JPH02229168A - Pyrazolone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is (substituted) 8-20C chain hydrocarbon group or polyether chain group having sum of (substituted) carbons and oxygen of 8-20 atoms; R<2> is substituent group-containing CH3 or (substituted) cyclic group], a compound shown by formula IV or a salt thereof. EXAMPLE:3-Cyclopropyl-1-octyl-2-pyrazolin-5-one. USE:A drug. An inhibitor of formation of peroxy lipid or lipoxygenase inhibitor and collagenase inhibitor, having low toxicity and side effects, useful for treating and preventing diseases such as diseases of circulatory organs, inflammations, allergies, etc., and cancer metastatis. PREPARATION:1mol beta-keto-acid derivative shown by formula II (R<3> is 1-5C alkyl) is reacted with 1-3mol hydrazine derivative shown by formula III in a solvent such as ethanol under cooling with ice-100 deg.C for about 30 minutes - 15 hours to give a compound shown by formula I or formula IV. The compound shown by formula IV is isolated and heated to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is a lipid peroxide production inhibitor and lipoxykenase inhibitor useful for the prevention and treatment of diseases such as cerebrovascular disorders, arteriosclerosis, liver diseases, cancer metastasis, and various inflammations. , phospholipase A, inhibitory action, collagenase inhibitory action, etc.

Conventional technology and its challenges As it becomes clearer that the production of lipid peroxide in the body and the accompanying Lasityl reaction have an adverse effect on the living body through membrane damage and enzyme damage in various tissues. ,
Attempts have been made to apply antioxidants and riboxygenase inhibitors that can act as lipid peroxide production inhibitors to pharmaceuticals. It is also known that collagenase and protease activity is high in areas where tissue damage has progressed. Therefore, there are expectations in the medical field for the development of drugs that have a combination of lipid peroxide production inhibiting action, riboquinkenase inhibiting action, collagenase inhibiting action, and the like.

The antioxidants currently in use are mainly vitamin C.
and derivatives of natural antioxidants such as vitamin E, and
The basic skeleton is limited, and is not necessarily satisfactory in practical terms.

For pyrazolone derivatives, JP-A-62-10881414
96 ratio JP-A-63-130592.130593 Compound 1 that suppresses the production of lipid peroxide JP-A-59-1754
No. 69 describes a compound having riboquinase inhibitor activity. However, through further investigation, the present invention was completed, which also has collagenase inhibitory activity.

The present invention also relates to the pyrazolone derivatives represented by []'] or [1'-A], which are simply compounds [bi], [
It is sometimes referred to as B A]. ) or a salt thereof as an active ingredient, particularly a lipid peroxide production inhibitor, a riboquinase inhibitor, and a collagenase inhibitor.

Furthermore, among the compounds represented by the formulas [Bi] and [1'-A], compounds in which R2 is a methyl group having a substituent or a cyclic group which may have a substituent, the Zunawara formula [in the formula , R1 has 8 to 2 carbon atoms, which may have a substituent
0 chain hydrocarbon group or a polyether chain group having the sum of carbon number and oxygen number 8 to 20 which may have a substituent,
R2 represents a methyl group having a substituent or a cyclic group which may have a substituent. ] There is no mention of compounds.

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors synthesized a number of new compounds and investigated the effects of each of them on the inhibition of lipid peroxide production, the inhibition of pokinkenase, the inhibition of collagenase, etc. . As a result, in formula 1, R1 has 8 to 2 carbon atoms, which may have a substituent.
0 chain hydrocarbon group or a polyether chain group having the sum of carbon number and oxygen number 8 to 20 which may have a substituent,
R2/ represents methyl bt which may have a substituent or a cyclic group which may have a substituent. ] It has been discovered that the pyrazolone derivatives represented by or their salts have useful effects as pharmaceuticals such as excellent lipid peroxide production inhibiting action, ribokinogenase inhibiting action, and collagenase inhibiting action, and the compound represented by (hereinafter simply referred to as compound [11, [I
A]. ) or its salt is Sentence 11i1
1 are unknown compounds, and the present invention also provides these novel compounds.

In formula [J], [B], [I-A], [B-A],
The chain hydrocarbon group having 8 to 20 carbon atoms represented by R1 may be saturated or unsaturated, and may be linear or branched. Examples of such chain hydrocarbon groups include alkyl groups, alkenyl groups, and alkynyl groups. Examples of the saturated straight-chain alkyl group include octylnonyldecylundecyl dotesyltridenyl, tetrathenerupentatenhexadecylheptadecyloctatenylnonadecyleicosyl, and the like. Branched alkyl (including 1-ethyloctyl, 37-ramethyloctyl, 3,7
．． 11. , ],, 5-te[・ramethylhexadecyl. The unsaturated alkyl group represented by R1 includes 9-thecenyl, 11-hexatecenyl, 9-
One example is octadecenyl. In addition, when the chain hydrocarbon group represented by R1 has a substituent, examples of the substituent include a hydroxyl group, a nonorpoquinyl group, a metquine group, a lower (C, -8) alkoxo group such as an ethoxy group, and an ethoxycarbonyl group. Examples include lower alkoxycarbonyl groups such as, and the substitution position is not particularly limited. Examples of the polyether chain represented by R1 include 3,6-thioxaoctyl and 3,6.9-1-rioxatridenyl.

Examples of substituents for the methyl group having substituents represented by R2 and R2' in the above formula include lower (C3-6)
Cycloalkyl, lower (C, -1) alkyl group optionally substituted with phenyl group, phenoxy group, etc., halokene atom, hydroxyl group, ce-1° alkyl group, phenyl group, (II (C, -5) Alkoxynonorponyl group (e.g.
Hensen rings such as etquinnonorphonyl, metquincarbonyl), pennluoquine group, carboxyl group, benzylthio group pensoylamino group [tubonyl group, ), f-noquine group, etc.] are respectively halokene atoms, amino groups, hydroxyl groups, It may be substituted with a C1-6 alkyl group, a C1-, an alkoxy group, or the like. ], etc. can be mentioned.

The cyclic group which may have a substituent represented by R2,R'' includes not only a saturated cyclic group but also an unsaturated cyclic group.In the case of unsaturated, even if it is an aromatic cyclic group, Often, such an aromatic ring group may be an aromatic carbocyclic group or an aromatic heterocyclic group. Examples of such an aromatic carbocyclic group include a tubonyl group, a naphthyl group, and an aromatic heterocyclic group. As a ring group, quinolyl group, pyridyl group, furirino;
t, thienyl group, etc.

Examples of the saturated cyclic group include a cyclopropyl group and a cyclohexyl group. Examples of the unsaturated non-aromatic cyclic group include a cyclohexenyl group and a cyclopentenyl group.

In addition, as substituents for the cyclic group represented by R2, R'', hydroxyl group, t-butyl, phenyl, halogen atom (e.g., chlorine atom), amine group, dimethylamino group + CI
-G alkoxyl group (eg, methoxy/group), C alkylthio group, and the like.

Compounds of the present invention II], [1'], II-AI, [l
-A'] is preferably a pharmaceutically acceptable salt; examples of pharmaceutically acceptable salts include hydrogen halide (e.g., hydrogen chloride) when R2 has a basic substituent; Inorganic acids and organic carboxylic acids such as hydrogen, hydrogen bromide), phosphoric acid, sulfuric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid), sulfonic acids (e.g. methanesulfonic acid, hensensulfonic acid) Organic acids such as Nato can be mentioned. Also R1 and R2
When -1- has an acidic group such as a carboxyl group as a substituent, an alkali metal (e.g., sodium, )Jium)
Alternatively, inorganic base salts with alkaline earth metals (eg, magne/lamb) and salts with organic bases (eg, amines such as cyclohexylamine, triethylamine, 2,6-lutisone, etc.) can be mentioned. These salts are also included within the scope of the present invention.

Compounds [11 and [1-AI] and salts thereof of the present invention can be produced, for example, by the method of Scheme =1.

In addition, in producing compound [1] and [I-AI or a salt thereof, whether they can be obtained in a free form or as a salt thereof, in the following explanation of the manufacturing method, such salts will also be explained. Including, they are simply referred to as compounds [1] and [1-AI.

(The following is a blank space) The derivative can be produced by a known production method or a method analogous thereto, and for example, it can also be synthesized according to scheme -■.

Diagram-■ [In the formula, R2 and R3 have the same meanings as above, R' COX
Ac represents a reactive derivative of hacarboxylic acid, and Ac represents an acetyl group. That is, a reactive derivative of a carbonic acid represented by R2C0X[V] (1 mol), a malonic acid macinolate (approximately 1 to 3 mol) prepared from malonic acid half ester potassium salt, and magnesium/rum chloride.

Alternatively, by reacting acetic acid ester (A, cOR3) in the presence of a base (eg, lithium diisopropylamide), a β-ke].acid derivative represented by the formula [■] can be obtained. To be more specific, about 1 mol of the β-keto acid derivative represented by compound [V] and malo, i.e., compound []T], is mixed with about 1 mol of the hydrazine derivative represented by compound [1111].
Add ~3 mol, preferably about 1-12 mol, cool on ice ~lo
o'c, the compound [+
] or [I-Δ] can be obtained. For example, when R2 is trifluoromethyl, a reaction under water cooling to room temperature yields a compound represented by formula [J-A], and a reaction under heating yields compound [1]. [+] can also be obtained by heating after isolating A-A]. The solvent used at this time is alcohol such as methanol or ethanol, or benzene, toluene, xylene, or tetrahydrofuran.
Dioxane, dimethylformamide, etc.

If necessary, add potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium acetate, base such as ethylamine, mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, para-toluenesulfone. A catalyst such as an organic acid such as an acid is used. The reaction time is typically 30 minutes to 15 hours hot.

When reacting the raw material compound β-keto acid magnesium enolate represented by the formula [n], the reaction is carried out at room temperature to 2.
00°C2i! ! It usually progresses smoothly at 50°C to 100'C. The solvent used at this time is not particularly limited as long as it is inert to the reaction, and tetrahydrofuran, dioxane, dimethylformamide, etc. are often used. The reaction time depends on the temperature of the solvent, but is usually 30 minutes or more.
Fever for 15 hours. In addition, when compound [V] and acetate are reacted in the presence of a base, one reaction is from -78°C to
Proceeds smoothly at room temperature. The solvent used at this time may be any solvent as long as it is inert to the reaction. Although not particularly limited, tetrahydrofuran and dimethylformamide are often used. The reaction time is usually about 30 minutes to 5 hours with a little heat.

In Scheme-H, reactive derivatives of carboxylic acid represented by Formula 1 [V] include acid chloride, acid bromide, imidazolyte
・Acid anhydrides, N-phthalimi I-ester, N-oxinsuccinimide ester, etc.

In Scheme-I, the other starting compound nirUi
] The human ranane derivative shown can be produced by a known method or a method analogous thereto, or, for example, can be synthesized by a method not shown in the scheme -■.

Schema-1■ H3NNH2・11,0 RI-OII−−−−−−−−−→RY
IIJIIIR [■] [
■] [■] 1 scheme-■ In 1, R1 has the same meaning as above R'-Y or alcohol R10I]
Reactive derivatives of ] In the scheme -In, R'-
Reactive derivatives of alcohol (R' OH) represented by Y include halokenides (e.g., chloride, bromide) and sulfonic acid esters (e.g., methanesulfonite, ethanesulfonite) derived from alcohol (RI-01t).
I can give it to you.

When obtaining a sulfonic acid ester, alcohol [VI] may be reacted with methanesulfonyl chloride, ethanesulfonyl chloride, etc. in the presence of triethylamine or pyridine. The solvent used at this time is chloroporum, methylene chloridone, and the salt of methylporum amide. citric acid)
metabolic modification, especially the effect of suppressing the lipid peroxide production reaction (
(antioxidant effect), 1 example of 5-lipoxygepase metabolite, leukotriene I, 5-human lobeloquineicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraene (HETE), 10 lipoquinones Iftoquinones, etc.], inhibition of rolonphoxane fluorase, prostaglan 2-1, synthetic enzyme retention promoting effect, active oxygen species scavenging effect, and anti-allergic effects and circulatory system improvement effects. have It also exhibits collagenase inhibitory activity and phospholipase inhibitory activity.

In particular, the compounds [do] and [I'-AI or their salts of the present invention have an effect of suppressing the lipid peroxide production reaction (antioxidant effect), and inhibiting the 5-riboxingenase system. It tends to significantly inhibit the production of metabolites.

In addition, compounds [bi] and [1'-AI or their torsion
Tetrahydrofuran, etc.

The reaction between compound [■] and hydrazine is usually carried out in alcohol (e.g., methanol, ethanol) with 5
This is carried out using a 10-fold molar amount of hydrated hydrazine.

The reaction proceeds smoothly at O'C to 100°C, usually at O'C to 30°C, and is completed in 30 minutes to 15 hours.

The salts of compound [1]] include, for example, salts with inorganic acids such as hydrochloride and sulfate; and the salts of compound [TI] include, for example, salts with inorganic acids such as hydrochloride and sulfate. Can be mentioned.

Compounds [1] and [IA
] can be isolated and purified by conventional separation means such as recrystallization, distillation, and chromatography. When the compounds [+1 and [IA] obtained in this way are obtained in free form, they can be converted into salts by neutralization etc. by methods known per se. By law, it can be converted into a free form.

The toxicity and side effects of the compounds [Bi] and "I'-A" of the present invention or their salts are low.

Therefore, the compounds [Bi] and [■'-A] of the present invention or their salts can be used in mammals (mouse, rat, rabbit dog,
Ischemic diseases (e.g., myocardial infarction, stroke) caused by contraction or vasospasm of arterial vascular smooth muscle in the heart, lungs, brain, and kidneys (monkeys, humans, etc.), chronic neurological diseases (Parkinson's disease, Alzheimer's disease, etc.) Mr. disease,
muscular dystrophy), head trauma, spinal cord trauma, and other central damage disorders; memory and emotional disorders (disorders associated with nerve cell necrosis caused by oxygen deficiency, brain damage, stroke, cerebral infarction, cerebral thrombosis, etc.); Convulsions and epilepsy that occur after a stroke, cerebral infarction or brain surgery 2 head trauma, nephritis pulmonary failure, bronchial asthma, inflammation, arteriosclerosis, atherosclerosis, hepatitis, acute hepatitis, liver cirrhosis, hypersensitivity pneumonitis immunodeficiency, Cardiovascular diseases (myocardial infarction, stroke,
It has therapeutic and preventive effects on various diseases such as cerebral edema, nephritis, etc.), tissue fibrosis, carcinogenesis, and tissue invasion of cancer accompanied by collagenase and reactive oxygen species. agent, anti-allergy agent, heart and brain circulatory system improving agent, nephritis treatment agent, hepatitis treatment agent 5 tissue fibrosis μm1 inhibitor, cancer metastasis inhibitor, reactive oxygen species scavenger, arachidonic acid cascade-1. It is useful as a drug for improving substance regulation.

Compounds [B] and "B∆" or their salts can be used as such or in pharmaceutical compositions (e.g., tablets, capsules, liquids, injections) mixed with known pharmaceutically acceptable carriers and excipients. It can be safely administered orally or parenterally as a tablet, skewer, or inhaler.The dosage may vary depending on the recipient, route of administration, and symptoms, such as
When orally administered to adult patients, the single dose is usually about 1 mg/kg to 50 mg/kg body weight, preferably about 02 to 20 mg/kg body weight, more preferably 0.5 mg/kg = 10 Is it convenient to administer mg/kg body weight 101 to 3 times?2
It is more preferable to increase or decrease the amount as appropriate depending on age, medical condition, presence or absence of simultaneous administration, etc.

After mixing the effects of the invention, subjecting it to high performance liquid chromatography, 5-1
(ETE was quantified. 5-HETE is 2
Absorption at 40 nm was measured using an ultraviolet absorption monitor.

Table 1 shows the inhibition rate of 5-HETE production calculated from the peak area.

In addition, the production suppression rate (lE) of 5-HETE is (1-
b/a)X], OO. In the formula, a is the peak height or peak area value when it does not contain [bi] or [bi A], and 1) is the peak height or peak area when it contains the compound [do] or [1'-A]. represents a value.

Table 1 8 Sample Concentrations (M) The compounds [Bi] and [Bi A] of the present invention, or their salts, have an effect of inhibiting lipid peroxide production (antioxidant effect), an inhibitory effect of lipoxyganase, as shown in the following test. It has phospholipase A inhibitory activity, collagenase inhibitory activity, etc., and is useful as a medicine for the treatment and prevention of diseases such as circulatory system disease 1, inflammatory allergy, and cancer metastasis.

Test Examples, Examples and Reference Examples are described below, but the present invention is not limited thereto.

Effect test example 15-Lipoxykenase inhibitory effect RB L-1
cell (rat basophilic leuke)
miacel Is) 1. MCM (mas
The test solution was suspended in T cell medium) 09d and mixed to a temperature of 0 μM, ] μM, O, l 8M caranal).
was added and incubated at 37°C for 5 minutes.

Next, 50 μg of arachidonic acid and Cal/Ionopore A
MCMO, Id containing 10 μg of -23187 was added and the ink was further incubated at 37° C. for 15 minutes. After the reaction, add 1 d of ethanol and shake well.The above results show that the compound of the present invention inhibits riboxykenase even at low concentrations.
It can be seen that the production of 5-HETE is suppressed.

Test Example 2 Inhibition of Lipid Peroxide Production Method by Kaimoto et al. [Chem, Pharm, Bull,
, 342821 (] 986),], the amount of lipid peroxide produced was determined by the thiobarbic acid method, and the concentration of the compound of the present invention required to suppress the amount of lipid peroxide produced by 50% was determined. It is shown in Table 2.

(The following is a blank space) Table 2 From the above results, it can be seen that the compound of the present invention exhibits an effect of suppressing the production of stale lipid peroxide.

Test Example 3 A2 inhibitory activity CaC on Phospolyper (!z,
Tris-HCC bufrer (pH 8,0), thioquincholic acid or 3, 5 mM, 50 mM, respectively;
Enzyme (Porc
inePancrease Pl,,ase A2)
08μg/11! Concentration of ρ The above results indicate that the compound of the present invention has excellent phospholipase A inhibitory activity.

Test Example 4 Collagenase inhibitory activity Collagenase inhibitory activity was determined by a fluorescence method according to the method of Hyochi et al. [Inflammation, C123 (1984,)], and the results are shown in Table 4.

(Margin below) Add 1 g of the enzyme solution dissolved in the test solution (
The final concentration consists of 100μM, 10dM, lμM)0
．． 01d was added and incubated at 37°C for 5 minutes. Next, the substrate (1-Palmitoyl-2(2)
-hexadecenoyl) -sn -glyce
ro-3phosphotidylchol 1ne)
solution (CaC(!2. TrisHCQ buff
er (pH 8,0), deochincholic acid or 3.
02d (a solution prepared by dissolving the substrate at a concentration of 0.3 mg/2.0) was added to solutions prepared to have concentrations of 5 mM, 50 mM, and 0.5 mM, and the mixture was incubated at 537°C for 1 hour. Then, the internal standard solution [Linolei
c acid) 15 μg/methanol 1d]0.
:M was added, and further 0.3 d of acetic acid, 2 d of methanol were added. This liquid was subjected to high performance liquid chromatography,
Linoleic Ac1d and 211exa
The inhibitory activity of phospholipase A was calculated from the height of the decenoic acid peak.

From the above results, it can be seen that the compound of the present invention has collagenase inhibitory activity.

Hereinafter, the present invention will be explained in more detail with reference to reference examples and examples, but the present invention is not limited to these examples.

The elution in Karato chromatography in the following Reference Examples and Examples is TLC (Thin Layer Ch
romat.

The ratio of solvent described in the section of separation by chromatography indicates the volume ratio.

In the TLC observation, Kisekel 60 F 254 manufactured by Merck was used as the T I-C play 1, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and UV detection was used as the detection method. A device was adopted. Kieselkel 60 (70 to 230 mesh), also manufactured by Merck, was used as the column material.

Moreover, the compound numbers described in the reference examples and examples correspond to the description numbers in the table.

Reference Example 1 3-oxo-3-(2-quinolyl)propanoic acid methyl ester (Method A) Methylmalonic acid half potassium salt 34. ．． 4g (02
10.5 g (0.11 mol) of powdered magnesilla chloride A was added to 100 d of a dimethylformamide solution of 2 mol), and the mixture was heated and stirred at room temperature for 30 minutes and then at 95°C for 15 hours.

On the other hand, 50 TIf of a dimethylformamide solution of 1.7.39 (0.1 mol) of quinaluronic acid! To this, 17.8y (0.1 mol) of N,N'-carphonyl imitasol was added, and the solution was prepared by stirring the chamber for 40 minutes with crystals. The resulting solution was cooled to -65 to -70 °C, 23.4 d (0.24 mol) of ethyl acetate was added, and after stirring for 30 minutes, a THF solution of 25 g of cyclopropanoyl chloride (<0.24 mol) was added. was dripped. This mixture -65～-
After stirring for 1 hour at 70°C, it was treated with an aqueous ammonium chloride solution. Ltf+ with ethyl acetate, sodium bicarbonate solution, water (
3 was purified, dried over magnesium sulfate/ram, and the solvent was distilled off under reduced pressure. The residue was purified on Rikakel column chromatography using ethyl acetate-hexane (20:80) as a developing solvent to obtain the title compound (compound No. 10) 28.1
9 was obtained as an oil.

Yield 753% Reference Examples 11 to 14 Compound No. ] ] to 1 in Table 1 in the same manner as Reference Example 2
A compound shown as /I was synthesized.

was added to the reaction solution.

This mixture was heated and stirred at 95°C for 2 hours. The slurry was cooled to room temperature, treated with IN hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate/ram, and the solvent was distilled off under reduced pressure. The residue was purified using ethyl acetate-to-beef sanitation (20:80) as a developing solvent to obtain 15.2 g of the title compound (compound N○I) as a white solid.

Yield 662% Melting point 54-56°C Reference Examples 2-9 Compounds shown in Table 1 as Compounds NO2-9 were synthesized in the same manner as in Reference Example 1.

Reference Example 10 3-Cyclofuropyru-3-oxopropanoic acid ethyl ester (Method B) Isopropylamine 4.8.4 y (0.48 mol)
THFl, 1ffl] To 0vtfl, 30.6y (0,4
, 8 mol) was added dropwise to the lithium diisopropylamide solution. Triethylamine 4-2.19 (0.42 mol) of methanesulfonyl chloride 29 in dichloromethane 1iffllOOd
, 7d (0.42 mol) was added dropwise under water cooling, and the mixture was stirred at room temperature for 2 hours. After adding water, the mixture was extracted with dichloromethane.

The organic layer was dried with magnesium sulfate and the compound (compound N
○30) was obtained as a 20.49 ml product. This compound was used in the next reaction without purification.

Reference Example 31 A compound shown as Compound No. 31 in Table 2 was synthesized in the same manner as Reference Example 30.

(The following is a blank space) The solvent was distilled off under reduced pressure. Ethanol solution of residue 10
100 g (2 mol) of water-containing hydrazine was added to 0d, and the mixture was stirred at room temperature for 12 hours.

The solvent of this mixture was distilled off under reduced pressure, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and vacuum F.
The solution was distilled off to obtain the title compound (compound No. 1.5
) was obtained in the form of 43.7 g. This compound was used in the next reaction without being purified.

Reference Examples 16 to 29 Compounds shown as Compounds Nos. 16 to 29 in Table 2 were synthesized in the same manner as in Reference Example 15.

Reference Example 30 11-Hydroxy-1-undecylhydrazine (Method B) An ethanol solution of 25.1 g (0.1 mol) of 11-bromo-1-undecanol at 10 fM! hydrated hydrazine 50%
．． 1 g (1 mol) was added and stirred at room temperature for 12 hours. The solvent of this mixture was distilled off under reduced pressure and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give R-NHNH.

Example 1 50 d of ethanol solution of cyclofuropyru-1 octyl-2 pyrazolin-5-one 3-7 chlorofuropyru-3-ocyppropanoic acid ethyl ester 39 (19.2 mmol)
333 g (23.1 mmol) of 1-octylhytoranane was added to the mixture, and the mixture was stirred at room temperature for 15 hours. After diluting with water, it was extracted with chloroform. The organic layer was diluted with aqueous sodium bicarbonate solution for 6 hours, dried over magnesium sulfate in the afternoon, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using ethyl acetate-hexa/<50.50) as a developing solvent to obtain 974 mg of the title compound (compound No. 32) as white crystals.

Yield 21.5% Melting point 51-54°C Examples 2-5
5 Compound Nos. 33 to 60 are shown in Table 3 in the same manner as in Example 1.
, Table 4 shows compound Nos. 61 to 66. Table 5 shows compound no.
, 67-72. Table 6 shows compound numbers 73 to 75. Compound No. 76 to 77 is shown in Table 7, and compound N is shown in Table 8.

78-80. Table 9 shows compound No. 8 ], , Table 10
Compounds shown as Compound Nos. 82 to 92 were synthesized.

Example 56 Table 3 (CH2)nCH3 Continued ■-Thene-3-1-lifluoromethyl-2-pyrasolin=5-one 4.4. Ethyl 1-1-lifluoroacetoacetate/Ig(
Add 4.87y (28.2 mmol) of 1 tesilhydranone to 50 ml of ethanol solution (21.7 mmol),
The mixture was heated under reflux for 5 hours. After diluting with water, it was extracted with chloroform. The organic layer was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography using ethyl acetate-hexane (2080) as a developing solvent to obtain the title compound (compound no.

56), 2859 was obtained as white crystals.

Yield: 449% Melting point: 60-6 pC Examples 57-60 Compounds No. 57-6 are shown in Table 3 in the same manner as Example 56.
A compound designated as 0 was synthesized.

Table 5 (CH2) □ H Table 4 Table 6 (CH2)1 OOH Table 7 R2 (CH2CH2O) C112CI+3 Below margin table 9 CH, CH2CH (CH7) nC113 below margin table 8 (CH7) nCH(CH3) (CH2)nCl] ,
Cl1(CH3) 2Table 10

Claims (1)

[Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a carbon number 8 which may have a substituent ~
20 chain hydrocarbon groups or a polyether chain group with a sum of carbon number and oxygen number of 8 to 20 which may have a substituent, and R^2 is a methyl group having a substituent or a substituent. Indicates an optional cyclic group. ] or its salt. 2. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc.
20 chain hydrocarbon groups or a polyether chain group with a total number of carbon atoms and oxygen numbers of 8 to 20, which may have a substituent, and R^2' may have a substituent Indicates a methyl group or a cyclic group which may have a substituent. ] A lipid peroxide production inhibitor characterized by containing a compound represented by the following or a salt thereof. 3. A lipoxygenase inhibitor comprising the compound according to claim 2 or a salt thereof. 4. A collagenase inhibitor comprising the compound according to claim 2 or a salt thereof.