JPS61118382A - Morpholine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is H or lower alkyl; X is O or two H atoms; n is 1, 2 or 3) and its acid addition salt. EXAMPLE:2-[2-(2-Thenyl)-4-methoxyphenoxymetehyl]morpholine. USE:Remedy for cerebral function disorder, and antidepressant. It has reserpine- antagonistic activity, protecting activity to the cerebral disorder in hypoxic state, and remedying effect to dysmnesia. It has low toxicity. PREPARATION:The compound of e.g. formula IV is prepared by reacting the compound of formula II (R' is lower alkyl) with the compound of formula III [Z' is reactive atom or group of an alcohol (e.g. Cl, Br, etc.)] in the presence of a basic substance such as NaOH, KOH< etc., in a solvent at a temperature between room temperature and the boiling point of the solvent.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound useful as a new medicine. [Prior Art] JP-A-49-82676 discloses substituted phenoxymethylmorpholine derivatives. , has been shown to have protective effects against brain damage in hypoxic conditions.

[Problem that the invention seeks to solve]

The present inventors were interested in these effects and conducted extensive research with the aim of searching for compounds with even stronger activity.

[Means for solving problems]

As a result, the present inventors found that a novel morpholine derivative represented by the following general formula (I) has a remarkable antidepressant effect, a protective effect against brain damage in hypoxic conditions, an ameliorating effect on memory impairment, and has low toxicity. The present invention was completed based on this discovery.

That is, the present invention relates to novel morpholine derivatives represented by the general formula and acid addition salts thereof.

The formula "P," represents hydrogen, lower alkyl (methyV, ethylρ, proyl, isopropyl, butyl, etc.), X represents oxygen or two hydrogens, and n represents 1.2 or 3.

In the present invention, the compound of general formula (I) is
-826110, JP 856-59771, JP 54-34745, JP 55-500
It can be synthesized as follows according to the manufacturing method disclosed in Publication No. 28 and the like.

Method 1 A compound in which R represents lower alkyl and X represents two hydrogen atoms in the general formula (I), that is, a general compound (wherein Ro represents lower alkyl and n has the same meaning as above). In the case of a compound represented by the general formula (in which each symbol has the same meaning as above), a compound represented by the general formula % formula % () [where zl is a reactive atom or group of 7 alcohol] (chlorine, bromine, iodine, etc.) rogens or -oso2y
(y represents a hydroxyl group, lower alkyl such as methyl or ethyl, or phenyl, or 7-aryl such as p-)'J). ] It can be obtained by reacting with the compound represented by:

The reaction is performed using water, alcohol (methanol, ethanol, propatool, isopropanol, etc.) in the presence of a basic substance (hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, etc.). (butanol, etc.), ethylene glycol, ether, tetrahydrofuran, dioxane, benzene, toluene, etc., or a mixture thereof (aqueous ethanol, aqueous dioxane, etc.) at a temperature between room temperature and the boiling point of the solvent used. can.

Method 2 In the case of a compound in which R represents lower alkyl and X is oxygen in the general formula (I), that is, a compound represented by the general formula (wherein each symbol has the same meaning as above): (Formula (wherein, each symbol has the same meaning as above) is aminated and then noroacetylated to obtain a general formula [wherein z2 represents a halogen (chlorine, bromine, iodine, etc.), and the other symbols are Same meaning as above. ] can be produced by subjecting it to a closed field reaction.

The reaction is carried out in the presence of a basic substance (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alcoholade, sodium hydride, etc.), alcohol (methanol, ethanol, isopropanol, etc.),
It can be carried out in a solvent such as benzene, tetrahydrofuran, dimethylformamide, etc. at a temperature between room temperature and the boiling point of the solvent used for 1 to 8 hours.

Method 3 In the case of a compound in which R is hydrogen in the general formula (I), that is, a compound represented by the general formula (in the formula, the symbols have the same meanings as above): Compounds represented by
Itt M, V, Kulkmarni S, U:
It can be obtained by using the pyridine hydrochloride method, aluminum chloride method, boron tribromide method, methanesulfonic acid-methionine method, etc. described in 5ynthesis, No. 2491983).

As an example, in demethylation using the pyridine hydrochloride method,
A compound represented by the general formula (I or (Ib)) was mixed with 3 to 10 molar equivalents of lysine hydrochloride without a solvent and 180 to
It can be produced by heating at ZOO°C for 2 to 10 hours.

The compounds of the present invention represented by the above general formulas (Ia) and (I:) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or maleic acid, fumaric acid, oxalic acid, and methanesulfonic acid. A pharmaceutically acceptable acid addition salt can be obtained by treatment with an organic acid such as , lactic acid, or picric acid.

[Action and effect of the invention]

The compound of the general formula (I) and its acid addition salt obtained in this way have reserpine antagonistic activity, protective effect against brain damage often caused by hypoxia, and improving effect on memory impairment, and have low toxicity, so they improve brain function. It is useful as a disorder improving agent and an antidepressant.

When the compound of the present invention is used as a medicine, it is mixed with appropriate pharmacologically acceptable excipients, carriers, diluents, etc.
It can be administered orally or parenterally in the form of tablets, capsules, granules, powders or injections. The dose varies depending on the compound selected, the age of the subject, the symptoms, etc., but is usually about 20 to 301++v per day for adults, and is administered once or in divided doses.

〔Example〕

EXAMPLES Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

→Hakushi Gyuhaku Example 1 Add 6.9 g of acidic sulfuric acid 2-aminoethyl ester to a solution of 2.0 g of sodium hydroxide in 2 d of water at 35-40°C.
and continued stirring at 40° C. for 40 minutes. A solution of 4.5 g of 1-C2-(2-tenyl)-4-methoxyphenoxy)-Z,3-epoxypropane dissolved in 18++e of ethanol is added to this solution, and the mixture is stirred at 40°C for 3 hours. A solution prepared by dissolving 6.6 g of sodium hydroxide in 6.6 me of water is added to this reaction solution, and the mixture is heated under reflux for 4.5 hours. Now add ethyl acetate and water. The organic layer is separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (1 liter solution: chloroform-methanol, 40:
1), 2-(2-(
4.3 g of 2-tenyl)-4-methoxyphenoxymethyl 3-morpholine are obtained.

Similarly, the following compounds are obtained.

Example 2 2-(2-(2-tenyl)-5-methoxyphenoxymethyl 3-morpholine, melting point 43-46°C Example 3 2-(2-(2-tenyl)-4,5-dimethoxymethyl) [phenoxymethyl]morpholine Example 4 1-(2-(2-tenyp)-5-methoxyphenoxyfur-3-chloroacetamide-2-propatol 14) was added to a solution of 1.3 g of sodium metal dissolved in 65-ethanol.
= and heated under reflux for 15 hours. After distilling off the solvent under reduced pressure, water and ethyl acetate are added for extraction, and the ethyl acetate layer is separated. After washing with water, the ethyl acetate layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography and 0.5% methanol-
The portion eluted with chloroform is recrystallized from ethanol to obtain 7.5 g of 2-C2-(2-tenyl)-5-methoxyphenoxymethyl]-5-oxomorpholine having a melting point of 126-127°C.

Similarly, the following compounds are obtained.

Example 5 2-(2-(2-tenyl)-4-methoxyphenoxymethyl-5-omorpholine, melting point 134-135°C) Example 6 2-(2-(2-tenyl)-4,5 -dimethodiphenoxymethyl]-5-oxomorpholine Example 7 2-C2-(2-thenyl)-4-methoxyphenoxymethyl 3 morpholine + 7.9 g pyridine hydrochloride 32
．． 2 g at 180° C. for 6 hours.

After the reaction solution is cooled to about 60° C., water and then an aqueous sodium bicarbonate solution are added to make it alkaline.

After extraction with ethyl acetate, the ethyl acetate layer is separated, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized twice from ethanol (treated with activated carbon) to give 2. -(2-(2-
14.1 g of (thenyl)-4-hydroxyphenoxymethyl]morpholine are obtained.

Similarly, the following compounds are obtained.

Example 8 2-(2-(2-tenyl)-5-hydroxyphenoxymethyl 3-morpholine, +La 159-160°C Example 9 2-C2-(2-tenyl)-4,5-dihydroxyphenoxymethyl 3-morpholine Example 10 2-(2-(2-thenitv)-4-hydroxyphenoxymethyl]-5-oxomorpholine, melting point 19ON
191°C Example 11 2-(2-(2-tenyl)-5-hydroxyphenoxymethyl]-5-oxomorpholine, melting point 183-184
°C Example 12

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is hydrogen or lower alkyl, and X is oxygen or 2
hydrogen, and n represents 1, 2 or 3. ) and its acid addition salts.