JPS6245864B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (In the formula, R ¹ represents hydrogen or lower alkyl. ^{R 2}
is hydrogen, R ³ and R ⁴ each represent hydrogen or lower alkyl, or when R ² and one of R ³ or R ⁴ combine with each other to form a single bond,
The other of R ³ and R ⁴ represents hydrogen or lower alkyl. ^R5
represents hydrogen or lower alkyl. R ⁶ and R ⁷ are bonded to each other and together with the adjacent nitrogen atoms are morpholino,
forming a piperidino or 4-methylpiperazin-1-yl group. X represents carbonyl or hydroxymethylene. ) or an acid addition salt thereof.

In the above definition, lower alkyl includes methyl, ethyl, propyl, butyl, and the like.

According to the present invention, the compound of general formula () can be produced, for example, by the following method.

(a) General formula (In the formula, each symbol has the same meaning as above.) A compound represented by, formaldehyde and the general formula (In the formula, each symbol has the same meaning as above.) By subjecting the acid addition salt of the amine represented by the following to the Mannitz reaction, the general formula (In the formula, each symbol has the same meaning as above.) A compound represented by the following is obtained.

The reaction can be carried out using the general Mannitz reaction method, such as using formalin, paraformaldehyde, etc. in a solvent such as alcohol or acetic acid.
The process is preferably carried out at a temperature of 100°C for 1 to 10 hours.

(b) By subjecting the compound of general formula () to a reduction reaction, the general formula (In the formula, each symbol has the same meaning as above.) A compound represented by the following is obtained.

Various reduction reactions can be used for the reaction, such as a catalytic hydrogenation method and a method using a complex metal hydride. For example, reduction using sodium borohydride in a solvent such as methanol or ethanol at 0 to 30 °C Then the process will proceed smoothly.

The compound of general formula () thus obtained can be converted into the corresponding acid addition salt by treating with hydrochloric acid, sulfuric acid, hydrobromic acid, maleic acid, fumaric acid, succinic acid, etc. in a conventional manner. can.

Compounds of general formula () and acid addition salts thereof are:
It has pharmacological effects such as analgesic effect, anti-inflammatory effect, platelet aggregation inhibitory effect, and central nervous system depressant effect, and is an anti-inflammatory and analgesic agent.
It is useful as a medicine such as an antithrombotic agent, and as a synthetic intermediate thereof.

When the compound of the present invention is used as a medicine, it can be used as a medicine or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., and can be used as a powder, granule, tablet, etc.
It can be administered orally or parenterally in the form of capsules, injections, etc. The dosage depends on the target disease, symptoms,
Although it varies depending on the compound used, in the case of oral administration, the dose is usually about 1 to 1000 mg per day for adults.

Next, the present invention will be specifically explained with reference to examples.

Example 1 9.0 g of piperidine hydrochloride and 5 ml of 37% formalin
Mix and add 35 ml of acetic anhydride at 80℃ over 30 minutes. After keeping at 80-90°C for 1 hour, 11 g of 1-methyl-6-propionyl-1,2,3,4-tetrahydroquinolin-2-one was added and kept at 70°C for 1 hour. After the reaction is complete, add 40 ml of acetone and reflux for 5 minutes. After cooling, the crystals were collected and recrystallized from methanol to give 1-methyl-6-(3-piperidino-2-methylpropionyl)-1,2,
9.5 g of 3,4-tetrahydroquinolin-2-one hydrochloride are obtained. Melting point 222-224℃ ◎ 6-(3-morpholino-2-methylpropionyl)-1,2,3,4-tetrahydroquinolin-2-one hydrochloride Melting point 194-195℃ ◎ 6-(3-Piperidino-2 1-Methyl-6-(3-morpholino-2-methylpropionyl)-1,2,3 ,4-tetrahydroquinolin-2-one hydrochloride Melting point 206
~207℃ ◎ 1-Methyl-6-[3-(4-methylpiperazin-1-yl)-2-methylpropionyl]-
1,2,3,4-tetrahydroquinoline-2-
4-methyl-6-(3-piperidino-2-methylpropionyl)-1,2-dihydroquinolin-2-one hydrochloride Melting point 215-216℃ ◎ 1,4-dimethyl-6-(3-piperidinopropionyl)-1,2-dihydroquinoline-2
1,4-dimethyl-6-(3-piperidino-
2-Methyl-6-(3-piperidino-2-methylpropionyl)-1,2,3, Dissolve 8.6 g of 4-tetrahydroquinolin-2-one hydrochloride in 100 ml of methanol, add 3 g of sodium borohydride little by little under ice cooling, and then keep at room temperature for 3 hours. After the reaction, concentrate under reduced pressure, add water to decompose the residue, and extract with 100 ml of ethyl acetate. After drying with Glauber's salt, the solvent is distilled off under reduced pressure, and the hydrochloride is prepared using alcoholic hydrochloric acid. When the obtained crystals are recrystallized from ethanol, 1-methyl-6-(3-piperidino-1-hydroxy-2-methylpropyl)-1,2,3,4-tetrahydroquinoline-
5.6 g of 2-one hydrochloride are obtained. Melting point 214~
The following compounds are synthesized in the same manner below 215°C.

◎ 6-(3-morpholino-1-hydroxy-2
-Methylpropionyl)-1,2,3,4-tetrahydroquinolin-2-one hydrochloride Melting point
210℃ (decomposition)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents hydrogen or lower alkyl. ^{R 2}
is hydrogen, R ³ and R ⁴ each represent hydrogen or lower alkyl, or when R ² and one of R ³ or R ⁴ combine with each other to form a single bond,
The other of R ³ and R ⁴ represents hydrogen or lower alkyl. ^R5
represents hydrogen or lower alkyl. R ⁶ and R ⁷ are bonded to each other and together with the adjacent nitrogen atoms are morpholino,
forming a piperidino or 4-methylpiperazin-1-yl group. X represents carbonyl or hydroxymethylene. ) A quinolone derivative represented by