JPH04120069A - Tropolone derivative and agent for prevention and treatment of ischemic disease containing same as effective ingredient - Google Patents

Abstract

NEW MATERIAL: A compound of formula I (R¹ and R² are each H, a lower alkyl, an aryl or a heterocycle; R³ is H, an aralkyl, etc.; Ar¹ and Ar² are each an aryl optionally substd. by halogen or a lower alkoxy, etc.), or its ester or salt.

EXAMPLE: 7-[4-(4-Chlorobenzhydryl)peperazino-1-methyl]-2-hydroxy-4- isopropyl-2,4,6-cycloheptatrien-one.

USE: An agent for treatment or prophylaxis of ischemic diseases such as cerebrovascular diseases or cardiovascular diseases.

PROCESS: A compound of formula II is aminomethylated with a piperazine derivative of formula III and formaldehyde in solvent (e.g. methanol) at room temperature-100°C to give the compound of formula I.

COPYRIGHT: (C)1992,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an ischemic medical, preventive, and therapeutic agent containing a novel troborone derivative or a pharmacologically acceptable ester or salt thereof as an active ingredient. More specifically, cerebrovascular disorders such as cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, hyperischemic attack, head trauma, sequelae of brain surgery, or variant angina pectoris,
Unstable angina, myocardial infarction, PTCA/PTCR/CAB
The present invention relates to a preventive/therapeutic agent for cardiovascular disorders such as arrhythmia associated with resumption of coronary blood flow due to G.G.

[Conventional techniques have shown that cell damage due to ischemia is divided into two types: (1) a process that progresses under anoxia during ischemia, and (2) a damage process caused by active oxygen that inevitably occurs when blood flow resumes after ischemia. It is broadly classified (Hyakuyen et al., Metabolism Vol. 24.379.1987). Typical ischemic diseases include cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient ischemic attack, head trauma, cerebrovascular disorders such as sequelae of brain surgery, variant angina, and unstable angina. Cardiovascular disorders such as myocardial infarction, arrhythmia associated with resumption of coronary blood flow due to PTCA/PTCR/CABG, etc., as well as transplant organ disorders during organ transplantation, organ disorders due to decreased blood flow during organ transplantation, and surgery. Examples include temporary blockage of blood flow to organs. It is difficult to explain these rapid sales using a single mechanism, and it is currently understood that several factors are intricately related. Therefore, in clinical practice, a wide variety of drugs are currently used, selecting them according to the etiology and pathology of each disease. For example, as preventive/therapeutic drugs for cerebrovascular disorders, glycerol, ozacrel, nidiphenone, ticlopidine, AVS, etc. have been used and studied from the viewpoint of preventing cerebral edema and cerebrovascular disarmament in the acute phase. On the other hand, in the chronic phase, cerebral circulation improving agents such as nicardipine, cinnarizine, flunarizine, and dirazep are used to increase blood flow to tissues that have survived the ischemic injury and improve metabolism. , cerebral circulation and metabolism improving agents such as ifenprodil, and cerebral metabolism improving agents such as idebenone, GABA, and calcium hopatenate.

Nitro compounds, C for variant angina and unstable angina
Vasodilators such as a-antagonists are used, and the use of 5-lipokinogenase inhibitors and radical scavengers is being considered for disorders in resuming coronary blood flow due to myocardial infarction and PTCA/PTCR/CABG. The current situation is that there is no established drug available for clinical evaluation.

[Problems to be Solved by the Invention] The present inventors believe that this ischemic disease is a result of damage to cell membranes and tissues caused by active oxygen, and excessive and rapid influx of extracellular calcium ions into cells, or are closely related. I thought it might happen.

In other words, when the cell membrane is damaged by active oxygen, extracellular calcium flows into the cell, and as a result, intracellular proteases are activated and cell functions are deactivated, and phospholipase is activated. An amplification reaction proceeds in which further calcium influx is induced by decomposing the constituent components of the cell membrane. Arachidonic acid, which is excised from cell membrane components by activation of phospholipase, is metabolized by substances that induce phagocytes (e.g., leukotrienes) and substances that aggregate platelets and cause thrombus formation (
Not only is it converted to (eg, tromphoxane At), but also active oxygen is generated again during this conversion process, leading to worsening of the disorder.

From this point of view, the present inventors have conducted intensive research on drugs that are effective for the prevention and treatment of ischemic diseases.As a result,
We have discovered that certain new tropolone derivatives are effective, and have completed the present invention.

[Means for Solving the Problems] The present invention provides a general solution to the problem, wherein R1 and R2 are the same or different and each represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl group. a heterocyclic group, R3 is a hydrogen atom, a lower alkyl group optionally substituted with a hetero atom, a substituted or unsubstituted aralkyl group, Ar'
and Ar', which are the same or different, each mean an aryl group optionally substituted with a halogen atom, a trihalogenomethyl group, or a lower alkokene group. ], or a pharmacologically acceptable ester or salt thereof, and a prophylactic/therapeutic agent for ischemic diseases containing the same as an active ingredient.

In the compound represented by the general formula [1] of the present invention, the lower alkyl group represented by R and R2 has a carbon number of 1
-5 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isoamyl, and the like. The aryl group includes an aryl group having 6 to 1 o carbon atoms, which has 1 to 7 substituents selected from the lower alkyl group, halogen, nitro, ano, and lower alkokyne group as described above. Good too. Halogens include chloro, fluoro,
Examples include bromo and iodo, and examples of lower alkokino groups include alkokino groups having 1 to 5 carbon atoms. Examples of these aryl groups are phenyl, p-chlorophenyl,
m-Chlorphenyl, 0-chlorophenyl, 1m-dichlorophenyl-fluorophenyl, p-trifluorophenyl, p-nitrophenyl, m-nitrophenyl, O-nitrophenyl, p-anophenyl, m-anophenyl, O -noanophenyl, p-methquinophenyl, m-methquinophenyl, 0-methquinophenyl,
Examples include m1p nomethquine phenyl. Examples of the heterocyclic group include 5- to IO-membered heterocyclic groups containing one or more heteroatoms, which may be substituted with the same substituents as the aryl group. Examples of heterocyclic groups include 2-
Examples include pyrinol, 3-pyridyl, 4-pyrinol, and the like.

The lower alkyl group which may be substituted with a heteroatom represented by R3 is an amino, a lower alkyl group, or a mono- or di-substituted amino or hydroquine substituted with a substituted or unsubstituted aralkyl group having 1 to 20 carbon atoms.
An alkyl group may be mentioned. Examples of the lower alkyl group of the substituent include an alkyl group having 1 to 5 carbon atoms, and examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms. You can leave it there. Examples of lower alkyl groups optionally substituted with such heteroatoms include, for example, methyl, ethyl, n-propyl, n-butyl, 2-[N,N-tumethylaminocoethyl, 3-[N, N-trimethylaminocopropyl, 2-[Nmethyl-N-phenethylaminocoethyl, 3-[Nmethyl-N-phenethylaminocopropyl, 2-[N-methyl-N(2,3-nomethoquinophenethylamino) ]ethyl, 3-[N-methyl-N-(2,
3-dimethquinphenethylamino]propyl, 2-hydroxyethyl, 3-amino-2-hydroquinopropyl, 3-
Examples include trimethylamino-2-hydroxypropyl, 3-diisopropylamino-2-hydroquinopropyl, and the like. Examples of the aralkyl group include aralkyl groups having 7 to 20 carbon atoms, which may be substituted with the same substituents as the above-mentioned aryl group. For example, benzyl, phenethyl, 3,4-dimethoxyphenethyl, and 234-trimethoxyphenethyl can be mentioned.

The aryl groups represented by Ar' and Ar2 include those similar to the aryl groups represented by R1 and R2, such as phenyl, p-chlorophenyl, m-chlorophenyl, O-chlorophenyl, o, m-dichloro Phenyl, o, p-dichlorophenyl, m, p-dichlorophenyl, p-fluorophenyl, m-fluorophenyl, ○-fluorophenyl, p-trifluorophenyl,
m-trifluorophenyl, 0-trifluorophenyl, p-methquinphenyl, m-methquinphenyl, O-
Examples include metquin phenyl.

Specific examples of the compound of the present invention represented by general formula [1] include the following.

1) 7-[4-(4-chlorobenzhydryl)piperazino-1-methyl]-2-hydroquine-4isopropyl-2,4,6-cyclohebutatriene l-one2) 7-[4-(4 -chlorobenzhydryl)piperafno-1-methyl]-4-isopropyl-2methoquino-246-chlorohebutatrien-1-one3) 7-(1-C4-(4-chlorobenzhydryl)L-piperazinomethyl -α-phenyl)-4-isopropyl-2-methquine-2,4,6-nochlorohebutatrien-1-one 4) 7-(1-[4-(4-chlorobenzhydryl)nipibelanono Methyl-α-methyl]-4-isopropyl-2-methquine-2,4,6-chlorohebutatrien-1-one5) 7-(1-[4-(4-chlorobenzhydryl)]]piperazi Nomethyl-alpha-butyl-4-isopropyl-2-methoxy-2,4,6-chlorohebutatrien-1-one6) 7-(4-henshydrylbiperazinol-1-methyl)-4-isopropyl-2-methquine -24,6-nocrohebutatrien-l-one 7) 7-[4-(4
,4'-nofluoroheneshydryl)piperazino-1-
methyl]-4-isopropyl-2-methoxy-2,4,
6-7 clohebutatrienol-one 8) 7-(4-C4,4'-di(trifluoromethyl)henshydryl-biperano-1-methyl)-4isopropyl-2-methoquino-2,4, 6-chlorohebutatrien-1-one9) 4-isopropyl-2-methoquino-7-24(4
-trifluoromethylbenzhydryl)piperazino-1
-Methyl l-2,4,6-cyclohebutatriene-1-
10) 7-[4-(4-chloro-4'-methquinebenzhydryl)piperazino-1-methyl]-4-isopropyl-2-methquine-2,4,6-7 clohebutatriene-1 -one 11) 7-[4-(4-fluoro-3°,4°-dimethoquinobenzhydryl)piperazino-1-methyl]-
4-isopropyl-2-methoxy-2,4,6-chlorohebutatrien-1-one 12) 7-i:4-(4,4'-nofluorobenzhydryl)piperazino-1-methyl-2-ethoquino-
4-isopropyl-2,4,6-nocrohebutatrieno=1-one 13) 2-butoquino-7-C4-(4,4°-nofluorohenzhydryl)piperazino-1-methylmi4-isoprop0 Pyr-2,4,6-7 clohebutatrien-1-one 14) 7-C4-(4,4°-nofluoroheneshydryl)piperazino-1-methyl]-4-isopropyl-2-phenoquino 2 .46-nochlorohebutatrien-l-one is) 2-henzyluoquine-7-74-(4,4-nofluorohenozohydryl)piperanol-methyl]-
4-isopropyl-2,4,6-7 clohebutatrienol-1-one 16) 7-[4-(4,4°-nofluorohenezhydryl)piperazino-1-methylni 2-(2-(34
-nometoquinophenyl)ethquin-4-isopropyl-246-cycloheptatrien-1one 17) 7-[4-(4,4'-nofluorohenozhydryl)piperazino-1-methylco-2-[3-( trimethylamino) propokushroom-4-isopropyl-246
-7 Clohebutatrien-1-one 18) 7-44
-(4,4°-nofluoroheneshydryl)piperazino-1-methyl]-2-C3-(N-methyl-N-phenethylamino)propo mushroom-4 isopropyl-2,46
-Chlorheptatrien-1-one 19) 7-[4-(4-chlorobenzhydryl)piveranono-1-methyl]-2-methoquino-2,4,6-chloroheptatrien-1-one 20) 7- [4-(4-chlorobenzhydryl)piperazino-1-methyl]-2-methquin-4-phenyl-246-cyclohebutatrien-■-one Trobolone derivative drug of the present invention represented by general formula (1) Physically acceptable salts include salts of mineral acids such as hydrochloric acid and sulfuric acid; salts of organic sulfonic acids such as methanesulfonic acid and P-toluenesulfonic acid; acetic acid, propionic acid, succinic acid, lactic acid, tartaric acid, and malic acid. , salts of organic carboxylic acids such as citric acid, and the like. Examples of esters include organic carbonic acid esters such as acetic acid, butionic acid, and oxalic acid.

The troborone derivative of the present invention represented by the general formula (I) can be produced, for example, according to the reaction formula of GG.

The reaction formula (wherein R1, R1, R3, Ar' and Ar" are as defined above, and halo represents a halogen atom, such as chloro, bromo, iodo, etc.), that is, represented by the general formula "II] The tropolone obtained is subjected to an aminomethylation reaction with formaldehyde and a piperazine derivative to synthesize a trobolone derivative: Ia';. This reaction involves alcohols such as acetone, trimethyl sulfoxide, trimethyl formaldehyde, methanol, and ethanol.
1 for compound [■] in the presence or absence of an inert solvent such as ethers such as tetrahydrofuran, halogen-containing solvents such as dichloromethane, and chloroform.
This is done by heating ~3 equivalents of formaldehyde and piperazine derivative and 0.5-3 equivalents of acetic acid at room temperature to 100<0>C. Particularly preferred is a method in which 1 to 1.2 equivalents of formaldehyde and piperazine derivatives and acetic acid are heated at room temperature to 65° C. relative to compound [II] in the presence of a solvent such as methanol. The alkylation reaction of the troborone derivative [I a] can be carried out by a method normally used in the alkylation reaction of phenols. For example, the alkylating agent is methyl iodide, an alkyl halide such as benol chloride, an aryl halide, or a sulfuric acid ester such as trimethyl sulfate, and the base is sodium hydride, an amine such as triethylamine, or water. Use an alkali such as sodium oxide, potassium hydroxide, potassium carbonate, or sodium bicarbonate. Compound [Ia3: 1 to 3 equivalents of the above alkylating agent, catalytic amount to 5 equivalents of the base
Compound [Ia] in an inert solvent as described above using an equal amount
The troborone derivative [+bl is obtained by heating to 0°C to 100°C.

On the other hand, trobolone [II] is prepared by a method known in the literature (Proc.
Japan Acad,, 27. 561 (+9
After reacting with formaldehyde according to 51)) to obtain compound [I11] with a hydroxymethyl group introduced at the 7-position, it can be converted to compound [IV] by the alkylation reaction described above. The compound [IV] is prepared in the presence or absence of an inert solvent such as acetone, trimethyl sulfoxide, dimethyl formaldehyde, ethers such as tetrahydrofuran, halogen-containing solvents such as dichloromethane, and dichloroform. Tropolone derivatives can be obtained by halogenation with amines such as pyridine or triethylamine and 1 to 3 equivalents of methanesulfonyl chloride at °C:
■] It is possible to do this. The conversion from tropolone derivative [vl to [Ib] can be carried out using alcohols such as acetone, methyl sulfoxide, dimethyl formaldehyde, methanol, and ethanol, ethers such as tetrahydrofuran, and halogen-containing solvents such as dichloromethane and chloroform. in the presence or absence of an active solvent,
1 to 3 equivalents of a piperazine compound and an amine such as birinone or triethylamine or an alkali such as sodium carbonate or sodium bicarbonate at room temperature to 100°C.
This can be easily done by heating to .

A compound [IC] when substituent R2 is present in the tropolone derivative [I] can be synthesized as follows.

Compound [IV] is prepared in a hydrogen halide solvent such as methylene chloride or chloroform using manganese dioxide in an amount equivalent to 5 to 20 times the amount of the compound, at 0 to 50° C., preferably at room temperature. An oxidation reaction is carried out to synthesize compound J■al. The compound [Vr a; is equimolar according to a conventional method!
It can be converted to compound [VIb] by hydrolysis at room temperature using an aqueous or alcoholic solution of sodium hydroxide, potassium hydroxide, etc. in a molar amount of ~5 times. Compound [VI b;
A compound into which a substituent R1 is introduced by reacting with [
■a″J can be derived. Compound [■a] can be converted into compound [■b] by the same operation as the alkylation method described above. From compound [■b], tropolone derivative [I
Conversion to cl is carried out in an equimolar amount to 5
Compound 7 ] After passing through 4-
It can be carried out in a two-step process by reacting with a substituted piperazine.

The compound of the general formula [I] of the present invention thus obtained can be isolated by conventional methods such as recrystallization and chromatography.
Can be purified.

Next, using the compound of the present invention and a control drug,
In vitro and in vivo pharmacological studies and their results are presented.

1. In vitro antilipid peroxidation test method A A microsomal fraction from SD male rat brain was prepared, and the amount of 0219 protein was measured using IOmMHEPES and I
50mM KC (0.2mM in (pH 7,4)
NADPH1 test compound and Fe3+ (0,1mM)
1 ml of a mixture of -ADP (0.5 mM) was incubated at 37° C. for 15 minutes. After water cooling, TCA-TBA
-HC12 reagent (16.7% trichloroacetic acid, 0.4%
1.5 m of thiobarbic acid, 0278N hydrochloric acid)
Q was added and heated in boiling water for 15 minutes. After cooling with water, centrifugation and measuring the absorbance of the supernatant at 535r+m,
The amount of thiobalchturic acid reactant (TBAR) was calculated. The test compound was subjected to the reaction at concentrations of 10 μM and 50 μM, and the inhibition rate of TBAR production at each concentration was determined, thereby indicating the antioxidative activity of the drug. The results are shown in Table 1. A compound with a large inhibition rate means a strong anti-lipid peroxidation effect.

Compound number Compound (1) Compound (2) Compound (3) Compound (4) Compound (5) Compound (6) Compound (7) Compound (8) Compound (9) Compound (10) Compound (12) Compound (13) Compound (15) Compound (16) Compound (18) Table 1 Antilipid peroxidation effect Antilipid peroxidation effect (% inhibition) 10 μM 50 μM 6.7 <21.3 28.8 84 7 13.8 163 25.8 75 ,1 30.5 38.7 15.963.2 27.259,2 32.351,8 29.2 88,1 24.0 8+ 6 21.450,4 23.1 27.4 22.4 29, 0 19.1 19.1 37.0 93.1 2. In vitro Ca-antagonism test method
-! -B A porcine right coronary artery strip was depolarized for 30 minutes by adding 75 mM K to allow 45 Ca to flow into the strip cells. EGT
Extracellular 45Ca was chelated by addition of A, and after washing and removal, the strips were dissolved at 100°C. The 45 Ca in this lysate was defined as intracellular 4 S Ca, and was measured using a non-tyrene counter. The concentration of the test compound was 10-
', IO-6, 10-5M, applied until the end of depolarization by K+.

The inhibition rate at each concentration of the test compound against the increase in intracellular Ca caused by K+ was determined. The results are shown in Table 2. A compound with a large inhibition rate means a strong Ca antagonism.

Compound number Compound (1) Compound (2) Compound (3) Compound (4) Compound (5) Compound (6) Compound (7) Compound (8) Compound (9) Compound (10) Compound (12) Compound (13) Compound (15) Compound (16) Compound (18) 3. In vitro coronary vasodilatory effect test method C Porcine coronary artery right rotation was removed, a rectangular specimen with a width of 3 mm was prepared, and a rectangular specimen with a volume of 20 mQ was prepared.
It was poured into a Magnus tube filled with EIT solution (37°C). During the experiment, a mixed gas of 95% O7 + 5% CO2 was sufficiently aerated. Tension changes were measured using an isogenetic transducer. After the load tension stabilizes, PGF2α10
−6 to 3 Bapaverine 10-'M was applied to obtain. The results are expressed as the relaxation rate when papaverin relaxation is taken as 100%, and the concentration of the test compound that causes 25% relaxation of papaverine relaxation is E.
D = s value. A case where the E D 25 value is smaller than to-'M is considered to be active. Table 3 shows the results.
Shown below.

A compound with a small value means a strong coronary vasodilator effect.

Table 3 Coronary vasodilator effect Compound number Coronary vasodilator effect (EDtsμM) Compound (1) >10 Compound (2) 1.8 Compound (7) 1.9 4, In vivo ischemic heart/reperfusion test Test method D Pent Experiments were carried out on rats that were artificially ventilated under Barchtal anesthesia. After resection of the fourth rib, the chest was opened, the heart was exposed, a suture was passed under the origin of the left coronary artery, the heart was returned to its original position, and the suture inside the polytube was passed.

The drug was administered through the tail vein, and 10 minutes later, the coronary artery was occluded by pulling the thread inside the polytube. Reperfusion was performed by loosening the suture again after 5 minutes of occlusion, and then 4 minutes after occlusion.
Ventricular arrhythmia observed per minute was observed and recorded on an electrocardiogram. Electrocardiograms were observed in the second lead by inserting needle electrodes into the right forefoot and left hindlimb. The duration of ventricular tachycardia occurring after reperfusion and the incidence of ventricular fibrillation were compared between the test compound administration group and the vehicle group operated in the same manner. A test compound was considered effective when either parameter in the test compound-treated group was less than half of those in the vehicle-treated group. The results are shown in Table 4.

Table 4 Ischemic heart/reperfusion test Compound number Minimum effective dose (If?/kg, i, v,) Compound (2) 0.3# Compound (7)
<s 5, In vivo behavioral test Test method E Under light ether anesthesia, ICR strain male mice (approximately 8 associations)
Both common arteries were ligated for 5 minutes, and then blood was reperfused. The test compound was administered intraperitoneally 10 minutes before ligation and within 3 hours of blood reperfusion.

From the day after blood reperfusion, behavioral disorders were evaluated by the amount of locomotor activity during exploratory behavior, the suspension test, and the performance of the -trial passive avoidance learning test. In other words, locomotor activity was determined by placing a mouse in a measurement cage using a group-type locomotor activity measuring device, measuring the locomotor activity for 30 minutes immediately after the f mouth, and calculating the average locomotor activity of the vehicle-administered group - "2xS".
When the amount of momentum is D or more, it is determined as a valid example.

In the suspension test, both forelimbs of the mouse were hung on a horizontally stretched wire, and a case where the hind legs were hung within 2 seconds was considered effective. -In the trial passive avoidance learning test, Step -through
Using a type of device, an electric shock of approximately 0.5 mA for 3 seconds was applied as an acquisition trial to learn blood reperfusion, and a regeneration trial was performed the next day. Mice that remained in a light room for more than 300 seconds were considered effective examples. It was judged as. If a test compound showed an appearance rate of 50% or more of effective cases in any test, it was determined to be effective in that test. The results are shown in Table 5.

Table 5 Mouse cerebral ischemia/reperfusion test Compound number Minimum effective dose (+9/kg, i, p,) Compound (1) > IO compound (2)
3# compound (7)
<10 The compound of the general formula [Ir] of the present invention has been found to be effective in cerebrovascular disorders such as cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient ischemic attack, head trauma, sequelae of brain surgery, etc. from the above pharmacological tests. Angina pectoris, unstable angina, myocardial infarction, PTCA
It is useful as a prophylactic/therapeutic agent for ischemic diseases such as cardiovascular disorders such as arrhythmia associated with resumption of coronary blood flow by /PTCR/CABG and the like.

When used as such prophylactic/therapeutic agents, the compound of the general formula Dosage forms may be for oral or parenteral administration. The dosage varies depending on the route of administration, the age and weight of the patient, the actual symptoms to be treated, etc., but for example, when administered orally to adults, 10 to 50 iy per day, preferably,
The dosage can be 10 to 2,519 times a day, and can be administered in 1 to several doses per day. In this dosage range, the compounds of general formula [I] of the present invention do not exhibit any toxicity.

[Examples] Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Practical Example 1 7-[4-(4-chlorobenzhydryl)piperazino-1-methylio2-hydroquine-4-isopropyl=2.4.6-Cyclohebutatriene l-one Production Hinokitiol 500JI9 (3,5 mmol), 1-
(4-chlorobenzhydryl)piperazine 1.059 (
3,66 mmol), and acetic acid 0.21 m12 (3,65
mmol) was dissolved in 1 mC methanol and heated to 60°C. While stirring this solution, 37% formalin 0,
27 mC (3.60 mmol) was added and stirring continued for an additional 2 hours. The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product.

This was crystallized from methanol and 7-[4-(4chlorobenzhydryl)piperazin-1-methyl]-2-hydroquine-4-isopropyl-2,46-cyclohebutatrien-1-one 1.19 ( (Yield: 78%) was obtained as pale yellow crystals. Melting point 6971'C MS m/z 462.2067CC28H3,CQN,
Calculated value as O2 462.2074) l HNMR (CD CQs) δ1.26 (d, 6H,
J=7.0Hz), 2.43(m, 4H), 2.57(
m, 4H).

2.88 (qui, I H, J = 7.0Hz), 3.
70 (s.

2H), 4.23 (s, IH), 6.95 (dd, IH
, J=14 and 10.3Hz), 7.1-7.4(l
0H) 7.72 (d, IHj=10.3Hz) Example 2 7-[4-(4-chlorobenzhydryl)piveranono-1-methyl]-4 isopropyl-2-methquine 2.46-cyclohebutatriene l Preparation of -one Dissolve 209 (0.12 mol) of hinokitiol and 8 g (0.12 mol) of potassium hydroxide in 80 m4 of water.
Add 12 mQ (0.16 mol) of formalin.

The reaction solution is heated to 100° C. for 5 hours while stirring. After neutralizing the reaction solution with 6N HCQ, the reaction product was extracted with dichloromethane. After drying the extract over sodium sulfate, it is concentrated under reduced pressure.

The residue was dissolved in 200 mQ (7 mQ) of acetone, 349 mQ (0.25 mol) of potassium carbonate, 16 mQ (0.
16 mol) was added, and the solution was heated to reflux for 1 hour while stirring. The precipitate is filtered and the filtrate is concentrated under reduced pressure. The filtration residue was washed with dichloromethane, the washing liquid and the concentrated filtrate were combined, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (1:4)] to give 7-hydroxymethyl-4-isopropyl-2-methquine-2, 4,6-cyclohebutatriene-
18.5 g (74% yield) of 1 ion was obtained as a pale yellow oil. This oil solidified upon standing at room temperature.

l HNMR (CDCC3) δ1.29 (d, 686.
9Hz), 2.89 (qui, LH, J=6.9Hz)
3.97 (s, 3H), 4.67 (s, 2H), 6.7
7 (sIH), 6.84 (d, IH1J=9.2Hz)
, 7.44 (d, lH, J=9.2Hz) 7-Hytroquinemethyl-4-isopropyl-2=methoxy-2,4,6-cyclohebutatrien-1-one 2.
819 (13.5 mmol), pyridine 1.31 mQ (
16.2 mmol) was dissolved in 5 mf2 of dichloromethane and cooled to 0°C. While stirring the solution, 1.25 mQ (16.2 mmol) of methanesulfonyl chloride was added,
After stirring at 0°C for 2 hours, the reaction solution was gradually warmed to room temperature. After 2 hours, the reaction solution was diluted with dichloromethane and diluted with saturated aqueous sodium bicarbonate, water and then 2N HC.
After washing with water, it was dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (1:l)] to give 7-chloromethyl-4-isopropyl-2methoxy-246-chloro. Hebutatrien-l-one t,3
8y (yield 45%) was obtained as a pale yellow oil. This oil solidified upon standing at room temperature.

M S m/z 226 (M”) I HNMR (
CD C (23) 61.29 (d, 6H, J=6.8H
z), 2.89 (qui, IH, J=6.8Hz)4
．． 00 (s, 3H), 4.73 (s, 2H), 6.7
2 (sIH), 6.82 (d, IH, 9, 2Hz), 7
．． 62 (dIH, J=9.2H2) 7-chloromethyl-4-isopropyl-2-methoxy-
2,4,6-cyclohebutatrien-1-one 408+
9 (1,80 mmol), ■-(4-chlorobenzhydryl)piperazine 61919 (2,16 mmol), triethylamine 0.3 m12 (2,15 mmol) in 5
The solution was dissolved in chloroform and heated under reflux for 20 hours.

The reaction solution was diluted with dichloromethane, washed with water, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [eluent: hexane-ethyl acetate (1:I)]. 7-(4
-(4-Chlorobenzhydryl)bibellanonol-1-methyl-4-isopropyl-2-methquine-2,4,6-chlorohebutatrien-1-one 703 x9c Yield 82
%) as a pale yellow, non-grade powder.

MS m/z 476 (M IHNMR (CDCQ3) δ1.26 (d, 6H, J-
7.3Hz), 2.43 (m, 4H), 2.57 (m,
4H).

2.85 (qui, IH, J=7.3Hz), 3.6
5 (s, 2H), 3.93 (s, 3H), 4.23 (s
, IH), 6.68 (s, LH), 6.80 (d, IH
, J=9.2Hz), 7.17.4 (9H), 7.67
(d, IH,, J=9.2Hz) Example 3 "1-(
Preparation of 1-[4-(4-chlorobenzhydryl)]]piperazinomethyl-αphenyl-4-isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-one 7-hytroquinemethyl- 4-isopropyl-2methquin-2,4,6-cyclohebutatrien-1-one 209 (
96 mmol) was dissolved in 300 mC of chloroform, 80 g (920 mmol) of activated manganese dioxide was added in several portions, and the mixture was stirred at room temperature for 4 hours. Insoluble matter was filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the resulting crude reaction product was recrystallized from toluene to give 7-formyl-4-isopropyl-2-methoxy-2,4 as yellow needles.゜6-chlorohebutatrien-1-one 12.319 (yield 62
%) was obtained. The melting point of this product was 73-75°C. To 5 g (24 mmol) of the aldehyde was added 50.0 g of a 10% aqueous sodium hydroxide solution. mQ was added and stirred at room temperature overnight. The reaction solution was acidified with 10% diluted hydrochloric acid, extracted with methylene chloride, washed with water, dried, and the solvent was distilled off to obtain 478 g of crude crystals.

By recrystallizing the crude crystals from ethyl acetate-hexane, colorless needle-like crystals of 7-formyl-4-isopropyl-
2-Hydroxy-2,4,6-cyclohebutatrien-l-one was obtained (yield quantitative).

The second compound is described in the literature (Sci, Repts, Tohoku
It exhibited a melting point of 76°C similar to that described in Univl, 37.367 (1953)). This compound 1.949 (10
Dissolve 7 mmol) in 20 mg of tetrahydrofuran,
2M phenyllithium solution 5,2 while cooling to 8°C.
m ((approximately IO mmol) was added dropwise under a nitrogen atmosphere,
Stir for 10 minutes. A saturated aqueous sodium chloride solution was added to the reaction mixture, extracted with methylene chloride, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain brown oily 7-(α-hydroxybenzyl).
-4-isopropyl-2-methoxy-2,46-chlorohebutatrien-1-one 1.959 (yield 71%) was obtained.

1 g (3.7 mmol) of the compound was mixed with 1.271 ml of 1-(4-chlorobenzhydrylpiperazine). After partial reflux for 2 hours in 20 mff of xylene with (4.4 mmol),
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:2) to give a brown oily 7-(1-[4(4-chlorobenzhydryl)copiperazine). 1.719 (yield: 86%) of (thi-α-phenyl)-4-isopropyl-2-human 0x-246-cyclohebutatrien-1one was obtained.

MS m/z538.540 (M'') IHNMR (C
DCσ3) δ1.21 (d, 6H, J=6.7Hz),
2.42 (bs, 8H), 2.82 (m, IH) 4.2
2 (s, IH), 5.03 (s, LH), 6.8-8
1 (m, l78) 1.59 (2.8 mmol) of the compound was dissolved in dimethyl sulfate 0
．． 469 (3,6 mmol) and potassium carbonate 1.1
The mixture was heated under reflux with 59 (8.3 mmol) in 20 mQ of acetone for 1 hour. After adding water to the reaction solution, extraction with methylene chloride, washing with water, and drying, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (ethyl acetate-hexane 1-, 3-1: I). 7-[1-[4-(4
-chlorobenzhydryl)]]piperazinomethyl-α-
phenyl]4isopropyl-2-methoxy-2,4,6
-chlorohebutatrien-1-one 0.999 (yield 6
4%) obtained f2.

MS m/z552, 554 (M= )IH
N M R (CD C (23) δt, 22 (d, 6H,
J=6.5Hz), 2.38 (bs, 8H), 2.80
(m, IH) 3.87 (s, 3H), 4.21 (s, I
H), 5.06 (s, IH), 6.59 (s, IH),
6.82 (s, IH, J=1 (IH2), 7.0-7
．． 6 (m, 14H), 7.97 (dIHJ=lOHz) Example 4 7-N-[4-(4-chlorobenzhydryl)]]piperazinomethyl-αmethyl-4-isopropyl-2-methoxy- Preparation of 2,4,6-chlorohebutatrien-1-one 7-formyl-4-isopropyl-2-hydroxy-2
,4,6-cyclohebutatrien-1-one 2.009
(10 mmol) was dissolved in 20 tQ of tetrahydrofuran and cooled to -78°C in a dry ice-acetone bath. In this hemethyllithium ether solution (1.4M)
15 was added dropwise, and then the triice-acetone bath was removed, and the mixture was stirred until the insoluble matter was dissolved. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with methylene chloride.

The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give a reddish-brown oil of 7-(α-hydroxyethyl)-4-isopropyl-2 to hydroquine-2,
2.189 (yield quantitative) of 4,6-7 clohebutatrien l-one was obtained.

MS m/z208 (M''') IHNMR (CDC&3) 61.28 (d, 6H, J=
6.7Hz), 1.53 (d, 3H9J=6.2Hz)
2.92 (m, IH), 5.17 (quar, IH9J
= 6.2Hz), 7.03(d, L HlJ = 1
0.3 Hz), 7.36 (s, lH), 7.66
(d, I H, J = 10.3 Hz) The compound 2
．． After heating and refluxing 099 (10 mmol) with 3.179 (II mmol) of 1-(4chlorobenzhydrylpiperazine) in 3 (Jt) toluene for 1.5 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in acetone. 50JIQ, 4.199 (30 mmol) of potassium carbonate and 1.669 (13 mmol) of dimethyl sulfate were added, and the mixture was heated under reflux.2
After a period of time, 0.649 (5.1 mmol) of dimethyl sulfate and 2.1 g (15 mmol) of potassium carbonate were added and the mixture was heated under reflux for 30 minutes. The reaction solution was filtered, the filtrate was concentrated, and the resulting product was purified by gel column chromatography (ethyl acetate-hexane 1:1) to obtain 7-(1) as a pale brown oil. -[4-(4-chlorobenzhydryl)]]piperazinomethyl-α-methyl 1
1.829 of 4-isopropyl-2-methquine-2,4°6-chlorohebutatrien-1-one (yield 37%) was obtained.

MS m/z490.492 (M= )l HNM
R (CD CQa) δ1.21 (d, 3H, J = 6.5
Hz), 1.25 (d, 6H, J=6.5Hz) 1.2
7 (s, 3H), 2.3-2.6 (8H), 2.83 (
I H, m), 3.92 (s, 3 H), 4.07 (m
, lH).

4.18 (s, IH), 6.66 (s, IH), 6.7
9 (dIH, J=9.7Hz), 7.1-7.4 (m
, 9H).

7.7 (d, IH, J = 9.7H2) Example 5 7-(1-[4-(4-chlorobenzhydryl)copiverazinomethyl-α-butyl)-4-isopropyl-2-methocino- Preparation of 2,4,6-cyclohebutatrien-1-one 7 ~ Formyl-4-isopropyl-2-hydroquine-2
46-ink C heptatrien-1-one 1.959 (1
0 mmol) was dissolved in tetrahydrofuran 30z4,
Cool to -78°C in a tri-ice-acetone bath.

Into this, n-butyllithium hexane solution (1.6M)
Add 14xσ dropwise, then remove the dry ice-acetone bath and stir until the insoluble matter is dissolved. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. After washing the methylene chloride layer with water, it was dried over anhydrous sodium sulfate and the solvent was distilled off to give a reddish brown oily 7-α-hydroxybutyl)-4-isopropyl-2-hydroquino-2,4,6-cyclohebutatriene-1. -on 2.7
2 g (yield quantitative) was obtained.

After heating and refluxing the compound (2.49C9 mmol) with 1=(4-chlorobenzhydrylpiperazine) 2.69 (10 mmol) in toluene 30 Pass for 2 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in acetone 50xQ. Dissolve 4,239 (31 mmol) of potassium carbonate and 1.
939 (15 mmol) was added, and the mixture was heated under reflux for 15 hours. The reaction solution was filtered, the filtrate was concentrated, and the resulting residue was purified by Norica gel Kara B chromatography (ethyl acetate-hexane 1.2-1.1) to obtain 7-(1- C4-(4-chlorobenzhydryl)1piperazinomethyl-α-butyl)-4-isopropyl-2-methquine-2,4,6-cyclohebutatrien-I-one 1.559 (yield 32%) was obtained. Ta.

MS m/z532.534 (M=)l HNMR (
CD C(is) δ0.788(t, 3H.

J=6.8Hz) 1.0-1.8(m, 6H), 1.2
7 (d, 6H, J = 6.7Hz), 2.1-2.7 (8
H).

2.84 (m, IH), 3.92 (s, 3H), 4.1
6 (sI H), 4.22 (m, I H), 6.66
(s, LH).

6.78 (d, l H, J = l 0Hz), 7.
1-7.4 (m9H), 7.51 (d, IH, J=l
0Hz) Example 6 Preparation of 7-(4-benzhydrylpiperazino-1-methyl)-4-isopropyl-2-methquine-2,4,6-cyclohebutatrien-1-one 7-hydroquinemethyl-4 -isopropyl-2-methquine-2,4,6-cyclohebutatrien l-one 400
Shoulder 9 (1,92 mmol) was dissolved in 25x (chloroform) and triethylamine 291xii (2,8
8 mmol) and methanesulfonic acid chloride 263z9 (2,
30 mmol) and stirred at room temperature for 14 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in 3011Q chloroform, and triethylamine 291*9
(2,88 mmol) and 4-benzhydrylpiperazine 485o (1,92 mmol) were added and stirred at 60° C. for 14 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and from the fraction eluted with hexane-ethyl acetate (1:I), 7-(4-benzhydrylpiperazino-■-methyl)-4-isoprop a
Bir-2-methquin-2,4,6-cyclohebutatrien-I-one 4173!9 (yield 49%) was obtained as a yellowish brown, impure powder.

MS m/z442 (M″) IHNMR (CDCQ3) δ1.26 (d, 6HJ=6
．． 8Hz), 2.4-2.6(8H), 2.83(qu
i, l H, J=6.8Hz), 3.64(s, 2H)
3.93 (s, 3H), 4.24 (s, IH), 6.6
8 (s.

IH), 6.80 (d, IH, J=9.8Hz), 7.
1-7.5 (10H), 7.66 (d, IH, J=9.
8Hz) Example 7 7-[4-(4,4'-nofluorobenzhydryl)piperazino-1-methyl]-4-isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-one Preparation of 7-chloromethyl-4-isopropyl-2-methoxy-
4-isopropyl-2,4,6-cyclohebutatrien-1-one 500319 (2,21 mmol), 1-(
4,4'-difluorobenzyl(L'lyl)piperazine 8
20119 (2,84 mmol), triethylamine 0
．． 4iff (2.87 mmol) was dissolved in 5 m (10) chloroform and heated under reflux for 20 hours. The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (3N)] to give 7-[4-(4,4")
-difluorobenzhydryl)piperazino-1-methyl2-4-isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-one 808xLi (yield 76
%) was obtained as a pale yellow, non-grade powder.

M S m/z47 B (M”) I HNMR (
CD C125) δ1,26 (d, 6H, J=6.8H
z), 2.41 (m, 4H), 2.57 (+a, 4H)
.

2.85 (qui, lH, J=6.8Hz), 3.66
(s.

2H), 3.93(s, 3H), 4.23(s, I H
).

6.69 (s, IH), 6.80 (d, IH, J=9
．． 2Hz).

6.96 (t, 4 H, J = 8.9 Hz), 7.34 (
dd, 4 HJ=8.9.5.4Hz), 7.66(d
, IH, J = 9.2Hz) Example 8 7-(4-[4,4°-di(trifluoromethyl)benzhydryl]piperazino■-methyl)-4-isopropyl-2-methoxy-2,4,6 -Preparation of cyclohebutatrien-1-one 7-Hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-one 42
3. o (2,03 mmol) was dissolved in chloroform at 25xC, and triethylamine 284z9 (2,8
1 mmol) and methanesulfonic acid chloride 2683!9 (2
, 34 mmol) and stirred at room temperature for 13 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in 30xQ chloroform, and triethylamine 237*9
(2,34 mmol) and 4-[4,4°-di(trifluoromethyl)benzhydrylcopiperazine 50019 (
1,56 mmol) and heated under reflux for 4 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and hexane-ethyl acetate (
1:1) From the elution fraction, 7-(4-[4,4'-di(trifluoromethyl)benzhydrylcopiperazino-1-
Methyl)-4-isopropyl 2-methquine-2,4,6
-cyclohebutatrien-1-one 520o (yield 65
%) was obtained as a yellow, non-grade powder.

MS m/z57B (M=) IHNMR (CDCQs) δ1.27 (d, 6H, J=
6.8Hz), 2.4-2.6(8H), 2.85(q
ui, IH, J=6.8Hz), 3.65(s, 2H)
.

3.94 (s, 3H), 4.39 (s, IH), 6.6
9 (s.

lH), 6.80 (d, 3H, J=9.6Hz), 7.
6 (6H), 7.65 (d, IH, J = 9.6Hz).

Example 94-isopropyl-2-methoxy-7-[4-
Production of (4-trifluoromethylbenzhydryl)piperazino-■-methyl]-2,4,6-cyclohebutatrien-1-one 7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6 -cyclohebutatriene-■-one 23
4 mg (1,12 mmol) of 151 (2) was dissolved in chloroform, and triethylamine 171i9 (1,
69 mmol) and methanesulfonic acid chloride 161n (1,
41 mmol) and stirred at room temperature for 11 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in chloroform of 201e, and triethylamine 142i+y was added to it.
(1,41 mmol) and 4-(4-trifluoromethylbenzhydryl)piperazine 364319 (0,94 mmol) were added and stirred at 60° C. for 14 hours. After washing the reaction solution with water and drying the organic layer with anhydrous sodium sulfate,
Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography, and hexane-ethyl acetate (1:
1) From the elution fraction, 4-isopropyl-2-methoxy-
7-[4-(4-trifluoromethylbenzhydryl)
Piperazino-1-methylco2.4.6-cyclohebutatriene-! -Saiken 272m9 (yield 50%) was obtained as a yellow, non-grade powder.

MS m/z510 (M”) IHNMR (CDCf23) δ1,26 (d, 6H, J
=6.8Hz), 2.4-2.6(8H), 2.85(
qui, IH, J=6.8Hz), 3.64(s, 2H
) 3.93 (s, 3H), 4.31 (s, IH), 6.
68 (s.

IH), 6.80 (d, IH, J=9.2Hz), 7.
2-7.4 (5H), 7.45-7.60 (4H)7.
66 (d.

IH, J = 9.2 Hz) Example 10 7-[4-(4-chloro-4'-methoxybenzhydryl)piperazino-1-methyl to 4-isopropyl-2-methoxy-2,4,6-cyclo Preparation of butatrien-1-one 7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-off 48
0x9 (2,30 mmol) was dissolved in 20x (10) chloroform and triethylamine 350i9 (
3,45 mmol) and methanesulfonic acid chloride 33011
g (2.88 mmol) and stirred at room temperature for 11 hours. The reaction solution is washed with water, the organic layer is dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was 30xQ
of triethylamine 29
1 mg (2,88 mmol) and 4-(4-chloro-4'-methquinbenzhydryl)piperazine 608o (1,
92 mmol) and heated under reflux for 7 hours. After washing the reaction solution with water and drying the organic layer with anhydrous sodium sulfate,
Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography, and hexane-ethyl acetate (1:
l) From the elution fraction, 7-[4-(4-chloro-4'-methoxybenzhydryl)piperazino-1-methyl]-4
-Isopropyl-2-methoxy-2,4,6-cyclohebutatrien-1-one (4821 g (yield: 49%)) was obtained as a pale yellow, impure powder.

MS m/z510 (M"") IHNMR (CDCI23) 61.26 (d, 6H, J
=6.8Hz), 2.4-2.6(8H), 2.85(
qui, IH, J=6.8Hz), 3.64(s, 2H
).

3.93 (s, 3 H), 4.31 (s, I H),
6.68 (s.

IH), 6.80 (d, IH, J=9.2Hz), 7.
27.4 (5H), 7.45-7.60 (4H) 7.6
6 (d.

IH, J = 9.2H2) Example 11 7-[4-(4,4'-difluorobenzhydryl)piperazino-1-methyl]-2-ethoxy4-isopropyl-2.4.6-cyclohebutatriene Preparation of -1-one 2-hydroxy-7-hydroxymethyl-4isopropyl-2,4,6-cyclohebutatrien-1-one1.
After adding 256 m9 (6.4 mmol) of 60% oily sodium hydride with stirring to a solution of 139 (5.82 mmol) in 5 m17 dimethylformamide, the reaction solution is stirred at 70° C. for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (2:3)] to give 2-ethoxy-7-hydroxymethyl-4-isopropyl-2, 46-cyclohebutatrien-1-one 485+9 (yield 76%) was obtained as a pale yellow, impure powder.

IHNMR (CDC123) δ1.26 (d, 6H, J
= 6.8Hz), 1.55 (t, 3H, J = 6.8Hz
).

2.87 (qui, 2H, J=6.8Hz), 4.16
(q2H, J=6.8Hz), 4.66(s, 2H),
6.80 (sI H), 6.85 (d, I H, J=9
．． 2Hz), 7.46 (dIH, J=9.2Hz) 2-ethoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cyclohebutatrien-1-one 48
5xg (2.18 mmol), triethylamine 0.3
6iQ (2,58 mmol) was dissolved in 2xQ dichloromethane and cooled to 0°C. While stirring this solution,
Methanesulfonyl chloride 0.2 m9 (2,58 mmol)
After stirring was continued for 1 hour at 0°C, the reaction solution was gradually returned to room temperature.

After 4 hours, the reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue contains 1-(4,4'
-difluorobenzhydryl)piperazine 756u (2
, 62 mmol) and trientylamine 0.36i+Q
(2.58 mmol) and dissolve it in 15xf2 chloroform. This reaction solution was heated under reflux for 7 hours, diluted with dichloromethane, washed with water, and dried over sodium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography [elution solvent: hexane-ethyl acetate (3
7-[4-(4゜4'-difluorobenzhydryl)piperazino-1-methyl]-2
-Ethoxy4-isopropyl-2,4,6-cyclohebutatrien-1-one 638y9 (yield 59%) was obtained as a pale yellow, impure powder.

MS m/z492 (M= ) I HNMR (CD CQ3) 61.25 (d, 6H,
J=7.0Hz), 1.52(t, 3H9J=7.0H
z).

2.40 (ra, 4 H), 2.55 (+++, 4 H
), 2.82 (qui.

tH, J=7.0Hz), 3.62 (s, 2H), 4.
12 (q.

2H, J = 7.0Hz), 4.23 (s, IH),
6.70 (s.

I H), 6.78 (d, I H, J = 9.2
Hz), 6.70 (t4H, J=8.9Hz), 7.3
4 (dd, 4H, J=8.9°5.4Hz), 7.63
(d, IH, J=9.2Hz) Example 122-Butoxy-7-[4-(4,4-difluorobenzhydryl)piperazino-1-methylio4-isopropyl-2.4.6-cyclohebutatriene -1-one production 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cyclohebutatrien-1-one 1
．． To a stirred solution of 269 (6.49 mmol) in 5 ml of dimethylformamide, 60% oily sodium hydride 285B (7.13 mmol) was added portionwise. Next, butyl iodide 1. After adding Ix (9.6 mmol), the reaction solution was heated at 80 °C for 4 hours. The reaction solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, The residue was subjected to silica gel column chromatography [elution solvent.

Purified with hexane-ethyl acetate (1:1),
-butoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cyclohebutatrien-1-one 612
Q (38% yield) was obtained as a tan oil.

I HNMR (CD CQ3) δ1,00(t, 3H0
J-7,3Hz), 1.27(d,6H, J=6.8H
z) 1.55 (m, 2H), 1.92 (m, 2H), 2
．． 89 (quiIH, J=6.8Hz), 4.07 (t
, 2H, J=7.0Hz), 4.65(d, 2H, J=
5.4Hz), 6.79 (sIH), 6.81 (d, I
H, J = 9.2Hz) 7.40 (d, lH, J = 9.2
Hz) 2-butoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cyclohebutatrien-1-one 61
21 g (2.44 mmol), triethylamine 0.4
1zf2 (2,94 mmol) was dissolved in 2x (l) of dichloromethane and cooled to 0°C. While stirring the solution, 0.23xf2 (2,97 mm!J mol) of methanesulfonyl chloride was added and a further 0. After continued stirring for 1 hour at °C,
The reaction solution is gradually returned to room temperature. After 4 hours, the reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, 846 mg (2,93 mmol) of 1-(4,4'-difluorobenzhydryl)piperazine and 0.41 ml (2,94 mmol) of triethylamine were added to the residue, and this was added to the residue of 153112. Dissolve in chloroform.

This reaction solution was heated under reflux for 12 hours, diluted with dichloromethane, washed with water, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography [elution solvent: hexane ethyl acetate (7:3)].
] to give 2-butoxy-7-[4-(4,4
823 x g (yield: 64%) of °-difluorobenzhydryl)piperazino-1-methyl]-4-isopropyl-2,4,6-cyclohebutatrien-I-one was obtained as a pale yellow, non-grade powder.

MS m/z520 (M”) IHNMR (CDC123) δ0,98 (t, 3H, J
=7.3Hz), 1.25(d,6H,J=7.0Hz
) 1.53 (m', 2H), I, 89 (m, 2H),
2.40 (m.

4H), 2.55 (m, 4H), 2.82 (qui, I
H1J=7.0Hz), 3.62(s, 2H), 4.0
3 (t, 2HJ=6.8Hz), 4.23 (s, IH)
, 6.70 (s, IH) 6.77 (d, IH, J=9.
2Hz), 6.96 (t, 4HJ=8.9Hz), 7.
34 (dd, 4H, J=8.9°5.4Hz), 7.6
2 (d, IH, J = 9.2 Hz) Example 13 2-benzyloxy-7-[4-(4,4'-difluorobenzhydryl)piperazino-1-methyl]-4-isopropyl-2,4, Preparation of 6-cyclohebutatrien-1-one 2-hydroxy-7-hydroxymethyl-4isopropyl-2,4,6-cyclohebutatrien-1-one 1.
While stirring a solution of 159 (5,92 mmol) in dimethylformamide, 60% oily sodium hydride 260JI9 (6,50 mmol) was added in small portions. Then, Hensyl chloride 1j+(( 8,41
After addition of 1 mmol), the reaction solution was heated at 80° C. for 4 hours. The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (1:l)] to obtain 2-
Benzyloxy-7-hydroxymethyl-4-isopropyl-2,4,6-ink0 heptatrien-1-one 72
9319 (43% yield) was obtained as a tan oil.

I HNMR (CD CQ3) δ1.12 (d, 6H,
J=6.8Hz), 2.77(qui, IH1J=6.
8Hz) 4.67 (d, IH, J=5.9Hz), 5.
29(s, 2H).

6.80 (d, IH9J=9.4Hz), 6.83 (s
, IH) 7.3-7.5 (6H) 2-benzyloxy-7-hydroquinemethyl 4-isopropyl-2,4,6-cyclohebutatrien-1-one 729x9C2,56 mmol), triethylamine 0
．． 4311a (3.09 mmol) was dissolved in 2xQ dichloromethane and cooled to 0°C.

While stirring this solution, add 0.2 methanesulfonyl chloride.
After adding 4z(2 (3.1 mmol)) and continuing stirring at 0°C for 1 hour, the reaction solution was gradually returned to room temperature. After 4 hours, the reaction solution was diluted with dichloromethane and diluted with saturated aqueous sodium hydrogen carbonate solution. After washing, it was dried with sodium sulfate.

After the solvent was distilled off under reduced pressure, 1-(4,4°-difluorobenzhydryl)piperazine 887o (3,08
mmol) and triethylamine 0.43x (2(3,0
This reaction solution was heated under reflux for 6 hours, diluted with dichloromethane, washed with water, and dried over sodium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography [elution solvent: hexane-ethyl acetate (7
:3)] to give 2-benzyloxy-7-[
4-(4,4°-difluorobenzhydryl)piperazino-1-methyl]-4-isopropyl-2,4,6-cyclohebutatrien-1-one 77619 (yield 55%)
) was obtained as a pale yellow, non-grade powder.

MS m/z554 (M”) I HNMR (CDC (23) δ1.11 (d, 6H,
J-6,8Hz), 2.41 (m, 4H), 2.5
6 (m, 4 H).

2.73 (qui, IH, J=6.8Hz), 3.64
(s2H), 4.23 (s, IH), 5.24 (s, 2
H) 6.76 (s, LH), 6.77 (d, IH, J=
9.4Hz) 6.96(t, 4 H9J=8.9Hz)
, 7.34 (dd, 4H.

J=8.9, 5.4Hz), 7.2-7.5(5H)7
．． 62 (d, IH, J=9.4Hz) Example +4 7-
[4-(4,4'-difluorobenzhydryl)piperazino-■ methyl]-2-[2-(34-nomethoxyphenyl)ethoxyco-4 isopropyl-2,4,6-cyclohebutatrien-1-one Preparation of 2-hydroxy-7-hydroxymethyl-4isopropyl-2,4,6-cyclohebutatrien-■-one 84
While stirring a solution of 4 mg (4.35 mmol) dissolved in 5 m dimethylformamide, 60% oily sodium hydride 191xy (4.78 mmol) was added little by little. Next, iodide-3 After adding 2.54 mmol of 4-nomethoquinophenethyl (8.70 mmol), the reaction solution was heated at 80°C for 7 hours.The reaction solution was diluted with methane, washed with water, Dry with sodium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate (3:
2)] to give 2-J2-(3,4-dimethoxyphenyl)ethoxyco-7-hydroxymethyl-4-
Isopropyl-246=cycloheptatrien-■-one 169xy (yield 11%) was obtained as a tan oil.

IHNMR(CDC(!3)δ1.24(d,6HJ=
6.8Hz), 2.80(qui, IHj=6.8Hz
) 3.19 (t, 2H, J = 6.8Hz), 3.86 (
s, 3H) 3.91 (s, 3H), 4.22 (t, 2H
j=6.8Hz) 4.66(s, 2H), 6.75(s
, IH), 6.8-7.0 (4H), 7.43 (d, I
H, J = 9.2 Hz) 2-[2-(3,4-dimethoxyphenyl)ethoxy]-7-hytroquinemethyl-4-isopropyl-246-cyclohebutatrien-1-one 169R9 (0,472 mmol), Dissolve 0.08zC (0,574 mmol) of triethylamine in dichloromethane of IRQ and add 44μ of methanesulfonyl chloride at room temperature.
12 (0,568 mmol) is added. After stirring the reaction solution at room temperature for 5 hours, the solvent and the like were distilled off under reduced pressure. 164 m9 (0,569 mmol) of 1-(4,4°-difluorobenzhydryl)piperazine and 0.08zC (0,574 mmol) of triethylamine are added to the residue, which is dissolved in chloroform at 5×C. Add this reaction solution to 12
After heating under reflux for an hour, the mixture was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (1:1)] and purified with 7-[4-(4,4°-difluorobenzhydryl). )
Piperazino-1-methyl]-2-[2-(3,4-dimethoxyphenyl)ethoxycou-4-isopropyl 2.4
．． 6-cyclohebutatrien-1-one 1571+9(
Yield: 53%) was obtained as a tan oil.

MS m/z628 (M= ) I HNMR (CD Cl23) 61.21 (d, 6H
J = 7.0Hz), 2.41 (m, 4H), 2.55 (
m, 4H) 2.78 (qui, IH, J=7.0Hz)
, 3.17 (t.

2H1J=7.0Hz), 3.62(s, 2H), 3.
86 (s3H), 3.90 (s, 3H) 4.18 (t,
2Hj=7.0Hz), 4.23(s, IH), 6
．． e! 6 (s, IH).

6.7-6.9(4)(), 6.96(t, 4HJ=8
．． 9Hz), 7.34Cdd, 4H, J=8.9, 5.
4Hz) 7.63 (d, IH, J = 9.2Hz) Example 15 7-[4-(4,4'-difluorobenzhydryl)piperazino-1-methyl]-4-isopropyl-2-[3 -(N-Methyl-Nphenethylamino)propoxylo 2.4.6 Preparation of cyclohebutatrien-1-one 2-Hydroquine-7-hydroxymethyl-4-itubrovir-2,4,6-cyclohebutatriene ■- On 1.
299 (6.64 mmol) 5! While stirring the solution of lρ in trimethylformamide, 60% oily sodium hydride 2927!9 (7.3 mmol) was added in small portions. Next, 1.35-dibromopropane
After adding x12 (13,3 mmol), the reaction solution was reduced to 8
Heat to 0°C for 4 hours.

The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: cohexane-ethyl acetate (1:I)].
3-bromopropoquine)-7-hydroxymethyl-4-
Isopropyl-246-cyclohebutatrien-■-one 2930 (yield 14%) was obtained as a pale yellow crystalline material.

IHNMR (CDC(23)δ1.29(d,6H,J
7.0Hz), 2.46(qui, 2H, J=5.9H
z) 2.88 (qui, IH, J=7.0Hz), 3.
69 (t.

2H9J=5.9Hz), 4.22(t, 2H, J=5
．． 9Hz), 4.66(s, 2H), 6.84(s, I
H), 6.85 (d, lH, J=9.4Hz), 7.4
4 (d, l H, J = 9.4 Hz) 2-(3-bromopropoxy)-7-human quinomethyl-4-isopropyl-2,4,6-chlorohebutatrien-1-one 280 m? (0,89 mmol), N-methylphenethylamine O,l5iQ (1,03 mmol), triethylamine 0.15 m (7 (1,08 mmol)) were dissolved in 5x (i) of chloroform, and this solution
The mixture was heated to reflux for an hour. The reaction solution was diluted with dichloromethane, washed with water, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [eluent: chloroform-methanol (10:1)] to obtain 7-hydroxymethyl-4-isopropyl-2-[3-(N -methyl-N-phenethylamino)
Propoxylone 2.4.6-encrohebutatriene-1
-one 242m9 (74% yield) was obtained as a tan oil.

I HNMR (CD CQs) δl 27 (d, 6H
, J=6.8Hz), 2.10(qui, 2H, J=6
．． 5Hz) 2.34 (s, 3H), 2.6-2.9 (7
H), 4.07 (t2HJ=6.5Hz), 4.66(
s, 2H), 6.78 (s.

IH), 6.83 (d, LH, J=9.5Hz), 7,
17.3 (5H), 7.46 (d, lH, J = 9.5H
z) 7-hydroxymethyl-4-isopropyl-2C3
-(N-methyl-N-phenethylamino)propoquin2.4.6-nchlorhebutatrien-1-one 242
m9 (0,655 mmol), triethylamine 0.1
Dissolve 1x(2 (0,789 mmol) in 1x(i) of dichloromethane and add 61μ of methanesulfonyl chloride (
(Q, 788 mmol) is added.

After stirring the reaction solution at room temperature for 5 hours, the solvent and the like were distilled off under reduced pressure. To the residue are added 1-(4,4°-nofluoroheneshydryl)piperazine 23019 (0,798 mmol) and triethylamine 0.11x (7 (0,789 mmol)), which are dissolved in chloroform. This reaction solution was refluxed for 16 hours, diluted with dichloromethane, washed with water, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography [eluent: chloroform-methanol (30: I
)] to give 7-[4-(4,4°-fluoroheneshydryl)piperazino-1-methyl]-4-isopropyl-2-[3-(N-methyl-N-phenethyl) Amino)propoxy]-2,4,6-chlorohebutattrien-l-one 156JI9 (37% yield) was obtained as a tan oil.

MS m/z639 (M= ) IHNMRCCDCQ, ) δ1.24 (d, 6H, J=
6.8Hz), 2.07(qui, 2H, J=6.5H
z) 2.32 (s, 3H), 2.40 (m, 4H), 2
．． 54 (m4H), 2.3-2.9 (6H), 3.62
(s, 2H) 4.03 (t, 2H, J=6.5Hz),
4.23 (I H) 6.69 (s, IH), 6.78 (
d, IH, J=9.2Hz) 6.96(t, 4H, J=
8.9Hz), 7.1-7.3(5H), 7.34(d
d, 4H, J=8.9, 5.4Hz).

7.63 (d, IH, J=9.2Hz) Example 16 7
-[4-(4-chlorobenzhydryl)biperanol
-Methyl] Preparation of -2-methoxy-2,4,6-cyclohebutatrien-1-one Troborone 19 (8.0 mmol), 4-(4-chlorobenzhydryl)piperazine 28+6i9 (96 mmol) in 401 of methanol, 37% formalin 800m9 (9,6 mmol) and acetic acid 590m9 (9,6 mmol)
6 mmol) and stirred at 60°C for 1 hour. Water is added to the reaction solution, extracted with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol 100:1) to obtain 7-[4
-(4chlorobenzhydryl)piperazino-1-methyl]-2-hydroquine-2,4,6-cyclohebutatrien-1-one 600J19 (yield 18%) was obtained as a slightly yellowish brown non-grade powder. .

MS m/z420.422 (M= )I HNMR
(CD Cl2s) 62.4-2.6 (8H) 3.73
(s, 2H), 4.24 (s, IH, 3H) 7.04 (
+n, IH), 7.2-7.4 (11H), 7.85 (
d, IH9J = 9.7 Hz) 7-E4-(4-chlorobenzhydryl)bibellano-1-methino-2-hydroquine-2,4,6-nochlorohebutatrien-1-one 200 sites (0.47 mmol ) in acetone 50*I2, potassium carbonate 263xg
(1,9 mmol) and trimethyl sulfate 78z9 (0,
62 mmol) and heated under reflux for 1 hour. Water is added to the reaction solution, extracted with chloroform, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by gel column chromatography (chloroform-methanol (1
7-[4-(
4-chlorobenzhydryl)piperazino-■Methylio2-methokino-2,4,6-cyclohebutatriene-1
-ON 20 Takumi (yield: 10%) was obtained as a pale brown, non-grade powder.

MS m/z434, 436 (M= )IHNM
R(CDCρ3)62.4-2.6(8H)3.67(
s, IH), 3.92 (s, 3H), 4.23 (sI
H), 6.72 (d, I H, J = 9.5 Hz
), 6.90 (bt, IH, J=9.7Hz), 7.0
3 (bt, LH, J-9, 7Hz), 7.2-7.4 (
9H), 7.76 (d, IHJ=9.7Hz) [Effects of the Invention] According to the present invention, a novel tropolone derivative useful as a prophylactic/therapeutic agent for ischemic diseases and a prevention of ischemic diseases containing the same are provided. - A therapeutic agent is provided.

Claims (2)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. Unsubstituted heterocyclic group, R^3
is a hydrogen atom, a lower alkyl group optionally substituted with a heteroatom, or a substituted or unsubstituted aralkyl group,
Ar^1 and Ar^2 are the same or different, and each
It means an aryl group optionally substituted with a halogen atom, a trihalogenomethyl group, or a lower alkoxy group. ] A tropolone derivative or a pharmacologically acceptable ester or salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and each represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or an unsubstituted heterocyclic group, R^
3 is a hydrogen atom, a lower alkyl group optionally substituted with a heteroatom, or a substituted or unsubstituted aralkyl group, Ar^1 and Ar^2 are the same or different, and each is a halogen atom, a trihalogenomethyl group, or It means an aryl group which may be substituted with a lower alkoxy group. ] A prophylactic/therapeutic agent for ischemic diseases characterized by comprising a tropolone derivative represented by the following or a pharmacologically acceptable ester or salt thereof as an active ingredient.