JPH0443913B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention is based on the general formula (1) [In the formula, when A is an alkoxy group having 1 to 3 carbon atoms, Y is a piperidyl group, a morpholinyl group, a group

[Formula] (Here, R ¹ represents an alkyl group having 1-3 carbon atoms)
or group

[Formula] (where R ² and R ³ are the same or different carbon numbers 1
-5 represents an alkyl group or an aralkyl group; When A is a halogen atom, Y is a morpholinyl group, a group

[Formula] (Here, R ¹ represents an alkyl group having 1-3 carbon atoms)
or group

[Formula] (where R ² and R ³ are the same or different carbon numbers 1
-5 represents an alkyl group or an aralkyl group). ] and a pharmacologically acceptable salt thereof. 1-benzoxepine represented by general formula (1)
5-one derivatives are compounds effective in improving and treating symptoms based on organic disorders and mental dysfunctions in the brain. Organic disorders in the brain are symptoms derived from cerebral ischemic disorders such as cerebral infarction sequelae, cerebral hemorrhage sequelae, cerebral arteriosclerosis sequelae, senile dementia, presenile dementia, amnesia, head injury sequelae, and brain surgery. Refers to various organic disorders resulting from after-effects. In addition, mental dysfunction means mania, depression, neurosis, Parkinson's disease, schizophrenia and schizophrenia-like disorder, chorea, and psychotic dysfunction derived from drugs and alcohol. Prior Art Brain cells maintain an intracellular environment that is completely different from the surrounding environment (extracellular fluid), and live by maintaining this difference. For this reason, energy must be constantly produced and supplied. Most of this energy is supported by oxygen and glucose, which is not stored in the brain and is constantly supplied from the blood. If a brain disorder occurs and the supply of oxygen and buddle sugar is cut off, the energy metabolism disorder generally progresses in stages, with cells losing function over time and eventually becoming organically impaired. It collapses and is no longer able to perform its functions normally. Therefore, in order to stably supply the brain tissue with an energy source and maintain a constant external environment for brain neurons, the cerebral blood vessels themselves have a well-developed mechanism for regulating cerebral blood flow. A number of drugs have been developed to medically treat organic disorders and mental dysfunctions in the brain. 1-Benzoxepine derivatives are already well-known skeletons, and their pharmacological effects include anti-inflammatory, antihypertensive, local anesthetic, and analgesic effects, as well as anti-reserpine, monoamine oxidative oxygen disorders,
It is known to have anti-adrenergic effects. Because it has such various effects, it is being considered to develop it as a drug for the nervous system and circulatory system by appropriately inducing it. For example, 1-benzoxepin-5-one derivatives are described in M. Protiva et al. Collection Czechoslov.Chem.
It is also described in Commun. Vol. 37, pp. 868-886, 1972. Problems to be Solved by the Invention Therefore, the present inventor has conducted research in order to find a compound that is effective in improving and treating the symptoms caused by the various disorders in the brain described above. As a result, 1-benzoxepine-5- represented by the general formula (1)
On derivatives are thought to be closely involved in the improvement and treatment of symptoms caused by the various disorders mentioned above, and are extremely effective against lipid peroxidation and the oxygen-deficient state (cerebral anoxia) of various brain nerve cells. I found that. Means for solving the problem The present invention is based on the general formula (1) [In the formula, when A is an alkoxy group having 1 to 3 carbon atoms, Y is a piperidyl group, a morpholinyl group, a group

[Formula] (Here, R ¹ represents an alkyl group having 1-3 carbon atoms)
or group

[Formula] (where R ² and R ³ are the same or different carbon numbers 1
-5 represents an alkyl group or an aralkyl group; When A is a halogen atom, Y is a morpholinyl group, a group

[Formula] (Here, R ¹ represents an alkyl group having 1-3 carbon atoms)
or group

[Formula] (where R ² and R ³ are the same or different carbon numbers 1
-5 represents an alkyl group or an aralkyl group). ] and a pharmacologically acceptable salt thereof. 1-benzoxepine-5- represented by the above general formula (1)
On derivatives and salts thereof can be synthesized by the following method. That is, general formula (2) (wherein A represents a halogen atom or an alkoxy group having 1 to 3 carbon atoms) and γ-butyrolactone are reacted in the presence of a base to form the general formula (3). A 4-phenoxybutyric acid derivative represented by the formula (wherein A has the same meaning as above). The base used is preferably sodium metal, sodium alkoxide, potassium alkoxide or sodium hydride. Although it depends on the type of A, it is better to carry out the reaction under heating conditions. This 4-phenoxybutyric acid derivative is converted into polyphosphoric acid,
By treatment with an acid such as phosphorus oxychloride, phosphorus pentoxide, p-toluenesulfonic acid, benzenesulfonic acid or sulfuric acid, the general formula (4) can be obtained. 1-benzoxepine represented by the formula (wherein A has the same meaning as above) is obtained. This compound (4) is combined with excess formalin or paraformaldehyde and the general formula Y-H [wherein Y is a piperidyl group, a morpholinyl group, or a group

[Formula] (where R ¹ represents an alkyl group having 1, 2 or 3 carbon atoms) or a group

[Formula] (wherein R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an aralkyl group)] or a salt of this amine in the presence of an acid or By heating in the absence of an acid, a condensation reaction takes place and the compound of the present invention is obtained. As the acid used here, hydrochloric acid, sulfuric acid, etc. are preferable. The 1-benzoxepin-5-one derivatives thus obtained can be prepared using various acids such as hydrochloric acid, sulfuric acid,
Phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid,
Salts can be made by treatment with succinic, oxalic, malic, tartaric, fumaric, maleic and propionic acids. Effects Pharmacological tests of the compounds according to the present invention were conducted as follows. 1. Anti-cerebral ischemic effect (cerebroprotective effect against decapitation ischemia) ddY male mice weighing 22 to 30 g were included in each group of 6 mice. The test drug was administered intraperitoneally, and the animals were decapitated 30 minutes after administration. After decapitation, measure the time until gasping breathing stops (Gaspig Time),
Comparisons were made with a control group given only liquid medium. As a result, among the test compounds, the compounds of Example Nos. 1 and 10 significantly prolonged the respiration time at 50 mg/Kg. 2 Antihypoxia effect (brain protective effect against decompression hypoxia) ddY male mice weighing 22 to 30 g per group
10 were used. The mouse was placed in a desiccator (volume: approximately 1), suction was applied using a vacuum pump, and the inside of the desiccator was adjusted to 180 mmHg. The test drug was administered intraperitoneally, and the pressure was reduced 30 minutes after administration. The survival time was defined as the time from the start of decompression to the end of breathing, and if the animal remained alive even after 15 minutes of pipoxia challenge, it was calculated as 15 minutes and compared with the vehicle-administered group. As a result, among the test compounds, the compound of Example 1 significantly prolonged the survival time at 50 mg/Kg. 3 Antiperoxidant lipid effect Group of ddY male mice weighing 24 to 27 g
Nine animals were used. After fasting mice for 16-17 hours, 85
mg/Kg of alloxan was administered bolus into the tail vein. After alloxan administration, the mice were given free access to water and 24 hours later, the test drug was administered intraperitoneally. Furthermore, 24 hours later, the mice were anesthetized with ether, and blood was collected from the abdominal aorta and vena cava. The amount of lipid peroxide in serum was determined by the method of Yagi et al. (K. Yagi et al. Biochem, Med., Vol. 15, p. 212,
(1967) and compared with the vehicle-administered group. As a result, among the test compounds, the compound of Example No. 1 significantly inhibited the production of lipid peroxide when administered at a dose of 5 mg/Kg. Examples Next, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples. Example 1 4-(N-methylpiperazinyl)methyl-8-
Chlor-2,3,4,5-telolahydro-1-
Benzoxepin-5-one hydrochloride 8-chloro-2,3,4,5-terolahydro-
1-benzoxepin-5-one 60 mmol, N
- 180 mmol of methylpiperazine hydrochloride, 180 mmol of paraformaldehyde and 0.5 ml of concentrated hydrochloric acid.
It was dissolved in 200 ml of 95% ethanol and heated under reflux for 5 to 6 hours. Dilute hydrochloric acid (150 ml) was added to the residue obtained by distilling off the solvent, and then ether was added.
After separating the ether layer, the aqueous layer was made basic with concentrated aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained oil was dissolved in ether, ether saturated with hydrogen chloride gas was added, and the obtained crystals were recrystallized from a mixed solvent of ethanol and ether. Compounds of Examples 2 to 9 were obtained in the same manner as in Example 1. The yield and physical properties of the products of Examples 1 to 9 are shown in Table 1.

[Table] Example 10 4-isopropylaminomethyl-7-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-one hydrochloride 7-methoxy-2,3,4,5-tetrahydro- 1-benzoxepin-5-one 50 mmol,
200 mmol of isopropylamine hydrochloride, 200 mmol of paraformaldehyde and 15 drops of concentrated hydrochloric acid.
The mixture was dissolved in 200 ml of 95% ethanol and heated under reflux for about 10 hours. The treatment was carried out in the same manner as in Example 1 to obtain the title compound in a yield of 50%. Properties: Colorless needle crystals Melting point: 155.5-157°C Example 11 4-benzylaminomethyl-7-methoxy-
2,3,4,5-tetrahydro-1-benzoxepin-5-one hydrochloride The title compound was obtained using benzylamine in the same manner as in Example 10 (yield 77%) Properties: Colorless needles Melting point: 161-163℃ Reference Example 1 Method for producing 4-(4-methoxy)phenoxybutyric acid (A) 24 g (1.04 mmol) of metallic sodium was added to 99.5
% ethanol, 124 g (1.0 mol) of p-methoxyphenol and 87 g (1.01 mol) of γ-butyrolactone were added, and the mixture was refluxed for 5 hours. While ethanol was being distilled off, the temperature was gradually raised to 150°C, and heating was continued until the precipitated solid matter became dry. This solid substance was dissolved in 700 ml of water, acidified with concentrated hydrochloric acid under ice-cooling, and the obtained crystals were recrystallized from ethanol/hexane to form needle-like crystals with a melting point of 103-104°C (150.5°C).
g (yield 72%) was obtained. (B) Commercially available sodium methoxide 54g (1.0mol)
was dissolved in 200 ml of commercially available anhydrous methanol, and 124 g of p-methoxyphenol and 87 g of γ-butyrolactone were added thereto and treated in the same manner as in (A). 173 g of the obtained crude crystals (yield 82%) were added to 350 ml of ethanol.
The crystals were recrystallized using 270 ml of hexane to obtain 146 g (yield: 70%) of the title compound as needle-like crystals. Reference Example 2 Production method of 4-(3-methoxy)phenoxybutyric acid (A) Metallic sodium 10g (0.434 mol), 99.5% ethanol 200ml, p-methoxyphenol 50g
(0.4 mol) and 36 g of γ-butyrolactone
(0.42 mol) was treated in the same manner as in Reference Example 1 to obtain 76.8 g (yield 91%) of crude crystals of the title compound.
This crude crystal was mixed with 77 ml of ethanol and hexane.
Recrystallized from 154ml to yield needle-shaped crystals with a melting point of 66-68℃ 66.6
g (yield 79%) was obtained. (B) Using 43.8 g (0.81 mol) of commercially available sodium methoxide, 200 ml of commercially available anhydrous methanol, 100 g (0.806 mol) of m-methoxyphenol, and 69.5 g (0.81 mol) of γ-butyrolactone, the needle-shaped 120 g (yield 71%) of crystals were obtained. Reference Example 3 Production method of 4-(3-chloro)phenoxybutyric acid (A) Metallic sodium 9.5g (0.413 mol), 99.5% ethanol 190ml, m-chlorophenol 51.4g
(0.4 mol) and 35 g (0.407 mol) of γ-butyrolactone were treated in the same manner as in Reference Example 2. Recrystallization from 300 ml of hexane gave 68.4 g (yield: 80%) of pale brown needles with a melting point of 51-53°C. (B) Treated in the same manner as in (A) using 43.2 g (0.8 mol) of commercially available sodium methoxide, 200 ml of commercially available anhydrous methanol, 102.8 g (0.8 mol) of m-chlorophenol, and 68.8 g (0.8 mol) of γ-butyrolactone. 122.8 g (yield 72%) of brown needles were obtained. Reference Example 4 Method for producing 2,3,4,5-tetrahydro-7-methoxy-1-benzoxepin-5-one 500 g of commercially available polyphosphoric acid was heated to 85 to 90°C in advance, and 4-(4 30 g (0.142 mol) of -methoxy) phenoxybutyric acid was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water 2 and excess polyphosphoric acid was completely decomposed with water, then 300 ml (once) and 200 ml (twice) with chloroform or methylene chloride.
Extracted. The organic layer was washed with water, a 5% aqueous sodium hydroxide solution, and water, and then dried. After distilling off the solvent, the obtained brown oil was distilled under reduced pressure to obtain 17.8g of colorless oil.
I got it. Boiling point: 98-105℃/0.1mmHg Reference example 5 Method for producing 2,3,4,5-tetrahydro-8-methoxy-1-benzoxepin-5-one Commercially available polyphosphoric acid 500g, 4-(3-methoxy)phenoxybutyric acid Reference example 4 using 31.5g (0.15mol)
15.6g (yield: 54g) of colorless oil
%) was obtained. Boiling point: 113-114℃/0.2mmHg Reference example 6 8-chloro-2,3,4,5-tetrahydro-
Method for producing 1-benzoxepin-5-one The same procedure as in Reference Example 4 was carried out using 500 g of commercially available polyphosphoric acid and 25 g of 4-(3-chloro)phenoxybutyric acid. The title compound is a pale yellow oil (solidifies upon standing)
15.2g (yield 66%) was obtained. Boiling point: 92-97℃/0.1mmHg

Claims (1)

[Claims] 1. General formula [In the formula, when A is alkoxy having 1-3 carbon atoms,
Y is a piperidyl group, a morpholinyl group, a group [formula] (where R ¹ represents an alkyl group having 1 to 3 carbon atoms)
or a group [formula] (where R ² and R ³ are the same or different and have 1 carbon number)
-5 represents an alkyl group or an aralkyl group); When A is a halogen atom, Y is a morpholinyl group, a group [Formula] (where R ¹ represents an alkyl group having 1 to 3 carbon atoms)
or a group [formula] (where R ² and R ³ are the same or different and have 1 carbon number)
-5 represents an alkyl group or an aralkyl group). ] A 1-benzoxepin-5-one derivative and a pharmacologically acceptable salt thereof. 2 A is 7-methoxy group, 8-methoxy group, 7-
Ethoxy group, 8-ethoxy group, 7-propoxy group, 8-propoxy group, 7-isopropoxy group,
The compound according to claim 1, which is an 8-isopropoxy group, 7-chloro group, 8-chloro group, 7-brome group or 8-brome group. 3 Y is a group [formula], and R ² and R ³ are methyl group, ethyl group, isopropyl group, propyl group, n-butyl group, isobutyl group, sec-butyl group, n-pentyl group, isopentyl group, benzyl The compound according to claim 1, which is a phenethyl group or a phenethyl group.