JPH04247077A - Tropolone derivative and agent for prophylaxis and therapy of ischemic disease having same as effective component - Google Patents

Abstract

PURPOSE: To obtain a new tropolone derivative and its ester or salt useful for preventing and treating cerebral hemorrhage, etc., as a preventive/curative medicine for ischemic heart diseases.

CONSTITUTION: The compound of the formula I, e.g. 2-(2'-oxo-3'-methoxy-5'- isopropyl-3',5'-7'-cycloheptatrienyl)-3-(2-phenyl) ethylbenzothiazoline is obtained by allowing the starting substance of tropolone of the formula II to react with formaldehyde, then alkylating and heating with amines, then to carry out oxidation reaction, and to condensate with 2-aminothiophenols and further to oxidize the reaction product. In the formula I, R¹ is H, lower alkyl, aromatic; R² is H, alkyl, arylalkyl, etc.; R³, R⁴ are each H, lower alkyl, halogen, etc.; X is OR⁶ (R⁶ is H, alkyl, etc.), etc.; (n) is 0,1,2.

COPYRIGHT: (C)1992,JPO

Description

Detailed Description of the Invention [0001] The present invention is a novel tropolone derivative or a pharmacologically acceptable ester or salt thereof, and the prevention and treatment of ischemic diseases using the same as an active ingredient. Regarding drugs. The preventive/therapeutic agent of the present invention can be used to treat cerebrovascular disorders such as cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, transient ischemic attack, head trauma, sequelae of brain surgery, or variant angina pectoris or unstable angina pectoris. Prevention of cardiovascular disorders such as myocardial infarction, arrhythmia associated with resumption of coronary blood flow due to PTCA/PTCR/CABG, etc.
Used for treatment. [0002] Cell damage caused by ischemia is caused by (1) a process that progresses under anoxic conditions during ischemia, and (2) a damage process caused by active oxygen that inevitably occurs when blood flow resumes after ischemia. It is roughly divided into two types (Nishida et al., Metabolism Vol. 24, 379, 19
87). 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 heart failure, myocardial infarction, arrhythmia associated with resumption of coronary blood flow due to PTCA/PTCR/CABG, etc. Furthermore, transplant organ failure during organ transplantation, organ failure due to decreased blood flow during shock, and during surgery. Examples include temporary blockage of blood flow to certain organs. It is difficult to explain these diseases by 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 while being selected according to each etiology and pathological condition. For example, as preventive/therapeutic drugs for cerebrovascular disorders, glycerol, ozacrel, nizophenone, ticlopidine, AVS, etc. have been used and studied from the viewpoint of preventing cerebral edema and cerebral vasospasm in the acute phase. On the other hand, in the chronic phase, cerebral circulation improving agents such as nicardipine, cinnarizine, flunarizine, and dilazeb, vinpocetine, nicergoline, and pentoxifylline 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. Vasodilators such as nitro compounds and Ca-antagonists are used to treat variant angina and unstable angina, and to prevent myocardial infarction and P.
The use of 5-lipoxygenase inhibitors and radical scavengers is currently being considered for the failure to resume coronary blood flow due to TCA/PTCR/CABG, etc., but currently there are no drugs for which clinical evaluation has been established. It is. [0003] Problems to be Solved by the Invention The present inventors have discovered that ischemic diseases are closely related to damage to cell membranes and the blocking phase caused by active oxygen, and excessive and rapid influx of extracellular calcium ions into cells. I thought it might happen as a result of doing so. In other words, when the cell membrane is damaged by active oxygen, extracellular calcium flows into the cell, and as a result, proteases in the cell are activated and cellular 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 to form blood clots (e.g., thromboxane A2). ), and in this conversion process, active oxygen is generated again, leading to worsening of the disorder. From this point of view, the present inventors have conducted intensive research on drugs effective for the prevention and treatment of ischemic diseases, and as a result, have discovered that certain new tropolone derivatives are effective, and have completed the present invention. reached. [Means for Solving the Problems] The present invention provides general formula [I]
[Formula 2] [In the formula, R1 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aromatic group, and R2 is a hydrogen atom or an alkyl group in which each constituent carbon atom may be substituted with a heteroatom. group, arylalkyl group or arylsulfonyl group (these aryl rings may be nuclear-substituted), R3 and R4 are the same or different,
Each of hydrogen atom, lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, CN, -CO2R5 or NO
2, X is OR6 or NR7R8, R5 is a hydrogen atom or a lower alkyl group, R6 is a hydrogen atom or, respectively,
An alkyl group or an arylalkyl group in which a carbon atom of a constituent component may be substituted with a heteroatom (the aryl ring may be substituted with a nucleus), R7 and R8 are independently a hydrogen atom or a carbon atom of a constituent component. The alkyl group whose atoms may be substituted with heteroatoms or R7 and R8 together form a 5- to 7-membered ring, which includes -CH2-, -O- and -NR9- within the ring. Selected 1
-3 groups, R9 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted arylalkyl group,
n means 0, 1 or 2. ] or a pharmacologically acceptable ester or salt thereof and the prevention and treatment of ischemic diseases using this as an active ingredient.
It provides a therapeutic agent. In the compound represented by the general formula [I] of the present invention, the lower alkyl group represented by R1 is an alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, n
-pentyl, isoamyl, etc. Examples of the aromatic group include an aryl group having 6 to 10 carbon atoms, which has 1 to 7 substituents selected from the above-mentioned lower alkyl group, halogen, nitro, cyano, hydroxyl group, and lower alkoxy group. You may do so. As a halogen, chloro,
Examples include fluoro, bromo, and iodo, and examples of lower alkoxy groups include alkoxy groups having 1 to 5 carbon atoms. Examples of these aryl groups include phenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,
o,m-dichlorophenyl, p-fluorophenyl, p
- trifluorophenyl, p-nitrophenyl, m-nitrophenyl, o-nitrophenyl, p-cyanophenyl, m-cyanophenyl, o-cyanophenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, Examples include m,p-dimethoxyphenyl. [0006] The alkyl group whose constituent component R2 may be substituted with a heteroatom is a straight or branched alkyl group having 1 to 20 carbon atoms, including the same lower alkyl group as in R1, or Amino, carbon number 1-5
Examples include an amino group mono- or di-substituted with a lower alkyl group or a substituted or unsubstituted aralkyl group, a cyclic amino group such as pyrrolidinyl, or an alkyl group having 1 to 20 carbon atoms substituted with a hydroxyl group. Examples of these groups include, for example, methyl, ethyl, n-propyl, n-butyl, 2-[N,N-
dimethylamino]ethyl, 2-(1-pyrrolidinyl)ethyl, 3-[N,N-dimethylamino]propyl, 2-
[N-methyl-N-phenethylamino]ethyl, 3-[
N-methyl-N-phenethylamino]propyl, 2-[
N-Methyl-N-(2,3-dimethoxyphenethylamino]ethyl, 3-[N-methyl-N-(2,3-dimethoxyphenethylamino]propyl, 2-hydroxyethyl, 3-amino-2-hydroxypropyl , 3-dimethylamino-2-hydroxypropyl, 3-diisopropylamino-2-hydroxypropyl, etc. The arylalkyl group whose constituent components may be substituted with a hetero atom has 7 to 20 carbon atoms. and arylalkyl groups having 7 to 20 carbon atoms containing one or more heteroatoms selected from N, S, and O. These include arylalkyl groups having a carbon number of 7 to 20 and containing one or more heteroatoms selected from N, S, and O. For example, benzyl, phenethyl, 3,4-dimethoxyphenethyl, 2,3,4-
Examples include trimethoxyphenethyl, pyridylmethyl, pyridylethyl, and quinolylmethyl. The arylsulfonyl group whose constituent components may be substituted with a heteroatom include an arylsulfonyl group having 6 to 10 carbon atoms, and 1 selected from N, S and O.
Examples include arylsulfonyl groups having 6 to 10 carbon atoms and containing at least one heteroatom. These may be nuclear-substituted with the same substituent as the aromatic group. Examples include phenylsulfonyl, naphthylsulfonyl, ninolylsulfonyl, isoquinolylsulfonyl, and the like. Examples of the lower alkyl group, halogen atom, and lower alkoxy group in R3 and R4 include the groups described above. Examples of the lower alkyl group, the alkyl group whose constituent carbon atoms may be substituted with a heteroatom, and the arylalkyl group for R5 to R8 include the same groups as described for R2 above. R3 and R
Examples of the 5- to 7-membered ring formed by 4 together include indene, indane, naphthalene, tetraline, quinoline, isoquinoline, quinoxaline, indole, indoline,
Examples include chromene and chromane. The lower alkyl group for R9 is as mentioned above, and the substituted or unsubstituted arylalkyl group is a group having 7 carbon atoms.
-20 arylalkyl groups may be mentioned, which may have the same substituents as the aromatic group. Specific examples of the compound of the present invention represented by the general formula [I] include the following. (1) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline, (2) 2-(2'-oxo-3'-methoxy-
5'-isopropyl-3',5',7'-cycloheptatrienyl)-3-methylbenzothiazoline, (3) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-benzylbenzothiazoline, (4) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-picolyl)benzothiazoline, (5) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(3-picolyl)benzothiazoline, (6) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(4-picolyl)benzothiazoline, (7) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-(2-picolyl)ethyl)benzothiazoline, (8) 2-(2'-oxo-3'-methoxy-5 '-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-(3,4-dimethoxyphenyl)ethyl)benzothiazoline, (9) 2-(2'-oxo-3'-methoxy-5'
-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-quinolyl)methylbenzothiazoline, (10) 2-(2'-oxo-3'-methoxy-5'-isopropyl- 3',5',7'-cycloheptatrienyl)-3-(3-(N-methyl-N-(2-
phenyl)ethyl)amino)propylbenzothiazoline, (11) 2-(2'-oxo-3'-methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-(N,N-dimethyl)amino)
Ethylbenzothiazoline, (12) 2-(2'-oxo-3'-methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(3-(N,N-dimethyl)amino)
Propylbenzothiazoline, (13) 2-(2'-oxo-3'-methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(3-(4-(4',4'-difluorobenzhydryl)piperazin-1-yl)propyl)
Benzothiazoline, (14) 2-(2'-oxo-
3'-hydroxy-5'-isopropyl-3',5',
7'-cycloheptatrienyl)-3-methylbenzothiazoline, (15) 2-(2'-oxo-3'-(1-piperazinyl)-5'-isopropyl-3',5',7'-cyclo heptatrienyl)-3-(2-phenyl)ethylbenzothiazoline, (16) 2-(2'-oxo-3'-(2-(N,
N-dimethyl)aminoethyl)amino-5'-isopropyl-3',5',7'-cycloheptatrienyl)-
3-(2-phenyl)ethylbenzothiazoline, (17) 2-(2'-oxo-3'-methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethyl-1,1-dioxobenzothiazoline, (18) 2-(2'-oxo-3' -methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethyl-1-oxobenzothiazoline. Pharmaceutically acceptable salts of the tropolone derivative of the present invention represented by the general formula [I] include salts of mineral acids such as hydrochloric acid and sulfuric acid; organic sulfones such as methanesulfonic acid and p-toluenesulfonic acid; Examples include salts of acids, salts of organic carboxylic acids such as acetic acid, propionic acid, succinic acid, lactic acid, tartaric acid, malic acid, and citric acid. Examples of esters include organic carboxylic acid esters such as acetic acid, propionic acid, and oxalic acid. The tropolone derivative of the present invention represented by general formula [I] can be produced, for example, according to the following reaction formula. [0013] In the formula, R1, R2, R3, R4, R6, R7, R8, n
and X have the same meanings as above. That is, tropolone represented by the general formula [VI] can be prepared by a method known in the literature [Proc. Japan
Acad. , 27, 561 (1951)] to obtain compound [V] with a hydroxymethyl group introduced at the 7-position, and then alkylation reaction to obtain compound [IVa]. For the alkylation reaction, a method commonly used in the alkylation reaction of phenols is employed. For example, as an alkylating agent, use an alkyl halide corresponding to the target alkyl group such as methyl iodide or benzyl chloride, or a sulfate ester corresponding to the target alkyl group such as dimethyl sulfate, and It can be done below. Examples of the base include sodium hydride, amines such as triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium hydrogen carbonate. The alkylating agent to be used is 1 to 3 molar equivalents to compound [V], and the amount of base varies greatly depending on the reaction reagent used, but for example, when sodium hydride is used, 1 to 1 molar equivalent is used. For amines, potassium carbonate, etc., 2 to 5 molar equivalents are usually used. The reaction solvent is not particularly limited as long as it is an inert solvent that can dissolve compound [V], but preferably ethers such as tetrahydrofuran, halogen-containing solvents such as dichloromethane and chloroform, or dimethyl sulfoxide and dimethyl. Mention may be made of polar solvents such as formamide. The reaction temperature varies depending on the type of base and alkylating agent used, but is generally preferably in the range of 0 to 100°C. Compound [IVa] can be converted to compound [IVb] by simply heating the desired amine in an aromatic hydrocarbon such as benzene, toluene, or xylene, or a halogen-containing solvent such as carbon tetrachloride or tetrachlorethylene. can be converted. The amines used are the compound [IVa
], usually 1 to 2 molar equivalents, particularly preferably 1.
2 to 1.5 molar equivalents are used, but an excess amount may be used. The oxidation reaction of compounds [IVa] and [IVb] can be carried out by a known method. For example, manganese dioxide is added to compounds [IVa] and [IVb] at a rate of 5 to
[IIIa
] and [IIIb]. When compound [IIIa] or [IIIb] is condensed with 2-aminothiophenols [II], compounds [Ia] and [Ib] are obtained, respectively. The condensation reaction uses solvents such as halogen-containing solvents such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, nitrogen-containing aromatic hydrocarbons such as pyridine and quinoline, and lower alcohols such as methanol, ethanol, and propanol. It can be carried out preferably at room temperature to 100°C. 2-aminothiophenols [II] may be used in excess or in a small amount relative to compound [III], but considering the reaction yield and product isolation/purification process, it is recommended to use around equimolar amounts. It is preferable to do so. Note that the condensation reaction may be performed under reducing conditions using its oxidized dimer, compound [II'], instead of compound [II]. That is, a compound having an SH group, such as compound [II], sometimes undergoes air oxidation during storage or handling for reaction and is converted into compound [II']. In such a case, as a reducing agent, for example, reprocessing with sodium boride etc. to return the compound [II], or using a trivalent phosphorus compound such as triethyl phosphite, triphenylphosphine, tricyclohexylphosphine, etc. /3 mol to equimolar amount of compound [II
[Ia] or [Ib
] can be synthesized. Compound [Ia] can also be prepared by reacting with various amines under the above reaction conditions [
Ib]. For a compound [I] in which R2 has an arylsulfonyl group, use the corresponding compound [I] where R2=H and react with an equimolar amount of the corresponding arylsulfonyl chloride in the presence of an organic amine such as pyridine or triethylamine. According to
Can be easily synthesized. The compound of the general formula [I] of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and column chromatography. Next, an in vitro test using a compound of the present invention and a control drug
and in vivo pharmacological studies and their results. 1. In vitro antilipid peroxidation test method A microsomal fraction from SD male rat brain was prepared, and 0.2 mg of the protein was added to 10 mM HEPES.
and 0.2 in 150 mM KCl (pH 7.4)
mMNADPH, test compound and Fe3+ (0.1 m
1 ml of the mixture of M)-ADP (0.5 mM) was incubated at 37°C for 15 minutes. After cooling on ice, TCA-TB
A-HCl reagent (16.7% trichloroacetic acid, 0.4%
1.5 ml of thiobarbituric acid, 0.278N hydrochloric acid)
and heated in boiling water for 15 minutes. After cooling on ice, the mixture was centrifuged, and the absorbance of the supernatant at 535 nm was measured to calculate the amount of thiobarbituric acid reactive substance (TBAR). 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 antiperoxidant activity of the drug. The results are shown in Table 1. A compound with a higher inhibition rate means a stronger antilipid peroxidation effect. [Table 1] Table 1 Antilipid peroxidation effect


compound number
Antilipid peroxidation effect (% inhibition)
10
μM 50μM
1
91.8
93.1 2
95.5
-4
95.7
99.3 5
95.9
100 6
93.1
96.6 7
91.9
94.3 8
93.4
93.8 9
94.9
96.6 10
93.0
94.5 11
89.3
-12
89.4
-13
91.8
94.4 14
90.0
-15
93.0
94.4 16
91.2
95.1 [0021]2. In Vivo Cardiac Ischemia/Reperfusion Arrhythmia Test Test Method The experiment was conducted on rats that were artificially ventilated under pentobarbital anesthesia. After resection of the fourth rib, the chest was opened and the heart was exposed. A thread was passed under the origin of the left coronary artery, the heart was returned to its original position, and the thread was threaded inside the polytube. 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 5 minutes after occlusion, and ventricular arrhythmia observed during the subsequent 4 minutes was observed and recorded on an electrocardiogram. Electrocardiograms were observed in the second lead by inserting needle electrodes into the right forelimb and left hindlimb. The duration of ventricular tachycardia and ventricular fibrillation occurring after reperfusion were compared between the test compound treated group and the similarly operated vehicle group. A test compound was judged to be effective when either of the parameters in the test compound-treated group was less than 1/2 of that in the vehicle-treated group. The results are shown in Table 2. [Table 2] Table 2
Cardiac ischemia reperfusion arrhythmia test


compound number
Minimum effective dose (mg/kg
, i. v. ) Compound (10
)
<5 Compound (11)

<5 0023]3. In Vivo Behavioral Test Test Method Under light ether anesthesia, both common carotid arteries of male ICR mice (approximately 8 weeks old) were ligated simultaneously 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. In the case of intravenous administration, it was administered only 5 minutes before ligation. From the day after blood reperfusion, behavioral disturbances were evaluated by the amount of locomotor activity during exploratory behavior, the performance of the suspension test, and the one-trial passive avoidance learning test. In other words, the amount of locomotor activity was measured using a group-type locomotor activity measuring device for 30 minutes immediately after the mouse was placed in the measurement gauge, and when the amount of locomotor activity was greater than or equal to the average locomotor activity of the vehicle-administered group + 2 x SD, it was judged as an effective 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 one-trial passive avoidance learning test, Step-t
Using a hrough-type device, we applied an electric shock of about 0.5 mA for 3 seconds as an acquisition trial on the day after blood reperfusion, and performed a regeneration trial the next day, using mice that remained in the light room for more than 300 seconds as an effective example. I judged it. 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 3. [Table 3] Table 3
Mouse cerebral ischemia/reperfusion study


compound number
Route of administration Minimum effective dose (mg/kg) Compound (1)
i. p.
0.1 Compound (2
) i. p.
1.0 Compound (6) i. v
．． <1.0
Compound (11) i.
p. 1.0
Compound (12)
i. p. 1.0
4. Test method for normal cerebral blood flow experiment An experiment was conducted using rats under urethane anesthesia. After inserting cannulas for blood pressure measurement and drug administration into the femoral artery and vein, the temporal bone was resected on a stereotaxic device, and
A probe for measuring cerebral blood flow was placed on the dura mater. Blood flow was measured using a laser Toppler blood flow meter. The vehicle of the test compound was first administered intravenously, and then three doses of the test compound were administered at 15 minute intervals starting from the lowest dose. A dose was considered effective if the average increase in cerebral blood flow caused by the test compound -2xSE was greater than the average change in cerebral blood flow caused by the vehicle. Compound (1) was administered at 3 mg/kg i. v. The above was effective. The compound of general formula [I] 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, Cardiac disease, unstable angina, myocardial infarction, PTCA/PT
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 due to CR/CABG and the like. When used as such a prophylactic/therapeutic agent, the compound of general formula [I] is combined with a suitable pharmacologically acceptable carrier, excipient, or diluent to form a powder, granule, tablet, capsule, It can be made into a dosage form for oral or parenteral administration, such as an injection. Dosage depends on route of administration, age of patient,
Although it varies depending on body weight, actual symptoms to be treated, etc., for example, when administered orally to adults, 10 to 50 mg per day,
Preferably, it can be 10 to 25 mg, 1 day per day.
~ Can be administered in several doses. 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. Example 1 2-(2'-oxo-3'-methoxy-5
Preparation of '-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline 1a) Benzothiazolin-2-one
5.15 g (34.1 mmol) was dissolved in 100 ml of dimethylformamide, 1.36 g (34.1 mmol) of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature until the generation of hydrogen gas was completed. Next, 4.89 ml (35.8 mm) of beta-phenylethyl bromide
ol) was added thereto, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and then with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography, and n-hexane-ethyl acetate (4:
1) 6.49 g of 3-(2-phenyl)ethylbenzothiazolin-2-one was obtained as a white amorphous powder from the eluted fraction. (Yield 80%) 1H NMR (CDCl3), δ (ppm) = 5.1
6 (2H, s), 6.96 (1H, dd, J = 8, 1H
z), 7.13 (1H, ddd, J=8,8,1Hz)
, 7.27-7.36 (5H, m), 7.43 (1H,
ddd, J=8,1Hz) 1b) 3-
(2-phenyl)ethylbenzothiazolin-2-one
2.0 g (7.83 mmol) was heated under reflux in ethanol (90 ml)-potassium hydroxide (10.0 g) for 17 hours under a nitrogen atmosphere. After cooling, the reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-(2-phenyl)ethylaminothiophenol. Dissolve this in 18 ml of toluene and add 7-formyl-4-isopropyl-2-
1.63 g (7.90 mmol) of methoxy-3,5,7-cycloheptatrien-1-one was added, and the mixture was heated under reflux for 17 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography.
g of 2-(2'-oxo-3'-methoxy-5'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline as a brown amorphous substance. Obtained as a powder. (Yield 62%) 1H NMR (CDCl3), δ (ppm) = 1.2
5 (6H, d, J = 7Hz), 2.77-2.97 (3
H, m), 3.22 (1H, ddd, J = 15, 10,
6Hz), 3.69 (1H, ddd, J=15,10,
6Hz), 3.97 (3H, s), 6.43 (1H, s
), 6.61 (1H, d, J = 8Hz), 6.69 (1
H, ddd, J = 8, 8, 1Hz), 6.74 (1H,
s), 6.80 (1H, d, J=10Hz), 6.69
-7.03 (2H, m), 7.13-7.30 (5H,
m), 7.48 (1H, d, J = 10Hz) MS (m/e): 417 (M+, 35%), 402 (
100%), 312 (17%). Examples 2a to 13a Various N-substituted benzothiazolines were synthesized by the same reaction procedure as in Example 1a). The results are shown in Tables 4-8. [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] (Note 1) A sodium ethoxide solution was used instead of sodium hydride. (Note 2) 3-(3-bromopropyl) was prepared in the same manner as in Example 1a) using 1,3-dibromopropane.
Benzothiazolin-2-one was obtained in a yield of 64%. By heating and refluxing the bromine compound and 4-(4,4-difluorobenzhydryl)piperazine in toluene in the presence of potassium carbonate, the N-substituted benzothiazolinone compound 13a) was obtained in a yield of 85%. . Examples 2b to 14b Compound [Ia] was prepared by the same reaction procedure as in Example 1b).
were synthesized in various ways. The results are shown in Tables 9-13. [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] Example 15 2(2'-oxo-3'-
piperazinyl-5'-isopropyl-3',5',7'
-cycloheptatrienyl)-3-(2-phenyl)-
Production of ethylbenzothiazoline 2-(2'-oxo-3'-methoxy-5'-isopropyl-3',5',7'-cycloheptatrienyl)-
100 mg (0.24 mmol) of 3-(2-phenyl)ethylbenzothiazoline (compound 1b) and piperazine 3
3. 1 mg (0.36 mmol) in 6 ml toluene.
The mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel thin layer chromatography (developing solvent: chloroform-methanol (10:
1)), 105 mg of 2-(2'-oxo-3'-piperazinyl-5'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline. Obtained as an orange viscous liquid. (Yield 9
3%) 1H NMR (CDCl3), δ (ppm) = 1.2
2 (6H, d, J=7Hz), 2.71 (1H, br.
s), 2.80 (1H, m), 2.88 (2H, m),
3.17 (4H, br.s), 3.22 (1H, m),
3.34 (4H, br.s), 3.70 (1H, m),
6.38 (1H, s), 6.59 (1H, d, J=8H
z), 6.65-6.74 (3H, m), 6.97 (2
H, d, J = 8Hz), 7.14-7.30 (5H, m
), 7.40 (1H, d, J=10Hz) Example 16 2-(2'-oxo-3'
-(2-(N,N-dimethylamino)ethyl)amino-
Preparation of 5'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline 2-(2'-oxo-3'-methoxy-5
'-isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethylbenzothiazoline (compound 1b) 100 mg (0.24 mmol) and 2-(N,N-dimethyl)amino Ethylamine 36mg
(0.41 mmol) was heated under reflux in 6 ml of toluene for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel thin layer chromatography (
Developing solvent: chloroform-methanol (10:1),
82.5 mg of 2-(2'-oxo-3'-(2-(N
, N-dimethylamino)ethyl)amino-5'-isopropyl-3',5',7'-cycloheptatrienyl)
-3-(2-phenyl)ethylbenzothiazoline was obtained as a yellow amorphous powder. (Yield 73%) 1H NMR (CDCl3), δ (ppm) = 1.2
6 (6H, d, J=7Hz), 2.32 (6H, s),
2.68 (2H, m), 2.38-2.94 (3H, m
), 3.22 (1H, m), 3.37 (2H, m), 3
．． 68 (1H, m), 6.53 (1H, s), 6.59
(1H, t, J=8Hz), 6.64-6.70 (2H
, m), 6.98 (2H, d, J=7Hz), 7.15
-7.30 (6H, m), 7.55 (1H, d, J=1
0Hz), 7.77 (1H, br.s) Example 17 2-(2'-oxo-3'
-methoxy-5'-isopropyl-3',5',7'-
Production of cycloheptatrienyl)-3-(2-phenyl)ethyl-1,1-dioxobenzothiazoline Compound 1b 50 mg (0.12 mmol) was added to 10 m
The solution was dissolved in 1 ml of chloroform and cooled to 0°C. 83 mg (0.48 mmol) of methachloroperbenzoic acid was added to this, and the mixture was stirred at 0°C for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 36 mg of 2-(2'-oxo-3'-methoxy-5') was extracted from the toluene-acetone (4:1) elution fraction.
-Isopropyl-3',5',7'-cycloheptatrienyl)-3-(2-phenyl)ethyl-1,1-dioxobenzothiazoline was obtained as a brown amorphous powder. (
Yield 66%) 1H NMR (CDCl3), δ (pp
m) = 1.26 (6H, d, J = 7Hz), 2.83-
2.92 (3H, m), 3.27 (1H, m), 3.8
2 (1H, m), 3.99 (3H, s), 6.17 (1
H, s), 6.73-6.94 (2H, m), 7.13
-7.29 (6H, m), 7.47 (1H, ddd, J
=8,8,1Hz), 7.57(1H,dd,J=8,
1Hz). MS (m/e): 449 (M+, 13%), 342 (
100%), 105 (64%), 91 (89%) Example 18 2-(2'-oxo-3'
-methoxy-5'-isopropyl-3',5',7'-
Production of cycloheptatrienyl)-3-(2-phenyl)ethyl-1-oxo-benzothiazoline Compound 1b 52 mg (0.13 mmol) in 5 ml
of chloroform and cooled to 0°C. 22.9 mg (0.13 ml) of methachloroperbenzoic acid was added to this and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 49 mg of 2-(2'-oxo-3'-methoxy-5'-isopropyl-3',5 ',7'-cycloheptatrienyl)-3-(2-phenyl)ethyl-1-oxo-benzothiazoline was obtained as a brown amorphous powder. (Yield 90%) 1H NMR (CDCl3), δ(p
pm) = 1.25 (6H, d, J = 7Hz), 2.77
(6H, s), 2.83 (1H, m), 3.95 (3H
,s), 4.27(2H,s), 6.68-6.71(
2H, m), 6.94 (1H, m), 7.03-7.1
6 (3H, m), 7.52 (1H, d, J=10Hz)
[0035] According to the present invention, novel tropolone derivatives useful for the prevention and treatment of ischemic diseases can be obtained.

Claims (2)

[Claims] Claim 1: General formula [Formula 1] [wherein R1 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aromatic group, and R2 is a hydrogen atom or a carbon atom of each component is a heteroatom] an optionally substituted alkyl group, arylalkyl group or arylsulfonyl group (these aryl rings may be nuclear-substituted), R3 and R4 are the same or different,
Each of hydrogen atom, lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, CN, -CO2R5 or NO
2, X is OR6 or NR7R8, R5 is a hydrogen atom or a lower alkyl group, R6 is a hydrogen atom or, respectively,
An alkyl group or an arylalkyl group in which a carbon atom of a constituent component may be substituted with a heteroatom (the aryl ring may be substituted with a nucleus), R7 and R8 are independently a hydrogen atom or a carbon atom of a constituent component. The alkyl group whose atoms may be substituted with heteroatoms or R7 and R8 together form a 5- to 7-membered ring, which includes -CH2-, -O- and -NR9- within the ring. Selected 1
-3 groups, R9 is a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted arylalkyl group,
n means 0, 1 or 2. ] A tropolone derivative or a pharmacologically acceptable ester or salt thereof. 2. A prophylactic/therapeutic agent for ischemic diseases, comprising the tropolone derivative according to claim 1 or a pharmacologically acceptable ester or salt thereof as an active ingredient.