JPS62161769A - Novel sulfoxide compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A sulfoxide compound of formula I [R1-R3 are H or lower alkyl; X is CH or N; Z is (substituted) 2-pyridyl or (substituted) 2-aminophenyl of formula II (R4 and R5 are H or lower alkyl)]. EXAMPLE:2-(2-Pyridylmethylsulfinyl) quinoxaline. USE:An anticulcer agent exhibiting excellent activity to suppress the secretion of gastric juice by its specific H<+>+K<+>ATPase-inhibiting activity. PREPARATION:The compound of formula I can be produced by reacting a mercapto-derivative of formula III with the compound of formula IV (Q is reactive group) or its salt and oxidizing the resultant compound of formula V.

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 (1) [wherein R, R and R are each a hydrogen atom or a lower alkyl group, X represents CH or N, Z is an optionally substituted 2-pyridyl group or an optionally substituted-
The present invention relates to a sulfoxide compound represented by the formula (E[) (in which R4 and R3 each represent a hydrogen atom or a lower alkyl group) represents a 2-aminophenyl group] and a method for producing the same.

[Conventional technology]

It is well known in the art that H"K" ATPase is the ultimate gastric acid secretion mechanism in gastric cells [Scandinavian Journal of Gastroenterology (Scand, J.).

Ga5troentero1. ) 14, 131
'l 35 (1979)), Norinium bromide is known as a substance with H" + K" ATPase inhibitory action [Proceedings of the Society for Experimental] (Iology).
and mezzosin (Proceeding of th
e 5oci-ety for Experiment
tal Biology and Medicine
ine).

172, 308-315 (1983)).

On the other hand, 2-(2-(3,5-dimethyl-4-methoxy)
-pyridylmethylsulfinyl]-(5-methoxy)-
Benzimidazole [omeprazole] is H” + =
It has been developed as an anti-ulcer agent with an ATPase inhibitory effect [American Journal of Physiology (Am, J, or Physiol) 245,
G64-G71 (1983)).

[Problems that inventions can solve]

Therefore, it is desired to develop a new compound that has an inhibitory effect on ATPase.

[Comprehensive means to solve problems]

Under these circumstances, the present inventors conducted intensive research and found that a novel sulfoxide compound expressed by the general formula (1) has an excellent gastric acid secretion suppressing effect based on a specific H"+K" ATPase inhibitory action. The present invention was completed based on the discovery that the present invention has the following properties.

Therefore, the present invention provides a unique sulfoxide compound (I) as an anti-ulcer agent.

Furthermore, the present invention provides a novel method for producing the sulfoxide compound (1).

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

(In the formula, Q represents a reactive group, and R1, R2, Rs, X and Z are the same as above.) The raw material ([[) for 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
Journal, Knowledge, Organic Chemistry〇,
Org, Chem, )21. 470 (1956). In addition, examples of the reactive group represented by Q in the raw material (I'/) include salt 2, halogen atoms such as bromine, sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups, and acetoquino groups. .

The reaction between compound ([) and compound (IV) or its salt is
In an inert solvent such as toluene, benzene, ethanol, acetone, etc. at room temperature to reflux temperature for 30 minutes to 24 hours.
This is done by stirring for a period of time. At that time, Na
OH, K OH%K 2 CO3, Na HCOz
An alkaline agent such as the like can be present to receive the acid produced.

Oxifation of compound (V) can be carried out by a conventional method, for example, using hydrogen peroxide, a finite peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium hypochlorite. can be oxidized. The anti-2a reaction is carried out in an inert solvent such as ÷→→ form, dichloromethane, methanol, ethyl acetate, etc. at a temperature of -30°C to 50°C, preferably -15°C to 5°C.

Representative compounds of the compound (1) of the present invention thus obtained are shown below.

Representative Compound Examples 1.2-(2-pyridylmethylsulfinyl)quinoxaline 23-Methyl-2-(2-pyrinolmethylsulfinyl)quinoxaline 3.2-42-(4-methquinbyrinol)methylsulfinyl-3-methylquinoxaline 4.3-methyl-2
-42-(3-methylpyridyl)methylsulfinylcoquinoxaline 5.6.7-dimethyl-2-(2-pyridylmethylsulfinyl)quinoxaline 62-methyl-3-(2-pyridylmethylsulfinyl)pyrido[2,3-N Pyranone 7. 2-(2-dimethylaminobenzylsulfinyl)quinoxaline 8. 2-(2-dimethylaminobenzylsulfinyl)
-3-Methylquinoxaline 9.2-(2-methylaminobennorsulfinyl)
-3,6,7-drimethylquinoxaline 10.2-(2
-dimethylamino-3-methylbenzylsulfinyl)
-3-Methylquinoxaline LL, 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 effects of the compound (1) of the present invention will be shown.

(1) H-2 = ATPase inhibitory effect (F)
orte) et al. [Journal of Applied
Physiology (J, Applied Phy-si)
ol, ) 32, 714-717 (1972)),
Gastric acid-secreting cells from rabbit gastric mucosa were isolated and converted to H-++AT.
Vencle containing Pase was prepared by centrifugation in a Ficoll discontinuous density gradient. The enzyme was incubated for 25 minutes at room temperature in 0.5mf of a solution containing 5mM imidazole buffer (pH 6.0), test substance 2XIO-'M, then transferred to 37°C and left for an additional 5 minutes. 4mM magnesium chloride, 80mM imidazole buffer (pH 7,4), 20mM salt, potassium chloride and 4+n
Add 0.5 m of a solution containing MATP, 5 ml, and incubate at 37°C
After reacting for 5 minutes, 1 m2 of 24% trichloroacetic acid was added to stop the reaction, and the liberated inorganic phosphorus was
Assky) and Shorr's method [Journal of Biological Chemistry (J
Biol, Chem, ) 202, 675-685 (19
53)). K+ dependent ATPase activity was determined by subtracting the activity when potassium chloride was not included, and the results are shown in Table 1.

(The following is a blank space) Table 1 (Compounds 1 to 6 of the present invention represent the compounds obtained in Examples 1 to 6, respectively) (2) Gastric acid secretion suppressing effect Conventional method [Nei et al., Gastroenterol. Logie (S
hay, H. et al., Gastroente
logy), 5.

43-61 (1945)), weight 200-250g
After 24-hour administration of Donryu male rats (with free access to water), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was administered into the duodenum. After 4 hours, the animals were The stomachs were removed and gastric juice was collected. Acid output was titrated to pH 7.0 with 0.1N NaOH using an automatic metering device. The values were compared with those of control animals not given the compound.The results are shown in Table 2.

Table 2 〔Example〕 Next, the present invention will be explained with reference to Examples.

Example 1 (i) 2 (2-Pyridylmethylthio)quinoxaline hydrochloride: 2.0 g of 2-mercaptoquinoxaline was dissolved in 50 mff1 of acetone to prepare 2-picolyl chloride hydrochloride 2.
．． 02g, potassium carbonate 4.0g and water 5ml were added and stirred at room temperature for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was
The sample was extracted with chloroform and water. The organic layer was separated and dried with Glauber's salt. After separating the Glauber's salt, the solvent was distilled off under reduced pressure, and the residue was mixed with 20 m of ethanol and 1.03 mJ of concentrated hydrochloric acid.
1 was added, ether was added, and the precipitated crystals were collected. After washing the crystals with ethanol/ether (1:l),
After drying under reduced pressure, 2.09 g of 2-(2-pyridylmethylthio)quinoxaline hydrochloride was obtained as a yellow crystalline powder.

'HNMR (CD30D) δ: 4.97 (S, 2H), 7.6-8.7 (m, 7H
) 8.73 (S, IH), 8.84 (m, L H) (
ii) 2 (2-Pyridylmethylsulfinyl)quinoxaline (Compound 1 of the present invention): 2.51 g of 2-(2-pyridylmethylthio)quinoxaline hydrochloride was dissolved in a mixed solvent of 20 mjZ of chloroform and 5 mf of methanol, and the mixture was cooled to an internal temperature under water cooling. 1.95 g of m-chloroperbenzoic acid (purity 70%) was added so as to maintain the temperature below 0°C. After the reaction was completed, chloroform and saturated NaHCO3 solution were added, and the organic layer was separated and dried with mirabilite. After separating Glauber's salt from I, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (acetone/hexane), crystallized from ethanol/ether, and 0.2
7 g of 2-(2-pyridylmethylsulfinyl)quinoxaline was obtained as a light brown crystalline powder.

mp: 117-122°C (decomposition).

1200, 10g0.1050.995.960°76
5,745'HNNIR(CDC13)δ: 4.43 and
4.70 (eachd, 2H.

14Hz), 7.0-8.2 (m, 7) [), 8.38
:'j (m, lH), 9.06 (S, LH) Example 2 (1) 3-Methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride: 1.9 g of 2-mercapto-3-methylquinoxaline and 1.95 g of 2-picolyl chloride hydrochloride in 70 g of acetone.
The mixture was suspended in a mixed solvent of 100ml of water and 7ml of water, 4.0g 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 sulfuric acid layer was separated and dried over Glauber's salt. After separating the Glauber's salt, the solvent was distilled off under reduced pressure, the residue was dissolved in 20 ml of ethanol, and while cooling with water, 3.2 ml of 5.2N ethanolic hydrochloric acid was added, and then ether was added to precipitate the crystals. -methyl-2-(2
-pyridylmethylthio)quinoxaline hydrochloride was obtained as a purple crystalline powder.

'l(NMR(CD,OD)δ:, 2.68(S,
3H) 4.98 (S, 2H), 7.5-8.7 (
m, 7H) 8.84 (m, LH) (ii) 3-methyl-2-(2-pyridylmethylsulfinyl)quinoxaline (invention compound 2); 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride 2.6 g of salt in 36 ml of chloroform and 18 ml of methanol
Dissolved in a 1M mixed solvent of mf, m-chloroperanan9 under water cooling.
．． 1.77 g of aromatic acid (purity 70%) was gradually added until the internal temperature was below O'C. After the reaction was completed, chloroform and saturated NaHCOp solution were added under cooling, and several layers were separated and dried with mirabilite. Glauber's salt: After separating each house, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (chloroform/
Ig using methanol) and crystallizing from ether/hexane to give 1.63 g of 3m'; I: 85-88°C
(Decomposition) 10g 0.1035.770'HNMR (CDCI δ: 2.73 (S, 3H)
, 4.55 and 4.71 (each d, 2t
1. J = 13tlz), 7.0-8.3(m, 7t
( ), C39 (m, 18) Example 3 (1) 2-Methyl-3-(2-pyridylmethylthio)pyrido(2,3-b)pyrazine: 3-mercapto-2-methylpyrido(2,3-b ) Ethanol lOI++ was added to 1.87 g of pyrazine, and a solution of 1.15 g of 2-picolyl chloride hydrochloride and 067 g of sodium hydroxide in 10 mff1 of water was added, followed by heating under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate.

After separating the Glauber's salt, the solvent was distilled off under reduced pressure, and 20 mf of acetonitrile was added to the residue to separate insoluble matter. ; PM was concentrated to give 1.5 g of 2-methyl-3-(2-pyridylmethylthio)pyrido(2,3-b)pyrazine as a brown oil.

'HNMR (CDCI*) δ: 2.74 (S, 3H
), 4.72 (S, 28) 7.0-9.0 (m, 7H) (ii) 2-methyl-3-(2-pyridylmethylsulfinyl)pyrido(2,3-b) pyrazine (invention Compound 3) 8 2-methyl-3-(2-pyrinolmethylthio)pyrido (
1.4 g of 2,3-[1]pyrazine and 14 m of aa form
1 and m-chloroperbenzoic acid (purity 80%) under water cooling.
)1 1 σ streak 11>l f −)
Ganshi f-2 ＆l-shin≧,・Large 1m
t, Yut 1 - The mixture is saturated with Na
It was poured into HCO3 solution and extracted with chloroform. The chloroform layer was washed with water and saturated brine, and then dried with mirabilite. After separating the Glauber's salt, 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)pyranone. was obtained as a brown crystalline powder.

mp: 120-125℃ (decomposition) 1080, 1
060.795'HNMR (CDC1,) δ: 2.78 (S, 311
), 4.57 and 4.74 (each d, 2
H, J = 13Hz), 7.0-7.9 (m, 4H>,
8.220-8J8 (, IH), 8.50 (dd, I
II J = 2Hz.

8 HZ), 9.16 (ad, l)1. J=21
1z, 4Hz) Example 4 (i) 2-(2-dimethylaminobenzylthio)quinoxaline/2-mercaptoquinoxaline 1g ethanol 40mN
After adding water (hysodium; If1mσ) to the solution, add 2-methylaminohene norchloride hydrochloride 1
．． Add 27g. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. 5% organic layer
After washing with sodium hydroxide solution, water, and saturated brine, it was dried with sodium sulfate. After separating the P from Glauber's salt, the solvent was distilled off under reduced pressure and the resulting residue was purified by Norica gel column chromatography (hexane/acetone) to obtain 1.5 g of 2-(2-methylaminobenzylthio)quinoxaline with a yellowish color. You can get it as a gift.

'HNMR (CDC13) δ・2.76 (S, 6) 1)
, 4.72 (S, 2H) 6.8-7.6 (m, 9H) (ii) 2 (2-dimethylaminobenzylsulfinyl) quinoxaline (compound of the present invention 4): 2-(2-dimethylaminobenzylsulfinyl) Dissolve 1.47 g of quinoxalino in 50 m of chloroform under cooling to 0°C.
- 1.54 g of chlorperbenzoic acid (purity 80%) was added little by little. The reaction solution was washed with saturated NaHCOz solution, water, and saturated brine, and then dried over Glauber's salt.

After separating the Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting carrier was purified by solid gel column chromatography (hexane/acetono) to obtain 330 J of 2-(2-dimethylaminohensylsulfinyl)quinoxaline as a yellow powder. r:
mp, 114-115°C945, 760'HNMR (CDCl2) δ: 2.40 (S, 6H)
, 4.46 and 4.66 (ea, ch d 21
(, J = 14) 1z), 6.9-8.2 (m, 911
) Example 5 (i) 2-(2-dimethylaminobenzylthio)-3-
Methylquinoxaline hydrochloride.

2-Mercapto-3-methylquinoxaline 2,80, g
, 2-dimethylaminohenol chloride hydrochloride 328g
and 8.0 g of potassium carbonate were added to a mixed solvent of 50 m of acetone and 5 ml of water, and the mixture was stirred at room temperature for 40 minutes. 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 Glauber's salt. After the Glauber's salt was separated, the solvent was distilled off under reduced pressure, and the residue was diluted with 50 ml of ethanol.

To this was added 1.33 mf of agricultural hydrochloric acid and then ether under water cooling, and the precipitated crystals were filtered out to obtain 4.56 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride as a dark brown crystalline powder. Ta.

IHNMR (CD30D/CDC1ff) δ: 2.67
(S, 3H), 3,46 (S, 6H) 5.00 (S, 2
[1), 7.44-81(,8■)(ii)2-(2-
dimethylaminobenzylsulfinyl)-3-methylquinoxaline (invention compound 5).

1.73 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride was added to 10 mf of chloroform.
and methanol lomj! The mixture was dissolved in a mixed solvent of 1.14 g of m-chloraminated aromatic acid (purity 80%) was gradually added while cooling with water so that the internal temperature was kept below 0°C. After the reaction is complete, add chloroform and saturated NaHCOx solution,
The organic layer was separated and dried with mirabilite.

After separating the Glauber's salt from I, the solvent was distilled off under reduced pressure, and the residue was purified using phosphoric gel column chromatography (chloroform/methanol) and crystallized from ethyl acetate-hexane.
51 g of 2-(2-dimethylaminohensylsulfinyl)-3-methylquinoxaline was obtained as a light brown crystalline powder.

mp: 6g-70'C (decomposition) 'HNMR (CDC13) δ: 2.42 (S,
6H), 2.49 (S, 3H) 4.44 and
4.73 (each d, 2H, J=12H
z) 6.8-8.3 (m, 8H) Example 6 (i) 2-(2-dimethylaminobenzylthio)-3°6.7-)dimethylquinoxaline: 2-mercapto-3,6,7 - 4.08 g of trimethylquinoxaline, 4.12 g of 2-dimethylaminobenzyl chloride hydrochloride, and 10.0 g of potassium carbonate were added to a mixed solvent of 50 mf of acetone and 5 mj 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 matter was separated, and the organic layer was separated and dried with mirabilite. After separating the Glauber's salt, the solvent was distilled off under reduced pressure, hexane was added to the residue, and insoluble matter was separated. ? The liquid was dried under reduced pressure +t6.
48 g of 2-(2-dimethylaminobenzylthio)-3
, 6,7-trimethylquinoxaline was obtained as an orange-white crystalline powder.

'HNMR (CDC1,) δ: 2.43 (S, 6H
), 2.61 (S, 3H) 2.75 (S, 6H), 4.
73(S, 2H), 6.8-7.8(m, 6[()(i
i) 2 (2-trimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline (compound 6 of the present invention): 2-(2-dimethylaminobenzylthio)-3°6.7
- 3.71 g of dolimethylquinoxaline in chloroform
The mixture was dissolved in a mixed solvent of 5 mf and methanol and 3 mff of methanol, and 2.45 g of m-chloroperbenzoic acid (purity 80%) was gradually added thereto so as to keep the internal temperature below 0°C under water cooling.

After the reaction was completed, chloroform and saturated NaHCO3 solution were added, and the organic layer was separated and dried with sodium sulfate. After separating the Glauber's salt, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (acetone/hexane). After condensation of the eluate, the residue was crystallized from ether/hexane.1.
12 g of 2-(2-dimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline were obtained as a yellow crystalline powder.

mp: 83-88°C (decomposition) 'HNMR (CDC1z) δ: 2.46 (S, 91
(), 2.51 (S, 6H) 4.44 and
4.71 (each d, 2H, J=12Hz)
6.8-7.4 (m, 4H), 7.76 and
8.00 (eachS 2H) Example 7 (i) 2-(2-diethylaminobenzylthio)-3-
Methylquinoxaline: 1.5 g of 2-mercapto-3-methylquinoxaline.

was added to a solution of 0.73 g of sodium hydroxide, 2 mf of water and 50 m of ethanol, and then 1.99 g of 2-noethylaminobenzyl chloride hydrochloride was added and 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 5% sodium hydroxide solution, water and saturated brine, and then dried with sodium sulfate. After separating the Glauber's salt and removing the solvent under reduced pressure, the resulting oil was purified by silica gel column chromatography (hexane/acetone) to obtain 1.74 g of 2-(
2-Diethylaminobenzylthio)-3-methylquinoxaline was obtained as a yellow oil.

') I NMR (CDCIs) δ: 1,04 (t
,SR,J=,8Hz)2.64(S,3H),3.0
4(), 4Hj=8Hz) 4.76(S, 2[(),
6.8-8.0 (m, 8) (ii) 2-(2-diethylaminobenzylsulfinyl)-3-methylquinoxaline: 17 g of 2-(2-diethylaminobenzylthio)-3-methylquinoxaline was added to 50 ml of chloroform. Dissolved in and cooled to -10°C.
Add 1.21g (0%) little by little. Saturate the reaction solution with N
After washing with aHCO*'ig solution, water, and saline solution containing II cells, it was dried with mirabilite. After separating the Glauber's salt, the medium was distilled off under reduced pressure and the resulting layered product was subjected to Norikakel column chromatography (
12 g of 2-(2-
Diethylaminobenzylsulfinyl)-3-methylquinoxaline was obtained as a yellow oil.

'HNMR (CDC13) δ: 0.96
(t, 6H, J= 8Hz) 2.52 (S, 3'
H), 2.92 (7-, 4)1. J=8H
z) 4.44 and 4.70 (each d
, 2)1. J=12Hz)6.8-8.4
(m, 8H)

Claims (2)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1, R_2 and R_3 each represent a hydrogen atom or a lower alkyl group, and X represents CH or N. ,Z
is an optionally substituted 2-pyridyl group or an optionally substituted general formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) (In the formula, R_4 and R_5 are each a hydrogen atom or lower alkyl 2-aminophenyl group] (2) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R_1, R_2 and R_3 each represent a hydrogen atom or a lower alkyl group, and X represents CH or N] The mercapto derivative represented by the general formula (IV) QCH_2Z(IV) [wherein, Q represents a reactive group and Z is an optionally substituted 2-pyridyl group or an optionally substituted general formula (I
I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) A compound represented by 2-aminophenyl group represented by (in the formula, R_4 and R_5 each represent a hydrogen atom or a lower alkyl group) or its The salt is reacted to form a compound represented by general formula (V) ▲Mathematical formula, chemical formula, table, etc.▼(V) (wherein R_1, R_2, R_3, X and Z are the same as above), and then General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1, R_2, R_3, X and Z are the same as above) manufacturing method.