JPH0587049B2 - - Google Patents

Description

[Detailed description of the invention]

[Objective] The present invention relates to a brain disorder improving agent that also has antidepressant effects. When cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, and cerebral venous thrombosis occur, as well as brain disorders caused by head trauma, various symptoms appear as after-effects such as headache, dizziness, tinnitus, headache, and numbness in the limbs. do. The drug of the present invention is aimed at improving and treating the above symptoms. (Prior Art) The compound that is the active ingredient of the present invention is a compound synthesized by the applicant, and is known to have antidepressant action as a pharmacological action (Japanese Patent Application Laid-open No. 57
-203072, Japanese Patent Application Laid-open No. 1983-70). (Problems to be Solved by the Invention) As a result of further research into the pharmacological activity of the compounds that are the active ingredients of the present application, the present inventors have found that these compounds are effective in slowing cerebral cortical electroencephalograms caused by brain disorders. They discovered that it has an excellent effect of improving blood viscosity increase, etc., recognized that it is useful as an agent for improving brain disorders, and completed the present invention. [Constitution] The novel brain disorder improving agent of the present invention has the general formula

[Formula, R ¹ represents a hydrogen atom or a hydroxyl group] ] and its pharmacologically acceptable salts as active ingredients. The pharmacologically acceptable salt of the present invention is not particularly limited as long as it is an acid addition salt, but preferably as an acid,
Hydrohalic acids such as hydrofluoric acid, chlorine, hydrobromic acid, and hydroiodic acid; inorganic acids such as sulfuric acid and phosphoric acid; lower alkyl acids such as methanesulfonic acid, trifluorometasulfonic acid, and ethanesulfonic acid; Mention may be made of arylsulfonic acids such as sulfonic acid, benzylsulfonic acid, p-toluenesulfonic acid, organic acids such as oxalic acid, maleic acid, etc., and amino acids such as glutamic acid, aspartic acid. In the general formula (), when R ¹ represents a hydroxyl group, optical isomers exist because an asymmetric carbon atom is present. Therefore, when the compound having the general formula () is obtained as a mixture of these optical isomers, it can be optically resolved according to a conventional method,
Each isomer can be obtained. Although all optical isomers and mixtures of optical isomers are represented by a single formula in the compound having the general formula (), the scope of the description of the present invention is not limited thereby. The compound having the general formula (), which is the active ingredient of the present invention, can be produced by the method described below, for example, according to the method described in JP-A-57-203072 and JP-A-62-70. Ru.

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[Chemical] [Effect] The compound having the general formula () and the salt thereof of the present invention have an excellent effect of improving cerebral cortical electroencephalogram slowing, blood viscosity increase, etc., and therefore are effective in improving mental symptoms in patients with brain disorders. It is thought to be particularly effective for disorders of decreased motivation and spontaneity, emotional disorders, sleep disorders, and problem behavior, and since it has low toxicity, it is useful as a therapeutic agent for improving mental symptoms in brain disorders. Examples of the administration form of the brain disorder improving agent of the present invention include oral administration in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration in the form of injections, suppositories, etc. These various preparations are prepared according to conventional methods, and are added to the main drug as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, etc., which are commonly used in the field of formulation technology. It can be formulated using adjuvants that may be used. The dosage varies depending on the symptoms, age, etc., but it can be administered at 5 mg/kg body weight per day, once or in divided doses. The present invention will be explained in more detail below with reference to Examples, Formulation Examples, and Production Examples. Example 1 Improving effect on slowing of cerebral cortical electroencephalograms caused by internal capsule destruction in cats Adult cats of both sexes were used. The animal was fixed on a stereotaxic apparatus under ether anesthesia to prepare a lower dissected brain specimen, and the ether anesthesia was stopped. Then pancurnium bromide (0.4mg/Kg/hr, iv)
He was immobilized and experiments were conducted under artificial respiration. A hole was made in the skull and a pair of silver ball electrodes (diameter 1.5 mm) were attached to the cerebral cortex, and cortical electroencephalograms were recorded at least 3 hours after ether anesthesia had stopped. [RS Snider and W.
T. Niemer, A stereotoxic atlas of the cat
brain，The University of Chicago
Press.1961], bilateral inclusion (A: 10, L: 6
-9, H: -2.5 to +3.0), an electrode (TM type, manufactured by Radionics, diameter 0.7 mm) was inserted and electrically destroyed using an electrocoagulator (manufactured by Radionics, RFG-4). (20-30mA, 80℃, 3 minutes). After 30 minutes had passed, cerebral cortical electroencephalograms were recorded for about 40 minutes in the same manner as above. Next, a test compound suspended in a 0.5% CMC solution was administered through a cannula previously inserted into the duodenum, and electroencephalograms were recorded until 160 minutes after administration. The concentration of the test compound was adjusted so that the administered volume was 1 ml per 1 kg of body weight. Frequency analysis of brain waves every 10 minutes using a NEC Sanei signal processor (7T07A) revealed that when the internal capsule was destroyed bilaterally, the delta wave (0.585-3.9Hz) component of brain waves in the cerebral cortex increased. The waves become noticeably slower. Also, along with this, the θ wave (4.095
-7.995Hz) and alpha wave (8.19-13.065Hz) component ratios decreased significantly (Table 1). In the general formula (), when a compound (10 mg/Kg) in which R ¹ is a hydroxyl group is administered into the duodenum, the average and standard ratios of δ, θ, and α wave components of 4 cases at the time of maximum effect 30-80 minutes after administration. When the error was calculated and a significant difference test was performed between before and after drug administration, a significant decrease in the delta wave component ratio and a significant increase in the alpha wave component ratio were observed at a dose of 10 mg/Kg ( (Table 1).

[Table] Example 2 Improving effect on blood viscosity increase caused by ischemia Adult male Wistar rats were used. After oral administration of the test compound or vehicle (0.5% CMC solution), immediately administer pentobarbital (40 mg/day).
Kg, ip) The animal was fixed in the dorsal position under anesthesia, 0.6 ml of blood was collected from one side of the jugular vein, and a blood fluid characteristic testing device (BioRheolizer, Tokyo Keiki) was used to collect 37.5 ml of blood.
Blood viscosity was measured at each shear rate of 75, 150 and 375S ^-1 . Next, both common carotid arteries were ligated and
After a period of time had elapsed, blood was drawn from the contralateral jugular vein in the same manner as before, and the blood viscosity was measured. When both common carotid arteries were ligated for 1 hour, the viscosity of blood collected from the jugular veins increased significantly at all shear rates (Table 2, CMC administration group). but,
In rats to which the test compound (20 mg/Kg) had been orally administered in advance, blood viscosity did not increase at any shear rate despite bilateral common carotid artery ligation for 1 hour (Table 2). This result is 10mg/
Kg was weak, and at a shear rate of 375S ^-1 no significant increase in blood viscosity due to ischemia was observed;
No improvement effect was observed in the shear rate of 75S ^-1 . Although a significant increase in blood viscosity was observed at a shear rate of 150S ^-1 , the p value was
In CMC, it was 0.01, and in the test compound (10 mg/Kg) administration group, it was 0.05, which was slightly larger. That is, it has been revealed that the test compound improves blood fluidity, which is worsened by ischemia.

[Table] The upper row shows the value before ligation, and the lower row shows the value after ligation.
Example 3 Effect of promoting glucose uptake in the brain Adult male mice (5 weeks old, body weight 30-35 g) (DDY strain) were used, 6 mice per group. The compound of Production Example 1 was orally administered. Thirty minutes later, 0.3 μCi of [14C]-2-deoxyglucose was intravenously injected, and 10 minutes later, the blood was collected by decapitation and centrifuged at 3000 rpm for 20 seconds to obtain plasma components. 1 ml of NCS was added to 50 μl of this plasma. In addition, blood glucose content was measured using 10 μl of plasma. Furthermore, the entire brain except the cerebellum was removed,
The wet weight was measured, 2 ml of NCS was added to dissolve it, 10 ml of toluene scintillator was added, and radioactivity was measured using a scintillation counter. Radioactivity in the blood was also measured in the same manner. In addition, the amount of brain glucose uptake (mg/g/10min) was calculated using the following formula. Glucose uptake = [RI amount in brain tissue (dpm) ×
Blood glucose amount (mg/ml)]/[Plasma RI amount (dpm) x wet weight (g)] Table 3 Brain glucose uptake promotion effect (mg/g/10 min) CMC 2.810±0.267 (6 ) 5 mg/Kg 3.503±0.258 (6) 10 mg/Kg 3.797±0.282 (6) ^x *: Risk rate P<0.05 indicates a significant difference from the CMC administration group. ( ) indicates the number of cases. As mentioned above, the compound of Production Example 1 was prepared at 10 mg/Kg.
(po)no doses promoted glucose uptake in the brain. Example 4 Promoting oxygen consumption in the brain The method of Hashimoto et al. (Basic and Clinical Studies, 17 , 492-496)
(1983)), male maturity (5 weeks old, weight 30-
The test compound or CMC was orally administered to five DDY mice (35 g) per group. After 40 minutes, the brain was removed by decapitation, and the cerebral cortex was cut into 0.4 mm thick sections in Krebs-Ringer's solution under ice-cooling.
After weighing, 5ml in a glass container with a diameter of 20mm and a height of 70mm.
The specimens were immersed in Krebs-Ringer's solution at 37°C for 30 minutes, and the amount of oxygen consumed during that time was measured. Cerebral oxygen consumption (%/g/30 min) is calculated by dividing the oxygen concentration consumed during 30 minutes of incubation by the wet weight of the brain slice, relative to the dissolved oxygen concentration before inserting the brain slice. Expressed as % concentration per unit wet weight. Table 4 Effect on oxygen consumption in brain slices CMC 3.363±0.136 Production example 1 compound 10mg/Kg 4.240±0263 ^** CMC 3.272±0.167 Inderoxazine 10mg/Kg 3.590±0.217 *: Risk rate P<0.02 shows that there is a significant difference between the CMC administration group and the CMC administration group. As mentioned above, the compound of Production Example 1 was 10mg/Kg
(po) dose promoted oxygen consumption in brain slices. Example 5 Improving effect on neurological symptoms in ischemic brain specimen Male mature (20 weeks old) gerbil (Mongolian)
Gerbil) was used for each group of 20 animals. Pentobarbital (30mg/Kg, ip) and halothane (oxygen 95%)
and 5% carbon dioxide mixed at a rate of 1.5%)
Both common carotid arteries were occluded for 30 minutes under anesthesia. Thirty minutes later, the occlusion of the common carotid artery was released and blood flow was resumed. Thereafter, the animal was placed in a dorsal position, and the time from the resumption of blood flow until the righting reflex recovered, the time at which convulsion occurred, and the time to death were measured. The righting reflex recovery time and convulsion onset time were observed for up to 6 hours after blood flow was resumed, and the time of death was observed for up to 7 hours. If the righting reflex did not recover or convulsion did not occur within 6 hours, the recovery time and the onset time were each calculated as 360 minutes. Similarly, if the patient did not die within 7 hours, the time of death was calculated as 420 minutes. The compound of Production Example 1 was suspended in a 0.5% CMC solution, and the other test compounds were dissolved in 10% ascorbic acid. The target group includes
A 0.5% CMC solution was administered. The CMC solution and the compound of Production Example 1 were administered orally, and the other test compounds were administered intraperitoneally upon resumption of blood flow in the common carotid artery.
As shown in Table 5, the compound of Production Example 1 was 30mg/
A dose of Kg(po) delayed the death time and prolonged the survival time of ischemic brain specimens.

[Table] Example 6 Effect on spontaneous brain waves in rats Rats with electrodes chronically implanted in the cerebral cortex and dorsal hippocampus were placed in cages with feeding and water supply in a soundproof and shielded room one week after surgery. After allowing the subjects to become accustomed to the environment, electroencephalogram recording was started. After recording electroencephalograms 1 hour before administration, the test drug or CMC was orally administered, and electroencephalograms were recorded for 3 continuous hours. Based on the recorded electroencephalograms and electromyograms, the level of consciousness was distinguished into three phases: wakefulness, wave-eliminating sleep, and paradoxical sleep according to Curzan and Soyer's classification (Psychopharmacol., 5 , 457-466 (1964)), and Hofmeister's (Arzneim Forsch., 22 , 88-93 (1972)), the above three phases were classified every minute, and changes in the level of consciousness over a period of 3 hours after administration of the test compound were quantified. Furthermore, the brain waves recorded in advance on the data recorder were analyzed using a brain wave frequency analyzer (Nihon Kohden ATAC).
-450), we conducted frequency analysis of brain waves for 30 seconds while visually confirming the subject's wakefulness using an electroencephalograph. In addition, the power ratio of the band component is 1
-32Hz total power is taken as 100%, δ(1-3.5Hz),
θ (3.5−7.5Hz), α (7.5−10Hz) and β (13−32
The component ratios in four bands (Hz) were calculated.

[Table] It means that it was met.
As mentioned above, the compound of Production Example 1 was 30mg/Kg
(PO) dose decreased slow-wave sleep time and prolonged wake time. Furthermore, frequency analysis revealed that low frequency components (1
-7.5Hz) decreased and high frequency components (7.5-32Hz) increased in 3/5 cases, suggesting that it may activate the brain. Examples 3 to 5 show that the compounds of the present invention not only promote glucose uptake into the brain, but also have the potential to promote glucose consumption and oxygen consumption in the brain, and have the potential to activate the brain. This was also strongly suggested by electroencephalograms. Example 7 Acute toxicity Test compound was administered to adult male DDY mice.
It was suspended in a 0.5% CMC solution, the concentration was adjusted to a dosage volume of 0.1 ml per 10 g of body weight, and the solution was administered orally. Thereafter, the animals were observed for survival and behavioral abnormalities for 5 days, and LD ₅₀ was calculated. In addition, for those for which LD ₅₀ could not be calculated, for example, >5000mg/Kg
means that no death was observed up to 5000mg/Kg.

[Table] Formulation Example 1 Capsule 7-hydroxy-4-(4-cyanoanilino)-
6,7-dihydro-5H-cyclopetane [d]
Pyrimidine 25.0 mg Lactose 153.6 mg Corn starch 100.0 mg Magnesium stearate 1.4 mg Total 280 mg The powders of the above formulation were mixed and passed through a 60-mesh sieve, and 280 mg of this powder was placed in a No. 3 gelatin capsule to form a capsule. Formulation Example 2 Tablet 7-hydroxy-4-(4-cyanoanilino)-
6,7-dihydro-5H-cyclopenta[d]
Pyrimidine 10.0mg Lactose 83.3mg Corn starch 25.0mg HPC (Nippon Soda product) 1.2mg Magnesium stearate 0.5mg Total 120mg One tablet of the above formulation is prepared according to the normal formulation procedure.
It was made into a 120 mg tablet. Production Example 1 Synthesis of 7-hydroxy-4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1) 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine -1-oxide 77.5 g (0.5 mol) of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine was dissolved in chloroform 21, and 258.7 g (1.5 mol) of m-chloroperbenzoic acid was dissolved under ice cooling. of chloroform 0.11
A suspension of was added dropwise. The reaction solution was stirred overnight while cooling with water. Add sodium thiosulfate to the reaction solution under ice cooling.
375 g (2.37 mol) of an aqueous solution of 1.51 g was added dropwise, followed by an aqueous solution of 191 g (1.8 mol) of sodium carbonate.
0.71 was added dropwise. The chloroform layer was separated, and the aqueous layer was extracted with chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate. After concentrating the chloroform solution, it was subjected to silica gel column chromatography (developing solvent: ethyl acetate) to obtain colorless crystals of 4-chloro-6,7-dihydro-5H-cyclopenta. [d] Pyrimidine-1-oxide
43.9g was obtained. Melting point: 85-87°C (decomposition) Mass spectrum, m/e: 170 (M+) (2) 7-acetoxy-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine Anhydrous heated to 50°C Acetic acid 1.51 to 4-chloro-
A solution of 40 g (0.234 mol) of 6,7-dihydro-5H-cyclopenta[d]pyrimidine-1-oxide in acetic anhydride 11 was added dropwise, and the mixture was stirred at 110°C for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and a mixed solvent of 50 ml of toluene and 400 ml of hexane was added to the residue and stirred, and the solvent was washed with a gradient. This operation was performed three times. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform) to obtain a colorless liquid of 7-acetoxy-4-chloro-6,7-dihydro-5H-cyclopenta[d]. 39.3 g of pyrimidine was obtained. (3) 7-hydroxy-4-(4-cyanoanilino)
-6,7-dihydro-5H-cyclopenta[d]
Pyrimidine 7-acetoxy-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 39.3g
(0.185 mol) and 24 g of p-aminobenzonitrile
(0.2 mol) in 180 ml of ethanol was heated under reflux for 1.5 hours. The ethanol was distilled off under reduced pressure and the residue was washed with a 1:1 solution of ethanol-toluene to give gray crystals of 7-acetoxy-4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta[d ] 30 g of pyrimidine was obtained. Melting point: 215-217℃ Mass spectrum, m/e: 294 (M+) 251, 234 Furthermore, hydrolysis was performed with 1N sodium hydroxide, and the resulting residue was recrystallized from ethanol to obtain 7-hydroxy- 4-(4-cyanoanilino)
-6,7-dihydro-5H-cyclopenta[d]
Pyrimidine (colorless sand-like crystals, mp. 260-262°C (decomposition)) was obtained. Production Example 2 5-hydroxy-4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 7-hydroxy-4-
(4-cyanoanilino)-6,7-dihydro-
5H-Cyclopenta[d]pyrimidine 4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine 14.06g
(0.06 mol) was dissolved in 700 ml of acetic acid, 26.58 g (0.06 mol) of lead tetraacetate was added thereto, and the mixture was heated under reflux for 10 hours. After the reaction, insoluble matter was removed and the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate) to obtain 5-acetoxy-4
-(4-cyanoanilino)-6,7-dihydro-
3.0 g of 5H-cyclopenta[d]pyrimidine (colorless needle crystals, mp. 194-196°C, recrystallized from ethyl acetate) and 7-acetoxy-4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta [d] 3.3 g of pyrimidine (light brown prismatic crystals,
mp.215-217°C, recrystallized from ethyl acetate). 1.8 g of 5-hydroxy-4-(4-cyanoanilino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (colorless sand-like crystals, mp. 232-
234°C (decomposition)) and 7-hydroxy-4-(4-
cyanoanilino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (colorless sandy crystals,
mp.260-262°C (decomposition)) 1.4g was obtained.

Claims (1)

[Claims] 1 General formula: [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group. ] A brain disorder improving agent containing a compound having the following and its salt as an active ingredient.