JP2006342133A - Phenylpyrazole derivative or salt of the same, method for producing the same and anti-oxidative medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new phenylpyrazole derivative or salts of the same, a method for producing the compounds, an anti-oxidative medicine containing the compounds and a treating agent of renal diseases, cerebrovascular diseases, cardiovascular diseases and cerebral infarction, an inhibitor of an oxidative disorder of retina, a lipoxygenase inhibitor and a 20-HETE synthase inhibitor containing the anti-oxidative medicine. <P>SOLUTION: This phenylpyrazole derivative expressed by formula (1) and its salts, the method for producing the compounds, the anti-oxidative medicine containing the compounds, and the treating agent of the renal diseases, etc., inhibitor of the oxidative disorder of the retina, lipoxygenase inhibitor and 20-HETE synthase inhibitor containing the anti-oxidative medicine are provided. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel phenylpyrazole derivative or a salt thereof, a production method thereof, an antioxidant containing the derivative or a salt thereof, and a renal disease, cerebrovascular disease, cardiovascular disease, cerebral infarction containing the antioxidant Retinal oxidative disorder inhibitor, lipoxygenase inhibitor, 20-hydroxyeicosatetraenoic acid synthase inhibitor.

  In recent years, it has been clarified that the generation of lipid peroxide in vivo and the accompanying radical reaction have various adverse effects on the living body through membrane damage and cell damage. Accordingly, research and development of antioxidants and lipid peroxide production inhibitors (antioxidants, etc.) have been actively conducted (Non-patent Document 1, etc.).

  Conventionally, as an antioxidant, (a) a pharmaceutical composition (Patent Document 1) used for the treatment and prevention of endotoxin shock based on inflammation, infection and the like containing a specific quinone derivative, (b) cell growth inhibitory action, blood vessel Hydroxamic acid derivatives (patent document 2) used for the treatment and prevention of autoimmune diseases having an inhibitory effect on neoplasia (c) 2,3-dihydrobenzofuran derivatives (patent documents 3 to 5) useful as antioxidants and radical scavengers, (D) an imidazole compound having an antihyperlipidemic action and useful for the treatment and prevention of arteriosclerosis (Patent Document 6), (e) a benzothiazine carboxamide having an anti-arthritic activity (Patent Document 7), (F) Carbonylaminophenylimidazole derivatives (Patent Documents 8 to 10), (g) Prevention and treatment of various diseases such as arteriosclerosis, liver disease, cerebrovascular disorder Aminodihydrobenzofuran derivatives having a lipid peroxide production inhibitory action useful as (Patent Document 11), (h) Antihyperlipidemic drugs containing a benzoisoxazole compound, etc. (Patent Document 12), (i) Antioxidants Dihydrobenzofuran derivatives that significantly improve lipid, protein, carbohydrate and DNA damage resulting from oxidative stress that occurs when the defense system is insufficient (Patent Document 13), (j) Brain dysfunction associated with stroke and head trauma An optically active aminodihydrobenzofuran derivative (Patent Document 14) that is effective in improving, treating, and preventing the above is known.

  The brain is extremely vulnerable to ischemia because its supply depends on circulating blood, despite the high energy demand. When cerebral blood flow ceases due to various causes and causes cerebral ischemia, reactive oxygen species are generated due to mitochondrial damage and increased calcium in neurons, and oxygen radicals are restored when blood flow resumes after ischemia. Is known to explode. It is said that these reactive oxygen species eventually act on lipids, proteins, nucleic acids, etc., and oxidize each to cause cell death. Antioxidants are available as therapeutic agents for such pathological conditions, and edaravone is approved and used as a brain protective agent in Japan.

  Further, as lipoxygenase (LO) for adding oxygen to unsaturated fatty acids typified by arachidonic acid, 5-LO, 8-LO, 12-LO, 15-LO and the like are known depending on the oxygen addition site. 5-LO is the first enzyme that synthesizes leukotriene, a potent inflammatory mediator. Leukotrienes are involved in various inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, and their control is useful for the treatment of these diseases. In addition to arachidonic acid, 12-LO and 15-LO are known to react with linoleic acid, cholesterol esters, phospholipids, and low density lipoprotein (LDL) to add oxygen to the unsaturated fatty acids. (Non-patent document 2).

  Macrophages take in unlimited oxidatively modified LDL via scavenger receptors and become foam cells. It is widely known that this is the first step in atherosclerotic lesion formation. It has also been clarified that 12-LO and 15-LO are expressed at high levels in macrophages and are essential as triggers for oxidative modification of LDL (Non-patent Document 3). These controls are useful for the treatment of various diseases caused by arteriosclerosis (Patent Document 15).

  Arachidonic acid, which is a precursor fatty acid, becomes 20-HETE by 20-hydroxyeicosatetraenoic acid (hereinafter sometimes abbreviated as “20-HETE”) synthase when it is cleaved from phospholipids of cell membranes. 20-HETE is known to cause contraction or expansion of microvessels and induce cell proliferation in major organs such as kidney and cerebral blood vessels, and is involved in important physiological functions in vivo. It has been suggested that it is deeply involved in disease states such as diseases and cardiovascular diseases (Non-Patent Documents 4 to 6). Furthermore, it has been reported that phenylazole derivatives have an inhibitory action on 20-HETE synthase (Patent Documents 16 to 18).

Moreover, in many of the eye diseases such as cataract and macular degeneration that frequently occur with aging, oxidative stress related to free radicals and active oxygen is considered as one of the onset factors (Non-patent Document 7). ~ 9).
In the eye tissue, the retina is known as a tissue that is susceptible to aging together with the lens (Non-patent Document 10). The retina is rich in higher unsaturated fatty acids, receives nutrition from both retinal blood vessels and choroidal blood vessels, and is highly susceptible to various free radicals due to high oxygen consumption. The light received is representative of oxidative stress for the retina. Most of the sunlight that reaches the ground is occupied by visible light and infrared rays, and ultraviolet rays contained in several percent of them have a strong interaction with the living body and a greater effect on health than visible light and infrared rays.
In recent years, due to the emergence of ozone holes that are thought to be due to environmental destruction, the amount of ultraviolet rays reaching the earth has increased, and in the southern hemisphere, skin damage and skin cancer related to ultraviolet rays have increased rapidly. Retinopathy is thought to increase more and more in the future.

Among eye diseases, age-related macular degeneration is a retinal disorder with high degree of blindness. In the United States, 10 million people have mild symptoms, and more than 450,000 people have visual impairment due to this disease. (Non-Patent Document 11).
There are many unclear points about the mechanism of the onset of macular degeneration, but it has been pointed out that peroxidation due to light absorption in the retina is involved in the progression of this lesion (Non-patent Documents 12 and 13). In addition, the appearance of a lipofuscin-like fluorescent substance called drusen was recognized in the early stage of its onset, and lipofuscin is produced by the combination of aldehydes and proteins, which are secondary decomposition products of lipid peroxides, so It is possible that lipid peroxidation in the retina by visible light may induce this retinal disorder.

  Examples of drugs useful for the prevention and treatment of retinal diseases caused by such antioxidant action include therapeutic agents for retinal diseases (Patent Documents 19 to 22) containing specific dihydrofuran derivatives, propionyl-L-carnitine or salts thereof. In addition, a drug for visual acuity and retinal change including carotenoid, including macular degeneration of the retina (Patent Document 23) is known. However, the current situation is that the efficacy of existing antioxidants is not sufficient.

JP 61-44840 A Japanese Patent Laid-Open No. 1-104033 Japanese Patent Laid-Open No. 2-121975 European Patent Application No. 345593 European Patent Application No. 483772 International Publication No. 95/29163 Pamphlet German patent application DE 3,407,505 JP 55-69567 A European Patent Application No. 324377 European Patent Application No. 458037 Japanese Patent Laid-Open No. 5-140142 International Publication No. 00/006550 Pamphlet International Publication No. 96/28437 Pamphlet JP-A-6-228136 Japanese Patent Laid-Open No. 2-76869 International Publication No. 00/0168610 Pamphlet JP 2004-010513 A International Publication No. 03/022821 Pamphlet JP-A-6-287139 International Publication No. 04/092153 Pamphlet International Publication No. 04/092163 Pamphlet International Publication No. 00/092179 Pamphlet International Publication No. 00/077581 Pamphlet J. et al. Amer. Oil Chemists, Soc. 51, 200, 1974 Biochem. Biophys. Acta, 1304, 652 paragraph, 1996 J. et al. Clin. Invest. 103, 15972, 1999 J. et al. Vascular Research, Vol. 32, Item 79, 1995 Am. J. et al. Physiol. 277, 607, 1999 Physiol. Rev. 82, 131, 2002 Anderson R.D. E. Kretzer F., et al. L. , Rapp L., et al. M.M. “Free radicals and eye diseases” Adv. Exp. Med. Biol. 366, 73, 1994 Nishigori H.I. Lee J .; W. Yamauchi Y .; , Iwatsuru M .; “Effects of lipid peroxidation and ascorbic acid on glucoticoid-induced cataract in germinated chicken embryos” Curr. Eye Res. , Volume 5, page 37, 1986 Truscott R.D. J. et al. W. Augusteyn R .; C. “Effects of mercapto groups in normal or cataractous human lenses” Exp. Eye Res. 25, 139, 1977 Hiramitsu T. Armstrong D .; "Preventive effects of antioxidants on lipid peroxidation in the retina" Ophthalmic Research, Vol. 23, 196, 1991 Vitamin Public Relations Center (Tokyo) VIC Newsletter, Volume 105, Page 4, 2002 Yukimura Sadaaki, “Cataract and Active Oxygen / Free Radical, Active Oxygen / Free Radical” Vol. 3, p. 402, 1992 Solbach U. , Keilhauer C .; , Knabben H .; , Wolf S. "Retinal autofluorescence in age-related macular degeneration" Retina, 17, 385, 1997

  The present invention has been made in view of such a state of the art, a novel phenylpyrazole derivative or a salt thereof, an antioxidant containing this compound, and a renal disease containing this antioxidant, It is an object of the present invention to provide a therapeutic agent for cerebrovascular disease, cardiovascular disease, or cerebral infarction, an inhibitor of retinal oxidative damage, a lipoxygenase inhibitor, and a 20-hydroxyeicosatetraenoic acid synthase inhibitor.

  The present inventors thought that the reason why the efficacy of existing antioxidants is not sufficient is that the drug does not reach the target site or deactivates the activity before reaching the target site. And they conducted extensive research with the aim of developing antioxidants that are easier to pass through the organ migration, especially blood-brain barrier or blood-retinal barrier. As a result, it was found that the phenylpyrazole derivative represented by the formula (1) described later has an excellent in vivo antioxidant effect regardless of the administration route.

  Furthermore, as a result of studies on suppression of retinal damage, phenylpyrazole derivatives represented by the following formula (1) having a strong antioxidant ability are transferred to the retina in a short time by oral administration, and improvement of retinal damage due to oxidation. In particular, the present invention has been found to be effective for the progression of age-related macular degeneration of the retina that increases with aging and the reduction of symptoms, and the present invention has been completed.

Thus, according to the first aspect of the present invention, there is provided a phenylpyrazole derivative or a salt thereof of the following (1) or (2).
(1) Formula (1)

｛式中、Ｒ１、Ｒ２は、式（２）

{In the formula, R1 and R2 are defined by

[Wherein, R10 and R11 each independently represent a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group, or a C _2-6. An alkynyl group, a C _2-6 alkenyloxy group, a C _2-6 alkynyloxy group, an acyloxy group, or an optionally substituted G1 (C _3-8 cycloalkyl group or phenyl group);
G1 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.
k represents an integer of 0 to 15. When k is 2 or more, R10s and R11s may be the same or different.
Z has at least G2 as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman 2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group)
G2 is a group represented by the formula: NHR12 [wherein R12 is a hydrogen atom, a formyl group, a C _1-6 alkylcarbonyl group, or (a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom , A nitro group, an amino group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group). Or a group represented by the formula: OR13 [wherein R13 is a hydrogen atom, a formyl group, a C _1-6 alkylcarbonyl group, or (a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 An alkoxy group, a halogen atom, a nitro group, an amino group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group). . Represents a group represented by the formula: However, when R1 is a group represented by the formula (2), R2 does not exist, and when R2 is a group represented by the formula (2), R1 does not exist.

R3 may be substituted with a hydrogen atom or G3 (C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbamoyl) Group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkoxy group, phenyl group, or heteroaryl group), carboxyl group, hydroxyl group, or cyano group,
G3 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.

R4 represents a hydrogen atom or G4 (C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, phenyl group, or heteroaryl group) optionally substituted with G4,
G4 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.

R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom or G5 (C _1-6 alkyl group, C _1-6 alkoxy group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group, acyloxy group, mono-C _1-6 alkylamino group, or di-C _1-6 alkylamino group Group), or optionally substituted with G6 (piperazyl group, piperidyl group, C _3-8 cycloalkyl group, phenyl group, or heteroaryl group),
G5 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, diC _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group,
G6 is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, cyano group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 An alkylamino group, a diC _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group is represented.

Further, among R5, R6, R7, R8 and R9, two adjacent groups may be combined to form a ring, or R4 and R5 may be combined to form a ring. Good. }
Or a salt thereof.

(2) Z is the following (A), (B), (C), (D) or (E)

(Wherein, G2 are as defined above, * represents a chiral carbon atom, _{Y 1} represents an oxygen atom or a sulfur atom, R14～R34 are each independently a hydrogen atom or a _{C 1-6} A phenylpyrazole derivative or a salt thereof according to (1), wherein the phenylpyrazole derivative is a group represented by the following formula:
According to 2nd of this invention, the manufacturing method of the phenyl pyrazole derivative of following (3)-(8) is provided.
(3) Formula (a)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (b)

[Wherein R10, R11 and k represent the same meaning as described above, and Z1 has at least a nitro group or an acyloxy group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3- Dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman-2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolane- 2-yl group)
L represents a leaving group. ]
Wherein the compound represented by formula (1a-1) is reacted.

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above).
(4) Formula (c)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (d)

(Wherein R10, R11, k and Z1 represent the same meaning as described above) and a compound represented by the formula (1a-1)

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above).
(5) Formula (e)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (d)

（式中、Ｒ１０、Ｒ１１、ｋ及びＺ１は前記と同じ意味を表す。）で示される化合物とを反応させることを特徴とする、式（１ａ−１）

(Wherein R10, R11, k and Z1 represent the same meaning as described above) and a compound represented by the formula (1a-1)

又は式（１ｂ−１）

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above).

According to the third aspect of the present invention, the following antioxidant (6) is provided.
(6) An antioxidant comprising one or more of the phenylpyrazole derivatives or salts thereof of (1) or (2).

According to the fourth aspect of the present invention, the following therapeutic agents (7) and (8) are provided.
(7) A therapeutic agent for kidney disease, cerebrovascular disease or cardiovascular disease, comprising the antioxidant of (6).
(8) A therapeutic agent for cerebral infarction comprising the antioxidant of (6).

According to the fifth aspect of the present invention, the following inhibitors (9) and (10) are provided.
(9) An inhibitor of retinal oxidative damage, comprising the antioxidant of (6).
(10) The inhibitor of (9), wherein the retinal oxidative disorder is macular edema, age-related macular degeneration, or diabetic retinopathy.

According to the sixth aspect of the present invention, the following inhibitors (11) and (12) are provided.
(11) A lipoxygenase inhibitor comprising the antioxidant of (6).
(12) A 20-hydroxyeicosatetraenoic acid synthase inhibitor comprising the antioxidant of (6).

The phenylpyrazole derivative or salt thereof of the present invention has antioxidant activity, treatment of ischemic organ disorders such as arteriosclerosis, myocardial infarction, cerebral infarction, etc., treatment of diseases caused by oxidative cell damage such as kidney disease, This is effective for suppressing oxidative damage caused by light from the retina.
According to the production method of the present invention, the phenylpyrazole derivative of the present invention can be easily produced.
The antioxidant of the present invention is used as a therapeutic agent for renal diseases, cerebrovascular diseases, cardiovascular diseases, cerebral infarction diseases, etc., and also has retinal oxidative disorder inhibitors, lipoxygenase inhibitors, and 20-HETE synthase inhibitors with few side effects. Useful as a medicine.

  Hereinafter, the present invention includes 1) a phenylpyrazole derivative represented by formula (1) or a salt thereof, 2) a method for producing a phenylpyrazole derivative represented by formula (1), 3) an antioxidant, and 4) treatment. This will be described in detail by dividing it into drugs, inhibitors and inhibitors.

1) Phenylpyrazole derivative represented by formula (1) or salt thereof The first of the present invention is a phenylpyrazole derivative represented by formula (1) (hereinafter also referred to as “phenylpyrazole derivative (1)”). Or a salt thereof.
In the formula (1), R1 and R2 represent a group represented by the formula (2). However, when R1 is a group represented by the formula (2), R2 does not exist, and when R2 is a group represented by the formula (2), R1 does not exist.

In formula (2), R10 and R11 are each independently a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group, C _{2. It represents a -6} alkynyl group, a C _2-6 alkenyloxy group, a C _2-6 alkynyloxy group, an acyloxy group, or an optionally substituted G1 (C _3-8 cycloalkyl group or phenyl group).
G1 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl An amino group and a C _1-6 alkoxycarbonyl group are represented.
_{Incidentally, C 1-6 C 1-6} alkylcarbonyl group represents a number of carbon atoms in the alkyl _{group, C 1-6} of _{C 1-6} alkoxycarbonyl group represents a number of carbon atoms of the alkoxy group (the same hereinafter).

Examples of the halogen atom for R10, R11, and G1 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
As the C _1-6 alkyl group for R 10 and R 11, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, n-hexyl etc. are mentioned.
Examples of the C _1-6 alkoxy group for R10, R11, and G1 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, and a t-butoxy group.

As the C _2-6 alkenyl group for R 10 and R 11, a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl Group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group and the like.

Examples of the C _2-6 alkynyl group of R 10 and R 11 include ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2- Methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, Examples include 1,1-dimethyl-2-butynyl group.

Examples of the C _2-6 alkenyloxy group for R 10 and R 11 include an allyloxy group, a 2-propenyloxy group, a 2-butenyloxy group, and 2-methyl-3-propenyloxy.
Examples of the C _2-6 alkynyloxy group for R 10 and R 11 include a 2-propynyloxy group, a 2-butynyloxy group, and 1-methyl-2-propynyloxy.
Examples of the acyloxy group for R10 and R11 include an acetoxy group, a propionyloxy group, a butyryloxy group, and a benzoyloxy group.
Examples of the C _3-8 cycloalkyl group represented by R10 and R11 include a cyclopropyl group, a 1-methylcyclopropyl group, a 2-methylcyclopropyl group, a 2,2-dimethylcyclopropyl group, a cyclobutyl group, a cyclopentyl group, and cyclohexyl. Can be mentioned.

Examples of the C _1-6 alkylcarbonyl group for G1 include an acetyl group, a propionyl group, a propylcarbonyl group, a valeryl group, and a pivaloyl group.
Examples of the C _1-6 alkoxycarbonyl group for G1 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and a t-butoxycarbonyl group.

As mono-C _1-6 alkylamino group of G1, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, s-butylamino group, isobutylamino group, t-butyl An amino group, n-pentylamino group, n-hexylamino group, etc. are mentioned.
Examples of the di-C _1-6 alkylamino group of G1 include dimethylamino group, diethylamino group, di-n-propylamino group, diisopropylamino group, di-n-butylamino group, diisobutylamino group, methylethylamino group, methyln- And a propylamino group.

  Among these, R10 and R11 are preferably each independently a hydrogen atom, a methyl group, or a phenyl group.

  k represents an integer of 0 to 15, and an integer of 0 to 6 is preferable. When k is 2 or more, R10s and R11s may be the same or different.

  Z has at least G2 as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman 2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group).

G2 represents a group represented by the formula: NHR12 or OR13.
Formula: In NHR12, R12 represents a hydrogen atom, a formyl group, a C _1-6 alkylcarbonyl group, or (a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom, a nitro group, amino A benzoyl group which may be substituted with a group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group.
In the formula: OR13, R13 is a hydrogen atom, formyl group, C _1-6 alkylcarbonyl group, or (cyano group, hydroxyl group, C _1-6 alkyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino A benzoyl group which may be substituted with a group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group.

Such Z is preferably any group represented by the above (A), (B), (C), (D) or (E).
Formula (A), the (B), (C), (D) and in (E), G2 are as defined above, * represents a chiral carbon atom, _{Y 1} represents an oxygen atom or a sulfur atom To express.
R14 to R34 each independently represents a hydrogen atom or a C _1-6 alkyl group.
As the _{C 1-6} alkyl group R14～R34, include the same as listed as _{C 1-6} alkyl groups of said R10, R11.

In the formula (1), R3 is a hydrogen atom, optionally substituted with G3 _{(C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl _{group, C 1-6} alkoxycarbonyl group C _1-6 alkylcarbamoyl group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkoxy group, phenyl group, or heteroaryl group), carboxyl group, hydroxyl group, or cyano Represents a group.
G3 is the same as G1, cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di A C _1-6 alkylamino group and a C _1-6 alkoxycarbonyl group are represented.

R3 _{C 1-6} alkyl _{group, C 2-6 alkenyl, C 2-6} alkynyl _group, and the _{C 1-6} alkoxy groups, _{C 1-6} alkyl groups of said R10, _{R11, C 2-6} alkenyl group , C _2-6 alkynyl group, the same as those listed as C _1-6 alkoxy group.
R3 _{C 1-6} alkoxycarbonyl group, a mono _{C 1-6} alkylamino group, a di _{C 1-6} alkylamino group, _{C 1-6} alkoxycarbonyl group wherein G1, mono _{C 1-6} alkylamino group, It includes the same ones listed as the di-C _1-6 alkylamino group.
Examples of the C _1-6 alkylcarbamoyl group for R 3 include methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, s-butylcarbamoyl group, isobutylcarbamoyl group, t-butylcarbamoyl group and the like. It is done.
Examples of the heteroaryl group of R3 include pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group, pyrrolyl group, imidazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, pyrazolyl group and the like. .

In the formula (1), R4 is a hydrogen atom, optionally substituted with G4 _{(C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl group, a phenyl group, or heteroaryl group )
G4 is the same as G1, such as a cyano group, a formyl group, a C _1-6 alkylcarbonyl group, a hydroxyl group, a C _1-6 alkoxy group, a halogen atom, a nitro group, an amino group, a mono C _1-6 alkylamino group, di A C _1-6 alkylamino group and a C _1-6 alkoxycarbonyl group are represented.
R5, R6, R7, R8, and R9 are each independently substituted with a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, or G5 (C _1-6 alkyl group, C _1-6 alkoxy group). C _2-6 alkenyl group, C _2-6 alkynyl group, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group, acyloxy group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group Group), which may be substituted with G6 (piperazyl group, piperidyl group, C _3-8 cycloalkyl group, phenyl group, or heteroaryl group).

G5 is the same as G1, such as a cyano group, a formyl group, a C _1-6 alkylcarbonyl group, a hydroxyl group, a C _1-6 alkoxy group, a halogen atom, a nitro group, an amino group, a mono C _1-6 alkylamino group, di A C _1-6 alkylamino group and a C _1-6 alkoxycarbonyl group are represented.
G6 is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, cyano group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 An alkylamino group, a diC _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group is represented.

  Further, among the R5, R6, R7, R8 and R9, two adjacent groups may be combined to form a ring. Examples of such phenylpyrazole derivative (1) include, for example, formula (3)

A compound represented by formula (4):

The compound etc. which are represented by these are mentioned.
In formulas (3) and (4), R1 to R4 have the same meaning as described above.
In formula (3), R35 and R36 each independently represent a hydrogen atom or a C _1-6 alkyl group which may be substituted with G7. G7 is the same as G1, cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di A C _1-6 alkylamino group and a C _1-6 alkoxycarbonyl group are represented.

In formula (4), X represents a group represented by the formula: —NR ^a — or —CR ^b R ^c —. In the formula, each of R ^a , R ^b and R ^c may be independently substituted with a hydrogen atom or G7 (C _1-6 alkyl group, C _1-6 alkylcarbonyl group, benzyl group, benzoyl group) ) Or a formyl group, and G7 has the same meaning as described above. l represents 1 or 2;

  Further, R4 and R5 may be combined to form a ring. Examples of such a phenylpyrazole derivative (1) include, for example, the formula (5)

The compound etc. which are represented by these are mentioned.
In the formula, R1, R2, and R6 to R9 represent the same meaning as described above. E represents the formula: —CH ₂ —, —NR ^d —, —O—, —S—, —C (═O) —, —CH ₂ CH ₂ —, —CH═CH—, —N (R ^d ). CH ₂ —, —N═CH—, —CH ₂ NR ^d —, —CH═N— (wherein R ^d may be substituted with a hydrogen atom, G7 (C _1-6 alkyl group, C _1-6 alkylcarbonyl group, benzoyl group, benzyl group) or formyl group, and G7 represents the same meaning as described above.

  In addition, some optically active forms and tautomers may exist in the phenylpyrazole derivative (1) or a salt thereof. These are all within the scope of the present invention.

  Since the phenylpyrazole derivative (1) or a salt thereof of the present invention has an excellent antioxidant action, it is useful as an antioxidant or the like as described later.

2) Manufacturing method of phenyl pyrazole derivative (1) The phenyl pyrazole derivative (1) of this invention can be manufactured with the manufacturing methods 1-7 shown below, for example. According to these methods, the phenylpyrazole dielectric (1) of the present invention or its production intermediate can be produced efficiently.
Manufacturing method 1

  The production method 1 is a kind of the phenylpyrazole derivative (1) of the present invention or a production intermediate thereof by reacting the pyrazole derivative represented by the formula (a) with the compound represented by the formula (b). The compound represented by the formula (1a-1) or (1b-1) is obtained.

In the above formula, R3 to R11 and k represent the same meaning as described above.
L represents a leaving group. Examples of the leaving group include halogen atoms such as chlorine atom, bromine atom and iodine atom; alkylsulfonyloxy group such as methylsulfonyloxy group; arylsulfonyloxy group such as 4-methylphenylsulfonyloxy group; trifluoromethylsulfonyl A haloalkylsulfonyloxy group such as an oxy group; and the like.

  Z1 has at least a nitro group or an acyloxy group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3- Yl group, thiochroman-2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group).

  That is, by reacting the compound represented by the formula (b) with the pyrazole derivative represented by the formula (a) in the presence of a base in an organic solvent, the formula (1a-1) or (1b-1) is reacted. ) Can be obtained.

  In this reaction, the amount of the compound represented by the formula (b) is usually 0.5 to 3 moles per 1 mole of the compound (a), although it depends on the type of the compound used.

Examples of the base used in this reaction include amines such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] 7-undecene (DBU); metal alkoxides such as potassium t-butoxide and sodium methoxide; Metal carbonates such as sodium, sodium carbonate and potassium carbonate; metal hydroxides such as sodium hydroxide; metal hydrides such as sodium hydride and calcium hydride; and the like.
The usage-amount of a base is 1-3 times mole normally with respect to the compound represented by Formula (b).

  The organic solvent to be used is not particularly limited as long as it is an inert solvent for the reaction. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxin, 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, 1,2-dichloroethane, etc. Halogenated hydrocarbons; nitriles such as acetonitrile; formamides such as dimethylformamide (DMF); sulfoxides such as dimethylsulfoxide (DMSO); and the like. These solvents can be used alone or in combination of two or more.

The reaction temperature is usually in the temperature range from −15 ° C. to the boiling point of the solvent used, preferably −10 ° C. to + 80 ° C.
The reaction time is usually several minutes to several tens of hours depending on the reaction scale.

The compound represented by the formula (a) has tautomers as shown in the above formula. Therefore, in this production method, reaction products represented by the formulas (1a-1) and (1b-1) are obtained.
Manufacturing method 2

Production method 2 is a kind of phenylpyrazole derivative (1) of the present invention or a production intermediate thereof by reacting the compound represented by formula (c) with the compound represented by formula (d). A compound represented by the formula (1a-1) or (1b-1) is obtained.
In said formula, R3-R11, k, and Z1 represent the same meaning as the above.

  That is, the compound represented by the formula (c) and the compound represented by the formula (d) are reacted in an appropriate organic solvent, thereby being represented by the formula (1a-1) or (1b-1). Can be obtained.

  The organic solvent to be used is not particularly limited as long as it is an inert solvent for the reaction. For example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, s-butanol, and t-butanol; organic acids such as acetic acid and trifluoroacetic acid; These solvents can be used alone or in combination of two or more.

The reaction temperature is usually in the temperature range from 0 ° C. to the boiling point of the solvent used, preferably from 15 ° C. to the boiling point of the solvent used.
The reaction time is usually several minutes to several tens of hours depending on the reaction scale.
Although the usage-amount of the compound represented by the formula (d) to be used is based also on the kind of compound to be used, it is 0.5-3 times mole normally with respect to the compound represented by a formula (c).

The compound represented by the formula (c) has tautomers as shown in the above formula. Therefore, in this production method, reaction products represented by the formulas (1a-1) and (1b-1) are obtained.
Manufacturing method 3

The production method 3 is a kind of the phenylpyrazole derivative (1) of the present invention or a production intermediate thereof by reacting the compound represented by the formula (e) with the compound represented by the formula (d). A compound represented by the formula (1a-1) or (1b-1) is obtained.
In said formula, R3-R11, k, and Z1 represent the same meaning as the above.

  That is, the compound represented by the formula (e) and the compound represented by the formula (d) are reacted in an appropriate organic solvent, thereby being represented by the formula (1a-1) or (1b-1). Can be obtained.

Although the usage-amount of the compound represented by Formula (d) is based also on the kind of compound to be used, it is 0.5-3 times mole normally with respect to the compound represented by Formula (e).
Examples of the organic solvent to be used include the same organic solvents as exemplified in the production method 2.

The reaction temperature is usually in the temperature range from 0 ° C. to the boiling point of the solvent used, preferably from 15 ° C. to the boiling point of the solvent used.
The reaction time is usually several minutes to several tens of hours depending on the reaction scale.
In this production method, reaction products represented by the formulas (1a-1) and (1b-1) are obtained.
Manufacturing method 4

  In the production method 4, the compound represented by the formula (f) or the formula (g) is hydrolyzed to form one of the phenylpyrazole derivatives (1) of the present invention or a production intermediate thereof (1a-2) Or the compound represented by (1b-2) is obtained.

In the above formula, R4～R11, k and Z1 are as defined above, ^{R e} is methyl, ethyl, n- propyl group, an isopropyl group, t- butyl group, n- butyl group, isobutyl group, etc. Represents a C _1-6 alkyl group.

  Z2 has at least a nitro group, an acyloxy group or a hydroxyl group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran. -3-yl group, thiochroman-2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group).

That is, the compound represented by the formula (f) or the formula (g) is stirred in a solvent in the presence of an acid or a base to hydrolyze an alkoxycarbonyl group (COOR ^e ) bonded to the pyrazole ring. By converting to a carboxyl group, a compound represented by the formula (1a-2) or (1b-2) can be obtained. In this case, when a compound having an acyloxy group as Z1 is used, a reaction product in which the acyloxy group is hydrolyzed and converted to a hydroxyl group at the same time as the COOR ^e group is hydrolyzed is obtained. There is.

Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid.
Examples of the base to be used include metal hydroxides such as sodium hydroxide and potassium hydroxide; metal carbonates such as sodium carbonate and potassium carbonate;
Examples of the solvent to be used include water; water-containing alcohols such as water-methanol and water-ethanol; and the like.
The reaction temperature is usually from 0 to 100 ° C., and the reaction time is usually from several minutes to several hours depending on the reaction scale.
Manufacturing method 5

In the production method 5, the compound represented by the formula (h) or the formula (i) is decarboxylated to produce one of the phenylpyrazole derivatives (1) of the present invention or the production intermediate (1a-3). Or a compound represented by (1b-3).
In the formula, R4 to R11, k and Z2 represent the same meaning as described above.

  That is, the compound represented by the formula (h) or the formula (i) is stirred at a predetermined temperature in a solvent or without a solvent, optionally in the presence of an acid, to form a carboxyl group (COOH) bonded to the pyrazole ring. By decarboxylation, the compound represented by the formula (1a-3) or (1b-3) can be obtained.

Examples of the solvent to be used include high boiling point solvents such as nitrobenzene, dichlorobenzene, and diethylaniline.
Examples of the acid to be used include inorganic acids such as hydrochloric acid and sulfuric acid.
The reaction temperature is usually in the range of 50 to 300 ° C., and the reaction time is usually from several minutes to several hours depending on the reaction scale.
Manufacturing method 6

  In the production method 6, the compound represented by the formula (j) or the formula (k) is reduced, whereby one of the phenylpyrazole derivatives (1) of the present invention or the production intermediate thereof is represented by the formula (1a-4) Alternatively, a compound represented by (1b-4) is obtained.

In formula, R3-R11 and k represent the same meaning as the above.
Z3 has at least a nitro group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, A thiochroman-2-yl group, a 2,3-dihydrobenzothiophen-2-yl group, or a 1,3-benzoxathiolan-2-yl group).
Z4 has at least an amino group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, A thiochroman-2-yl group, a 2,3-dihydrobenzothiophen-2-yl group, or a 1,3-benzoxathiolan-2-yl group).

  That is, the compound represented by the formula (j) or the formula (k) is hydrogenated in an organic solvent in the presence of a hydrogenation catalyst, or is reduced using a reducing agent, and the nitro group of Z3 is reduced. Can be converted to an amino group to obtain a compound represented by the formula (1a-4) or (1b-4).

  Examples of the hydrogenation catalyst used include palladium carbon, palladium hydroxide, platinum dioxide, Raney nickel and the like.

  Organic solvents used for the hydrogenation reaction include alcohols such as methanol and ethanol; ethers such as diethyl ether, THF and 1,4-dioxane; hydrocarbons such as benzene, toluene, xylene and cyclohexane; DMF Amides such as for example; organic acids such as formic acid and acetic acid; esters such as ethyl acetate; and mixed solvents thereof.

As a method of reducing using a reducing agent, acetic acid and iron are used in a method of using hydrochloric acid and stannous chloride in an alcohol such as methanol and ethanol, or in a mixed solvent of water and an organic solvent such as acetone and methyl ethyl ketone. Methods and the like.
The reaction temperature is usually in the temperature range from 0 ° C. to the boiling point of the solvent used, and the reaction time is usually from several minutes to several hours, depending on the reaction scale.
Manufacturing method 7

  In the production method 7, the compound represented by the formula (l) or the formula (m) is hydrolyzed to form one of the phenylpyrazole derivatives (1) of the present invention or a production intermediate thereof (1a-5) Alternatively, a compound represented by (1b-5) is obtained.

In formula, R3-R11 and k represent the same meaning as the above.
Z5 has at least an acyloxy group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, A thiochroman-2-yl group, a 2,3-dihydrobenzothiophen-2-yl group, or a 1,3-benzoxathiolan-2-yl group).
Z6 has at least a hydroxyl group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman 2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group).

That is, the compound represented by the formula (l) or the formula (m) is stirred in a solvent in the presence of an acid or a base, and the acyloxy group of Z5 is hydrolyzed to be converted into a hydroxyl group. The compound represented by (1a-5) or (1b-5) can be obtained. In this case, when a compound in which R ³ is an alkoxycarbonyl group is used, a reaction product in which the acyloxy group of Z5 is hydrolyzed and at the same time the alkoxycarbonyl group is hydrolyzed and converted to a carboxyl group. Things may be obtained.

Examples of the solvent used include water; hydrous alcohols such as water-methanol and water-ethanol.
Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid.
Examples of the base to be used include metal hydroxides such as sodium hydroxide and potassium hydroxide; metal carbonates such as sodium carbonate and potassium carbonate;
The reaction temperature is usually in the range of 0 to 100 ° C., and the reaction time is usually from several minutes to several hours depending on the reaction scale.

In any of the production methods 1 to 7 described above, after completion of the reaction, the target product can be isolated by performing ordinary post-treatment operations and purification operations in organic synthetic chemistry.
Moreover, it can be guide | induced to the phenyl pyrazole derivative of this invention by the normal method in organic synthetic chemistry from the production intermediate of the phenyl pyrazole derivative of this invention obtained by the manufacturing methods 1-7.

  The salt of the present invention is not particularly limited as long as it is a salt of the phenylpyrazole derivative (1) of the present invention. Specific examples include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid, and heptagluconic acid. Salt;

  These salts can be easily produced from the phenylpyrazole derivative (1) of the present invention according to a conventional method.

  The structure of the phenylpyrazole derivative of the present invention or a salt thereof obtained as described above can be confirmed and identified by measurement of IR spectrum, NMR spectrum and MS spectrum, elemental analysis and the like.

3) Antioxidant The antioxidant of the present invention comprises the phenylpyrazole derivative of the present invention or a salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) as an active ingredient.

  The antioxidant of the present invention is useful as a therapeutic agent for ischemic organ damage because it can remove various active oxygens and lipid peroxides and prevent tissue damage of ischemic lesions.

  Antioxidants of the present invention are various diseases based on oxidative action, such as kidney disease, cerebrovascular disease, cardiovascular disease, cerebral infarction, arteriosclerosis, aging dementia disease, heart disease, cancer, diabetes, burn, eye disease It is also useful as a therapeutic agent. In ischemic organ diseases such as cerebral infarction and myocardial infarction, various active oxygens are generated during blood reperfusion of ischemic sites, and tissue damage is exacerbated by cell membrane destruction due to lipid peroxidation. For example, the occurrence and progression of arteriosclerotic lesions can be prevented by preventing oxidative degeneration of low density lipoprotein (hereinafter abbreviated as “LDL”), and thus the antioxidant of the present invention. Can be applied to therapeutic drugs for arteriosclerosis.

The antioxidant of the present invention has a lipoxygenase inhibitory action and a 20-HETE synthase inhibitory action. By inhibiting the action of lipoxygenase, it is possible to suppress the conversion of arachidonic acid into HPTE, and it is possible to suppress the production of 20-HETE by inhibiting 20-HETE synthase.
In addition, the compounds of the present invention include compounds that have a small dopamine release inhibitory action and are less likely to have side effects such as Parkinson's.

  The antioxidant of the present invention is a composition containing an active ingredient (the compound of the present invention) and a conventional pharmaceutical carrier or excipient, as well as other drugs, adjuvants, etc. within a range that does not react with other ingredients. be able to. Such a composition may contain 1 to 99% by weight of an active ingredient and 99 to 1% by weight of a suitable pharmaceutical carrier or excipient, depending on the mode of administration. 5 to 75% by weight, with the balance being a suitable pharmaceutical carrier or excipient.

  In the antioxidant of the present invention, regardless of the mode of administration, if desired, a small amount of auxiliary substances such as wetting agents, emulsifiers, pH buffering agents, antioxidants, etc., as long as they do not react with other components, for example, Citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene and the like can also be added.

The antioxidant of the present invention can be administered as a medicament for the above diseases in any manner, for example, orally, nasally, parenterally, topically, transdermally or rectally.
The dosage form can also be a solid, semi-solid, lyophilized powder or liquid dosage form such as tablets, suppositories, pills, soft and hard capsules, powders, solutions, injections, suspensions, aerosols, sustained release An appropriate dosage form can be obtained, which can be formulated into preparations, can be formulated with an accurate dosage, and can be easily administered.

  The preferred route of administration of the antioxidant of the present invention is oral, and the excipient applied to the oral antioxidant is any commonly used excipient, such as pharmaceutical mannitol, lactose, starch. And gelatinized starch, magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like.

  In addition, for oral antioxidants, as diluents, for example, lactose, sucrose, dicalcium phosphate, etc., as disintegrants, for example, croscarmellose sodium or derivatives thereof, as binders, for example, Magnesium stearate or the like can be used as a lubricant, for example, starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose ether derivatives and the like.

  When the antioxidant of the present invention is used as an injection, it is preferable to include a sterile aqueous or non-aqueous solution, suspension, or emulsion. As a diluent for an aqueous solution or suspension, for example, distilled water for injection and physiological saline can be used.

  Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate (trade name), and the like.

  Such injections may further contain additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (for example, lactose), solubilizing or solubilizing agents. These can be used, for example, by filtration through a bacteria retention filter, producing a solid composition of a bactericidal agent, and dissolving in sterile water or a sterile solvent for injection before use.

  When the antioxidant of the present invention is used as a suppository, a carrier that gradually dissolves in the body, such as polyoxyethylene glycol or polyethylene glycol (hereinafter abbreviated as PEG), specifically, PEG 1000 (96%) or PEG4000 (4%), and 0.5 to 50% by weight of the compound of the formula (1) or a pharmaceutically acceptable salt thereof is dispersed in such a carrier.

  When the antioxidant of the present invention is used as a liquid, water, saline, dextrose aqueous solution, glycerol, ethanol or the like is used as a carrier, and the compound of formula (1) or a pharmaceutically acceptable salt thereof is used as the carrier. A solution or suspension is preferably prepared by dissolving and dispersing an arbitrary pharmaceutical adjuvant together with 0.5 to 50% by weight.

  Such formulations are prepared in conventional manner, for example, Remington's Pharmaceutical Sciences, 18th edition, Mac Publishing Company, Easton, Pennsylvania (Mack Publishing Company, Easton, Pennsyl 90). Can be produced according to the description taught in the above.

  In the antioxidants of the present invention, the therapeutically effective amount of the compound of the present invention will vary depending on the individual and the condition of the disease being treated. Usually, the therapeutically effective daily dose can be 0.14 mg to 14.3 mg / day of the compound of the present invention per kg of body weight, preferably 0.7 mg to 10 mg / day of body weight, more preferably body weight. It can be set to 1.4 mg to 7.2 mg / day per kg.

  For example, when administered to a human weighing 70 kg, the dose range of the compound of the present invention is 10 mg to 1.0 g per day, preferably 50 mg to 700 mg per day, more preferably 100 mg to 500 mg per day. It is a guideline until it gets tired, and depending on the medical condition of treatment, a dose outside this range can be used.

4) Therapeutic agent, inhibitor and inhibitor The renal disease, cerebrovascular disease, cardiovascular disease, cerebral infarction therapeutic agent, retinal oxidative disorder inhibitor, lipoxygenase inhibitor, 20-HETE synthase inhibitor of the present invention Including the antioxidant of the invention. The administration mode, dosage form, and dosage of these therapeutic agents, inhibitors, and inhibitors can be the same manner, form, and dosage as the above antioxidants.

  In addition, the therapeutic agent, inhibitor and inhibitor of the present invention can include the same formulation components, carriers, adjuvants and the like as the above antioxidants, excipients, disintegrants, binders, etc. You may add suitably the 1 type (s) or 2 or more types of the other oxidation disorder inhibitor which does not react with an active ingredient. In addition to the above, other medicinal components may be included as appropriate.

(Retinal oxidative disorder inhibitor)
The inhibitor of retinal oxidative disorder of the present invention is a disease caused by retinal oxidative disorder; diabetes, hypertension, arteriosclerosis, anemia, leukemia, connective tissue diseases such as systemic lupus erythematosus and scleroderma, Vascular disorders of the retina due to systemic diseases such as congenital metabolic disorders such as Tay-Sacks disease, Vogt-Spielmeyer disease; inflammatory and degenerative lesions, retinopathy of prematurity, retinal vein occlusion Retinal vascular disorders such as retinal arterial occlusion and periretinal inflammation; retinal inflammation and degeneration resulting from retinal detachment and trauma; retinal degenerative diseases associated with wrinkles such as age-related macular degeneration; congenital It can be used for prevention and treatment of local diseases of the retina such as retinal degenerative diseases. In particular, it is useful as a therapeutic agent for diseases of macular edema, age-related macular degeneration, or diabetic retinopathy that develops due to photooxidation damage.

  Moreover, as an administration form, it can be set as an eye drop and an eye ointment other than the administration form in the case of the said antioxidant.

  When the retinal oxidative disorder inhibitor of the present invention is used as an eye drop, the compound of the present invention is added to a commonly used base solvent to form an aqueous solution or suspension, and the pH is adjusted to 4 to 10, preferably 5 to 9. can do.

  The eye drop is preferably sterilized to be a sterile product, and such sterilization can be performed at any stage of the production process. The concentration of the compound of the present invention in the eye drop is 0.001 to 3% (W / V), preferably 0.01 to 1% (W / V). Depending on the various conditions, it is possible to make several drops or the like 1 to 4 times a day. The above dose is a guideline until it gets tired, and can be administered beyond this range.

  Various additives such as buffers, isotonic agents, preservatives, pH adjusters, thickeners, chelating agents, solubilizers, etc., in a range that does not react with the compound of the present invention are appropriately added to the eye drops. Also good.

  Examples of the buffer include citrate buffer, tartaric acid buffer, acetate buffer, amino acid, and the like. Examples of the isotonic agent include saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol, and salts such as sodium chloride. Examples of the preservative include paraoxybenzoic acid esters such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or a salt thereof.

Examples of the pH adjuster include phosphoric acid and sodium hydroxide.
Examples of the thickener include hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof.
Examples of chelating agents include sodium edetate, sodium citrate, and condensed sodium phosphate. Examples of solubilizers include ethanol and polyoxyethylene hydrogenated castor oil.

  When the retinal oxidative disorder inhibitor of the present invention is used as an eye ointment, the compound of the present invention is mixed with a commonly used eye ointment base such as purified lanolin, white petrolatum, macrogol, plastibase, liquid paraffin, etc. Those that have been sterilized to make aseptic products are preferred.

  The concentration of the compound of the present invention in the eye ointment is 0.001 to 3% (W / W), preferably 0.01 to 1% (W / W), and the dosage is also the degree of symptoms, patient constitution, etc. Depending on various conditions, it can be 1 to 4 times a day. The above dose is a guideline until it gets tired, and can be administered beyond this range.

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

Example 1
Step 1: Preparation of 5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyl trifluoromethanesulfonate

To a solution of 6.7 g of trifluoromethanesulfonic anhydride in 50 ml of dichloromethane was added 5.0 g of 2-hydroxymethyl-2,4,6,7-tetramethylbenzofuran and 2.4 g of triethylamine in 50 ml of dichloromethane at 0 ° C. for 30 minutes. It was dripped at. After completion of dropping, the mixture was stirred at 0 ° C. for 1 hour, then warmed to room temperature, and further stirred for 1.5 hours.
After completion of the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate and filtered. The concentrate obtained by evaporating the solvent from the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 100: 1 (volume ratio)) to obtain 7.3 g of the desired product.

Step 2: Preparation of 1- (5'-nitro-2 ', 4', 6 ', 7'-tetramethyl-2', 3'-dihydrobenzofuran-2'-ylmethyl) -3-phenylpyrazole

(In the formula, Tf represents a trifluoromethanesulfonyl group.)
0.06 g of 60 wt% sodium hydride was added to a solution of 0.22 g of 3-phenylpyrazole in 5 ml of DMF, and the mixture was stirred at room temperature for 1 hour. To this reaction solution, 0.50 g of 5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyl trifluoromethanesulfonate was added and stirred at room temperature for 18 hours.
The reaction solution was concentrated under reduced pressure, chloroform was added, and the organic layer was washed four times with water, dried over anhydrous magnesium sulfate, and filtered. The concentrate obtained by concentrating the solvent from the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 20: 1 (volume ratio)) to obtain 0.49 g of the desired product.

Step 3: Preparation of 1- (5'-amino-2 ', 4', 6 ', 7'-tetramethyl-2', 3'-dihydrobenzofuran-2'-ylmethyl) -3-phenylpyrazole

  To 10 ml of ethanol, 0.49 g of 1- (5′-nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -3-phenylpyrazole, Stannous chloride dihydrate (0.88 g) and concentrated hydrochloric acid (4 ml) were added, and the whole volume was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into water, neutralized with sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (chloroform: methanol = 20: 1 (volume ratio)) to obtain 0.30 g of the desired product (amorphous).

(Example 2)
Step 1: Preparation of ethyl 2-oxo-3-benzoylpropionate

Sodium methoxide (3.61 g) and diethyl oxalate (14.7 ml) were added to benzene (37 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, and 3.00 g of acetophenone dissolved in 55 ml of benzene was added dropwise thereto over 1 hour, followed by stirring at room temperature for 3 hours.
The reaction solution was ice-cooled, and the cooled 10 wt% aqueous sulfuric acid solution was added to neutralize the reaction solution. After extraction with benzene, the organic layer was washed with water. Thereafter, back extraction was performed twice with a 2N aqueous potassium carbonate solution, and the aqueous layer was neutralized with a 10% aqueous sulfuric acid solution and then extracted with benzene. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 5.07 g of the desired product.

Step 2: Production of 5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethylhydrazine

To a solution of hydrazine monohydrate 7.81 g in ethanol 5 ml, 5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyltrifluoromethanesulfonate 4.00 g of ethanol 5 ml The solution was added dropwise at room temperature over 20 minutes and further stirred at room temperature for 1 hour and at 40 ° C. for 1.5 hours.
The reaction solution was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (chloroform: methanol = 9: 1 (volume ratio)) to obtain 2.94 g of the desired product.

Step 3: 1- (5′-nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -5-phenylpyrazole-3-carboxylic acid Ethyl production

  To 10 ml of ethanol was added 1.10 g of ethyl 2-oxo-3-benzoylpropionate and 1.46 g of 5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethylhydrazine, The whole volume was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrate obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 1.09 g of the desired product.

Step 4: 1- (5′-nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -5-phenylpyrazole-3-carboxylic acid Manufacturing of

1- (5′-nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -5-phenyl in a mixed solution of 15 ml of methanol and 9 ml of water 0.50 g of ethyl pyrazole-3-carboxylate and 0.38 g of sodium hydroxide were added, and the mixture was stirred at 50 ° C. for 2 hours.
Ethyl acetate was added to the reaction solution, the aqueous layer was separated, neutralized with hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 0.33 g of the desired product.

Step 5: Preparation of 1- (5'-nitro-2 ', 4', 6 ', 7'-tetramethyl-2', 3'-dihydrobenzofuran-2'-ylmethyl) -5-phenylpyrazole

  1- (5′-Nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -5-phenylpyrazole-3-carboxylic acid 0.33 g Was stirred at 200 ° C. for 6 hours. This was cooled, an aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrate obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 9: 1 (volume ratio)) to obtain 0.14 g of the desired product.

Step 6: Preparation of 1- (5'-amino-2 ', 4', 6 ', 7'-tetramethyl-2', 3'-dihydrobenzofuran-2'-ylmethyl) -5-phenylpyrazole

To 10 ml of ethanol, 0.14 g of 1- (5′-nitro-2 ′, 4 ′, 6 ′, 7′-tetramethyl-2 ′, 3′-dihydrobenzofuran-2′-ylmethyl) -5-phenylpyrazole, 0.25 g of stannous chloride dihydrate and 3 ml of concentrated hydrochloric acid were added, and the whole volume was refluxed for 2 hours. Thereafter, 0.50 g of stannous chloride dihydrate and 3 ml of concentrated hydrochloric acid were added, and the mixture was further refluxed for 1 hour.
The reaction solution was cooled, poured into water, neutralized with sodium hydroxide solution, and extracted twice with chloroform. The organic layer was collected, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The concentrate obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 20: 1 (volume ratio)) to obtain 0.13 g of the desired product.
Melting point: 84-87 ° C

Specific examples of the phenylpyrazole derivative of the present invention produced as described above are shown in Tables 1 to 6. About the compound described as NMR in the column of the physical constant in a table | surface, NMR data are shown after a table | surface.
In the table, h1 to h8 in column Z represent the groups shown below. In the table, Ac of NAc represents an acetyl group.

(Example 3) Production of antioxidant A preparation containing the compound of the present invention was prepared by the following method.
Oral (active ingredient 10mg tablet)
10 mg of the present compound
Lactose 81.4mg
Corn starch 20mg
Hydroxypropylcellulose 4mg
Carboxymethylcellulose calcium 4mg
Magnesium stearate 0.6mg
―――――――――――――――――――――――――――
120mg total

  In order to obtain the composition as described above, 50 g of the present compound, 407 g of lactose and 100 g of starch were mixed uniformly using a fluidized granulation coating apparatus (Okawara Seisakusho). This was sprayed and granulated with 200 g of a 10% by weight hydroxypropylcellulose aqueous solution. After drying, a 20-mesh sieve is passed through, 20 g of carboxymethylcellulose calcium and 3 g of magnesium stearate are added, and a 7 mm × 8.4 R mortar is used on a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd.). 120 mg tablets were obtained per tablet.

[In vitro lipid peroxide production inhibitory effect]
The in vitro lipid peroxide production inhibitory action test of the compound of the present invention was carried out by the method of Malvy et al. (Malvy, C., et al., Biochemical and Biophysical Research Communications, 1980). 95, pp. 734-737). The organ used was the retina stored at −80 ° C. after being separated from the porcine eyeball. At the time of use, 5 times the amount of phosphate buffered saline (pH 7.4) was added and homogenized with a microhomogenizer (PHYSCOTRON, NITI-ON). 0.15 M KCl, the compound of the present invention, 500 μM cysteine, and 5 μM FeSO ₄ were added to this porcine retina homogenate and incubated at 37 ° C. for 30 minutes. Malondialdehyde produced by the decomposition of lipid peroxide was measured by the thiobarbituric acid method. The 50% inhibitory concentration (IC ₅₀ ) of the compound of the present invention was determined from the measured value. The results are shown in Table 8. The compound of the present invention was found to have an in vitro lipid peroxide production inhibitory action.

[Organizational migration]
The tissue transferability of the compounds of the present invention was evaluated by measuring the ex vivo lipid peroxide production inhibitory action. The compound of the present invention was dissolved in DMSO (final concentration 20%) and dissolved or suspended in 0.1N hydrochloric acid physiological saline or 1% polyethylene hardened castor oil (NIKOL HCO-60, Nikko Chemical Co., Ltd.). This solution was orally administered to 3 SD male rats (Japan SLC, 6 weeks old) per group. One hour after administration, the brain and eyeball were removed after anesthesia. For the retina separated from the brain and eyeball, the amount of lipid peroxide of each tissue homogenate was measured by the method described in the section [In vitro lipid peroxide production inhibitory action]. The inhibition rate in each tissue of the compound of the present invention was determined from the amount of lipid peroxide produced in the control group (20% DMSO-0.1N hydrochloric acid physiological saline / 1% polyethylene hydrogenated castor oil group) and the compound administered group of the present invention. . The dose (IC ₅₀ ) that inhibits 50% was determined from the inhibition rate at each dose. The results are shown in Table 9. From the results, it was revealed that the compound of the present invention has a high tissue migration property.

Claims (12)

Formula (1)

{In the formula, R1 and R2 are defined by

[Wherein, R10 and R11 each independently represent a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group, or a C _2-6. An alkynyl group, a C _2-6 alkenyloxy group, a C _2-6 alkynyloxy group, an acyloxy group, or an optionally substituted G1 (C _3-8 cycloalkyl group or phenyl group);
G1 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.
k represents an integer of 0 to 15. When k is 2 or more, R10s and R11s may be the same or different.
Z has at least G2 as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3-dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman 2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolan-2-yl group)
G2 is a group represented by the formula: NHR12 [wherein R12 is a hydrogen atom, a formyl group, a C _1-6 alkylcarbonyl group, or (a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom , A nitro group, an amino group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group). Or a group represented by the formula: OR13 [wherein R13 is a hydrogen atom, a formyl group, a C _1-6 alkylcarbonyl group, or (a cyano group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 An alkoxy group, a halogen atom, a nitro group, an amino group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group). . Represents a group represented by the formula: However, when R1 is a group represented by the formula (2), R2 does not exist, and when R2 is a group represented by the formula (2), R1 does not exist.
R3 may be substituted with a hydrogen atom or G3 (C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbamoyl) Group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkoxy group, phenyl group, or heteroaryl group), carboxyl group, hydroxyl group, or cyano group,
G3 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.
R4 represents a hydrogen atom or G4 (C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, phenyl group, or heteroaryl group) optionally substituted with G4,
G4 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group.
R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a cyano group, a hydroxyl group, a halogen atom or G5 (C _1-6 alkyl group, C _1-6 alkoxy group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group, acyloxy group, mono-C _1-6 alkylamino group, or di-C _1-6 alkylamino group Group), or optionally substituted with G6 (piperazyl group, piperidyl group, C _3-8 cycloalkyl group, phenyl group, or heteroaryl group),
G5 is a cyano group, formyl group, C _1-6 alkylcarbonyl group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 alkylamino group, diC _1-6 alkyl Represents an amino group or a C _1-6 alkoxycarbonyl group,
G6 is a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, cyano group, hydroxyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, mono C _1-6 An alkylamino group, a diC _1-6 alkylamino group, or a C _1-6 alkoxycarbonyl group is represented.
Further, among R5, R6, R7, R8 and R9, two adjacent groups may be combined to form a ring, or R4 and R5 may be combined to form a ring. Good. }
Or a salt thereof. Z is the following (A), (B), (C), (D) or (E)

(Wherein, G2 are as defined above, * represents a chiral carbon atom, _{Y 1} represents an oxygen atom or a sulfur atom, R14～R34 are each independently a hydrogen atom or a _{C 1-6} The phenylpyrazole derivative or a salt thereof according to claim 1, wherein the phenylpyrazole derivative is a group represented by the following formula: Formula (a)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (b)

[Wherein R10, R11 and k represent the same meaning as described above, and Z1 has at least a nitro group or an acyloxy group as a substituent (chroman-2-yl group, chroman-4-yl group, 2,3- Dihydrobenzofuran-2-yl group, 2,3-dihydrobenzofuran-3-yl group, thiochroman-2-yl group, 2,3-dihydrobenzothiophen-2-yl group, or 1,3-benzoxathiolane- 2-yl group)
L represents a leaving group. ]
Wherein the compound represented by formula (1a-1) is reacted.

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above). Formula (c)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (d)

(Wherein R10, R11, k and Z1 represent the same meaning as described above) and a compound represented by the formula (1a-1)

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above). Formula (e)

(Wherein R3 to R9 represent the same meaning as described above), and the formula (d)

(Wherein R10, R11, k and Z1 represent the same meaning as described above) and a compound represented by the formula (1a-1)

Or formula (1b-1)

(Wherein R 3 to R 11, k and Z 1 represent the same meaning as described above).   An antioxidant comprising one or more of the phenylpyrazole derivatives or salts thereof according to claim 1 or 2.   A therapeutic agent for kidney disease, cerebrovascular disease or cardiovascular disease, comprising the antioxidant according to claim 6.   The therapeutic agent of cerebral infarction characterized by including the antioxidant of Claim 6.   A retinal oxidative disorder inhibitor, comprising the antioxidant according to claim 6.   The inhibitor according to claim 9, wherein the retinal oxidative disorder is macular edema, age-related macular degeneration, or diabetic retinopathy.   A lipoxygenase inhibitor comprising the antioxidant according to claim 6. A 20-hydroxyeicosatetraenoic acid synthase inhibitor comprising the antioxidant according to claim 6.