbon groups and the like. Specific examples include phenyl,
Examples thereof include C _6-14 aryl groups such as 1-naphthyl, 2-naphthyl, indenyl and anthryl. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
Particularly preferred are 1-naphthyl, 2-naphthyl and the like. The "aromatic heterocyclic group" is, for example, a 5- to 11-membered monocyclic ring containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom, or Examples thereof include condensed aromatic heterocyclic groups. Specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, thianthrene,
Furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,
Isoindole, 1H-indazole, purine, 4H-
Quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
Aromatic heterocycles such as carbazole, β-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine and isochroman, or one or more of these rings (preferably 1 or And a monovalent group formed by removing any hydrogen atom from a ring formed by condensation with (two) aromatic rings (eg, benzene ring, pyridine ring, etc.). Preferred examples of "aromatic heterocyclic group" include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2-thienyl, 3-thienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl and the like can be mentioned. More preferably, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,
4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiaozolyl and the like. 2-quinolyl, 4-quinolyl, 1-isoquinolyl and the like are particularly preferable. The "quinone ring group" is a group obtained by removing one hydrogen from a quinone ring, and examples thereof include p-benzoquinone, 1,4-naphthoquinone, anthraquinone, 5,6-chrysenequinone and 5,8-dioxo-.
Examples thereof include quinone ring groups obtained from 5,8-dihydroquinoline and the like. Examples of preferable quinones include p-benzoquinone and 1,4-naphthoquinone.

Examples of the substituent of the "optionally substituted aromatic group" represented by Ar include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy. Group (eg, methylenedioxy, ethylenedioxy, etc.), nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group (eg , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
C _1-6 alkoxy group which may be halogenated, C _1-6 alkylthio group which may be halogenated, hydroxyl group, amino group, mono-C _1-6 alkylamino group (eg, methylamino, ethyl Amino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino group (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), C _1-6
Alkylcarbonyl group (eg, acetyl, propionyl, etc.), carboxyl group, C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl group, mono-C _1-6 alkylcarbamoyl Groups (eg,
Methylcarbamoyl, ethylcarbamoyl, etc.), di-
C _1-6 alkylcarbamoyl group (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.), C _6-10 arylcarbamoyl group (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.), sulfo group, C _1-6 alkylsulfonyl group (eg, methyl Sulfonyl, ethylsulfonyl, etc.), C _6-10 aryl group (eg, phenyl, naphthyl, etc.), C _6-10 aryloxy group (eg, phenyloxy,
Naphthyloxy, etc.), optionally halogenated C
_Examples thereof include a _1-6 alkylsulfonylamino group and a C _6-10 arylsulfonylamino group which may have a substituent.

The above-mentioned "optionally halogenated C _1-6
As the “alkyl group”, for example, a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., and specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3
-Trifluoropropyl, isopropyl, butyl, 4,
4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
Examples include 6,6,6-trifluorohexyl and the like. The above-mentioned “optionally halogenated C _3-6 cycloalkyl group” is, for example, C _{3 — optionally} having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). ₆ cycloalkyl groups (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.) and the like.

The above "optionally halogenated C _1-6
Examples of the “alkoxy group” include C _1-6 alkoxy groups which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and specific examples include Methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. Can be given. Examples of the "optionally C _1-6 alkylthio group which may be halogenated", for example, 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine) optionally having C _1-6 And alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), and specific examples include methylthio,
Examples thereof include difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

The above-mentioned "optionally halogenated C _1-6
Examples of the “alkylsulfonylamino group” include C _1-6 alkylsulfonylamino groups which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), and specific examples As, methanesulfonylamino, trifluoromethanesulfonylamino,
Examples include ethanesulfonylamino. Examples of the substituent of the “optionally substituted C _6-10 arylsulfonylamino group” include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) or halogenated And _{optionally a} C _1-6 alkyl group. Examples of the "optionally halogenated C _1-6 alkyl group" include the same ones as described above. Specific examples of the “C _6-10 arylsulfonylamino group optionally having substituent (s)” include phenylsulfonylamino, tosylamino, p-fluorophenylsulfonylamino,
Examples thereof include 1-naphthylsulfonylamino and 2-naphthylsulfonylamino.

The “aromatic group which may have a substituent (s)”
Is, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions on the ring.
And when the number of substituents is two or more, they may be the same or different. As the substituent of the “optionally substituted aromatic group” represented by Ar, a halogen atom, a nitro group, an optionally halogenated C _1-6 alkyl group, or a halogenated group is preferable. May be C
_1-6 alkoxy group, cyano group, hydroxyl group, amino group, C _6-10 aryl group, optionally halogenated C
_Examples thereof include a _1-6 alkylsulfonylamino group and a C _6-10 arylsulfonylamino group which may have a substituent. More preferably, it is a halogen atom, an optionally halogenated C _1-6 alkoxy group or the like. When the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar is a quinone ring group, the substituent which the quinone ring group may have may be a lower alkyl ( For example, C _1-6 alkyl such as methyl and ethyl), lower alkoxy (eg C _1-6 alkoxy such as methoxy and ethoxy)
Are preferred. Among the “quinone ring group optionally having substituent (s)”, 3-methyl-1,4-naphthoquinone-2
-Yl, 3,5,6-trimethyl-1,4-benzoquinone-2-yl, 5,6-dimethoxy-3-methyl-1,4-
Benzoquinone-2-yl, 2-naphthoquinonyl and the like are particularly preferable.

"Divalent aliphatic hydrocarbon group" represented by Q
Represents a divalent group formed by removing one hydrogen atom bonded to each of two different carbon atoms of a saturated or unsaturated aliphatic hydrocarbon. Of these, those having 2 to 8 carbon atoms are preferable. As a concrete example,

Embedded image

Embedded image More preferably, a C _2-8 alkylene group (eg, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.), a C _2-6 alkenylene group (eg, vinylene, propenylene, butenylene, pentanylene, hexanylene, etc.) , C _2-6 alkynylene groups (eg, propynylene, butanylene, pentanylene, etc.)
And so on. Among them, C _2-6 alkylene group, especially C
_{A 3-6} alkylene group is preferred.

The "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by R ¹ , R ³ or R ⁴ is a group obtained by removing one hydrogen atom from a hydrocarbon compound. ,
Examples thereof include chain or cyclic hydrocarbon groups such as alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups and aryl groups. Of these, the following linear or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferable. a) C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), b) C _2-6 alkenyl group (for example, vinyl, Allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), c) C _2-6 alkynyl group (eg, propargyl, ethynyl, butynyl, 1-hexynyl, etc.), d) C _3-6 cycloalkyl group (eg, Cyclopropyl,
Cyclobutyl, cyclopentyl, 1 to 3 C _1-6
An alkoxy group (eg, methoxy, etc.), which may have a benzene ring and may be condensed with cyclohexyl, etc.) e) a C _6-14 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl) , 2-indenyl, 2-
Anthryl and the like), preferably a phenyl group. Among these, C _1-6 alkyl group, C _3-6 cycloalkyl group,
A C _6-14 aryl group and the like are preferable.

The "substituent" of the "hydrocarbon group which may have a substituent" represented by R ¹ , R ³ or R ⁴ is
For example, halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), C _1-3 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy etc.), nitro group, cyano group, optionally halogenated A C _1-6 alkyl group, an optionally halogenated C _3-6 cycloalkyl group, an optionally halogenated C _1-6 alkoxy group, an optionally halogenated C _1-6 alkylthio group, Amino group, mono-C _1-6 alkylamino group (eg, methylamino, ethylamino, etc.), di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), hydroxyl group, C _1-6 alkyl Carbonyl group (eg, acetyl, ethylcarbonyl, etc.), carboxyl group, C _1-6
Alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), C _1-6 alkylcarbonyloxy group (eg, acetoxy, propionyloxy, etc.), carbamoyl group, mono-C _1-6 alkylcarbamoyl group (Eg,
Methylcarbamoyl, ethylcarbamoyl, etc.), di-
C _1-6 alkylcarbamoyl group (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.), sulfo group, C _1-6
Alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 aryl group (eg, phenyl,
Naphthyl, etc.), a C _6-10 aryloxy group (eg, phenyloxy, naphthyloxy, etc.), a 5- or 6-membered heterocyclic group, and the like. "Optionally halogenated C _1-6 alkyl group" of the "optionally halogenated good cycloalkyl group", "optionally halogenated a C _1-6 alkoxy group", "halogenated Examples of the “optionally substituted C _1-6 alkylthio group” include the aforementioned Ar.
The same as those described in detail for the substituent of the aromatic group represented by Examples of the above-mentioned "5- or 6-membered heterocyclic group" include 5- or 6-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. . Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-
Imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1
-Or 2-piperazinyl, morpholino, 2-or 3
-Thienyl, 2-, 3- or 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl,
3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl and the like can be mentioned. The above-mentioned “C _6-10 aryl group” and “C _6-10 aryloxy group” may be further substituted with 1 to 3 halogen atoms, C _1-6 alkyl groups, C _1-6 alkoxy groups or the like. . "Hydrocarbon group" of the "hydrocarbon group optionally having substituent (s)"
May have, for example, 1 to 5, preferably 1 to 3 substituents at the substitutable position of the hydrocarbon group. When the number of substituents is 2 or more, each substituent is the same. Or it may be different.

The "acyl group" represented by R ¹ , R ² , R ² ', R ³ or R ⁴ is, for example, --CO--R, --SO ₂
-R, -SO-R, -CONH-R, -CO-OR,
-CS-NH-R, -CS-O-R (In the formula, R represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. ) And the like. Of these, preferably -CO-
R, is a -SO ₂ -R, -CONH-R, the acyl group represented by like -CO-O-R. Examples of the “hydrocarbon group which may have a substituent (s)” represented by R include, for example, R described above.
^The "hydrocarbon group which may have a substituent" represented by ¹ , R ³ or R ⁴ and the like can be mentioned. Examples of the “heterocyclic group” of the “heterocyclic group which may have a substituent” represented by R include, for example, 1 type or 2 types selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, Preferred are 5- to 10-membered (monocyclic or bicyclic) heterocyclic groups containing 1 to 3 heteroatoms, for example, 1
Non-aromatic such as-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl Heterocyclic group, or, for example, 2-thienyl, 3-thienyl, 2
-Pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 4-quinolyl, 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3 -Isothiazolyl, 3-isoxazolyl, 1-indolyl,
Examples thereof include aromatic heterocyclic groups such as 2-isoindolyl. Of these, aromatic heterocyclic groups are preferred. More preferably, for example, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom (eg, 2-thienyl, 3-thienyl). , 2-pyridyl, 4-pyridyl, etc.) and the like. Examples of the substituent which the “heterocyclic group” of the “heterocyclic group which may have a substituent” may have are, for example, “having a substituent of the above R ¹ , R ³ or R ⁴ ”. The same number and the like as the substituent that the “hydrocarbon group which may have” may have are used.

The "ring" formed by R ³ and R ⁴ together with the adjacent nitrogen atom is, for example, at least 1 other than carbon atom.
And a 5- to 7-membered nitrogen-containing heterocyclic ring containing 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom or sulfur atom. Specifically, for example, piperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, azetidine, 2-oxoazetidine, 2-oxopyrrolidine, 2
-Oxopiperidine and the like.

In the above formulas (I) and (II), Ar is (i) a C _6-14 aryl group which may have a substituent, (ii) a nitrogen atom, a sulfur atom and a carbon atom other than the carbon atom. A 5- to 11-membered monocyclic or condensed aromatic heterocyclic group containing at least one heteroatom selected from oxygen atoms or (ii
i) Quinone ring groups are preferred. More preferably, i) nitro group, ii) optionally halogenated C _1-6 alkyl group, iii) optionally halogenated C _1-6 alkoxy group, iv) hydroxyl group, v) amino group , Vi) Mono-
C _1-6 alkylamino group, vii) di-C _1-6 alkylamino group, viii) optionally halogenated C _1-6 alkylsulfonylamino group, ix) 1 to 3 halogen atoms or halogenated C _6-10 arylsulfonylamino group optionally substituted by optionally substituted C _1-6 alkyl group or x) phenyl optionally substituted by 1 to 4 halogen atoms, 1-naphthyl, 2- Naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiaozolyl, p-benzoquinone-2. -Il, 1,4
-Naphthoquinone-2-yl, anthraquinolyl, 5,6
-Chrysenequinolyl or 5,8-dioxo-5,8-dihydroquinolin-6-yl. In particular, i) 2-quinolyl, ii) 4-quinolyl, iii) 1-isoquinolyl or iv) optionally substituted by optionally halogenated C _1-6 alkyl groups a) p-benzoquinone-
2-yl or b) 1,4-naphthoquinone-2-yl. Q is preferably a C _2-8 alkylene group or the like. C
_{A 2-5} alkylene group and the like are more preferable. In particular, a trimethylene group [- (CH _{2) 3} -], tetramethylene [- (CH _2)
4 -] and the like are preferable. R ¹ is a hydrogen atom, a cyano group, an optionally substituted C _6-14 aryl group, a formula

Embedded image (In the formula, each symbol has the same meaning as described above) or -CO-OR (R has the same meaning as described above, preferably a C _1-6 alkyl group). An acyl group and the like are preferable. More preferably, it is a cyano group or a C _6-14 aryl group which may have a substituent. Among them,
1 to 3 cyano groups or i) halogen atoms, ii) optionally halogenated C _1-6 alkyl groups or iii) optionally halogenated C _1-6 alkoxy groups, preferably 1 Optionally (a) phenyl group or (b)
A naphthyl group is preferred. Particularly preferred is a cyano group or i) a halogen atom or ii) a phenyl group optionally having one C _1-6 alkoxy group. R ³ is preferably a hydrogen atom. R ⁴ is preferably an acyl group. The acyl group is preferably an acyl group represented by —CO—R or —SO ₂ —R (R has the same meaning as above). Among them, R is a C _1-6 alkyl group or C _6-14 which may be substituted with a halogen atom or a C _1-6 alkyl group, respectively.
Aryl groups and the like are preferred. R ² and R ² 'are -CO-
An acyl group represented by R or —CO—NH—R (R has the same meaning as described above) and the like are preferable. Among them, R is a hydrogen atom or i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group, iii) an optionally halogenated C _1-6 alkoxy group, iv) C _1-6 Alkylcarbonyloxy group or V) C _1-6 alkyl group or C _1-6
1 to 3 optionally substituted C _6-14 aryl groups optionally substituted by alkoxy groups (a) C _1-6 alkyl groups, (b) C _3-6 cycloalkyl groups or (c) A C _6-14 aryl group and the like are preferable.

Embedded image m is preferably 2.

In the above formula (I), Ar is i) a nitro group, i
i) an optionally halogenated C _1-6 alkyl group, ii
i) an optionally halogenated C _1-6 alkoxy group, i
v) hydroxyl group, v) amino group, vi) mono-C _1-6 alkylamino group, vii) di-C _1-6 alkylamino group, vi
ii) optionally halogenated C _1-6 alkyl-sulfonylamino group, ix) optionally substituted with 1 to 3 halogen atoms or optionally halogenated C _1-6 alkyl group C _{6 -10} arylsulfonylamino group or
x) Phenyl optionally substituted with 1 to 4 halogen atoms, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,
4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl, p-benzoquinone-2-yl, 1,4-naphthoquinone-2-yl, anthraquinonyl, 5,6 -Chrysenequinonyl or 5,8-dioxo-5,8-dihydroquinolin-6-yl, Q is a C _2-8 alkylene group, R ¹ is a cyano group or i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group or iii) 1 to 3 optionally halogenated C _1-6 alkoxy groups (a) phenyl group or (b) naphthyl group, R ³
Is a hydrogen atom, R ⁴ is —CO—R or —SO ₂ —R (R
Represents the same meaning as described above) (preferably C _1-6 alkyl group or C _6-14 in which R may be substituted with a halogen atom or a C _1-6 alkyl group, respectively).
Aryl group) R ² is an acyl group represented by —CO—R or —CO—NH—R (R is as defined above) (preferably R).
Is a hydrogen atom or i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group, iii) an optionally halogenated C _1-6 alkoxy group, iv) a C _1-6 alkylcarbonyloxy Group or V) C _1-6 alkyl group or C
1 to 3 optionally substituted by C _6-14 aryl group optionally substituted by _1-6 alkoxy group, (a) C _1-6 alkyl group, (b) C _3-6 cycloalkyl group or (C) C _6-14
Aryl group),

Embedded image Are preferred.

In the above formula (II), R ¹ is a cyano group, an optionally substituted C _6-14 aryl group, a formula

Embedded image (Wherein each symbol has the same meaning as defined above) or an acyl group, and a compound in which R ² 'is an acyl group is preferable. More preferably, Ar is i) a nitro group, i
i) an optionally halogenated C _1-6 alkyl group, ii
i) an optionally halogenated C _1-6 alkoxy group, i
v) hydroxyl group, v) amino group, vi) mono-C _1-6 alkylamino group, vii) di-C _1-6 alkylamino group, vi
ii) optionally halogenated C _1-6 alkyl-sulfonylamino group, ix) optionally substituted with 1 to 3 halogen atoms or optionally halogenated C _1-6 alkyl group C _{6 -10} arylsulfonylamino group or
x) Phenyl optionally substituted with 1 to 4 halogen atoms, 1-naphthyl, 2-naphthyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,
4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl, p-benzoquinone-2-yl, 1,4-naphthoquinone-2-yl, anthraquinonyl, 5,6 -Chrysenequinonyl or 5,8-dioxo-5,8-dihydroquinolin-6-yl, Q is a C _2-8 alkylene group, R ¹ is a cyano group or i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group or iii) 1 to 3 optionally halogenated C _1-6 alkoxy groups (a) phenyl group or (b) naphthyl group, R ³
Is a hydrogen atom, R ⁴ is —CO—R or —SO ₂ —R (R
Represents the same meaning as described above) (preferably C _1-6 alkyl group or C _6-14 in which R may be substituted with a halogen atom or a C _1-6 alkyl group, respectively).
Aryl group) R ² 'is -CO-R or -CO-NH-
Acyl group represented by R (R has the same meaning as described above) (preferably R is hydrogen atom or i) halogen atom, ii)
An optionally halogenated C _1-6 alkyl group, iii) an optionally halogenated C _1-6 alkoxy group, iv) C
_1-6 alkylcarbonyloxy group or V) 1-3 substituted by C _6-14 aryl group which may be substituted by C _1-6 alkyl group or C _1-6 alkoxy group (a) C _1-6 alkyl group, (b) C _3-6 cycloalkyl group or (c) C _6-14 aryl group,

Embedded image Is a compound.

In the above compounds, Ar is i) nitro group, i
i) an optionally halogenated C _1-6 alkyl group, ii
i) an optionally halogenated C _1-6 alkoxy group, i
v) hydroxyl group, v) amino group, vi) mono-C _1-6 alkylamino group, vii) di-C _1-6 alkylamino group, vi
ii) optionally halogenated C _1-6 alkyl-sulfonylamino group, ix) optionally substituted with 1 to 3 halogen atoms or optionally halogenated C _1-6 alkyl group C _{6 -10} arylsulfonylamino group or
x) p-benzoquinone-2-yl optionally substituted with 1 to 4 halogen atoms, 1,4-naphthoquinone-
2-yl, anthraquinonyl, 5,6-chrysenequinonyl or 5,8-dioxo-5,8-dihydroquinoline-
6-yl, R ¹ has ¹ to 3 i) halogen atoms, ii) optionally halogenated C _1-6 alkyl groups or iii) optionally halogenated C _1-6 alkoxy groups Optionally (a) a phenyl group or (b) a naphthyl group, and R ² or R ² ′ is —CO—R or —CO—NH—
An acyl group represented by R (R has the same meaning as described above) is also preferable. R ¹ is a cyano group, and R ² or R
It is also preferable that ² ′ is an acyl group represented by —CO—R or —CO—NH—R (R has the same meaning as above). Ar is i) nitro group, ii) optionally halogenated C _1-6 alkyl group, iii) optionally halogenated C _1-6 alkoxy group, iv) hydroxyl group, v) amino group, vi) mono-C _1-6 alkylamino group, vii) di-C
_1-6 alkylamino group, viii) optionally halogenated C _1-6 alkylsulfonylamino group, ix) 1 to 3 halogen atoms or optionally halogenated C
C _6-10 arylsulfonylamino group optionally substituted by _1-6 alkyl group or x) 2-quinolyl, 3-quinolyl, 4-quinolyl optionally substituted by 1 to 4 halogen atoms Also preferred are isoquinolyl or 4-isoquinolyl, and those in which R ¹ is a hydrogen atom.
Further, Ar has 1 to 4 substituents selected from i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group, and iii) an optionally halogenated C _1-6 alkoxy group. Optionally a) p-benzoquinone-
2-yl group or b) 1,4-naphthoquinone-2-yl group, R ¹ is i) halogen atom, ii) optionally halogenated C _1-6 alkyl group and iii) optionally halogenated Substituent selected from good C _1-6 alkoxy groups is 1
To phenyl group which may have 3 to 3 and R ² is a formula —CO—R (wherein, R is a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
A C _3-6 cycloalkyl group or a phenyl group is shown. And is more preferably an acyl group represented by the formula (1). Specific preferred examples of the compound include 6- (1-isoquinolyl) hexanohydroxamic acid, 7- (1-isoquinolyl) heptanohydroxamic acid, 6-phenyl-6- (2
-Quinolyl) hexanohydroxamic acid, 7-phenyl-
7- (2-quinolyl) heptanohydroxamic acid, 7-cyano-7- (2-naphthyl) heptanohydroxamic acid,
7- (benzothiazol-2-yl) -7-cyanoheptanohydroxamic acid, 7- (4-methoxyphenyl)-
7- (3-methyl-1,4-naphthoquinone-2-yl)
Heptanohydroxamic acid, 7- (3-methyl-1,4-
Naphthoquinone-2-yl) -7-phenylheptanohydroxamic acid, O-acetyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-
Il) hexanohydroxanthic acid, O-propionyl-
6- (4-methoxyphenyl) -6- (3-methyl-
1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-isobutyryl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-
Yl) Hexanohydroxamic acid, O-benzoyl-6-
(4-Methoxyphenyl) -6- (3-methyl-1,4
-Naphthoquinone-2-yl) hexanohydroxamic acid,
O-ethylcarbamoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-
Yl) hexanohydroxamic acid, O-acetyl-7-cyano-7- (2-naphthyl) heptanohydroxamic acid,
O-propionyl-7-cyano-7- (2-naphthyl)
Heptanohydroxamic acid, O-benzoyl-7-cyano-7- (2-naphthyl) heptanohydroxamic acid, O-
Benzoyl-6- (benzoxazol-2-yl) hexanohydroxamic acid, O-benzoyl-7- (benzothiazol-2-yl) heptanohydroxamic acid, O-
Propionyl-6- (benzoxazol-2-yl)
Hexanohydroxamic acid, O-acetyl-7- (2-quinolyl) heptanohydroxamic acid, O-propionyl-
7- (2-quinolyl) heptanohydroxamic acid O-propionyl-7- (4-methoxyphenyl) -7
-(3-Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, O-benzoyl-7- (4-methoxyphenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl) ) Heptanohydroxamic acid, O-propionyl-7- (3-methyl-1,4-naphthoquinone-
2-yl) -7-phenylheptanohydroxamic acid, O
-Propionyl-7- (4-fluorophenyl) -7-
Examples include (3-methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid. More preferably, O-acetyl-6- (4-methoxyphenyl) -6
-(3-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-propionyl-6- (4-
Methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-isobutyryl-6- (4-methoxyphenyl) -6- (3
-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-benzoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexano Hydroxamic acid, O-propionyl-7- (4-methoxyphenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, O-propionyl-7- (4-fluorophenyl) -7- (3-Methyl-1,4-naphthoquinone-2-
Il) Heptanohydroxamic acid and the like.

Compound (I) and compound (II) of the present invention
Examples of the salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among them, a pharmaceutically acceptable salt is preferable, and examples thereof include a hydrochloride, a sulfate, a phosphate, a hydrobromide and the like in the case where the compound has a basic functional group, or acetic acid. Salt, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate,
Examples thereof include tartrate salts, and when they have an acidic functional group, examples thereof include inorganic salts of alkali metal salts (sodium salt, potassium salt, etc.) or alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, etc. To be

The production method of compound (I) and compound (II) will be described. Compound (I) and Compound (II) are
For example, it can be obtained by the method represented by the following reaction formula or a method similar thereto. Each symbol of the compound in the reaction formula has the same meaning as described above.

Embedded image

Compound (I) can be obtained by subjecting compound (IIa) or a salt thereof to an acylation reaction according to a method known per se. For example, compound (IIa) or a salt thereof is reacted with a compound represented by the formula Y-R ² [wherein Y represents a leaving group and R ² has the same meaning as described above] or a salt thereof to give a compound (I ) Get. Here, the “leaving group” represented by Y is, for example, a halogen atom (eg, chlorine, bromine,
Iodine, etc.), C _1-4 alkylsulfonyloxy groups optionally substituted by 1 to 3 halogen atoms (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), 1 to 4 halogen atoms substituted Also a C _6-10 arylsulfonyloxy group (eg, p-toluenesulfonyloxy, benzenesulfonyloxy,
1 to 3 substituents selected from p-bromobenzenesulfonyloxy, mesitylenesulfonyloxy, etc.), C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), halogen atom and nitro. A C _6-10 aryloxy group which may have a group (eg, phenoxy, p-chlorophenoxy, p-nitrophenoxy etc.) and the like are used.

As the acylation reaction, a method known per se,
For example, it may be carried out according to the method described in Journal of Organic Chemistry (J. Org. Chem.) Vol. 26, p. 782, 1961. For example, compound (IIa) or a salt thereof or a reactive derivative thereof is reacted with a compound represented by the formula Y—R ² (each symbol has the same meaning as described above) or a salt thereof in the presence of a base. Examples of the reactive derivative include acid anhydrides, acid halides, activated esters and lower alkyl esters. Examples of the base include alkylamines such as triethylamine and diisopropylethylamine, and nitrogen-containing aromatic heterocycles such as pyridine. The amount of the compound represented by the formula Y—R ² or a salt thereof to be used is about 1 to 1.2 equivalents relative to compound (IIa). The amount of the base used is represented by the formula YR ²
It is about 1 to 3 equivalents relative to the compound represented by. The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction, for example, nitriles (eg, acetonitrile, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), ethers (eg, , Diethyl ether, tetrahydrofuran, dioxane, isopropyl ether, 1,2-dimethoxyethane, etc.) and the like. The reaction temperature is about −20 ° C. to room temperature, preferably room temperature. The reaction time may be appropriately selected depending on the reagents used and is, for example, about 0.2 to 5 hours. In addition, the compound (IIa) and the corresponding organic acid before and after the equivalent (a compound represented by the formula R ² —OH)
May be dissolved in an inert solvent (eg, halogenated hydrocarbons, acetonitrile, etc.), and a dehydration condensing agent such as dicyclohexylcarbodiimide may be added in an amount of about 1 to 1.5 to react. The reaction time is about -20 ° C to room temperature, and the reaction time is about 6 to 12 hours. When the carbamoylation reaction is carried out, it may be carried out under almost the same reaction conditions as the acylation reaction, and it is not always necessary to coexist a base.

The compound (IIa) can be obtained from the corresponding carboxylic acid compound (III) or a salt thereof by a method known per se, for example, JP-A-1-104033, Patai (S. Pata).
i) The Chemistry of Acid Derivative Supplement B (Supplement B. The chemistry of
acid derivatives) Volume 2 (John Wiley & Sons) 849-8
It can be obtained by a method similar to the method described on page 73 (1992). For example, compound (III) undergoes a reactive derivative of its carboxyl group in the presence of hydroxylamine and a base at 0 to 50 ° C., preferably room temperature (0 to 30 ° C.).
(IIC) for 10 minutes to 2 hours to react the compound (II
Get a). Examples of the reactive derivative include acid anhydrides, acid halides and activated esters. Examples of the base include alkali metal or alkaline earth metal salts of hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, such as alkali metal or alkaline earth metal salts of carbonic acid such as sodium carbonate and potassium carbonate, such as hydroxide. Examples thereof include inorganic bases such as alkali metal or alkaline earth metal hydroxides such as sodium, potassium hydroxide and calcium hydroxide, and organic bases such as alkylamines such as triethylamine and diisopropylethylamine. The amount of hydroxylamine used is equivalent to or more than compound (III), preferably about 2 to 5 equivalents.
The amount of the base used is at least twice the equivalent of the hydroxylamine used, preferably about 4 to 10 equivalents. The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction, for example, water, alcohols (eg, methanol, ethanol, n-propanol, isopropanol, etc.), nitriles (eg, acetonitrile, etc.), Examples thereof include halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.) and ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.). You may use these solvent individually or in mixture of 2 or more types. The reaction temperature is about 0 to 50 ° C., preferably room temperature.
The reaction time is about 10 minutes to 2 hours.

Alternatively, the lower alkyl ester form of compound (III) and hydroxylamine may be reacted in the presence of a base to give compound (IIa). This reaction is carried out by a method known per se, for example, New Experimental Chemistry Course, vol.
Page and the method described in the Chemical Society of Japan. Examples of the base include hydrides of alkali metals or alkaline earth metals (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), amides of alkali metals or alkaline earth metals (eg, Lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal lower alkoxide (eg sodium methoxide) , Sodium ethoxide, potassium t-butoxide, etc.); for example, alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), al Inorganic substances such as alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) Base; for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.
4.0] -7-undecene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and other amines, or basic aromatic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine Organic bases and the like. Among these, strong bases such as lower alkoxides of alkali metals or alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.) are preferable. The amount of hydroxylamine used is equivalent to or more than the lower alkyl ester compound, preferably about 3
To 20 equivalents. The amount of the base used may be in excess of hydroxylamine, for example, about 1.2 to 2 equivalents relative to hydroxylamine. The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction, and examples thereof include alcohols (eg, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethylene glycol, sec-butanol, etc.). , Ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.) and the like. You may use these solvent individually or in mixture of 2 or more types in a suitable ratio. The reaction temperature is about -20 ° C to 50 ° C.
C, preferably room temperature. The reaction time is about 1 to 1
8 hours.

The compound (III) is synthesized by a method known per se. When R ¹ in the compound (III) is a quinone ring, it can be obtained by the method described in JP-A No. 61-44840 or a method analogous thereto. In the compound (III), when R ¹ is an aromatic group excluding a quinone ring, for example, JP-A-63-4770.
No. 7, JP-A-59-101465, or a method analogous thereto. Compound (III)
In the case where R ¹ is a cyano group or an aryl group and m is 1, it can be obtained, for example, by the method described in JP-A-59-101465 or a method analogous thereto. Compound (III)
In the case where R ¹ is a cyano group or an aryl group and m is 2, it can be obtained, for example, by the method shown by the following reaction formula or a method analogous thereto.

Embedded image In the above formula, R ⁵ is a lower alkyl group, Y ′ is a leaving group, and other symbols have the same meanings as described above. Here, as the "lower alkyl group" represented by R ⁵ , for example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) and the like are used. "Leaving group" represented by Y '
Are the same as the above-mentioned "leaving group". Compound (IIIa) can be obtained by subjecting compound (IV) or a salt thereof to a substitution reaction of compound (V) or a salt thereof, and then subjecting the obtained compound (VI) or a salt thereof to a hydrolysis reaction. The substitution reaction may be carried out in the presence of a base. Examples of the base include the above-mentioned strong bases, inorganic bases, organic bases and the like. The amount of the base used is about 1-5 equivalents, preferably about 1-3 equivalents, relative to compound (IV). The amount of compound (V) used is about 1 to 3 equivalents relative to compound (IV).

The solvent used in this reaction may be any solvent that does not inhibit the reaction, for example, alcohols (eg, methanol, ethanol, etc.), ethers (eg,
Diethyl ether, tetrahydrofuran (THF), dioxane, etc., halogenated hydrocarbons (eg, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) ), Nitriles (eg, acetonitrile), acid amides (eg, N, N-dimethylformamide etc.), ketones (eg, acetone, methyl ethyl ketone etc.), sulfoxides (eg dimethyl sulfoxide etc.)
And the like, or a mixed system of two or more thereof. Among them, ethers (eg, THF, diethyl ether, etc.), nitriles (eg, acetonitrile, etc.), acid amides (eg, N, N-dimethylformamide, etc.), ketones (eg, acetone, etc.) and the like are preferable. The reaction temperature is about 0 ° C to 100 ° C, preferably about 10 ° C to 50 ° C.
It is. The reaction time is about 5 minutes to 100 hours, about 1 to 5 hours.

The hydrolysis reaction of the compound (VI) can be carried out by acid hydrolysis or alkali hydrolysis known per se. Further, this hydrolysis step may be accompanied by a deprotection step. In the case of alkaline hydrolysis, the compound (VI) is treated with an alkali (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide) in a solvent (eg, water, alcohols, ethers or a mixture of two or more thereof). , A hydroxide of an inorganic base such as barium hydroxide). The solvent is preferably a water-methanol mixed solvent. Sodium hydroxide is preferred as the alkali. The amount of alkali used is about 2 to 100 equivalents, preferably about 5 to 10 equivalents, relative to compound (VI). The reaction temperature is about 10 ° C to 120 ° C, preferably about 50 ° C to 120 ° C. The reaction time is about 5 minutes to 100 hours, preferably about 10 to 50 hours.
As a preferred reaction system, the solvent is a mixed solvent of water-methanol, the reaction temperature is about 50 ° C to 120 ° C, and the reaction time is about 10 to 50 hours. For the acid hydrolysis, the compound (VI) may be heated and stirred at room temperature to 120 ° C. for 0.5 to 18 hours in the excess of diluted hydrochloric acid alone or in the coexistence of diluted hydrochloric acid and acetic acid. Many of the compounds (IV) are easily available as commercial products.

In the compound (III), R ¹ is of the formula

Embedded image In the case of a group represented by the formula (wherein each symbol has the same meaning as described above), it can be obtained, for example, by the method represented by the following reaction formula or a method analogous thereto.

Embedded image In the above formula, R ⁶ is a lower alkyl group, and other symbols have the same meanings as described above. Here, examples of the "lower alkyl group" represented by R ⁶ include those similar to the above-mentioned "C _1-6 alkyl group" represented by R ⁵ . Compound (IIIb)
In the case where m is 1, by subjecting compound (VII) or a salt thereof to a compound (VIII) or a salt thereof, a dehydration reaction and subjecting the obtained compound (IX) or a salt thereof to a hydrolysis reaction can get. When m is 2 in the compound (IIIb),
A reduction reaction may be performed simultaneously with the dehydration reaction. The dehydration reaction is a method known per se, for example, an acid catalyst (eg, p-toluenesulfonic acid or the like in about 1 to 1.5 equivalents) in an inert solvent.
In the coexistence of about 1 to 10 hours, heating (about 40 to 100 ℃)
The method for doing so may be followed. The reduction reaction can be carried out by a method known per se, for example, in an inert solvent, using a metal catalyst (eg, palladium-
Carbon, etc., under a hydrogen pressure of about 1 to 10 atm, about 1 to 1
The method of reacting for 0 hours may be followed. Further, a reduction reaction with a metal hydride (eg, hydrogenated cyanoborohydride, etc.) may be performed. In this case, about 1 to 5 equivalents of metal hydride may be reacted at room temperature to 50 ° C. for 1 to 24 hours in an alcohol solvent (eg, methanol, ethanol, etc.). The hydrolysis reaction may be performed under the same conditions as the hydrolysis reaction of the compound (VI).

In the respective reactions of the present invention and the respective reactions for synthesizing the starting compound, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are generally used in peptide chemistry and the like. A protective group may be introduced, and the desired compound can be obtained by removing the protective group after the reaction, if necessary.

Examples of the amino-protecting group include C _1-6
Alkylcarbonyl group (eg, formyl, acetyl, ethylcarbonyl, etc.), C _1-6 alkyloxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), benzoyl group, C _7-10 aralkylcarbonyl group (eg, benzylcarbonyl, etc.) ), Trityl group, phthaloyl group, N, N-dimethylaminomethylene group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine etc.), nitro groups and the like. Examples of the protective group for the carboxyl group include C _1-6 alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), phenyl groups, trityl groups, silyl groups and the like. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl groups (eg, formyl, acetyl, propionyl, butylcarbonyl, etc.), nitro groups, etc. It may be substituted. Examples of the protective group for the hydroxyl group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a C _7-10 aralkyl group (eg, benzyl, etc.) ),
C _1-6 alkylcarbonyl group (eg, formyl, acetyl, propionyl etc.), benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl etc.),
Tetrahydropyranyl group, tetrahydrofuranyl group, silyl group and the like are used. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl groups (eg, methyl, ethyl, n-propyl, etc.), phenyl group, C _{7- 10} aralkyl groups (eg,
Benzyl, etc.), a nitro group and the like. Further, as a method for removing these protecting groups, a method known per se or a method analogous thereto can be used.
A method using a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

Compound (I) or Compound (II) of the present invention
Can be isolated and purified by a known means such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. The starting compound of the compound (I) or the compound (II) of the present invention or a salt thereof can be isolated and purified by a known means similar to the above, but can be directly used as a reaction mixture without isolation. It may be provided as a raw material in the step. Compound (I) of the present invention
In the case of containing optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as the compounds of the present invention. When compound (I) or compound (II) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, each can be obtained as a single product by a synthesis method and a separation method known per se. For example, when the compound of the present invention has an optical isomer, the optical isomer resolved from the compound is also included in the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving a racemic mixture of the final product according to a conventional method. As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used.

1) Fractional Recrystallization Method A method in which a racemate and an optically active compound are allowed to form a salt, which is separated by a fractional recrystallization method and, if desired, a neutralization step is performed to obtain a free optical isomer. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to be separated. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), water, various buffer solutions (eg, phosphate buffer solution), organic solvents (eg, ethanol, methanol). , Acetonitrile) alone or as a mixed solution,
Separate the optical isomers. Also, for example, in the case of gas chromatography, CP-Chirasil-DeX CB
Separation is performed using a chiral column such as (GL Science). 3) Diastereomeric method A mixture of racemates is made into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this is converted into a single substance through a usual separation means (eg, fractional recrystallization, chromatography method, etc.). After that, a method of obtaining an optical isomer by cleaving the optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, when the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MPTA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)
-Menthoxyacetic acid and the like) and the like are subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, the compound and the optically active amine or alcohol reagent are subjected to a condensation reaction to give an amide or ester diastereomer, respectively.
The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

Compound (I) and compound (II) of the present invention
Has an excellent action, for example, an action of suppressing neuronal degeneration in the cerebrum, an action of inhibiting brain tissue destruction, and a cytokine (eg, IL in human macrophage cells and cerebral cells).
-1β, TNFα, etc.), it is useful as a neurodegeneration inhibitor in mammals (eg, human, horse, cow, dog, cat, rat, mouse, monkey, etc.) Dysfunction due to neurodegeneration, such as neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, Down's syndrome,
Bacterial or viral meningitis such as Pick's disease, Creutzfeldt-Jakob disease, multiple sclerosis, Borna's disease,
It is useful for treatment / prevention or improvement of prognosis of post-vaccination encephalitis, AIDS encephalopathy, etc., cerebral dysfunction (eg, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, trauma, etc.). Also,
Compound (I) and compound (II) of the present invention are also effective against symptoms such as general malaise, fever, sleep, headache, arthralgia, loss of appetite derived from cytokines of the above mammals, and psychiatric symptoms such as depression. Is. Further, the compound (I) and the compound (II) of the present invention prevent abnormal release of nitric oxide due to acceleration of the above-mentioned mammalian immune system, and therefore, for example, septic shock, nephritis, arteriosclerosis, and asthma. ,
It is also effective in improving diabetes and bone diseases. The compound (I) and compound (II) of the present invention have low toxicity, and as they are or according to a method known per se, a pharmaceutical composition containing a pharmacologically acceptable carrier, such as a tablet (sugar-coated tablet, film-coated tablet, (Including), powder, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) safe Can be administered to. The content of the compound (I) or the compound (II) in the preparation of the present invention is 0.1 to 100% by weight based on the whole preparation. Although the dose varies depending on the administration subject, administration route, disease and the like, for example, as a neurodegenerative disease drug, about 0.1 to 500 mg, preferably about 0.1 to 500 mg, as an active ingredient per day for an adult (60 kg) as an oral preparation is preferable. About 1 to 1
The dose is 00 mg, more preferably about 5 to 100 mg, and the dose can be administered once or several times a day.

Examples of the pharmacologically acceptable carrier that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances conventionally used as preparation materials, such as an excipient in a solid preparation and a lubricant. Examples include agents, binders, disintegrants; solvents for liquid preparations, solubilizers, suspending agents, isotonic agents, buffering agents, soothing agents and the like. If necessary, additives such as antiseptics, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch,
Corn starch, crystalline cellulose, light silicic anhydride and the like can be mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. As the solvent, for example, water for injection, alcohol,
Propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D
-Mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, surfactants such as; polyvinyl alcohol, polyvinyl pyrrolidone, Carboxymethylcellulose sodium,
Examples thereof include hydrophilic polymers such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, and the like.

[0047]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
It will be described in detail by examples, formulation examples, and experimental examples.
These examples are merely implementations, are not intended to limit the invention, and may vary without departing from the scope of the invention. "Room temperature" in the following Reference Examples and Examples is 0.
To 30 ° C., anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic solvent. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz (hertz) Herz) CDCl ₃ : Deuterated chloroform THF: Tetrahydrofuran DMF: N, N-Dimethylformamide DMSO: Dimethylsulfoxide IPE: Diisopropyl ether ¹ H-NMR: Proton nuclear magnetic resonance (normally measured in free form) Me: Methyl Et: Ethyl Pr: Propyl Bu: Butyl Ac: Acetyl Ph: Phenyl Ms: Mesyl Ts: Tosyl

[0048]

【Example】

Reference Example 1 Ethyl 7- (1-hydroxy-2-naphthyl) -7-
Oxoheptanoic acid Pimelic acid monoethyl ester (50 g) was dissolved in methylene chloride (100 ml), and thionyl chloride (38 ml) was added dropwise. The mixture was stirred at 50 ° C for 2 hours and then concentrated to dryness. The obtained residue and 1-naphthol (36.6 g) were dissolved in toluene (300 ml), and boron trifluoride ether complex (43.3 g) was added dropwise. After stirring for 3 hours, the reaction solution was poured into cold water and extracted with diisopropyl ether. The organic layer was washed with water, dried and concentrated to dryness. The obtained residue was mixed with aluminum chloride (53.4 g) and xylene (300 ml), and the mixture was stirred at 130 ° C. for 1 hour. After cooling, the supernatant was removed by decantation, 2N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated to dryness. The obtained residue was heated under reflux with hydrogen chloride (22 g) and ethanol (450 ml) for 3 hours. After allowing to cool, the precipitated crystals were collected by filtration and washed with hexane-diisopropyl ether (9: 1) to obtain the desired product (62 g). mp: 77-78 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7Hz), 1.38-
1.60 (2H, m), 1.60-1.90 (4H, m), 2.34 (2H, t, J = 7Hz), 3.0
7 (2H, t, J = 7Hz), 4.13 (2H, q, J = 7Hz), 7.27 (1H, d, J = 9Hz),
7.55 (1H, m), 7.63 (1H, m), 7.67 (1H, d, J = 9Hz), 7.77 (1
H, br, d, J = 7Hz), 8.07 (1H, m)

Reference Example 2 Ethyl 7- (1-hydroxy-2-naphthyl) heptanoic acid Ethyl 7- (1-hydroxy-2-naphthyl) -7-
Oxoheptanoic acid (15 g), 10% palladium on carbon (1.5 g), triethylamine hydrochloride (6.6 g), triethylamine (4.86 g), and ethanol (3
(00 ml) was used to carry out a catalytic hydrogenation reaction at room temperature and atmospheric pressure for 5 days. The catalyst was filtered off, concentrated under reduced pressure, ether was added to the residue, and the mixture was washed successively with water, 1N hydrochloric acid and saturated brine and dried. The residue after concentration was applied to a silica gel column (hexane-ethyl acetate) and then recrystallized from ethyl acetate-hexane to obtain the desired product (7.28 g). mp: 41-42 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7Hz), 1.25-
1.50 (4H, m), 1.50-1.80 (4H, m), 2.30 (2H, t, J = 7Hz), 2.7
4 (2H, t, J = 8Hz), 4.13 (2H, q, J = 7Hz), 7.24 (1H, d, J = 9Hz),
7.35-7.55 (3H, m), 7.78 (1H, m), 8.13 (1H, m)

Reference Example 3 Ethyl 7- (2-hydroxy-1-naphthyl) -7-
Phenylheptanoic acid 2-naphthol (1.152 g) and ethyl 7-hydroxy-7-phenylheptanoic acid (2 g) were dissolved in methylene chloride (20 ml), and boron trifluoride ether complex (0.56 g) was added dropwise. After stirring for 5 hours, the mixture was extracted with chloroform, washed with water and dried. The residue after concentration was subjected to a silica gel column (hexane-ethyl acetate) to obtain the desired product (1.94 g). ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7Hz), 1.20-
1.65 (6H, m), 2.20 (2H, t, J = 7Hz), 2.20-2.50 (2H, m), 4.0
9 (2H, q, J = 7Hz), 5.03 (1H, dd, J = 9Hz, 6Hz), 7.01 (1H, d, J =
9Hz), 7.10-7.50 (7H, m), 7.67 (1H, d, J = 9Hz), 7.79 (1H, d
d, J = 8Hz, 1Hz), 8.05 (1H, br, d, J = 9Hz)

Reference Example 4 Ethyl 7- (4-chloro-1-hydroxy-2-naphthyl) -7-phenylheptanoic acid In the same manner, 4-chloro-1-naphthol (3.57) was prepared.
The title compound (6.3 g) was obtained from g). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7Hz), 1.25
-1.50 (4H, m), 1.50-1.70 (2H, m), 2.12 (2H, q, J = 7Hz), 2.
27 (2H, t, J = 7Hz), 4.12 (2H, q, J = 7Hz), 4.28 (1H, t, J = 8H
z), 7.15-7.40 (5H, m), 7.49 (1H, s), 7.43-7.65 (2H, m),
8.07-8.21 (2H, m)

Reference Example 5 Ethyl 7- (1-hydroxy-2-naphthyl) -7-
Phenylheptanoic acid Ethyl 7- (4-chloro-1-hydroxy-2-naphthyl) -7-phenylheptanoic acid (4.3 g), 10%
Palladium on carbon (0.4g), ethanol (90ml),
Using triethylamine (10 ml), a catalytic hydrogenation reaction was carried out at 50 ° C. under normal pressure for 16 hours. The reaction mixture was filtered, and the concentrated residue of the filtrate was applied to a silica gel column (hexane-ethyl acetate) to obtain the desired product (3.65 g). ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7Hz), 1.20-
1.45 (4H, m), 1.50-1.70 (2H, m), 2.13 (2H, br, q, J = 7Hz),
2.25 (2H, t, J = 7Hz), 4.11 (2H, q, J = 7Hz), 4.32 (1H, t, J = 8H
z), 7.10-7.33 (5H, m), 7.36-7.50 (4H, m), 7.72-7.80 (1
H, m), 8.02-8.10 (1H, m)

Reference Example 6 Ethyl 8- (isoquinolin-4-yl) octanoate Sodium hydride (4 g) in DMSO (40 g)
6 g of sodium gymsyl solution (8 ml) prepared from
-Carboxyhexyl triphenylphosphonium
Bromide (4.7g) in DMSO (10ml)
It was dripped at and stirred for 10 minutes as it was. 4-Formylisoquinoline (1.6 g) was added and the mixture was stirred at room temperature for 10 minutes. Water (50 ml) was added to the reaction solution, which was washed with toluene (50 ml). The pH was adjusted to 5 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), thionyl chloride (2 ml) was added, and the mixture was left overnight. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 ml), and the mixture was stirred overnight in the presence of Raney nickel under a hydrogen atmosphere at 1 atm.
The catalyst was filtered off, concentrated under reduced pressure, subjected to silica gel column chromatography, and developed with ethyl acetate-isopropyl ether (1: 1) to obtain the desired product (0.8 g).

Reference Example 7 8- (Isoquinolin-4-yl) octanoic acid Ethyl 8- (isoquinolin-4-yl) octanoate (0.8 g) was dissolved in a mixed solution of methanol (10 ml) and water (5 ml), Sodium hydroxide (1 g) was added, and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, add 2N hydrochloric acid and p
It was made H5 and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to obtain the desired product (0.6 g). Mp 99-100 Calculated ℃ Elemental Analysis _{C 17 H 21 NO 2 C;} 75.25 H; 7.80 N; 5.16 observations C; 75.36 H; 7.84 N; 5.12 1 H -NMR (CDCl ₃ ) δ: 9.15 (1H, s), 8.37 (1H, s),
8.01 (2H, m), 7.77 (1H, m), 7.61 (1H, m), 3.03 (2H, t, J = 8
Hz), 2.37 (2H, t, J = 8Hz), 1.41-1.80 (10H, m)

Reference Example 8 7- (Isoquinolin-4-yl) heptanoic acid 7- (Isoquinolin-4-yl) was prepared in the same manner as in Reference Example 7.
Heptenoic acid was obtained. Calculated melting point 108-109 ° C. Elemental Analysis _{C 16 H 19 NO 2 C;} 74.68 H; 7.44 N; 5.44 observations C; 74.68 H; 7.46 N; 5.46

Reference Example 9 6- (isoquinolin-4-yl) hexanoic acid 6- (isoquinolin-4-yl) was prepared in the same manner as in Reference Example 7.
Hexanoic acid was obtained. Calculated melting point 131-132 ° C. Elemental Analysis _{C 15 H 17 NO 2 C;} 74.05 H; 7.04 N; 5.76 observations C; 73.75 H; 7.08 N; 5.96

Reference Example 10 Ethyl (Z) -7- (2-quinolyl) -6-heptenoic acid 2-quinolinecarboxaldehyde (2 g) and (5-ethoxycarbonylpentyl) triphenylphosphonium bromide (12.5 g) were added to dimethyl ester. Sulfoxide (5
0 ml) and potassium t-butoxide (2.92)
A solution of g) in dimethylsulfoxide (10 ml) was added dropwise. After stirring for about 30 minutes, the mixture was poured into ice water and extracted with ether. The organic layer was washed and dried, and the concentrated residue was subjected to a silica gel column (hexane-ethyl acetate) to give the Z isomer (1 g) and E isomer (1.24 g) of the title compound. Z isomer: Oil ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7Hz), 1.50-
1.80 (4H, m), 2.33 (2H, t, J = 7Hz), 2.75 (2H, m), 4.12 (2H,
q, J = 7Hz), 6.01 (1H, dt, J = 12Hz, 7Hz), 6.66 (1H, dt, J = 12H
z, 2Hz), 7.37 (1H, d, J = 8Hz), 7.49 (1H, m), 7.68 (1H, m),
7.78 (1H, br, J = 8Hz), 8.06 (1H, d, J = 8Hz), 8.10 (1H, d, J = 8
Hz)

Reference Example 11 Ethyl (E) -7- (2-quinolyl) -6-heptenoic acid Ethyl (E) -7- (2-quinolyl) -6-heptenoic acid was obtained in the same manner as in Reference Example 10. . Oily substance ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J
= 7 Hz), 1.50-1.90 (4H, m),
2.30-2.43 (4H, m), 4.13 (2H,
q, J = 7 Hz), 6.71 (1H, d, J = 16H)
z), 6.82 (1H, dt, J = 16Hz, 7H
z), 7.40-7.50 (1H, m), 7.52
(1H, d, J = 8Hz), 7.61-7.80 (2
H, m), 8.00-8.11 (2H, m)

Reference Example 12 Ethyl 7- (2-quinolyl) heptanoic acid Ethyl 7- (2-quinolyl) -6-heptenoic acid (0.
Using 7 g), ethanol (7 ml) and 10% palladium carbon (0.1 g), a catalytic hydrogenation reaction was carried out at room temperature and normal pressure for 48 hours. The catalyst was filtered off and the filtrate was concentrated to dryness to obtain the desired product (0.56 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7Hz), 1.30-
1.52 (4H, m), 1.64 (2H, br, q, J = 7Hz), 1.82 (2H, br, q, J = 7H
z), 2.29 (2H, t, J = 7Hz), 2.97 (2H, t, J = 8Hz), 4.11 (2H, q,
J = 7Hz), 7.29 (1H, d, J = 8Hz), 7.48 (1H, m), 7.68 (1H, m),
7.78 (1H, br, d, J = 8Hz), 8.03 (1H, br, d, J = 8Hz), 8.07 (1H,
d, J = 8Hz)

Reference Example 13 (E) -6- (2-quinolyl) -5-hexenoic acid 2-quinolinecarbaldehyde 2.0 g and 1- (4-ethoxycarbonyl) butyltriphenylphosphonium bromide 9.0 g DMSO 18 ml Potassium tert in solution
-Slowly add 2.14 g of butoxide and let it stand at room temperature for 3
Stirred for 0 minutes. The reaction mixture was poured into ice water and extracted with ether. The ether layer was washed twice with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1), and (E)
Ethyl-6- (2-quinolyl) -5-hexenoate was added to 0.2.
65 g, and 1.45 g as a mixture of (E) and (Z) were obtained as oils. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1Hz), 1.8
8-1.98 (2H, m), 2.33-2.44 (4H, m), 4.13 (2H, q, J = 7.1Hz),
6.71 (1H, d, J = 15.8Hz), 6.81 (1H, dt, J = 15.8Hz, 5.8Hz),
7.43 (2H, m), 7.63-7.78 (2H, m), 8.01-8.09 (2H, m) (E) -6- (2-quinolyl) -5-ethylhexeneate 2.0g in 10 ml of methanol in ice Under cooling, 5 ml of 3N sodium hydroxide aqueous solution was added, the temperature was raised to room temperature, and the mixture was stirred for 6 hours as it was. Neutralize the reaction mixture with 3N hydrochloric acid,
The solvent methanol was distilled off under reduced pressure. The precipitated crude crystals were filtered, washed with water and then with ether. As it is, it is dried under reduced pressure to obtain (E) -6- (2-quinolyl) -5.
0.76 g of hexenoic acid were obtained as its colorless crystals. Melting point 142-144 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-1.94 (2H, m), 2.
33-2.45 (4H, m), 6.70 (1H, d, J = 15.9Hz), 6.85 (1H, dt, J = 1
5.9Hz, 6.9Hz), 7.45-7.72 (3H, m), 7.80 (1H, d, J = 7.8Hz),
7.98 (1H, d, J = 8.4Hz), 8.12 (1H, d, J = 8.4Hz)

Reference Example 14 6- (2-quinolyl) hexanoic acid 2-quinolinecarbaldehyde 5.0 g and 1- (4-carboxy) butyltriphenylphosphonium bromide 1
To a solution of 4.8 g of dimethyl sulfoxide (DMSO) in 50 ml was added gradually 8.34 g of potassium tert-butoxide, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and washed with toluene. The aqueous layer was neutralized with 3N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent and 5% Pd / C were added to methanol 10
It was suspended in 0 ml and stirred at room temperature under a hydrogen atmosphere for 2 hours.
The catalyst was filtered and the filtrate was concentrated to give a crude product. This crude product can be crystallized from methanol-ether 6- (2
-Quinolyl) hexanoic acid 5.18 g, melting point 105-10
Obtained as colorless crystals at 8 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.58 (2H, m), 1.68-
1.95 (4H, m), 2.40 (2H, t, J = 7.3Hz), 3.03 (2H, t, J = 7.9H
z), 6.68 (1H, brs), 7.26-7.35 (1H, m), 7.46-7.54 (1H,
m), 7.65-7.74 (1H, m), 7.78 (1H, d, J = 7.7Hz), 8.09-8.17
(2H, m)

The following compounds were synthesized by the same method as above. Reference Example 15 6- (4-quinolyl) hexanoic acid Melting point 99-102 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.60 (2H, m), 1.68-
1.90 (4H, m), 2.40 (2H, t, J = 7.1Hz), 3.11 (2H, t, J = 7.1H
z), 5.58 (1H, brs), 7.28 (1H, d, J = 4.6Hz), 7.48-7.61 (1
H, m), 7.66-7.75 (1H, m), 8.05 (1H, d, J = 8.5Hz), 8.15 (1
H, d, J = 7.6Hz), 8.80 (1H, d, J = 4.6Hz)

Reference Example 16 7- (4-quinolyl) heptanoic acid Melting point 155-158 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.53 (4H, m), 1.
54-1.66 (2H, m), 1.66-1.88 (2H, m), 2.27 (2H, t, J = 7.2H
z), 3.04 (1H, brs), 3.09 (2H, t, J = 7.7Hz), 7.27 (1H, d, J =
4.5Hz), 7.48-7.78 (3H, m), 8.07 (2H, d, J = 9.7Hz), 8.79
(1H, d, J = 4.5Hz)

Reference Example 17 Ethyl 6-cyano-6- (1-naphthyl) hexanoate 1-naphthalene Acetonitrile 12.54 g (75 mmo
l) is dissolved in 125 ml of DMF, and 3.30 g (82.5 mmol) of 60% sodium hydride is added at room temperature, and the temperature is 60 ° C.
Heated up. After stirring for 30 minutes, cool to room temperature, and
Bromovaleric acid ethyl ester 13.17 ml (82.5 mmo
l) was added. After reacting at 60 ° C. for 30 minutes, the mixture was cooled to 10 ° C. or lower and 500 ml of pure water was added. The mixture was extracted twice with 200 ml of ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-CH ₂ Cl ₂ -ethyl acetate, 4: 2: 1) to give the title compound (17.16 g, yield 77.5) as a pale yellow oil. %) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1Hz), 1.5
9-1.78 (4H, m), 2.02-2.14 (2H, m), 2.30-2.37 (2H, m), 4.
11 (2H, q, J = 7.1Hz), 4.55 (1H, t, J = 7.1Hz), 7.45-7.63 (3
H, m), 7.68 (1H, dd, J = 7.2Hz, 1.2Hz), 7.83-7.95 (3H, m)

Reference Example 18 6-Cyano-6- (1-naphthyl) hexanoic acid Ethyl 6-cyano-6- (1-naphthyl) hexanoate 7.38 g (25 mmol) was dissolved in 50 ml of methanol,
50 ml of 1N-sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 3 days.
Stir for 0 minutes. After diluting with 150 ml of pure water, ethyl acetate 1
It was washed with 50 ml. The aqueous layer is acidified with 100 ml of 1N hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (hexane-ethyl acetate, 1: 4) to give 6.66 g of the title compound as a colorless oil (yield 9
9.7%). ¹ H-NMR (CDCl ₃ ) δ: 1.55-1.76 (4H, m), 2.01-
2.12 (2H, m), 2.35-2.41 (2H, m), 4.55 (1H, t, J = 7.1Hz),
7.45-7.63 (3H, m), 7.66 (1H, dd, J = 7.2Hz, 1.1Hz), 7.83-
7.94 (3H, m)

Reference Example 19 6- (3-quinolyl) hexanoic acid The target product was obtained in the same manner as in Reference Example 14. Melting point 129-131 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.28-1.44 (2H, m),
1.48-1.79 (4H, m), 2.22 (2H, t, J = 7.1Hz), 2.79 (2H, t, J =
7.6Hz), 7.58 (1H, ddd, J = 1.3Hz, 6.8Hz, 8.1Hz), 7.70 (1H,
ddd, J = 1.6Hz, 6.8Hz, 8.4Hz), 7.92 (1H, dd, J = 1.6Hz, 8.1H
z), 7.98 (1H, dd, J = 1.3Hz, 8.4Hz), 8.14 (1H, d, J = 2.1Hz),
8.80 (1H, d, J = 2.1Hz), 12.00 (1H, brs)

Reference Example 20 7- (3-quinolyl) heptanoic acid The target product was obtained in the same manner as in Reference Example 14. Melting point 120-121 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.28-1.4
1 (4H, m), 1.43 to 1.59 (2H, m),
1.61-1.75 (2H, m), 2.20 (2
H, t, J = 7.1 Hz), 2.79 (2H, t, J
= 7.6 Hz), 7.57 (1H, ddd, J = 1.
3 Hz, 6.8 Hz, 8.2 Hz), 7.70 (1
H, ddd, J = 1.5Hz, 6.8Hz, 8.3H
z), 7.92 (1H, dd, J = 1.5 Hz, 8.
2Hz), 7.99 (1H, dd, J = 1.3Hz,
8.3 Hz), 8.13 (1H, d, J = 2.2H)
z), 8.79 (1H, d, J = 2.2 Hz), 1
2.00 (1H, brs)

Reference Example 21 7- (6-Methoxy-2-quinolyl) heptanoic acid The target product was obtained in the same manner as in Reference Example 14. Melting point 84-87 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.38-1.48 (4H, m), 1.59-
1.87 (4H, m), 2.37 (2H, t, J = 7.3Hz), 2.91-3.00 (2H, m),
3.92 (3H, s), 7.05 (1H, d, J = 2.8Hz), 7.27 (1H, d, J = 8.6H
z), 7.35 (1H, dd, J = 2.8Hz, 9.2Hz), 7.46 (1H, brs), 8.00
(1H, d, J = 8.6Hz), 8.04 (1H, d, J = 9.2Hz)

Reference Example 22 7-Phenyl-7- (2-quinolyl) heptanoic acid 2-benzoylquinoline (4.0 g) and (5-carboxy-1-pentyl) triphenylphosphonium bromide (1
To a solution of 1.8 g of DMSO (50 ml) was gradually added potassium t-butoxide (5.8 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and washed with toluene. The aqueous layer was neutralized with 3N hydrochloric acid and extracted with ethyl acetate.
The extract was washed with saturated aqueous sodium chloride solution and dried.
The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/1).
Purified with 7-phenyl-7- (2-quinolyl) -6-
Heptenoic acid as a mixture of (E) and (Z) isomers.
90 g was obtained. This mixture (0.90 g) and 5% palladium carbon (0.90 g) were suspended in methanol (10 ml), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound (1.0 g). ¹ H-NMR (CDCl ₃ ) δ: 1.26-1.50 (4H, m), 1.54-
1.71 (2H, m), 2.14-2.37 (4H, m), 4.30 (1H, t, J = 7.9Hz),
4.96 (1H, brs), 7.17-7.41 (6H, m), 7.48 (1H, dd, J = 7.0Hz,
8.4Hz), 7.64-7.77 (2H, m), 8.00 (1H, d, J = 8.8Hz), 8.13
(1H, d, J = 8.1Hz)

Reference Example 23 6-Phenyl-6- (2-quinolyl) hexanoic acid By the same method as in Reference Example 22, the target product was obtained. Oil ¹ H-NMR (CDCl ₃ ) δ: 1.31-1.46 (2H, m), 1.65-
1.81 (2H, m), 2.15-2.48 (4H, m), 4.11 (1H, brs), 4.35 (1
H, t, J = 7.7 Hz), 7.15-7.52 (7H, m), 7.65-7.77 (2H, m),
8.02 (1H, d, J = 8.5Hz), 8.15 (1H, d, J = 8.2Hz)

Reference Example 24 Ethyl 6-amino-6- (2-naphthyl) hexanoate 1) Ethanol solution (150 ml) of ethyl 6-oxo-6- (2-naphthyl) hexanoate (15 g) was treated with hydroxylamine hydrochloride. Salt (4.8 g) and sodium acetate (5.
7 g) was added to an aqueous solution (42 ml), and the mixture was heated under reflux for 2 hours. Ethanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated saline and dried. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 6-hydroxyimino-6- (2-naphthyl).
Ethyl hexanoate (19 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1Hz), 1.5
7-1.88 (4H, m), 2.36 (2H, t, J = 7.2Hz), 2.96 (2H, t, J = 7.5H
z), 4.11 (2H, q, J = 7.1Hz), 7.46-7.55 (2H, m), 7.81-7.92
(4H, m), 7.91 (1H, brs), 8.01 (1H, s)

2) Ethyl 6-amino-6- (2-naphthyl) hexanoate Under a hydrogen atmosphere, ethyl 6-hydroxyimino-6- (2-naphthyl) hexanoate (19.2 g) and platinum oxide (0.
96 g) was suspended in acetic acid (160 ml) and stirred at room temperature for 10 hours. The catalyst was filtered off and the filtrate was concentrated. The obtained residue was dispersed in saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate,
Concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give ethyl 6-amino-6- (2-naphthyl) hexanoate (12.1 g). ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1Hz), 1.2
6-1.49 (2H, m), 1.55-1.71 (2H, m), 1.73 (2H, brs), 1.74-
1.85 (2H, m), 2.26 (2H, t, J = 7.4Hz), 2.69-2.81 (1H, m),
4.08 (2H, q, J = 7.1Hz), 7.41-7.52 (3H, m), 7.73 (1H, s),
7.77-7.87 (3H, m)

Reference Example 25 Ethyl 6-benzoylamino-6- (2-naphthyl) hexanoate A solution of ethyl 6-amino-6- (2-naphthyl) hexanoate (1.0 g) in acetonitrile under ice cooling (5 ml). And 1
Benzoyl chloride (0.54 g) was added dropwise with vigorous stirring of a mixture of aqueous sodium hydroxide solution (4 ml),
The temperature was raised to room temperature as it was and stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, dried and concentrated to give 6-benzoylamino-6- (2
Obtained ethyl-naphthyl) hexanoate (1.5 g). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.1Hz), 1.3
2-1.56 (2H, m), 1.61-1.82 (2H, m), 1.95-2.11 (2H, m), 2.
28 (2H, t, J = 7.5Hz), 4.08 (2H, q, J = 7.1 Hz), 5.26-5.41
(1H, m), 6.52 (1H, d, J = 7.8Hz), 7.38-7.52 (6H, m), 7.74-
7.88 (6H, m)

Reference Example 26 Ethyl 6-acetylamino-6- (2-naphthyl) hexanoate The title compound was obtained in the same manner as in Reference Example 25. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1Hz), 1.2
8-1.44 (2H, m), 1.58-1.75 (2H, m), 1.83-1.95 (2H, m), 2.
01 (3H, s), 2.27 (2H, t, J = 7.4Hz), 4.09 (2H, q, J = 7.1Hz),
5.07-5.19 (1H, m), 5.81 (1H, d, J = 8.1Hz), 7.40 (1H, dd, J =
1.9Hz, 8.5Hz), 7.45-7.53 (2H, m), 7.73 (1H, s), 7.78-7.
85 (3H, m)

Reference Example 27 6- (4-Methylbenzenesulfonylamino) -6-
Ethyl (2-naphthyl) hexanoate Ethyl 6-amino-6- (2-naphthyl) hexanoate (1.0 g) and 4-methylbenzenesulfonyl chloride (0.73 g) in THF (10 ml) were added to triethylamine (0 ml). .39 g) was added dropwise and the mixture was stirred as it was at room temperature for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was dried and then concentrated to obtain a crude product. The crude product was recrystallized from ethyl acetate-hexane to give the title compound (1.3 g). Melting point 87-91 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.1 Hz), 1.
23-1.43 (2H, m), 1.49-1.66 (2H, m), 1.67-1.93 (2H, m),
2.16 (3H, s), 2.19 (2H, t, J = 7.1Hz), 4.08 (2H, q, J = 7.1H
z), 4.37-4.48 (1H, m), 4.96 (1H, d, J = 7.4Hz), 6.91 (2H,
d, J = 8.5Hz), 7.12 (1H, dd, J = 1.7Hz, 8.5Hz), 7.33 (1H, s),
7.40-7.51 (4H, m), 7.63 (2H, d, J = 8.5Hz), 7.70-7.79 (1
H, m)

Reference Example 28 Ethyl 6-methanesulfonylamino-6- (2-naphthyl) hexanoate The title compound was obtained in the same manner as in Reference Example 27. ¹ H-NMR (CDCl ₃ ) δ: 1.21 and 1.28 (3H, t, J = 7.
1Hz and t, J = 7.1Hz), 1.32-1.55 (2H, m), 1.62-1.98 (4H,
m), 2.26 (2H, t, J = 7.4Hz), 2.52 (3H, s), 4.09 and 4.13 (2
H, t, J = 7.1Hz and t, J = 7.1Hz), 4.54-4.71 (1H, m), 4.90
(1H, d, J = 7.3Hz), 7.41 (1H, dd, J = 1.8Hz, 8.5Hz), 7.46-7.5
8 (2H, m), 7.75 (1H, s), 7.83-7.91 (3H, m)

Reference Example 29 6-Benzenesulfonylamino-6- (2-naphthyl)
Ethyl hexanoate The title compound was obtained in the same manner as in Reference Example 27. Melting point 81-84 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.1Hz), 1.2
2-1.44 (2H, m), 1.50-1.65 (2H, m), 1.68-1.97 (2H, m), 2.
19 (2H, t, J = 7.3Hz), 4.07 (2H, q, J = 7.1Hz), 4.41-4.51 (1
H, m), 5.10 (1H, d, J = 7.7Hz), 7.07-7.23 (3H, m), 7.23-7.
34 (1H, m), 7.38-7.49 (3H, m), 7.57-7.78 (5H, m)

Reference Example 30 6- (4-Fluorobenzenesulfonylamino) -6-
Ethyl (2-naphthyl) hexanoate The title compound was obtained in the same manner as in Reference Example 27. Melting point 91-93 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.1Hz), 1.2
3-1.44 (2H, m), 1.52-1.66 (2H, m), 1.68-1.94 (2H, m), 2.
21 (2H, t, J = 7.3Hz), 4.08 (2H, q, J = 7.1Hz), 4.41-4.53 (1
H, m), 5.02 (1H, d, J = 7.3Hz), 6.71-6.83 (2H, m), 7.08 (1
H, dd, J = 1.6Hz, 8.4Hz), 7.40 (1H, s), 7.43-7.79 (7H, m)

Reference Example 31 Methyl 7- (1-isoquinolyl) heptanoate A solution of dimethyl 2-isopropoxycarbonyl-1,2-dihydroisoquinoline-1-phosphonate (7.4 g) in THF at -78 ° C. under an argon atmosphere. 2.0 in (40 ml)
THF solution of M lithium diisopropylamide (12m
l) was added dropwise and the mixture was stirred as it was for 5 minutes. A THF solution (5 ml) of methyl 7-oxoheptanoate (3.9 g) was added dropwise to the reaction mixture, and the temperature was raised to room temperature. The reaction mixture was stirred at room temperature for another 2 hours. 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The obtained residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 1.
It was purified by 0/1). The obtained oily substance was dissolved in 4N methanolic hydrochloric acid, and the mixture was heated with stirring at 50 ° C. for 1 hour. Methanol was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was washed with ether. The aqueous layer was made alkaline with aqueous sodium hydroxide solution and extracted with ethyl acetate. After drying the extract,
Concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1), and methyl 7- (1-isoquinolyl) heptanoate (1.
7 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.55 (4H, m), 1.56-
1.74 (2H, m), 1.78-1.96 (2H, m), 2.31 (2H, t, J = 7.1Hz),
3.25-3.33 (2H, m), 3.66 (3H, s), 7.50 (1H, d, J = 5.9Hz),
7.54-7.71 (2H, m), 7.84 (1H, d, J = 7.7Hz), 8.15 (1H, d, J =
8.4Hz), 8.43 (1H, d, J = 5.9Hz).

Reference Example 32 Methyl 6- (1-isoquinolyl) hexanoate The title compound was obtained in the same manner as in Reference Example 31. ¹ H-NMR (CDCl ₃ ) δ: 1.42-1.61 (2H, m), 1.64-
1.81 (2H, m), 1.81-2.00 (2H, m), 2.34 (2H, t, J = 7.4Hz),
3.30 (2H, dd, J = 7.8Hz, 8.0Hz), 3.66 (2H, s), 7.51 (1H, d, J
= 5.7Hz), 7.55-7.71 (2H, m), 7.82 (1H, dd, J = 1.3Hz, 7.5H
z), 8.15 (1H, dd, J = 1.2Hz, 8.3Hz), 8.43 (1H, d, J = 5.7Hz)

Reference Example 33 6- (Benzoxazol-2-yl) hexanoic acid 1) Ethyl 6- (benzoxazol-2-yl) hexanoate Monoethyl pimelic acid (9.41 g), o-aminophenol (5.46 g) ), Boric acid (3.09 g) and xylene (100 ml) were heated under reflux for 16 hours while dehydrating. After cooling to room temperature, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography (hexane-ethyl acetate, 2: 1), and ethyl 6- (benzoxazol-2-yl) hexanoate (10.1 g).
I got ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1Hz), 1.3
5-1.53 (2H, m), 1.16-1.77 (2H, m), 1.85-1.18 (2H, m), 2.
27-2.40 (2H, m), 2.95 (2H, t, J = 7.5Hz), 4.12 (2H, q, J = 7.1
Hz), 7.27-7.32 (2H, m), 7.43-7.51 (1H, m), 7.63-7.72 (1
H, m) 2) Then, 6- (benzoxazol-2-yl) hexanoic acid was obtained by the same method as in Reference Example 18. Melting point 82-83 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.57 (2H, m), 1.62-
1.80 (2H, m), 1.85-2.01 (2H, m), 2.39 (2H, t, J = 7.3Hz),
2.96 (2H, t, J = 7.7Hz), 7.28-7.35 (2H, m), 7.44-7.56 (1H,
m), 7.64-7.73 (1H, m)

Reference Example 34 6- (Thiazolo [5,4-b] pyridin-2-yl) hexanoic acid 1) Ethyl 6- (thiazolo [5,4-b] pyridin-2-yl) hexanoate Monoethyl pimelic acid (10.35 g) in THF (55 m
l), dissolved in 1 drop of DMF, oxalyl chloride (11.73
ml) was added and the mixture was stirred at room temperature for 15 minutes. The excess oxalyl chloride was distilled off under reduced pressure, and the residue was added to a solution of 3-amino-2-chloropyridine (6.43 g) in THF-saturated aqueous sodium hydrogen carbonate (1: 1) (100 ml). After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with 1N-hydrochloric acid and 1N-sodium hydroxide and then dehydrated with sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (hexane-ethyl acetate, 2: 1).
The product was dissolved in pyridine (50 ml) and Lawesson's reagent (15.04 g) was added. After reacting at 100 ° C. for 4 hours, saturated aqueous sodium hydrogen carbonate (10 ml) was slowly added at 50 ° C., and saturated aqueous sodium hydrogen carbonate (100 ml) was added at room temperature. Extract with ethyl acetate (200 ml), dry and concentrate, then silica gel column chromatography (hexane-ethyl acetate,
It was purified by 2: 1) to obtain ethyl 6- (thiazolo [5,4-b] pyridin-2-yl) hexanoate (4.4 g). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2Hz), 1.4
4-1.58 (2H, m), 1.65-1.80 (2H, m), 1.87-2.02 (2H, m), 2.
33 (2H, t, J = 7.4Hz), 3.14 (2H, t, J = 7.7Hz), 4.12 (2H, q, J =
7.2Hz), 7.41 (1H, dd, J = 8.2Hz, 4.7Hz), 8.19 (1H, dd, J = 8.
2Hz, 1.6Hz), 8.54 (1H, dd, J = 4.7Hz, 1.6Hz) 2) Subsequently, the title compound was synthesized by the same method as in Reference Example 18. ¹ H-NMR (CDCl ₃ ) δ: 1.46-1.61 (2H, m), 1.65-
1.82 (2H, m), 1.88-2.02 (2H, m), 2.40 (2H, t, J = 7.3Hz),
3.15 (2H, t, J = 7.6Hz), 7.41 (1H, dd, J = 8.3Hz, 4.7Hz), 8.21
(1H, dd, J = 8.3Hz, 1.6Hz), 8.55 (1H, dd, J = 4.7Hz, 1.6Hz)

Reference Example 35 6- (1-Phenylbenzimidazol-2-yl) hexanoic acid 1) Ethyl 6- (1-phenylbenzimidazol-2-yl) hexanoate Monoethyl pimelate (10.35 g) was added to THF ( 55m
l), dissolved in 1 drop of DMF, oxalyl chloride (11.73
ml) was added and the mixture was stirred at room temperature for 15 minutes. The excess oxalyl chloride was distilled off under reduced pressure, and the solution was added to a solution of N-phenyl-1,2-phenylenediamine (9.21 g) in THF-saturated aqueous sodium hydrogen carbonate (1: 1) (100 ml). After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with 1N-hydrochloric acid and 1N-sodium hydroxide and then dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 2: 1) to give crystals (14.72 g). Obtained crystals (13.54
g) was dissolved in ethanol (50 ml) and sulfuric acid (1 ml) was added. After reacting for 3 hours under reflux, the solvent was distilled off under reduced pressure.
1N-Sodium hydroxide (100 ml) was added to the residue, and the mixture was extracted with ethyl acetate (100 ml). After drying and concentration, the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 1: 1), and ethyl 6- (1-phenylbenzimidazol-2-yl) hexanoate (6.4
9 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.1H), 1.31
-1.42 (2H, m), 1.52-1.68 (2H, m), 1.73-1.90 (2H, m), 2.2
5 (2H, t, J = 7.4Hz), 2.79 (2H, t, J = 7.7Hz), 4.09 (2H, q, J =
7.1Hz), 7.07-7.39 (5H, m), 7.48-7.64 (3H, m), 7.75-7.8
1 (1H, m) 2) Then, hydrolysis was carried out in the same manner as in Reference Example 18 to obtain 6- (1-phenylbenzimidazol-2-yl) hexanoic acid. Melting point 132-133 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.48 (2H, m), 1.63-
1.85 (4H, m), 2.36 (2H, t, J = 7.4Hz), 2.85 (2H, t, J = 7.6H
z), 7.09 (1H, d, J = 7.6Hz), 7.17-7.40 (4H, m), 7.55-7.66
(3H, m), 7.84 (1H, d, J = 7.8Hz)

Reference Example 36 7- (Benzothiazol-2-yl) -7-cyanoheptanoic acid 1) 7- (Benzothiazol-2-yl) -7-cyanoheptanoic acid ethyl malonnitrile (6.61 g), acetic acid To a solution of (60 ml) in ethanol (100 ml) was added o-aminothiophenol (7 ml), and the mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (200 ml) and washed with 5% saline. The organic layer was further added with 3N-sodium hydroxide (200 m
l) and saturated saline (200 ml), and dried. The solvent was distilled off under reduced pressure and the residue was crystallized from IPE to give 2-benzothiazoleacetonitrile (13.8 g). The obtained crystals (10.45 g) were dissolved in DMF (100 ml), 60% sodium hydride (1.44 g) was added under ice cooling, and the mixture was heated to 60 ° C. After stirring for 30 minutes, the mixture was cooled to room temperature and ethyl 6-bromohexanoate (5.31 ml) was added. After reacting at 60 ° C. for 30 minutes, the temperature was cooled to 10 ° C. or lower, and pure water (300 ml) was added. Ethyl acetate (200ml)
2 times, the organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 4: 1) and ethyl 7- (benzothiazol-2-yl) -7-cyanoheptanoate (3.0 g). Got ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2Hz), 1.3
2-1.73 (6H, m), 2.10-2.35 (4H, m), 4.12 (2H, q, J = 7.2Hz),
4.35 (1H, t, J = 7.3Hz), 7.40-7.57 (2H, m), 7.88-7.94 (1
H, m), 8.02-8.04 (1H, m) 2) Then, hydrolysis was carried out in the same manner as in Reference Example 18 to obtain 7- (benzothiazol-2-yl) -7-cyanoheptanoic acid. . ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.76 (6H, m), 2.13-
2.30 (2H, m), 2.37 (2H, t, J = 7.0Hz), 4.38 (1H, t, J = 7.3H
z), 7.40-7.57 (2H, m), 7.87-7.93 (1H, m), 8.03-8.08 (1
H, m)

Reference Example 37 6- (Benzothiazol-2-yl) hexanoic acid 130 ° C. with stirring a mixture of monoethyl pimelic acid (9.41 g), o-aminothiophenol (5.35 ml) and polyphosphoric acid (150 g). The mixture was heated to room temperature and reacted at the same temperature for 2 hours. The mixture was cooled to 40 ° C, pure water (300 ml) was added, and the mixture was stirred at 50 ° C for 30 minutes. After cooling to room temperature, it was extracted with ethyl acetate (500 ml). The organic layer was extracted with 1N-sodium hydroxide solution, acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. After drying, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (4.6 g). Melting point 71-72 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 1.42-1.61 (2H, m), 1.64-
1.81 (2H, m), 1.85-2.00 (2H, m), 2.39 (2H, t, J = 7.3Hz),
3.15 (2H, t, J = 7.7Hz), 7.31-7.50 (2H, m), 7.82-7.87 (1H,
m), 7.97-8.01 (1H, m)

Reference Example 38 7- (Benzothiazol-2-yl) heptanoic acid The title compound was obtained in the same manner as in Reference Example 37. Melting point 62-63 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.52 (4H, m), 1.60-
1.75 (2H, m), 1.83-1.97 (2H, m), 2.36 (2H, t, J = 7.4Hz),
3.13 (2H, t, J = 7.6Hz), 7.35 (1H, td, J = 7.6Hz, 1.3Hz), 7.46
(1H, td, J = 7.6Hz, 1.3Hz), 7.84 (1H, dd, J = 7.6Hz, 1.3Hz),
7.99 (1H, dd, J = 7.6Hz, 1.3Hz)

Reference Example 39 7-Cyano-7- (2-naphthyl) heptanoic acid 1) In the same manner as in Reference Example 17, 7-cyano-7- (2
-Naphthyl) ethyl heptanoate was synthesized. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1Hz), 1.3
2-1.70 (6H, m), 1.92-2.07 (2H, m), 2.28 (2H, t, J = 7.3Hz),
3.95 (1H, t, J = 7.3Hz), 4.11 (2H, q, J = 7.1Hz), 7.40 (1H, d
d, J = 8.5Hz, 1.9Hz), 7.47-7.56 (2H, m), 7.81-7.89 (4H, m) 2) Subsequently, hydrolysis was carried out in the same manner as in Reference Example 18 to obtain 7-cyano- 7- (2-naphthyl) heptanoic acid was obtained. Melting point 88-89 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.47-1.70 (6H, m), 1.93-
2.04 (2H, m), 2.35 (2H, t, J = 7.2Hz), 3.95 (1H, t, J = 7.1H
z), 7.39 (1H, dd, J = 8.8Hz, 1.8Hz), 7.49-7.54 (2H, m), 7.8
0-7.89 (4H, m)

Reference Example 40 7-Ethoxycarbonyl-7- (1-naphthyl) heptanoic acid 1) In the same manner as in Reference Example 17, ethyl 7-ethoxycarbonyl-7- (1-naphthyl) heptanoate was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.5Hz), 1.2
3 (3H, t, J = 7.3Hz), 1.30-1.47 (4H, m), 1.52-1.66 (2H, m),
1.81-1.98 (1H, m), 2.18-2.35 (3H, m), 4.03-4.20 (4H,
m), 4.35 (1H, dd, J = 8.4Hz, 6.2Hz), 7.41-7.58 (4H, m), 7,
76 (1H, brd, J = 7.6Hz), 7.84-7.90 (1H, m), 8.13 (1H, brd, J
= 7.8 Hz) 2) Subsequently, 7-ethoxycarbonyl-7- (1-naphthyl) heptanoic acid was obtained by the same method as in Reference Example 18. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.2Hz), 1.2
4-1.46 (4H, m), 1.48-1.70 (2H, m), 1.77-2.00 (1H, m), 2.
16-2.40 (1H, m), 2.31 (2H, t, J = 7.1Hz), 4.03-4.20 (2H,
m), 4.39 (1H, dd, J = 8.5Hz, 6.7Hz), 7.40-7.58 (4H, m), 7.
77 (1H, brd, J = 7.8Hz), 7.83-7.89 (1H, m), 8.12 (1H, brd, J
= 7.8Hz)

Reference Example 41 1,4-naphthohydroquinone 1,4-naphthoquinone (25 g) was added to ethanol (100 g).
A solution of stannous chloride (368 g) in concentrated hydrochloric acid (150 ml) was gradually added to the suspension at room temperature. After heat generation, the mixture became homogeneous, returned to room temperature, and precipitated crystals were collected by filtration, washed with water and dried to obtain the title compound (18.2 g). Melting point 210-213 ° C

Reference Example 42 6- (4-Methoxyphenyl) -6- (1,4-naphthoquinone-2-yl) hexanoic acid 1,4-naphthohydroquinone (8 g) and 6-hydroxy-6- (4-methoxy) Phenyl) hexanoic acid (1
1.9 g) was reacted in toluene (200 ml) at 80 ° C. in the presence of p-toluenesulfonic acid (3.8 g) for 15 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and concentrated. The residue was dissolved in acetic acid (70 ml) and iron (III) chloride hexahydrate (31 g) (0.1 g) was added.
It was reacted with a 1 mol) aqueous solution (120 ml) at room temperature overnight.
The reaction solution was extracted with ethyl acetate, concentrated, and the residue was purified by silica gel column chromatography. Crystallization from hexane-ethyl acetate gave the title compound (4 g). Melting point 141-143 ° C

Reference Example 43 2-Methyl-1,4-naphthohydroquinone 1,4-diacetate 2-Methyl-1,4-naphthoquinone (50 g) was suspended in acetic anhydride (150 ml), and pyridine (140 ml) was added. Dissolved. While cooling the reaction solution to 0 ° C, zinc powder (2
1 g) was added and reacted at 0 ° C. for 1 hour and at room temperature for 1 hour.
The reaction solution was poured into ice water (700 ml), and the precipitated crystals were collected by filtration, extracted with ethyl acetate, washed with water and dried. The concentrated residue was crystallized from hexane to give the title compound (74 g).
Melting point 95-97 ° C

Reference Example 44 2-Methyl-1,4-naphthohydroquinone 1-monoacetate 2-Methyl-1,4-naphthohydroquinone 1,4-diacetate (74 g) was suspended in methanol (300 ml), and the mixture was allowed to stand at room temperature. 25% aqueous ammonia (22 ml) was added.
The reaction was carried out at 40 ° C. for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, dried, concentrated and purified by silica gel column chromatography. Crystallization from hexane-ethyl acetate gave the title compound (56 g). Melting point 124-126 ° C

Reference Example 45 7- (3-Methyl-1,4-naphthoquinone-2-yl)
-7-Phenylheptanoic acid 2-methyl-1,4-naphthohydroquinone 1-monoacetate (10.8 g) and 7-hydroxy-7-phenylheptanoic acid (11.1 g) in toluene (120 ml) at 50 ° C. And p-toluenesulfonic acid (3.8 g) (20 mmol) was added. After reacting at 50 ° C. for 22 hours, the mixture was extracted with ethyl acetate. After washing with water, concentration under reduced pressure (100 ml) to give iron (III) chloride hexahydrate (27
g) (0.1 mol) aqueous solution (100 ml) was added and the mixture was reacted for 3 days. The reaction solution was extracted with ethyl acetate, and the concentrated residue was purified by silica gel column chromatography. Crystallization from hexane-ethyl acetate gave the title compound (8.1
g) was obtained.

Reference Example 46 The following compound was obtained in the same manner as in Example 1 described later. Reference Example 46-1 7- (1-hydroxy-2-naphthyl) -7-phenylheptanohydroxamic acid Reference Example 46-2 6- (1-hydroxy-2-naphthyl) hexanohydroxamic acid Reference Example 46-37 -(2-Hydroxy-1-naphthyl) heptanohydroxamic acid Reference Example 46-47- (2-Methoxy-1-naphthyl)
Heptanohydroxamic acid Reference Example 46-5 7- (2-naphthyl) heptanohydroxamic acid

Reference Example 47 The following compound was obtained in the same manner as in Example 2 described later. The parenthesized carboxylic acid is shown in the parentheses. Reference Example 47-1 6- (benzothiazol-2-yl)
Hexanohydroxamic Acid (Raw Material: Reference Example 37) Reference Example 47-2 6- (Benzoxazol-2-yl) Hexanohydroxamic Acid (Raw Material: Reference Example 33) Reference Example 47-3 7- (Benzothiazole-2- Ill)
Heptanohydroxamic acid (raw material: reference example 38) Reference example 47-4 6- (1-phenylbenzimidazol-2-yl) hexanohydroxamic acid (raw material: reference example 35) Reference example 47-5 6- (thiazolo [ 5,4-b] Pyridin-2-yl) hexanohydroxamic acid (raw material: Reference Example 34)

Reference Example 48 7- (1-Nitro-2-naphthyl) heptanohydroxamic acid 1) 7- (1-Nitro-2-naphthyl) heptanoic acid Fuming nitric acid (81 ml) was ice-cooled and acetic anhydride (4 0.5 ml) was added dropwise. This was cooled to −78 ° C. and ethyl 7- (2-naphthyl) heptanoate (10 g) in acetic anhydride (20 ml).
The solution was added. Thereafter, the temperature was raised to -20 ° C over 2 hours, ethanol (10 ml) was added dropwise, and the mixture was stirred for 30 minutes as it was. Then, a 2N sodium hydroxide aqueous solution (300 ml) was added under ice cooling, the mixture was stirred for additional 2 hours, and then extracted with ether. The residue (11 g) obtained by washing the organic layer with water, drying and concentrating to dryness was added with a 5N aqueous sodium hydroxide solution (66
ml) and tetrahydrofuran (264 ml) and heated under reflux for 6 hours. Hydrochloric acid was added to the reaction solution to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness, and the resulting residue was recrystallized from hexane-ethyl acetate to obtain 7
-(1-Nitro-2-naphthyl) heptanoic acid (3.4
g) was obtained. Melting point 84-89 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.50 (4H, m) 1.50-1.
80 (4H, m) 2.36 (2H, t, J = 7Hz) 2.74 (2H, t, J = 8Hz) 7.38 (1
H, d, J = 9 Hz) 7.50-7.75 (3H, m), 7.83-7.95 (2H, m) 2) The obtained 7- (1-nitro-2-naphthyl) heptanoic acid (1 g) was used in Reference Example 47. The title compound (0.78 g) was obtained by treating in the same manner as.

Reference Example 49 7- (1-Amino-2-naphthyl) heptanohydroxamic acid 1) 7- (1-Amino-2-naphthyl) heptanoic acid methoxymethyl ester 7- (1-nitro-2-naphthyl) Heptanoic acid (2
g) and triethylamine (2.02 g) in DMF (10 m
l) dissolved in chloromethyl methyl ether (0.802)
g) was added and the mixture was stirred at room temperature for 20 hours. Cold saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. The residue thus obtained was subjected to catalytic hydrogenation reaction at room temperature and atmospheric pressure for 18 hours using 10% palladium carbon (0.23 g) and ethanol (23 ml). The catalyst was filtered off and concentrated under reduced pressure to give 7- (1-amino-2-naphthyl) heptanoic acid methoxymethyl ester (2.1 g). Oil ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.50 (4H, m) 1.55-1.
80 (4H, m), 2.36 (2H, t, J = 7Hz), 2.68 (2H, t, J = 7Hz), 3.45
(3H, s), 4.14 (2H, br), 5.23 (2H, s), 7.21 (1H, d, J = 8Hz),
7.29 (1H, d, J = 8Hz), 7.35-7.50 (2H, m), 7.73-7.86 (2H,
m) 2) The obtained 7- (1-amino-2-naphthyl) heptanoic acid methoxymethyl ester (0.3 g) was added to a 1M hydroxylamine methanol solution (2.85 ml), and the mixture was stirred at room temperature for 1.5 hours. . The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness, and the obtained residue was recrystallized from hexane-ether to give the title compound (0.116 g).

Reference Example 50 7- (1-Mesylamino-2-naphthyl) heptanohydroxamic acid 1) 7- (1-Mesylamino-2-naphthyl) heptanoic acid 7- (1-Amino-2-naphthyl) heptanoic acid methoxy Methyl ester (0.3 g) was dissolved in pyridine (3 ml), mesyl chloride (0.218 g) was added, and the temperature was 50 ° C.
For 2 hours. The reaction solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness, and the resulting residue was heated under reflux with 1N hydrochloric acid (3 ml) and tetrahydrofuran (6 ml) for 1.5 hours, allowed to cool, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. The obtained residue was recrystallized from hexane-diisopropyl ether to give 7- (1-mesylamino-2-naphthyl) heptanoic acid (0.281 g). Melting point 122-127 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.50 (4H, m), 1.55-
1.80 (4H, m), 2.35 (2H, t, J = 7Hz) 3.00 (2H, t, J = 8Hz) 3.08
(3H, s) 6.82 (1H, s) 7.40-7.70 (3H, m) 7.88-7.90 (2H, m)
8.17 (1H, d, J = 8Hz) The title compound was obtained from the obtained 7- (1-mesylamino-2-naphthyl) heptanoic acid (0.15 g) in the same manner as in Example 1 described later.

Reference Example 51 7- (1-Tosylamino-2-naphthyl) heptanohydroxamic acid 7- (1-Amino-2-naphthyl) heptanoate Same as Reference Example 50 using methoxymethyl and tosyl chloride. By the method, 7- (1-tosylamino-2-naphthyl) heptanoic acid was obtained. Melting point 128-133 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.70 (8H, m) 2.35 (2
H, t, J = 7Hz) 2.40 (3H, s) 2.57 (2H, t, J = 8Hz) 6.75 (1H, s)
7.13-7.43 (5H, m) 7.54 (2H, d, J = 8Hz) 7.70-7.80 (3H, m) The obtained 7- (1-tosylamino-2-naphthyl) heptanoic acid was used as Example 1 described later. The same treatment was performed to obtain the title compound.

Reference Example 52 6- (4-methoxyphenyl) -6- (3-methyl-
1,4-naphthoquinone-2-yl) hexanohydroxamic acid 1) 1,4-dimethoxy-2-methylnaphthalene 2-methyl-1,4-naphthoquinone 125 g was dissolved in 1250 ml of heated ethanol, and 500 ml of concentrated hydrochloric acid was dissolved therein.
500 g of stannous chloride dissolved in was added at room temperature.
Further, 2100 ml of water was added and the precipitated crystals were collected by filtration, washed with water,
Dried. The obtained crystals were dissolved in 1000 ml of ethanol, and 145 ml of 12N sodium hydroxide aqueous solution was added thereto at 30 ° C.
Added over time. The reaction mixture was heated under reflux for 3 hours, concentrated and extracted with ether to obtain 113 g of 1,4-dimethoxy-2-methylnaphthalene as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.85 (3H, s),
3.95 (3H, s), 6.59 (1H, s), 7.22-7.56 (2H, m), 8.02 (1H,
d, J = 8Hz), 8.19 (1H, d, J = 8Hz) 2) 1,4-dimethoxy-3-methylnaphthalene-2
113 g of -carbaldehyde 1,4-dimethoxy-2-methylnaphthalene was dissolved in 330 ml of methylene chloride, 123 ml of titanium tetrachloride was added at 0 ° C, and 48 ml of dichloromethyl methyl ether was added over 30 minutes. After the addition, the mixture was stirred at room temperature for 3 hours, poured into ice water and separated. The organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate). 75 g of the title compound was obtained. Melting point 89-91 ° C

3) 6- (1,4-dimethoxy-3-methylnaphthalen-2-yl) -5-hexenoic acid 1,4-dimethoxy-3-methylnaphthalene-2-carbaldehyde 1 g and (4-carboxoxy) Butyl) triphenylphosphonium bromide (3.85 g) at 2.5% t-
1.95 g of potassium t-butoxide was added while suspending in butanol / toluene at 60 ° C. 60 reaction mixture
After stirring at 30 ° C. for 30 minutes, the mixture was extracted with 1N aqueous sodium hydroxide solution and washed with toluene. The aqueous layer was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and then purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate). The desired product (0.9 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.98 (2H, m), 2.24-
2.57 (7H, m), 3.77 (s, O-Me of Z isomer), 3.81 (s, O-Me o
f E isomer), 3.87 (s, O-Me of E isomer), 3.88 (s, O-Me
of Z isomer), 5.86 (dt, J = 11Hz, 7Hz, olefinic H of Z
isomer), 6.21 (dt, J = 16Hz, 6.8Hz, olefinic H of E isom
er), 6.43 (d, J = 11Hz, olefinic H of Z isomer), 6.54
(d, J = 16Hz, olefinic H of E isomer), 7.42-7.50 (2H,
m), 8.00-8.13 (2H, m) 4) Methyl 6- (1,4-dimethoxy-3-methylnaphthalen-2-yl) -6- (4-hydroxyphenyl) hexanoate 6- (1,4- Dimethoxy-3-methylnaphthalene-2
2-yl) -5-hexenoic acid (25.6 g) and phenol (23 g) were dissolved in methylene chloride (250 ml), and boron trifluoride diethyl ether complex (20.6 ml) was added at 0 ° C.
The reaction solution was stirred at room temperature for 24 hours, poured into ice water and separated. The organic layer was washed with water, dried and concentrated, and the residue was added with methanol 4
It was dissolved in 00 ml and 8 ml of concentrated hydrochloric acid was added. The reaction mixture was stirred at 60 ° C for 1 hr, the solvent was concentrated, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate). 20.5 g of the title compound was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.82 (4H, m), 2.05-
2.43 (7H, m), 3.46-3.70 (6H, br), 3.84 (3H s), 4.57-4.8
4 (1H, br), 5.35 (1H, s), 6.71 (2H, d, J = 8.4Hz), 7.09 (2H,
d, J = 8.4Hz), 7.40-7.53 (2H, m), 7.97-8.10 (2H, m)

5) Methyl 6- (1,4-dimethoxy-3-methylnaphthalen-2-yl) -6- (4-methoxyphenyl) hexanoate 6- (1,4-dimethoxy-3-methylnaphthalene-2)
20.5 g of methyl -yl) -6- (4-hydroxyphenyl) hexanoate was dissolved in 200 ml of DMF, and 16 g of potassium carbonate and 10 ml of methyl iodide were added at 0 ° C. The reaction was carried out at 50 ° C for 16 hours, and the reaction solution was extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated, and the residue is subjected to silica gel column chromatography (developing solvent: hexane /
It was purified with ethyl acetate). 16.7 g of the title compound was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.08-1.81 (4H, m), 2.05-
2.50 (7H, m), 3.52-3.73 (6H, br), 3.77 (3H, s), 3.84 (3H,
s), 4.66-4 87 (1H, br), 6.81 (2H, d, J = 8.9Hz), 7.17 (2H,
d, 8.9Hz), 7.41-7.52 (2H, m), 7.98-8.11 (2H, m) 6) 6- (1,4-dimethoxy-3-methylnaphthalen-2-yl) -6- (4-methoxy Phenyl) hexanoic acid 6- (1,4-dimethoxy-3-methylnaphthalene-2
Methyl (17.6 g) of (-yl) -6- (4-methoxyphenyl) hexanoate was dissolved in 80 ml of methanol, and 53 ml of 3N aqueous sodium hydroxide solution was added at 60 ° C. The reaction solution was stirred at 60 ° C. for 1 hour, and the solvent was concentrated. The residue was neutralized, extracted with ethyl acetate, washed with water, dried and concentrated to obtain 17.5 g of the desired product as a syrup. ¹ H-NMR (CDCl ₃ ) δ: 1.08-1.80 (4H, m), 2.04-
2.51 (7H, m), 3.48-3.73 (3H, br), 3.77 (3H, s), 3.84 (3H,
s), 4.65-4.88 (1H, br), 6.80 (2H, d, J = 8.8Hz), 7.16 (2H,
d, J = 8.8Hz), 7.41-7.54 (2H, m), 7.97-8.11 (2H, m)

7) 6- (4-methoxyphenyl) -6
-(3-Methyl-1,4-naphthoquinone-2-yl) hexanoic acid 6- (1,4-dimethoxy-3-methylnaphthalene-2
-Yl) -6- (4-methoxyphenyl) hexanoic acid 1
4.7 g of acetonitrile was dissolved in 300 ml of acetonitrile, 57.2 g of cerium (IV) ammonium sulfate was dissolved in 147 ml of water, and the mixture was added at 0 ° C. over 5 minutes. 16 at room temperature
After reacting for a time and extracting with ethyl acetate, the organic layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 10.8 g of the title compound. Melting point 68-71 ° C. 8) 6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid 6- (4-methoxyphenyl) -6- (3 -Methyl-
1,4-naphthoquinone-2-yl) hexanoic acid 10.8 g
Was suspended in 250 ml of toluene and oxalyl chloride 1 was added.
0.2 ml was added and reacted at 50 ° C. for 1 hour. The reaction solution was concentrated and the residue was dissolved in 140 ml of dry THF. Hydroxylamine hydrochloride (5.2 g) was dissolved in saturated aqueous sodium hydrogencarbonate solution (140 ml), and the THF solution of the above acid chloride was added in an ice-water bath. The mixture was reacted at 0 ° C for 1 hour and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate-ethyl acetate). Recrystallization from hexane / ethyl acetate gave 7.9 g of the title compound. Melting point 129-130 ° C

Reference Example 53 6- (4-methoxyphenyl) -6- (3-methyl-
1,4-naphthoquinone-2-yl) hexanoic acid 1) 1-methoxy-3-methyl-2-naphthonitrile 1-hydroxy-3-methyl-2-naphthonitrile (4
7.23 g), potassium carbonate (71.3 g), methyl iodide (110 ml) and DMF (250 ml) were mixed, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into cold water and extracted with ether. After washing and drying the organic layer, the resulting residue is washed with water.
Recrystallization from methanol gave the title compound (50 g). ¹ H-NMR (CDCl ₃ ) δ: 2.63 (3H, s), 4.25 (3H, s),
7.45 (1H, s), 7.45-7.65 (2H, m), 7.77 (1H, dd, J = 8.0Hz, 1
Hz), 8.15 (1H, dd, J = 8.0Hz, 1Hz) 2) 1-methoxy-3-methyl-2-naphthaldehyde 1-methoxy-3-methyl-2-naphthonitrile (50
g) was dissolved in toluene (500 ml), a diisobutylaluminum hydride / toluene solution (0.38 mol) was added dropwise at -40 ° C cooling, and the mixture was stirred for 1 hour under ice cooling. After the reaction, the mixture was poured into cold water, concentrated hydrochloric acid (210 ml) was added, and the mixture was stirred at 70 ° C. for 5 hours. After allowing to cool, separate the organic layer,
The title compound (38.56 g) was obtained by washing and drying. This product was subjected to the next reaction without purification. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 4.10 (3H, s),
7.42 (1H, s), 7.45-7.65 (2H, m), 7.77 (1H, d, J = 7.6Hz),
8.19 (1H, d, J = 8.0Hz), 10.76 (1H, s)

3) 6- (1-Methoxy-3-methylnaphthalen-2-yl) -5-hexenoic acid 1-methoxy-3-methyl-2-naphthaldehyde (4
1.7 g), 4-carboxybutyltriphenylphosphonium bromide (184.4 g), 2.5% t-butanol / toluene solution (1251 ml) were mixed and mixed to obtain 60
Potassium t-butoxide (103 g) was added at ℃.
The mixture was stirred as it was for 30 minutes, allowed to cool, and then poured into cold water. The mixture was acidified with hydrochloric acid, extracted with ethyl acetate, washed and dried. The obtained residue was treated with potassium carbonate (200 g) and methyl iodide (8
0 ml) and DMF (500 ml) and stirred at room temperature overnight. The reaction mixture was poured into cold water and extracted with diisopropyl ether. The organic layer was washed and dried, and a sufficient amount of 20% ether / hexane was added to the obtained residue to precipitate triphenylphosphine oxide, which was then filtered off. The concentrated residue of the filtrate was dissolved in ethanol (482 ml), 2.5N aqueous sodium hydroxide solution (482 ml) was added, and the mixture was heated under reflux for 6 hr. Ethanol was distilled off under reduced pressure, acidified with hydrochloric acid, extracted with ethyl acetate, washed and dried to obtain the title compound. This product was subjected to the next reaction without purification. 4) Ethyl 6- (4-hydroxyphenyl) -6- (1-methoxy-3-methylnaphth-2-yl) hexanoate 6- (1-Methoxy-3-methylnaphthalen-2-yl) -5-hexenoic acid Thing (70g), phenol (70
g) was dissolved in methylene chloride (500 ml), and boron trifluoride ether complex (95 g) was added dropwise. 3 at 35 ° C
After stirring for a day, cold water was added to separate the organic layer. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed and dried. The concentrated residue was subjected to a silica gel column (toluene → 20% ethyl acetate / hexane → ethyl acetate) to give the title compound (30 g). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2Hz), 1.1
0-1.80 (4H, m), 2.05-2.45 (7H, m), 3.60 (3H, br), 4.06 (2
H, q, J = 7.2Hz), 4.60-4.75 (1H, m), 6.73 (2H, d, J = 8.0Hz),
7.11 (2H, d, J = 8.0Hz), 7.35-7.50 (3H, m), 7.68-7.76 (1
H, m), 7.93-8.03 (1H, m)

5) 6- (4-methoxyphenyl) -6
-(1-Methoxy-3-methylnaphth-2-yl) hexanoic acid Ethyl 6- (4-hydroxyphenyl) -6- (1-methoxy-3-methylnaphth-2-yl) hexanoate (3
0 g), potassium carbonate (90 g), methyl iodide (45
ml) and DMF (150 ml) were mixed and stirred overnight at room temperature. The reaction mixture was poured into cold water and extracted with IPC. The organic layer was washed, dried, and concentrated. The residue is ethanol (2
50 ml), 2.5N aqueous sodium hydroxide solution (250 ml) was added, and the mixture was heated under reflux for 5 hours. Ethanol was distilled off under reduced pressure, acidified with hydrochloric acid, extracted with ethyl acetate, washed and dried to obtain the title compound (25 g). ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.85 (4H, m), 2.05-
2.50 (7H, m), 3.61 (3H, br), 3.77 (3H, s), 4.65-4.80 (1H,
m), 6.80 (2H, d, J = 8.8Hz), 7.17 (2H, d, J = 8.8Hz), 7.38-
7.50 (3H, m), 7.69-7.78 (1H, m), 7.95-8.05 (1H, m) 6) 6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2- Yl) hexanoic acid 6- (4-methoxyphenyl) -6- (1-methoxy-
3-Methylnaphth-2-yl) hexanoic acid (27 g) was dissolved in 90% acetic acid (135 ml), and a solution of chromic anhydride (34.4 g) in water (34.4 ml) was added dropwise under ice cooling. After stirring for 30 minutes as it is, 2-propanol (20 ml)
Was added. An excess amount of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed and dried, and the obtained residue was subjected to a silica gel column (toluene → hexane-ethyl acetate) and recrystallized from diisopropyl ether to give the title compound.

Example 1 7- (2-Hydroxy-1-naphthyl) -7-phenylheptanohydroxamic acid (Compound 1-1) Hydroxylamine hydrochloride (1.4 g) was added to water (14 ml).
And was added to a solution of sodium hydroxide (93%, 2 g) in water (7 ml). A solution of 7- (2-hydroxy-1-naphthyl) -7-phenylheptanoic acid ethyl ester (1.08 g) in tetrahydrofuran (3 ml) was added thereto, and the mixture was stirred for 4 hours. The reaction solution was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. Wash and dry the organic layer,
The concentrated residue was subjected to a silica gel column (chloroform-methanol) to give the title compound (0.4 g). Similarly, the following compound was obtained. Compound 1-2: 7- (1-hydroxy-2-naphthyl)
-7-Phenylheptanohydroxamic acid compound 1-3: 7- (2-quinolyl) heptanohydroxamic acid compound 1-4: (Z) -7- (2-quinolyl) -6-heptenohydroxamic acid compound 1- 5: (E) -7- (2-quinolyl) -6-heptenohydroxamic acid compound 1-6: 6- (1-isoquinolyl) hexanohydroxamic acid (raw material compound: reference example 32) compound 1-7: 7 -(1-Isoquinolyl) heptanohydroxamic acid (raw material compound: Reference Example 31)

Example 2 6- (2-quinolyl) hexanohydroxamic acid (Compound 2-1) 6- (2-quinolyl) hexanoic acid (1.2 g) obtained in Reference Example 14 and 1 drop of DMF in dichloromethane ( Oxalyl chloride (1.0 ml) under ice cooling,
The temperature was raised to room temperature and stirring was continued for 15 minutes. The solvent was distilled off, and the obtained crude crystals were filtered and washed with hexane. A solution of these crystals dissolved in dichloromethane (30 ml) was added dropwise to a saturated sodium hydrogencarbonate solution (30 ml) of hydroxylamine hydrochloride (1.0 g) under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for 2 hours as it was. . The reaction mixture was neutralized with 3N-hydrochloric acid, and the precipitated crystals were filtered, washed with water and ether, and dried under reduced pressure. The obtained crude crystals were recrystallized from methanol-ether to give the title compound (0.34).
g) was obtained. Similarly, the following compound was obtained. The parenthesized after the compound name indicates the carboxylic acid as the raw material. Compound 2-2: (E) -6- (2-quinolyl) -5-hexenohydroxamic acid Compound 2-3: 6- (4-quinolyl) hexanohydroxamic acid Compound 2-4: 7- (4-quinolyl ) Heptanohydroxamic acid compound 2-5: 8- (4-isoquinolyl) octanohydroxamic acid compound 2-6: 6- (4-chlorophenyl) -6- (3
-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 2-7: 6- (3-quinolyl) hexanohydroxamic acid (raw material: Reference Example 19) compound 2-8: 7- (3- Quinolyl) heptanohydroxamic acid (raw material: reference example 20) compound 2-9: 7- (6-methoxy-2-quinolyl) heptanohydroxamic acid (raw material: reference example 21) compound 2-10: 6-phenyl-6 -(2-quinolyl)
Hexanohydroxamic acid (raw material: Reference Example 23) Compound 2-11: 7-phenyl-7- (2-quinolyl)
Heptanohydroxamic acid (Raw material: Reference Example 22) Compound 2-12: 7-cyano-7- (2-naphthyl) heptanohydroxamic acid (Raw material: Reference Example 39) Compound 2-13: 7-Ethoxycarbonyl-7- (1-
Naphthyl) heptanohydroxamic acid (raw material: Reference Example 4)
0) Compound 2-14: 7- (Benzothiazol-2-yl)
-7-Cyanoheptanohydroxamic acid (raw material: Reference Example 3
6)

Example 3 6-Cyano-6- (1-naphthyl) hexanohydroxamic acid (Compound 3-1) 6-Cyano-6- (1-naphthyl) hexanoic acid (4.0
g) (15 mmol) in THF (8.5 ml) -DMF (0.1
ml) and dissolve at room temperature in oxalyl chloride (3.2 m
l) (37.5 mmol) was added dropwise. After stirring for 15 minutes, excess oxalyl chloride was distilled off under reduced pressure. The residue was dissolved in dichloromethane (63 ml) and hydroxylamine hydrochloride (3.13 g) (45 mmol) in saturated sodium bicarbonate solution (63 m).
l) was added under ice cooling. After reacting for 2 hours at room temperature, it was made weakly acidic with concentrated hydrochloric acid to obtain an organic layer. The extract was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate and purified by silica gel column chromatography (hexane-ethyl acetate, 1: 9) to give the title compound (4.08 g) as a colorless oil (yield 9
6.3%). Similarly, the following compound was obtained. Compound 3-2: 7-cyano-7- (1-naphthyl) heptanohydroxamic acid

Example 4 6-Benzoylamino-6- (2-naphthyl) hexanohydroxamic acid (Compound 4-1) Ethyl 6-benzoylamino-6- (2-naphthyl) hexanoate (Reference Example 25) (0 0.8g) and hydroxylamine hydrochloride (0.71g) in methanol (4.2m)
A methanol solution of 4.9N sodium methoxide (4.9 ml) was added to (l) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The residue was acidified with 3N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to give the title compound (0.3
2 g) were obtained. The following compounds were obtained by the same method. Compound 4-2: 6-Acetylamino-6- (2-naphthyl) hexanohydroxamic acid (raw material: Reference Example 26) Compound 4-3: 6-methanesulfonylamino-6- (2
-Naphthyl) hexanohydroxamic acid (raw material: Reference Example 2)
8) Compound 4-4: 6-benzenesulfonylamino-6-
(2-Naphthyl) hexanohydroxamic acid (raw material: Reference Example 29) Compound 4-5: 6- (4-methylbenzenesulfonylamino) -6- (2-naphthyl) hexanohydroxamic acid (raw material: Reference Example 27) Compound 4-6: 6- (4-fluorobenzenesulfonylamino) -6- (2-naphthyl) hexanohydroxamic acid (raw material: Reference Example 30)

Example 5 7- (4-methoxyphenyl) -7- (3-methyl-
1,4-naphthoquinone-2-yl) heptanohydroxamic acid (Compound 5) 7- (4-methoxyphenyl) -7- (3-methyl-
1,4-naphthoquinone-2-yl) heptanoic acid (2 g)
(5.3 mmol) was converted to the corresponding acid chloride with oxalyl chloride (3 ml) (35 mmol) in toluene (50 ml), which was used as a solution in tetrahydrofuran (30 ml) and hydroxylamine hydrochloride (1.14 g) (16 mmol).
-Drop to saturated aqueous sodium hydrogen carbonate solution (30 ml). After completion of the reaction, the residue was extracted with ethyl acetate and the concentrated residue was purified by silica gel column chromatography to obtain the title compound (15.7 g).

Example 6 7- (3-Methyl-1,4-naphthoquinone-2-yl)
-7-Phenylheptanohydroxamic acid (compound 6-
1) 7- (3-methyl-1,4-naphthoquinone-2-yl)
-7-Phenylheptanoic acid (8.1 g) (22 mmol) in toluene (200 ml) oxalyl chloride (12 m).
l) (0.14 mol) converted to the corresponding acid chloride,
This was used as a tetrahydrofuran (120 ml) solution and added dropwise to hydroxylamine hydrochloride (4.6 g) (65 mmol) -saturated aqueous sodium hydrogen carbonate solution (120 ml). After completion of the reaction, the mixture was extracted with ethyl acetate and the concentrated residue was purified by silica gel column chromatography to give the title compound (7.0
g) was obtained. Similarly, the following compound was obtained. Compound 6-2: 6- (4-methoxyphenyl) -6-
(1,4-naphthoquinone-2-yl) hexanohydroxamic acid (raw material compound: 6- (4-methoxyphenyl)-
6- (1,4-naphthoquinone-2-yl) hexanoic acid)

Example 7 1) O-Acetyl-6- (4-methoxyphenyl)-
6- (3-methyl-1,4-naphthoquinone-2-yl)
Hexanohydroxamic acid (Compound 7-1) 6- (4-methoxyphenyl) -6- (3-methyl-
1,4-naphthoquinone-2-yl) hexanohydroxamic acid (215 mg) and pyridine (125 mg) were added to THF (1
ml), acetic anhydride (56 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ether, washed successively with 1N hydrochloric acid, saturated brine and saturated aqueous sodium hydrogen carbonate, dried and concentrated under reduced pressure. The residue was applied to a silica gel column and developed with hexane: ethyl acetate (1: 1) to obtain the desired product (150 mg). Similarly, the following compound was obtained. Compound 7-2: O-acetyl-7- (3,5,6-trimethylbenzoquinon-2-yl) -7-phenylheptanohydroxamic acid Compound 7-3: O-acetyl-7- (1-hydroxy-
2-naphthyl) heptanohydroxamic acid compound 7-4: O-acetyl-6- (2-quinolyl) hexanohydroxamic acid compound 7-5: O-propionyl-7- (3,5,6-trimethylbenzoquinone-2) -Yl) -7-phenylheptanohydroxamic acid compound 7-6: O-propionyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid Compound 7-7: O-propionyl-6- (2-quinolyl) hexanohydroxamic acid Compound 7-8: O-propionyl-7-cyano-7-
(1-naphthyl) heptanohydroxamic acid compound 7-9: O-isovaleryl-7- (3,5,6-trimethylbenzoquinon-2-yl) -7-phenylheptanohydroxamic acid compound 7-10: O-isobutyryl -6- (4-Methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 7-11: O-isobutyryl-7- (3,5,6-
Trimethylbenzoquinon-2-yl) -7-phenylheptanohydroxamic acid compound 7-12: O-benzoyl-7-cyano-7-
(1-Naphthyl) heptanohydroxamic acid compound 7-13: O-benzoyl-6-cyano-6-
(1-naphthyl) hexanohydroxamic acid compound 7-14: O-benzoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 7-14 -15: O-benzoyl-7- (3,5,6-trimethylbenzoquinon-2-yl) -7-phenylheptanohydroxamic acid Compound 7-16: O-benzoyl-6- (2-quinolyl) hexanohydroxam Acid compound 7-17: O-pivaloyl-7- (3,5,6-trimethylbenzoquinone-2-yl) -7-phenylheptanohydroxamic acid compound 7-18: O-cyclohexylcarbonyl-7-
(3,5,6-Trimethylbenzoquinon-2-yl) -7
-Phenylheptanohydroxamic acid 2) O-propionyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2
-) Hexanohydroxamic acid (Compound 7-6) 6- (4-methoxyphenyl) -6- (3-methyl-
A solution of 1,4-naphthoquinon-2-yl) hexanohydroxamic acid (2.8 g) in THF (40 ml) was cooled with ice and triethylamine (1.4 ml) and propionyl chloride (66 ml) were added.
9 mg) were added sequentially. After stirring for 1 hour, the mixture was transferred to water / ethyl acetate, the organic layer was dried and concentrated. Silica gel chromatography of the residue (developing solvent: hexane / ethyl acetate)
The title compound (2.1 g) was obtained.

Example 8 O-ethylcarbamoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-
Hexanohydroxamic acid (Compound 8-1) 6-
(4-Methoxyphenyl) -6- (3-methyl-1,4
To a THF solution of -naphthoquinone-2-yl) hexanohydroxamic acid (0.5 g) was added a solution of ethyl isocyanate (0.1 g) in THF (2 ml) at room temperature, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1). The obtained oily substance was crystallized from hexane to obtain the desired product (0.29 g). Similarly, the following compound was obtained. Compound 8-2: O-ethylcarbamoyl-6- (2-quinolyl) hexanohydroxamic acid Compound 11-11: O-carbamoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4- Naphthoquinone-2-yl) hexanohydroxamic acid compound 11-16: O-ethylcarbamoyl-7- (3
-Methyl-1,4-naphthoquinone-2-yl) -7-phenylheptanohydroxamic acid

Example 9 The following compound was obtained in the same manner as in Example 7. The parentheses after the compound name indicate the raw material used. Compound 9-1: O-benzoyl-7- (1-isoquinolyl) heptanohydroxamic acid (raw material: compound 1-7) Compound 9-2: O-propionyl-7- (1-isoquinolyl) heptanohydroxamic acid (raw material : Compound 1-7) Compound 9-3: O-benzoyl-7- (1-naphthyl)
Heptanohydroxamic acid compound 9-4: O-propionyl-7- (1-naphthyl) heptanohydroxamic acid compound 9-5: O-acetyl-6- (1-naphthyl) hexanohydroxamic acid compound 9-6: O -Acetyl-6- (benzothiazole-2
-Yl) hexanohydroxamic acid (raw material: Reference Example 47-
2) Compound 9-7: O-propionyl-6- (1-naphthyl) hexanohydroxamic acid Compound 9-8: O-propionyl-6- (benzothiazol-2-yl) hexanohydroxamic acid (raw material: reference example 47-3) Compound 9-9: O-benzoyl-6- (benzothiazol-2-yl) hexanohydroxamic acid (raw material: Reference Example 47-1) Compound 9-10: O-acetyl-7-cyano- ( 2-naphthyl) heptanohydroxamic acid (raw material: compound 2-1
2) Compound 9-11: O-propionyl-7-cyano-7-
(2-Naphthyl) heptanohydroxamic acid (raw material: compound 2-12) compound 9-12: O-benzoyl-7-cyano-7-
(2-Naphthyl) heptanohydroxamic acid (raw material: compound 2-12) Compound 9-13: O-benzoyl-6- (benzoxazol-2-yl) hexanohydroxamic acid (raw material: Reference Example 47-2) Compound 9-14: O-benzoyl-7- (benzothiazol-2-yl) heptanohydroxamic acid (raw material: Reference Example 47-3) Compound 9-15: O-propionyl-6- (benzoxazol-2-yl) Hexanohydroxamic acid (raw material:
Reference Example 47-2) Compound 9-16: O- (2-acetoxybenzoyl)-
7- (Benzothiazol-2-yl) heptanohydroxamic acid (raw material: Reference Example 47-3) Compound 9-17: O- (2-acetoxybenzoyl)-
6- (Benzoxazol-2-yl) hexanohydroxamic acid (raw material: Reference Example 47-1) Compound 9-18: O-propionyl-7-ethoxycarbonyl-7- (1-naphthyl) heptanohydroxamic acid (raw material : Compound 2-13) Compound 9-19: O-acetyl-7- (2-quinolyl)
Heptanohydroxamic acid (raw material: compound 1-3) Compound 9-20: O-propionyl-7- (2-quinolyl) heptanohydroxamic acid (raw material: compound 1-3) Compound 9-21: O-hexanoyl-7 -(2-quinolyl) heptanohydroxamic acid (raw material: compound 1-3) Compound 9-22: O-benzoyl-7- (2-quinolyl) heptanohydroxamic acid (raw material: compound 1-3) Compound 9-23 : O- (4-fluorobenzoyl) -7
-(2-quinolyl) heptanohydroxamic acid (raw material: compound 1-3) Compound 9-24: O- [2- (4-isobutylphenyl) propionyl] -7- (2-quinolyl) heptanohydroxamic acid (raw material : Compound 1-3)

Example 10 O-hexanoyl-7- (1-nitro-2-naphthyl)
Heptanohydroxamic acid (Compound 10) Treated as in Example 7 with 7- (1-nitro-2-naphthyl) heptanohydroxamic acid (0.7 g),
The title compound (0.54 g) was obtained.

Example 11 O-propionyl-5- (3-methyl-1,4-naphthoquinone-2-yl) -5-phenylpentanohydroxamic acid (Compound 11-1) 5- (3-methyl-1, 4-naphthoquinone-2-yl)
Treatment with -5-phenylpentanohydroxamic acid as in Example 7 gave the title compound. Similarly, the following compound was obtained. Compound 11-2: O-acetyl-6- (3-methyl-
1,4-naphthoquinone-2-yl) -6-phenylhexanohydroxamic acid compound 11-3: O-propionyl-6- (3-methyl-1,4-naphthoquinone-2-yl) -6-phenylhexano Hydroxamic acid compound 11-4: O-benzoyl-6- (3-methyl-
1,4-naphthoquinone-2-yl) -6-phenylhexanohydroxamic acid compound 11-5: O-acetyl-6- (4-fluorophenyl) -6- (3,5,6-trimethyl-1,4- Benzoquinone-2-yl) hexanohydroxamic acid compound 11-6: O-propionyl-6- (4-fluorophenyl) -6- (3,5,6-trimethyl-1,4-
Benzoquinone-2-yl) hexanohydroxamic acid compound 11-7: O-hexanoyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 11-8: O-cyclohexanecarbonyl-6-
(4-Methoxyphenyl) -6- (3-methyl-1,4
-Naphthoquinone-2-yl) hexanohydroxamic acid compound 11-9: O-diphenylacetyl-6- (4-
Methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 11-10: O- (3,3-diphenylpropionyl) -6- (4-methoxyphenyl)- 6- (3-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 11-12: O-propionyl-7- (4-methoxyphenyl) -7- (3-methyl-1,4- Naphthoquinone-2-yl) heptanohydroxamic acid compound 11-13: O-benzoyl-7- (4-methoxyphenyl) -7- (3-methyl-1,4-naphthoquinon-2-yl) heptanohydroxamic acid compound 11-14: O-propionyl-7- (3-methyl-1,4-naphthoquinone-2-yl) -7-phenylheptanohydroxamic acid compound 11-15: O- Nazoyl-7- (3-methyl-1,4-naphthoquinone-2-yl) -7-phenylheptanohydroxamic acid compound 11-17: O-propionyl-7- (4-fluorophenyl) -7- (3- Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid compound 11-18: O-benzoyl-7- (4-fluorophenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl ) Heptanohydroxamic acid compound 11-19: O-propionyl-6- (4-methoxyphenyl) -6- (1,4-naphthoquinone-2-yl) hexanohydroxamic acid compound 11-20: O-benzoyl-6 -(4-Methoxyphenyl) -6- (1,4-naphthoquinone-2-yl) hexanohydroxamic acid

The structural formulas and NMR spectra of the compounds obtained in the above Reference Examples and Examples are shown in the following table.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[0119]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[0120]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[0121]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[0122]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[0123]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

Formulation Example 1 A) Capsules (1) Compound 7-9 50 mg (2) Fine powder cellulose 30 mg (3) Lactose 37 mg (4) Magnesium stearate 3 mg Total 120 mg (1), (2), (3) and (4) was mixed and filled in a gelatin capsule. B) Soft capsule (1) Compound 7-10 50 mg (2) Corn oil 100 mg Total 150 mg These were mixed according to a conventional method and filled into a soft capsule. C) Tablets (1) Compound 7-8 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg These were mixed according to a conventional method and tableted using a tablet machine. Formulation Example 2 (1) Compound 7-6 10.0 g (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g Obtained in Example 7. A mixture of 10.0 g of the compound, 60.0 g of lactose and 35.0 g of corn starch was used in 30 ml of a 10% by weight aqueous gelatin solution (3.0 g as gelatin).
After granulating through a sieve of mm mesh, it was dried at 40 ° C. and sieved again. The granules obtained were mixed with 2.0 g of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain 1000 coated tablets.

Experimental Example 1 Inhibitory Effect on Lipopolysaccharide (LPS) -Induced Cell Degeneration in Rat Cerebral Cell Mixed Culture System (LIC Assay Method) A mixed cell culture system derived from rat cerebrum was subjected to glial treatment by the following method. Compounds that suppress cytopathicity induced by the addition of LPS, which is known to activate cells (astrocytes, microglia), were screened. [Experimental Method] (1) Mixed Culture of Neonatal Rat Cerebral Cells Brains were collected from neonatal Crj: CD (SD) rats (1 to 3 days old, Charles River Japan Co., Ltd.) and ice-cooled D-
MEM / 10% FCS (10% fetal calf serum, penicillin: 100 units / ml and streptomycin: 10
Dulbecco's cell culture basal medium containing 0 μg / ml)
I put it inside. Hereinafter, cerebral cell mixed culture was started by the following procedure. 1. The cerebrum portion of the collected brain was taken and the meninges were peeled off under a stereoscopic microscope. 2. Nerve mesh (100-2
(00 μm) and rubbed with a rubber policeman. 3. The cells were washed 3 times (1000 rpm, 8 minutes) by centrifugation with ice-cooled D-MEM / 10% FCS, and then Cell Strainer
The cell suspension was strained with (40 μm mesh, Falcon 2340) and the number of viable cells was counted by the trypan blue method. 4. Tissue culture flask (96-well microplate, Nun
In c), each well was seeded at a cell concentration of 1 × 10 ⁵ cells / 100 μl / well. 5.1 weeks later, 100 μl of D-MEM / 1 was added to each well.
0% FCS was added. 6. After further culturing for about 1 to 2 weeks, the following inhibitory effect evaluation was carried out.

(2) Inhibitory action evaluation method 1. Rat cerebral cell mixed culture of the above (1) (start 2-3
After a week), the medium in each well of the 96-well microplate was discarded and 50 μl of D-MEM / 2% FCS was added instead. 2.25 μl sample and 25 μl LPS at appropriate concentration
(Difco, E. coli 011: B4, Bacto) is added to each well. The medium used was D-MEM / 2% FCS. In addition, as a sample, DMSO was used to prepare a 10 ⁻² M solution using the compounds shown in [Table 32] below, and DM
It was diluted with EM / 2% FCS and used for the assay. 3. After culturing for an appropriate number of days (usually 4 to 5 days), the degree of cell degeneration was measured by microscope observation and the MTT method. (3) MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-dip
henyltetrazolium bromide] method 10 μl of MTT (5 mg / ml, manufactured by Sigma) dissolved in phosphate buffered saline was added to each well. After culturing for 4 to 6 hours (37 ° C, under 10% carbon dioxide gas phase), 10% SD
100 μl of 0.01N hydrochloric acid solution containing S was added to each well.
Add and dissolve the formed formazan. After completely dissolving, the absorbance (wavelength 540 to 590 nm) of each well was measured. By calculating the recovery rate from the formula below and plotting the concentration of the compound that gives a recovery rate of 50% in the graph,
The ED ₅₀ value was determined. Recovery rate (%) = (C−B) × 100 / (A−B) [A: Absorbance of control well containing only medium at wavelength of 550 nm B: Absorbance of LPS-added well at wavelength of 550 nm C: At wavelength of 550 nm Absorbance of wells to which LPS and compound were added]

[Experimental Results] The results are shown in [Table 32] below.

Table 32 Compound number ED ₅₀ value (μM) Compound A 0.02 Compound B 0.5 Compound C 0.3 Compound D 0.1 Compound E 0.6 Reference Example 46-1 0.05 Reference Example 46-2 0.5 Compound 1-3 0.02 Compound 1-4 0.04 Compound 7-1 0.05 Compound 7-2 0.05 Compound 7-3 0.4 Compound 7-4 0.4 Compound 7-50 .05 Compound 7-6 0.05 Compound 7-7 0.5 Compound 7-8 0.03 Compound 7-9 0.2 Compound 7-10 0.3 Compound 7-11 0.2 Compound 7-12 0.0. 03 Compound 7-13 0.05 Compound 7-14 0.2 Compound 7-15 0.5 Compound 7-16 0.3 Compound 7-17 0.2 Compound 3-2 0.03 Compound A: 6- (3 -Methyl-1,4-naphthoquinone-
2-yl) -6- (4-methoxyphenyl) -hexanohydroxamic acid compound B: 6- (4-fluorophenyl) -6- (3-
Methyl-1,4-naphthoquinone-2-yl) -hexanohydroxamic acid compound C: 7- (3,5,6-trimethyl-1,4-benzoquinone-2-yl) -7-phenylheptanohydroxamic acid compound D: 7- (3,5,6-Trimethyl-1,4-benzoquinon-2-yl) -7- (4-methylphenyl) heptanohydroxamic acid Compound E: 7- (4-Fluorophenyl) -7- (3,
5,6-trimethyl-1,4-benzoquinone-2-yl)
Heptanohydroxamic acid From this, the compound (I) and compound (II) of the present invention
It is found that the compound suppresses neuronal degeneration and cell death induced by LPS at a low concentration and has an excellent neurodegeneration suppressing effect.

Experimental Example 2 [Experimental method] Rat cerebral mixed culture cells were cultured 15
The one of the day was used. LPS after once removing the medium
(E. coli 011: B4, Bacto) (Difco Laboratorie
s): 10 μg / ml, Compound A: 10 ⁻⁶ , 10 ⁻⁷ M were added at the same time to give a final volume of 100 μl. 37 ° C, 24
After performing the time incubation, the collected culture supernatant was used as a sample for ELISA. TN
Mouse TNFα Elisa Kit (CENZY
ME) according to the assay protocol. [Experimental Results] The effect of compound A on TNFα production in rat cerebral mixed culture cells when LPS was added is shown in [Table 33] below.

Table 33 LPS (μg / ml) Compound A (M) TNFα (pg / ml) 0 0 48 10 0 1500 1500 10 10 ^-7 790 10 10 ^-6 230

Experimental Example 3 Inhibitory effect on apomorphine-induced turning movement in rats injected with LPS unilateral striatum [Experimental method] In the experiment, the body weight during injection surgery was 250-28.
0 g of Wistar male rats (8-9 weeks old) were used.
The animals have a 12-hour light-dark cycle (lighting time: 7: 00-
Group breeding in the breeding room of constant temperature (24 ± 1 ℃) and constant humidity (55 ± 1%) at 19:00) with free intake of food (CLEA Japan, CE-2 solid feed) and water (tap water). did. Dent the rat head under anesthesia with pentobarbital (50 mg / kg, ip)
Fixed on a small animal brain stereotaxic device made by d Kopf, Pellegrino
&Cushman's brain diagram, unilateral striatum (A8.2, L
2.8, H4.3) was inserted with a 30-gauge stainless steel injection needle. The injection amount of LPS was 5 μg, and the solution was dissolved in 1 μl of phosphate buffered saline (PBS, pH 7.2),
Slow infusion was performed at a rate of 2 μl / min. The injection needle is left at the injection site for 3 minutes after the injection is completed, and after the drug solution has sufficiently diffused,
Raised. Apomorphine 1 mg / kg 7 to 8 days after surgery
Was subcutaneously administered, and immediately after that, the number of turns induced for 30 minutes was measured by an automatic measuring device. Compound A was added as a 5% gum arabic suspension to 0.2 m per 100 g of rat body weight.
It was administered orally or intraperitoneally in a volume of l. The administration is LP
S 5 μg 30 minutes before injection, 3 hours after injection, 3 hours after 24 hours
I went there. As a control, physiological saline was intraperitoneally administered.

[Experimental Results] The results of Compound A administration on apomorphine-induced whirl movement in rats injected with LPS (5 μg) unilateral striatum are shown in [Table 34] below.

[Table 34] From this, it can be seen that the compound A significantly suppresses the brain tissue destruction induced by LPS and has an excellent neurodegenerative effect.

Experimental Example 4 LSP-induced inhibitory effect on NO (nitric oxide) production in rat cerebral cell mixed culture system [Experimental method] (1) Rat cerebral cell mixed culture By the same method as in Experimental example 1, rat cerebrum A cell mixed medium was obtained. (2) NO production 1. Twenty days after the start of the mixed culture of rat cerebral cells, the medium in each well of the 96-well microplate was discarded, and instead, the final concentration of LSP (Difco, E. coli 0
11: B4, Bacto) and 125 μl of D-MEM / 2% FCS containing the appropriately diluted compound was added to each well. The sample is DMSO with 10 ^-2 M stock.
A solution was prepared and diluted with D-MEM / 2% FCS before use. 2. After culturing for additional 5 days, NO ₃ contained in the culture supernatant ^- and NO ₂ ^- the total amount of NO ₃ ^- / NO ₂ ^- Ass
It was measured using an ay Kit (manufactured by CAYMAN CHEMICAL, catalog number 780001, USA). The measurement was performed according to the attached assay protocol. (3) Calculation of IC ₅₀ value The total amount of NO ₂ ⁻ and NO ₃ ⁻ contained in the culture supernatant of the well to which only the final concentration of 5 μg / ml was added and no compound A was added up to 50%. It was determined by plotting the concentration of the inhibitory compound on a graph. [Experimental Results] Inhibitory activity of Compound A on NO production in rat cerebral cell mixed culture system induced by LSP (I
The C ₅₀ value) was 0.08 μM. This shows that the compound of the present invention strongly inhibits NO (nitric oxide) production.

[0132]

INDUSTRIAL APPLICABILITY The compound (I) or a salt thereof and the compound (II) or a salt thereof of the present invention have an excellent neurodegenerative inhibitory action and have low toxicity, so that a neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, Down's syndrome, Pick's disease, multiple sclerosis, bacterial or viral meningitis such as Borna's disease, post-vaccination encephalitis, AIDS encephalopathy, cerebral dysfunction (eg, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage) , Trauma, etc.) and / or improvement of prognosis, and further, cytokine-derived general malaise, fever, sleep, headache,
It is also effective for symptoms such as joint pain, loss of appetite, and depression. In addition, compound (I), (II) or their salts inhibit the abnormal release of nitric oxide due to acceleration of the immune system, etc., and therefore septic shock, nephritis, arteriosclerosis, asthma, diabetes, bone diseases. It is effective for improvement.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/42 AAM A61K 31/42 AAM 31/425 ABA 31/425 ABA C07C 311/03 7419-4H C07C 311/03 311/19 7419-4H 311/19 C07D 215/14 C07D 215/14 217/04 217/04 235/16 235/16 263/56 263/56 277/64 277/64 295/14 295 / 14 A 513/04 341 513/04 341

Claims (16)

[Claims] (1) Formula (1) [In the formula, Ar represents an aromatic group which may have a substituent,
Q is a divalent aliphatic hydrocarbon group, R ¹ is a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent, 2. R ¹ is a hydrogen atom, a cyano group, a hydrocarbon group which may have a substituent or a compound represented by the formula: [Wherein R ³ and R ⁴ each represent a hydrogen atom, an acyl group or a hydrocarbon group which may have a substituent, or R ³ and R ⁴ form a ring with an adjacent nitrogen atom. May be. ] The compound of Claim 1 which is a group represented by these. 3. Ar is a halogen atom, a C _1-3 alkylenedioxy group, a nitro group, a cyano group, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _3-6. Cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6
Alkylthio group, hydroxyl group, amino group, mono-C
_1-6 alkylamino group, di-C _1-6 alkylamino group, C
_1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo Base, C
_1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10
Aryloxy group, optionally halogenated C _1-6
An alkylsulfonylamino group and an optionally substituted C _6-10 arylsulfonylamino group, which may have 1 to 5 substituents i) C _6-14 aryl group, ii) carbon A 5- to 11-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to atoms, or iii) quinone ring group, and Q is divalent C _2-8 Aliphatic hydrocarbon group, R ¹ is i) hydrogen atom, ii) cyano group, iii) halogen atom, C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 Alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino Base,
Mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group,
C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, A C _6-10 aryl group,
A) C _1-6 alkyl group, which may have 1 to 5 substituents selected from a C _6-10 aryloxy group and a 5- or 6-membered heterocyclic group, b) a C _2-6 alkenyl group, c) C
_2-6 alkynyl group, d) C _3-6 cycloalkyl group or e) C _6-14 aryl group, iv) formula: [In the formula, R ³ and R ⁴ are each a) hydrogen atom, b) formula —CO—R, —SO ₂ —R, —SO—R, —CONH.
-R, -CO-OR, -CS-NH-R or-
CS-OR (in the formula, R is a hydrogen atom, a halogen atom, a C _1-3 alkylenedioxy group, a nitro group, a cyano group, an optionally halogenated C _1-6 alkyl group, or a halogenated group) Optionally C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _{1- 6} alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group,
Carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy groups and 1 to 5 substituents selected from 5 or 6-membered heterocyclic groups a) C _1-6 alkyl groups, b) C
_2-6 alkenyl group, c) C _2-6 alkynyl group, d) C _3-6
Cycloalkyl group or e) C _6-14 aryl group or halogen atom, C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, halogenated Optionally C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _1-6 Alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _{1 -6} alkylcarbamoyl group, C
1 to 5 substituents selected from _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group. 1 to 3 selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to the carbon atom which may be present.
It represents a 5- to 10-membered heterocyclic group containing 4 heteroatoms. ) Acyl group, c) halogen atom, C _1-3
Alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated C _{1- 6} alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group Group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1- C _1-6 alkyl group optionally having 1 to 5 substituents selected from ₆ alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group , C _2-6 al Kenyl group,
A C _2-6 alkynyl group, a C _3-6 cycloalkyl group or a C _6-14 aryl group, or R ³ and R ⁴ contain at least one nitrogen atom other than carbon atoms together with adjacent nitrogen atoms, It may form a 5- to 7-membered nitrogen-containing heterocycle which may contain 1 to 3 heteroatoms selected from oxygen atom or sulfur atom. A group represented by
Or v) formula _{-CO-R, -SO 2 -R,} -SO-
R, -CONH-R, -CO-OR, -CS-NH-
R or -CS-OR (wherein R is a hydrogen atom,
Halogen atom, C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, halogenated Optionally substituted C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group , C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C
1 to 5 substituents selected from _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group. A) C _1-6 alkyl group, b) C _2-6 alkenyl group, c) C _2-6 alkynyl group, which may have one or more
D) C _3-6 cycloalkyl group or e) C _6-14 aryl group or halogen atom, C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group An optionally halogenated C _3-6 cycloalkyl group, an optionally halogenated C _1-6 alkoxy group, an optionally halogenated C _1-6 alkylthio group, a hydroxyl group, an amino group, Mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl Group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6
A nitrogen atom other than a carbon atom which may have 1 to 5 substituents selected from an alkylsulfonyl group, a C _6-10 aryl group, a C _6-10 aryloxy group and a 5- or 6-membered heterocyclic group, It represents a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen atom and sulfur atom. Acyl group, and R ² is the formula -C represented by)
_{O-R, -SO 2 -R,} -SO-R, -CONH-R,
-CO-OR, -CS-NH-R or -CS-
OR (wherein R is i) hydrogen atom, ii) halogen atom,
C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated Good C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C
_1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-
C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C
C _1-6 alkyl group, C _2-6 alkenyl which may have 1 to 5 substituents selected from _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group Group, C _2-6 alkynyl group, C _3-6 cycloalkyl group or C _6-14 aryl group or iii) halogen atom, C
_1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group,
Amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _{1- 6} alkylcarbamoyl group, di-C _1-6
Substitution selected from alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10 aryloxy group and 5- or 6-membered heterocyclic group It represents a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to the carbon atom which may have 1 to 5 groups. 3. The compound according to claim 1, which is an acyl group represented by 4. Ar is a halogen atom, a C _1-3 alkylenedioxy group, a nitro group, a cyano group, an optionally halogenated C _1-6 alkyl group, or an optionally halogenated C _3-6. Cycloalkyl group, optionally halogenated C _1-6 alkoxy group, optionally halogenated C _1-6
Alkylthio group, hydroxyl group, amino group, mono-C
_1-6 alkylamino group, di-C _1-6 alkylamino group, C
_1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo Base, C
_1-6 alkylsulfonyl group, C _6-10 aryl group, C _6-10
Aryloxy group, optionally halogenated C _1-6
An alkylsulfonylamino group and an optionally substituted C _6-10 arylsulfonylamino group _optionally having 1 to 5 substituents i) p-benzoquinon-2-yl group, ii ) 1,4-naphthoquinone-2-
Group, iii) anthraquinonyl group, iv) 5,6-chrysenequinonyl group or v) 5,8-dioxo-5,8-
A dihydroquinolin-6-yl group, R ¹ is a halogen atom,
C _1-3 alkylenedioxy group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _3-6 cycloalkyl group, optionally halogenated Good C _1-6 alkoxy group, optionally halogenated C _1-6 alkylthio group, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C
_1-6 alkylamino group, C _1-6 alkylcarbonyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono-C _1-6 alkylcarbamoyl group, di-
C _1-6 alkylcarbamoyl group, C _6-10 arylcarbamoyl group, sulfo group, C _1-6 alkylsulfonyl group, C
_{A 6-10} aryl group, a C _6-10 aryloxy group and an i) phenyl group or ii) naphthyl group which may have 1 to 5 substituents selected from a 5- or 6-membered heterocyclic group,
And R ² is of the formula —CO—R or —CONH—R
(In the formula, R has the same meaning as in claim 3.) The compound according to claim 3, which is an acyl group. 5. R ¹ is a cyano group and R ² is of the formula —CO—R.
The compound according to claim 3, which is an acyl group represented by -CONH-R (wherein R has the same meaning as in claim 3). 6. Ar is i) a halogen atom, ii) a nitro group,
iii) an optionally halogenated C _1-6 alkyl group, i
v) an optionally halogenated C _1-6 alkoxy group,
v) hydroxyl group, vi) amino group, vii) mono-C _1-6
Alkylamino group, viii) di-C _1-6 alkylamino group, ix) optionally halogenated C _1-6 alkylsulfonylamino group, and x) 1 to 3 halogen atoms or optionally halogenated Phenyl, 1-naphthyl, 2-naphthyl, 2-, which may have 1 to 4 substituents selected from C _6-10 arylsulfonylamino groups which may be substituted with a good C _1-6 alkyl group. Quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,
4-isoquinolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl, p-benzoquinone-2-yl, 1,4-naphthoquinone-2-yl or 5,8-dioxo -5,8
-Dihydroquinolin-6-yl group, Q is a divalent C _2-5 alkylene group, R ¹ is i) hydrogen atom, ii) cyano group, iii)
A phenyl group which may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group and an optionally halogenated C _1-6 alkoxy group, iv ) Formula [In the formula, R ³ is a hydrogen atom and R ⁴ is a formula —CO—R ′ or —SO ₂ —R ′ (in the formula, R ′ is a halogen atom or C
_{It represents a} C _1-6 alkyl group or a C _6-14 aryl group, each of which may be substituted with 1 to 3 _1-6 alkyl groups. ) Represents an acyl group. Or a) an acyl group represented by the formula: —CO—O—R ″ (in the formula, R ″ represents a C _1-6 alkyl group), and R ² represents a formula —CO.
—R ′ ″ or —CO—NH—R ′ ″ (wherein R ′ ″ is i) hydrogen atom or ii) a) halogen atom, b) optionally halogenated C _1-6 alkyl A group, c) an optionally halogenated C _1-6 alkoxy group, d) a C _1-6 alkylcarbonyloxy group and e) a C _1-6 alkyl group or a C _1-6 alkoxy group, with 1 to 3 substituents _{Represents a} C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _6-14 aryl group which may have 1 to 3 substituents selected from the optionally substituted C _6-14 aryl group. . ), A group represented by 7. Ar is a substituent selected from i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group and iii) an optionally halogenated C _1-6 alkoxy group. To b) 1,4-naphthoquinone-2 or a) p-benzoquinone-2-yl group which may have 4 to 4
An yl group, R ¹ is a substituent selected from i) a halogen atom, ii) an optionally halogenated C _1-6 alkyl group, and iii) an optionally halogenated C _1-6 alkoxy group. To phenyl group which may have 3 to 3 and R ² has the formula —CO—R ″ ″ (wherein R ″ ″ may be substituted with 1 to 3 halogen atoms, respectively). C _1-6
An alkyl group, a C _3-6 cycloalkyl group or a phenyl group is shown. 7. The compound according to claim 6, which is an acyl group represented by 8. The compound according to claim 3, wherein Q is a trimethylene group or a tetramethylene group. 9. O-Acetyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-
Il) hexanohydroxamic acid, O-propionyl-6
-(4-methoxyphenyl) -6- (3-methyl-1,
4-naphthoquinone-2-yl) hexanohydroxamic acid, O-isobutyryl-6- (4-methoxyphenyl)
-6- (3-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-benzoyl-6-
(4-Methoxyphenyl) -6- (3-methyl-1,4
-Naphthoquinone-2-yl) hexanohydroxamic acid,
O-propionyl-7- (4-methoxyphenyl) -7
-(3-Methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, O-propionyl-7- (4-
The compound according to claim 1, which is fluorophenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid or a salt thereof. 10. The formula: [The symbols in the formula are as defined in claim 1. ] The compound or its salt represented by these, and a formula Y-R < ² > [In formula, Y is a leaving group and R < ² > has the same meaning as the claim 1. The method for producing a compound according to claim 1, wherein the compound or a salt thereof is reacted. 11. A compound of the formula [In the formula, Ar represents an aromatic group which may have a substituent,
Q is a divalent aliphatic hydrocarbon group, R ¹ is a hydrogen atom, a cyano group, or a hydrocarbon group which may have a substituent, [12] A neurodegeneration inhibitor comprising the compound according to [1] or a salt thereof. 13. O-propionyl-6- (4-methoxyphenyl) -6- (3-methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid, O-propionyl-7- (4-methoxy). Phenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl) heptanohydroxamic acid, 7- (4-methoxyphenyl) -7- (3-methyl-1,4-naphthoquinone-2-yl) ) Heptanohydroxamic acid, 6- (4-methoxyphenyl) -6- (3
-Methyl-1,4-naphthoquinone-2-yl) hexanohydroxamic acid or a salt thereof, the neurodegeneration inhibitor according to claim 11. 14. The neurodegeneration inhibitor according to claim 11, which is a therapeutic / preventive drug for neurodegenerative diseases. 15. The neurodegeneration inhibitor according to claim 14, which is a therapeutic / prophylactic drug for Alzheimer's disease or multiple sclerosis. 16. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof.