JPH0674257B2 - Novel sulfoxide compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel sulfoxide compound, more specifically, the following general formula (I): [In the formula, R ₁ , R ₂ and R ₃ each represent a hydrogen atom or a lower alkyl group, X represents CH or N, and Z represents an optionally substituted 2-pyridyl group or an optionally substituted group. General formula (II) (In the formula, R ₄ and R ₅ each represents a hydrogen atom or a lower alkyl group) represents a 2-aminophenyl group] and a method for producing the same.

[Conventional technology]

Conventionally, H ^{+ +} K ⁺ ATP-ase it is the final gastric acid secretion mechanism in the stomach cells are well known in the art [Scandinavian Journal of Gastroenterology enteritidis Rollo diisopropyl (Scand.J.Gastroenterol.) 14, 131 ~ 135 (197
9)], Norinium bromide is known as a substance having an H ⁺ + K ⁺ ATPase inhibitory action [Proceeding of the Society for Experimental Biology and Medesin (Proceeding of th
e Society for Experimental Biology and Medicin
e), 172 , 308-315 (1983)].

On the other hand, 2- [2- (3,5-dimethyl-4-methoxy)-
Pyridylmethylsulfinyl]-(5-methoxy) -benzimidazole [omeprazole] is being developed as an anti-ulcer drug having H ⁺ + K ⁺ ATPase inhibitory action [American Journal of Physiology (Am.JP
hysiol.) 245 , G64-G71 (1983)].

[Problems to be solved by the invention]

Therefore, it is desired to provide a novel compound having an excellent H ⁺ + K ⁺ ATPase inhibitory action.

[Means for solving problems]

Under such circumstances, the present inventors have conducted diligent research, and as a result, the novel sulfoxide compound represented by the general formula (I) has an excellent gastric acid secretion inhibitory action based on the specific H ⁺ + K ⁺ ATPase inhibitory action. The present invention was completed by finding out that they have.

Therefore, the present invention provides a sulfoxide derivative (I) useful as an antiulcer agent.

The present invention also provides a novel method for producing the sulfoxide derivative (I).

The sulfoxide compound (I) of the present invention is produced, for example, by reacting the mercapto compound (III) with the compound (IV) to form the compound (V) according to the following reaction formula, and then oxidizing this.

(In the formula, Q represents a reactive group and R ₁ , R ₂ , R ₃ , X and Z are the same as above.) The raw material (III) of the method of the present invention can be synthesized from a diamino compound according to a conventional method.

For example, 2-mercapto-3-methylquinoxaline is the
Journal of Organic Chemistry (J.Or
g. Chem.) 21 , 470 (1956). Examples of the reactive group represented by Q of the raw material (IV) include halogen atoms such as chlorine and bromic acid, sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups, and acetoxy groups.

The reaction of compound (III) with compound (IV) or a salt thereof is
It is carried out by stirring in an inert solvent such as toluene, benzene, ethanol or acetone at room temperature to the temperature under reflux for 30 minutes to 24 hours. At that time, NaOH, KOH, K
An alkaline agent such as ₂ CO ₃ or NaHCO ₃ may be present to receive the acid produced.

Oxidation of compound (V) can be carried out by a conventional method. For example, hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium hypochlorite is used to give compound (V). ) Should be oxidized. The reaction is carried out in an inert solvent such as chloroform, dichloromethane, methanol and ethyl acetate at a temperature of -30 ° C to 50 ° C, preferably -15 ° C to 5 ° C. Representative compounds (1) of the present invention thus obtained are shown below.

Representative compound examples 1.2- (2-pyridylmethylsulfinyl) quinoxaline 2.3-methyl-2- (2-pyridylmethylsulfinyl) quinoxaline 3.2- [2- (4-methoxypyridyl) methylsulfinyl] -3-methylquinoxaline 4.3- Methyl-2- [2- (3-methylpyridyl) methylsulfinyl] quinoxaline 5.6,7-Dimethyl-2- (2-pyridylmethylsulfinyl) quinoxaline 6.2-Methyl-3- (2-pyridylmethylsulfinyl) pyrido [2, 3-b] Pyrazine 7.2- (2-Dimethylaminobenzylsulfinyl) quinoxaline 8.2- (2-Dimethylaminobenzylsulfinyl)-
3-Methylquinoxaline 9.2- (2-dimethylaminobenzylsulfinyl)-
3,6,7-Trimethylquinoxaline 10.2- (2-Dimethylamino-3-methylbenzylsulfinyl) -3-methylquinoxaline 11.2- (2-Dimethylamino-5-methylbenzylsulfinyl) -3-methylquinoxaline 12.2- (2 -Dimethylamino-5-methoxybenzylsulfinyl) -3-methylquinoxaline 13.2- (2-diethylaminobenzylsulfinyl) quinoxaline Next, the results of testing the pharmacological effect of the compound (I) of the present invention are shown.

(1) H ⁺ ＋ K ⁺ ATPase inhibitory action Forte et al. [J. Applied Physiol.] 32,714
~ 717 (1972)], gastric acid-secreting cells of rabbit gastric mucosa were isolated, and vesicles containing H ⁺ + K ⁺ ATPase were prepared by centrifugation in a discontinuous density gradient of Ficoll. 5 mM imidazole buffer (pH 6.0), test substance 2 x 10
^{After incubating the} enzyme in 0.5 ml of a solution containing ^-4 M for 25 minutes at room temperature, the enzyme was transferred to 37 ° C and left for another 5 minutes. 4m
M magnesium chloride, 80 mM imidazole buffer (pH 7.
4), 0.5 ml of a solution containing 20 mM potassium chloride and 4 mM ATP was added and reacted at 37 ° C. for 15 minutes, then 1 ml of 24% trichloroacetic acid was added to stop the reaction, and the liberated inorganic phosphorus was removed by Tosky (Taussky) and Shorr Method [Journal of Biological Chemistry (J.Biol.C
hem.) 202,675-685 (1953)]. The K ⁺ -dependent ATPase activity was calculated by subtracting the activity in the absence of potassium chloride. The results are shown in Table 1.

(2) Gastric acid secretion inhibitory action Conventional method (Shay Etch et al., Gastroenterology (Sh
a.H. et al., Gastroenterology), 5 , 43-61 (194
According to 5)], male DonRyu rats weighing 200-250 g were fasted for 24 hours (water intake was allowed freely), and the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was administered intraduodenally. did. After 4 hours, the animals were killed, the stomach was removed and the gastric juice was collected. The acidity (Acid output) was titrated to pH 7.0 with 0.1 N NaOH using an automatic titrator, and the value obtained was compared with that of a control animal which was not treated with the test compound. The results are shown in Table 2.

EXAMPLES Next, the present invention will be described with reference to examples.

Example 1 (i) 2- (2-pyridylmethylthio) quinoxaline hydrochloride: 2.0 g of 2-mercaptoquinoxaline was dissolved in 50 ml of acetone and 2.02 g of 2-picolyl chloride hydrochloride, 4.0 g of potassium carbonate and 5 ml of water were added. The mixture was stirred at room temperature for 0.5 hours. The solvent was distilled off under reduced pressure, and chloroform and water were added to the residue for extraction. The organic layer was separated and dried over Glauber's salt. After removing Glauber's salt, the solvent was distilled off under reduced pressure, and 20 ml of ethanol and concentrated hydrochloric acid were added to the residue.
After adding 1.03 ml, ether was added and the precipitated crystals were collected. After washing the crystals with ethanol / ether (1: 1),
It was dried under reduced pressure to obtain 2.09 g of 2- (2-pyridylmethylthio) quinoxaline hydrochloride as a yellow crystalline powder. ¹ HNMR (CD ₃ CD) δ: 4.97 (S, 2H), 7.6-8.7 (m, 7H) 8.73 (S, 1H), 8.84 (m, 1H) (ii) 2- (2-pyridylmethylsulfinyl) quinoxaline (Inventive Compound 1): 2.51 g of 2 (2-pyridylmethylthio) quinoxaline hydrochloride was dissolved in a mixed solvent of 20 ml of chloroform and 5 ml of methanol, and m-chloroperoxide was kept under ice-cooling to keep the internal temperature at 0 ° C or lower. Benzoic acid (purity 70
%) 1.95 g was added. After the reaction, chloroform and saturated N
After adding the aHCo ₃ solution, the organic layer was separated and dried over sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (acetone / hexane), and crystallized from ethanol / ether to obtain 0.27 g of 2
-(2-Pyridylmethylsulfinyl) quinoxaline was obtained as a light brown crystalline powder.

mp: 117-122 ° C (decomposition).

Example 2 (i) 3-Methyl-2- (2-pyridylmethylthio) quinoxaline hydrochloride: 1.9 g of 2-mercapto-3-methylquinoxaline and 2-
70 ml of acetone and 7 ml of water with 1.95 g of picolyl chloride hydrochloride.
The mixture was suspended in the mixed solvent of 4.0 g, 4.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, chloroform and water were added to the residue, and the organic layer was separated and dried over sodium sulfate. After separating the sodium sulfate, the solvent was distilled off under reduced pressure, the residue was dissolved in 20 ml of ethanol, 3.2 ml of ice-cold 5.2N ethanolic hydrochloric acid was added, and then ether was added to remove the precipitated crystals. 2.25 g of 3-methyl-2- (2-Pyridylmethylthio) quinoxaline hydrochloride was obtained as a purple crystalline powder. ¹ H NMR (CD ₃ CD) δ: 2.68 (S, 3H) 4.98 (S, 2H), 7.5-8.7 (m, 7H) 8.84 (m, 1H) (ii) 3-methyl-2- (2-pyridyl) Methylsulfinyl) quinoxaline (inventive compound 2): 2.6 g of 3-methyl-2- (2-pyridylmethylthio) quinoxaline hydrochloride was added to 36 ml of chloroform and 18 ml of methanol.
1.77 g of m-chloroperbenzoic acid (purity 70%) under ice-cooling was gradually added so that the internal temperature was kept at 0 ° C or lower. After completion of the reaction, chloroform and saturated NaHcO ₃ solution were added under cooling, and the organic layer was separated and dried over sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform / methanol) and crystallized from ether / hexane to give 1.63 g of 3-methyl-2.
-(2-Pyridylmethylsulfinyl) quinoxaline was obtained as an orange crystalline powder.

mp: 85-88 ℃ (decomposition) Example 3 (i) 2-Methyl-3- (2-pyridylmethylthio)-
Pyrido [2,3-b] pyrazine: 3-mercapto-2-methylpyrido [2,3-b] pyrazine 1.67 g and ethanol 10 ml are added, and 2-picolyl chloride hydrochloride 1.15 g and sodium hydroxide 0.67 g water 10 ml. The solution was added and heated to reflux for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate.

After separating out Glauber's salt, the solvent was distilled off under reduced pressure and acetonitrile was added to the residue.
20 ml was added and the insoluble matter was separated. Concentrate the liquid to 1.5 g of 2
-Methyl-3- (2-pyridylmethylthio) pyrido [2,
3-b] pyrazine was obtained as a brown oil. ¹ H NMR (CDCl ₃ ) δ: 2.74 (S, 3H), 4.72 (S, 2H) 7.0-9.0 (m, 7H) (ii) 2-methyl-3- (2-pyridylmethyl) sulfinyl) pyrido [2 , 3-b] Pyrazine (Compound 3 of the present invention): 1.4 g of 2-methyl-3- (2-pyridylmethylthio) pyrido [2,3-b] pyrazine was dissolved in 14 ml of chloroform, and m-chloroperoxide was added under ice cooling. Benzoic acid (purity 880%) 1.1 g was added little by little. Gradually return to room temperature and saturate the reaction mixture
It was poured into a NaHCO ₃ solution and extracted with chloroform. The chloroform layer was washed with water and saturated saline and then dried over sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 420 mg of 2-methyl-3- (2-pyridylmethylsulfinyl) pyrido [2,3-b] pyrazine. Obtained as a brown crystalline powder.

mp: 120-125 ℃ (decomposition) Example 4 (i) 2- (2-Dimethylaminobenzylthio) quinoxaline: To a solution of 2-mercaptoquinoxaline (1 g) in ethanol (40 ml) was added sodium hydroxide (530 mg) in water (2 ml), and then 2-dimethylaminobenzyl chloride hydrochloride (1.27 g). Was added. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with a 5% sodium hydroxide solution, water and saturated saline and then dried over sodium sulfate. . After removing the sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography hexane / acetone to obtain 1.5 g of 2- (2-
Dimethylaminobenzylthio) quinoxaline was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) δ: 2.76 (S, 6H), 4.72 (S, 2H) 6.8-7.6 (m, 9H) (ii) 2- (2-dimethylaminobenzylsulfinyl) quinoxaline (inventive compound 4) : 2- (2-dimethylaminobenzylthio) quinoxaline
1.47 g was dissolved in 50 ml of chloroform and cooled to -10 ° C.
1.54 g of chloroperbenzoic acid (80% purity) was added in small portions. The reaction solution was washed with saturated NaHCO ₃ solution, water and saturated saline, and dried over sodium sulfate. The crude product obtained by removing the sodium sulfate and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane / acetone) to obtain 330 mg of 2- (2-dimethylaminobenzylsulfinyl) quinoxaline as a yellow powder. . . mp.114-115 ° C Example 5 (i) 2- (2-Dimethylaminobenzyl) -3-methylquinoxaline hydrochloride: 2.80 g of 2-mercapto-3-methylquinoxaline, 3.28 g of 2-dimethylaminobenzyl chloride hydrochloride and 8.0 g of potassium carbonate The mixture was added to a mixed solvent of 50 ml of acetone and 5 ml of water and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, chloroform and water were added to the residue, the organic layer was separated, and dried over sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was ethanol.
Diluted with 50 ml. Under ice-cooling, 1.33 ml of concentrated hydrochloric acid and then ether were added to precipitate crystals to obtain 4.56 g of 2- (2-dimethylaminobenzylthio) -3-methylquinoxaline hydrochloride as a blackish brown crystalline powder. ¹ H NMR (CD ₃ OD / CDl ₃ ) δ: 2.67 (S, 3H), 3.46 (S, 6H) 5.00 (S, 2H), 7.4-8.1 (m, 8H) (ii) 2- (2-dimethyl Aminobenzylsulfinyl) -3-methylquinoxaline compound 5) of the present invention: 1.73 g of 2- (2-dimethylaminobenzylthio) -3-methylquinoxaline hydrochloride is dissolved in a mixed solvent of 10 ml of chloroform and 10 ml of methanol, and the mixture is cooled with ice. M-Chloroperbenzoic acid (purity 80%) 1.14 to keep the internal temperature below 0 ℃
g was added slowly. After completion of the reaction, chloroform and saturated N
The aHCO ₃ solution was added, and the organic layer was separated and dried over sodium sulfate.

After removing the sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform / methanol) and crystallized from ethyl acetate-hexane to give 0.51.
g of 2- (2-dimethylaminobenzylsulfinyl)
-3-Methylquinoxaline was obtained as a light brown crystalline powder.

mp: 68-70 ℃ (decomposition) Example 6 (i) 2- (2-Dimethylaminobenzylthio) -3,6,7
-Trimethylquinoxaline: 2-mercapto-3,6,7-trimethylquinoxaline 4.08
4.12 g of g, 2-dimethylaminobenzyl chloride hydrochloride and 10.0 g of potassium carbonate were added to a mixed solvent of 50 ml of acetone and 5 ml of water, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water and chloroform were added to the residue, insoluble materials were separated, and the organic layer was separated and dried over sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure, and hexane was added to the residue to remove insoluble matter. The liquid was evaporated to dryness under reduced pressure to obtain 6.48 g of 2- (2-dimethylaminobenzylthio) -3,6,7-trimethylquinoxaline as an orange-white crystalline powder. ¹ H NMR (CDClC) δ: 2.43 (S, 6H), 2.61 (S, 3H) 2.75 (S, 6H), 4.73 (S, 2H), 6.8-7.8 (m, 6H) (ii) 2- (2 -Dimethylaminobenzylsulfinyl) -3,6,7-trimethylquinoxaline (inventive compound 6): 2- (2-dimethylaminobenzylthio) -3,6,7-trimethylquinoxaline 3.71 g of chloroform 35 ml and methanol 3 ml Dissolve in a mixed solvent and keep the internal temperature at 0 ° C under ice cooling.
Keep m-chloroperbenzoic acid (80% purity) 2.
45g was added slowly. After the reaction, chloroform and saturated N
The aHCOC ₃ solution was added, and the organic layer was separated and dried over sodium sulfate. After separating the sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetone / hexane).
After concentrating the eluate, the residue was crystallized from ether / hexane to give 1.12 g of 2- (2-dimethylaminobenzylsulfinyl) -3,6,7-trimethylquinoxaline as a yellow crystalline powder.

mp: 83-88 ℃ (decomposition) Example 7 (f) 2- (2-diethylaminobenzylthio) -3-
Methylquinoxaline: 2-mercapto-3-methylquinoxaline (1.5 g) was added to a solution of sodium hydroxide (0.73 g) in water (2 ml) and ethanol (50 ml), and then 2-diethylaminobenzyl chloride hydrochloride (1.99 g).
Was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate.

The organic layer was washed with a 5% sodium hydroxide solution, water and a saturated saline solution and then dried with sodium sulfate. The oily substance obtained by separating the sodium sulfate and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane / acetone) to give 1.74 g of 2- (2
-Diethylaminobenzylthio) -3-methylquinoxaline was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) δ: 1.04 (t, 6H, J = 8Hz) 2.64 (S, 3H), 3.04g (q, 4H, J = 8Hz) 4.76 (S, 2H), 6.8-8.0 (m, 8H) (ii) 2- (2-diethylaminobenzylsulfinyl) -3-methylquinoxaline: 1.7 g of 2- (2-diethylaminobenzylthio) -3-methylquinoxaline is dissolved in 50 ml of chloroform and -10 ° C.
Under cooling, 1.21 g of m-chloroperbenzoic acid (purity 80%) was added little by little. The reaction solution was washed with a saturated NaHCo ₃ solution, water and a saturated saline solution, and dried with sodium sulfate. The oily substance obtained by separating the sodium sulfate and distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane / acetone) to obtain 1.2 g of 2-
(2-Diethylaminobenzylsulfinyl) -3-methylquinoxaline was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) δ: 0.96 (t, 6H, J = 8Hz) 2.52 (S, 3H), 2.92 (q, 4H, J = 8Hz) 4.44and4.70 (each d, 2H, J = 12Hz) 6.8-8.4 (m, 8H)

Claims (2)

[Claims] 1. The following general formula (I): [In the formula, R ₁ , R ₂ and R ₃ each represent a hydrogen atom or a lower alkyl group, X represents CH or N, and Z represents an optionally substituted 2-pyridyl group or an optionally substituted group. General formula (II) (In the formula, R ₄ and R ₅ each represent a hydrogen atom or a lower alkyl group) and represents a 2-aminophenyl group]. 2. A general formula [III) [Wherein R ₁ , R ₂ and R ₃ are each a hydrogen atom or a lower alkyl group, and X represents CH or N], and a mercapto derivative represented by the general formula (IV) QCH ₂ Z (IV) [ In the formula, Q represents a reactive group, and Z represents an optionally substituted 2-pyridyl group or an optionally substituted general formula (I
I) (In the formula, R ₄ and R ₅ each represent a hydrogen atom or a lower alkyl group) and represent a 2-aminophenyl group.]
A compound represented by the formula (V) (Wherein R ₁ , R ₂ , R ₃ , X and Z are the same as defined above), and the compound is then oxidized to give a compound of the general formula (I) (In the formula, R ₁ , R ₂ , R ₃ , X and Z are the same as defined above).