JPS6145987B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 4-oximino-1,2,3,4-tetrahydroquinoline derivatives having anti-edema and diuretic effects. More specifically, the present invention relates to the general formula: (wherein, R represents a hydrogen atom, a straight-chain or branched alkyl group, a halogen-substituted lower alkyl group, a phenyl-substituted lower alkyl group, a phenylalkenyl group, a pyridyl group, or an alkyl- or phenyl-substituted amino group). Represented, new 4
-Oxiimino-1,2,3,4-tetrahydroquinoline derivatives. Since gastrointestinal disorders associated with non-steroidal anti-inflammatory drugs, particularly acidic non-steroidal anti-inflammatory drugs, have become a problem, development of neutral or basic anti-inflammatory analgesics that cause less gastrointestinal disorders and have strong effects has progressed actively. It is being As a result of many years of research on the synthesis of tetrahydroquinoline derivatives, the present inventors have discovered that 4-oximino-1,2,3-
They discovered a 4-tetrahydroquinoline derivative and completed the present invention. The compound of the present invention can generally be produced as follows. That is, p-chloroaniline and acrylic ester are heated in a solvent such as benzene, toluene, ethyl acetate, or ethanol, or
Alternatively, if desired, a Michael addition reaction is performed using a base such as sodium hydride or sodium alkoxide at room temperature or by heating,
3-(p-chlorophenylamino)-propionic acid ester is obtained. After hydrolyzing the ester of the compound obtained in this way, using phosphorus pentoxide, polyphosphoric acid, etc. as a dehydrating agent, benzene, toluene,
By heating in the presence of a solvent such as xylene or in the absence of a solvent, 6-chloro-4-oxo-
1,2,3,4-tetrahydroquinoline can be synthesized. Alternatively, the 3-propiolactone obtained by condensing p-chloroaniline with β-propiolactone in the presence of a catalyst such as a Lewis acid such as zinc chloride or aluminum chloride, or in the presence of a solvent such as acetonitrile without a catalyst.
(p-Chloro-phenylamino)-propionic acid is dehydrated and ring-closed with phosphorus pentoxide, polyphosphoric acid, etc., or if desired, the carboxyl group is converted into acid chloride, and then ring-closed by Friedel-Crafts reaction, 6- Chlor-4-oxo-1, 2, 3,
Obtain 4-tetrahydroquinoline (J.Medicinal.
Chem., 8 , 566-571). N- of 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline synthesized in this way
Acylation is carried out by condensing reactive derivatives of carboxylic acids such as acid anhydrides, acid chlorides, acid bromides, etc. with 6-chloro-4-oxo-1,2,3,
4-tetrahydroquinoline and triethylamine,
It can be obtained by reacting in the presence of an organic base such as pyridine in a solvent such as ether, tetrahydrofuran, dioxane, chloroform, benzene, etc.
Alternatively, the reactive derivative of the carboxylic acid may be 6-
It can also be obtained by reacting chloro-4-oxo-1,2,3,4-tetrahydroquinoline with an alkali metal amide such as sodium, potassium, or lithium in the above-mentioned solvent. When forming a carbamoyl bond, 6-chloro-4-oxo-1,2,3,4-tetrahydroquinoline in the presence of a solvent such as tetrahydrofuran, dioxane, ether, or chloroform,
6-chloro-4-oxo-
It can be synthesized by synthesizing 1-chloroformyl-1,2,3,4-tetrahydroquinoline and then reacting this product with amines. N-substituted-6-chloro- synthesized in this way
By heating the 4-oxo-1,2,3,4-tetrahydroquinoline derivative with hydroxylamine hydrochloride in a mixed solvent of pyridine-alcohol, the N-substituted-6-chloro-4-oximino-1,2 of the present invention can be prepared. - A 3,4-tetrahydroquinoline derivative can be obtained. The compounds of the present invention represented by the general formula obtained in this way all have strong anti-edema and diuretic effects, and cause very little gastrointestinal disorder, so they have excellent properties as pharmaceuticals. The compounds of the invention, alone or together with other pharmaceutically active compounds, can therefore also be used, if desired, in combination with binders, fillers, etc. used in the pharmaceutical industry.
It can be converted into a medicinally usable product by suitable conventional methods along with fragrances and the like. The present invention will be explained below with reference to Examples. In addition, parts and % in the examples are parts by weight and weight %, respectively.
means. Example 1 Synthesis of 6-chloro-4-oximino-1-formyl-1,2,3,4-tetrahydroquinoline 18.16 parts of 6-chloro-4-oxo-1,2.
3,4-tetrahydroquinoline and 150 parts of formic acid (purity of 98% or more) were mixed and reacted for 3 hours under stirring and reflux. For the reaction product, excess formic acid was distilled off under reduced pressure, 100 ml of ethanol was added to the residue, and the mixture was dissolved by heating.
Next, the crystals precipitated by cooling are filtered and dried.
18.03 parts of 6-chloro-4-oxo-1-formyl-1,2,3,4-tetrahydroquinoline were obtained. Next, the above compound was dissolved in 270 ml of ethanol, and 15.0 parts of hydroxyamine hydrochloride and
17.0 parts of pyridine was added, and the mixture was reacted under reflux for 1.5 hours. The reaction product was poured into 1 water, filtered, washed with water, dried, and then recrystallized with ethanol to obtain white crystals of 6-chloro-4-oximino-1-formyl-
18.3 parts of 1,2,3,4-tetrahydroquinoline were obtained. When the melting point of this product was measured by the method specified in the Japanese Pharmacopoeia, it showed a value of 192-193°C, and the results of elemental analysis were as follows. Elementary analysis C h -clock 53.45 4.01 15.81 12.47 14.25 Active value 53.41 4.00 15.79 12.50 14.30 Example 2 6 -chlor -4 -Oxyjimino -1 -acetyl -1.3.3.4 -Tetrahidrokinoline synthesis 18.16 copies 6-chloro-4-oxo-1・2・
3,4-tetrahydroquinoline and 11.23 parts of acetic anhydride were mixed and reacted with stirring at 90°C for 3 hours. The reaction product was poured into 300 ml of water, the precipitated crystals were filtered, washed with water, dried, and added with 20.1 parts of 6-chloro-4.
-Oxo-1-acetyl-1,2,3,4-tetrahydroquinoline was obtained. Next, the above compound was dissolved in 300 ml of ethanol, 15.64 parts of hydroxylamine hydrochloride and 17.8 parts of pyridine were added thereto, and the mixture was reacted under reflux for 1.5 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain white crystals of 6-chloro-4-oximino-1-acetyl-1,2,3,4-tetrahydroquinoline.
I got the department. The melting point of this product was determined to be 214-215.5°C by the method specified in the Japanese Pharmacopoeia, and the results of elemental analysis were as follows. Elemental analysis C H Cl N O Calculated value 55.35 4.61 14.88 11.74 13.42 Actual value 55.40 4.65 14.85 11.71 13.40 Example 3 Synthesis of 6-chloro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline 18.1 6 parts 6-chloro-4-oxo-1・2・
3,4-tetrahydroquinoline, 24.0 parts of pyridine, and 100 ml of dioxane were mixed, and 11.1 parts of propionyl chloride was added dropwise to the mixture while stirring and maintaining the mixture at 0-5°C. After completion of the dropwise addition, the mixture was allowed to react at room temperature for 5 hours. The reaction product was poured into 1 water, and the precipitated crystals were filtered, washed with water, further washed with petroleum ether, and dried to give 20.4 parts of 6-chloro-4-oxo-1-
Propionyl-1,2,3,4-tetrahydroquinoline was obtained. The above compound was then subjected to an oxime treatment in the same manner as in Example 1 to obtain 20.6 parts of white 6-chloro-4-oximino-1-propionyl-1,2,3,4-tetrahydroquinoline. When the melting point of this product is measured by the method specified in the Japanese Pharmacopoeia,
The temperature was 166-169°C, and the results of elemental analysis were as follows. Elemental analysis C H Cl N O Calculated value 57.03 5.15 14.06 11.09 12.67 Actual value 56.98 5.09 14.01 11.10 12.70 Example 4-15 The same procedure was used to obtain the desired results, except that propionyl chloride in Example 3 was replaced with the corresponding acid chloride. The compound was obtained. . Its properties are shown in Table 1 below.
It was shown to. Example 16 Synthesis of 6-chloro-4-oximino-1-methylcarbamoyl-1,2,3,4-tetrahydroquinoline (a) 54.5 parts of 6-chloro-4-oxo-1,2.
3,4-tetrahydroquinoline and 300 parts of dioxane were mixed, kept at 20-25°C with stirring, and 44.6 parts of phosgene gas was introduced over about 30 minutes. After the introduction, the temperature was gradually increased to 40-45℃.
After reacting for 2.5 hours, the temperature was further raised to 70°C, nitrogen was bubbled through, the solvent dioxane was then distilled off under reduced pressure, and petroleum ether was added to the residue.
After filtering, washing and drying, 70.3 parts of 6-chloro-4-
Oxo-1-chloroformyl-1, 2, 3, 4
-Tetrahydroquinoline was obtained (melting point 114-116
℃). (b) 2.6 parts of the above compound was dissolved in 30 ml of dioxane, and this solution was added dropwise to 10 ml of a dioxane solution containing 1.0 part of monomethylamine while maintaining the temperature at 0-5°C. After the addition was completed, the mixture was further stirred at room temperature for 4 hours. The reaction product was poured into water, and the precipitated crystals were filtered and washed with water, further washed with petroleum ether, dried, and then recrystallized from a mixed solvent of ethanol-n-hexane to give 22 parts of 6-chloro-4. -oxo-1-methylcarbamoyl-1.2.3.
4-tetrahydroquinoline was obtained. Dissolve this product in 30 ml of ethanol, add 2.0 parts of hydroxyamine hydrochloride and 2.2 parts of pyridine,
The reaction was carried out under reflux for 2 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain white crystals of 6-chloro-4-oximino-1-methylcarbamoyl-1.2.
2.2 parts of 3,4-tetrahydroquinoline were obtained.
The melting point of this product was measured by the method specified in the Japanese Pharmacopoeia and showed a value of 211-212°C, and the results of elemental analysis were as follows. Elemental analysis C H Cl N O Calculated value 52.07 4.73 14.00 16.57 12.62 Actual value 52.05 4.75 13.97 16.49 12.61 Example 17-19 6-chloro-4-oxo- obtained in Example 16 (a)
Using 1-chloroformyl-1,2,3,4-tetrahydroquinoline, the same treatment was performed as described below except that the monomethylamine in (b) of Example 16 was replaced with the corresponding amine or aniline to obtain the desired compound. Obtained. Its properties are shown in Table 1.

【table】

【table】

Claims (1)

[Claims] 1. General formula: (In the formula, R represents a hydrogen atom, a straight-chain or branched alkyl group, a halogen-substituted lower alkyl group, a phenyl-substituted lower alkyl group, a phenylalkenyl group, a pyridyl group, or an alkyl- or phenyl-substituted amino group.) , a novel 4-oximino-1,2,3,4-tetrahydroquinoline derivative.