JPH0430957B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to benzoxazole derivatives having a substituted pyridylmethylsulfinyl group in the side chain,
More specifically, the present invention relates to a benzoxazole derivative that specifically inhibits the activity of potassium ion-dependent adenosine triphosphatase (hereinafter abbreviated as (H ⁺ +K ⁺ )ATPase). Conventional technology (H ⁺ +K ⁺ ) ATPase is an enzyme involved in hydrochloric acid production within the gastric endoplasmic reticulum vesicles, and recent research has revealed that substances that inhibit this enzyme activity are useful as anti-ulcer agents. I've come (Gastroenterology; Gastroenterology Volume 1)
420 pages 1943, Vol. 73, 921 pages 1977). In the course of this research, one of the benzimidazole derivatives, 5-methoxy-2-[2-(4-methoxy-3,5-dimethyl)pyridylmethylsulfinyl]benzimidazole (hereinafter abbreviated as omeprazole), was discovered. It has been reported that (H ⁺ +K ⁺ )ATPase activity is significantly inhibited, and its development as an anti-ulcer agent is currently underway (Japanese Patent Application Laid-open No. 141783/1983, British Medical Journal, Vol. 287, 12 p. 1983).
On the other hand, as a compound containing a pyridine skeleton via a sulfur atom in the side chain at the 2-position in a benzoxazole derivative, 2-(2-pyridimethylthio)benzoxazole (hereinafter referred to as compound A) exhibits anti-inflammatory and expectorant effects. (tentative name) has been reported (Japanese Unexamined Patent Publication No. 58-203965, Journal of Medicinal Chemistry).
Medicinal Chemistry Vol. 26, No. 2, p. 218, 1983). Problems to be solved by the invention However, the (H ⁺ +K ⁺ ) of this compound A
No investigation has been made regarding the inhibitory activity against ATPase, and follow-up experiments conducted by the present inventors revealed that there is no such activity. The present inventors have been actively searching for substances that inhibit (H ⁺ +K ⁺ )ATPase activity for many years, and found that there are other compounds in addition to benzoxazole derivatives that have a substituted pyridylmethylsulfinyl group in the side chain. We have arrived at the present invention by finding that it significantly inhibits such enzyme activity, and that its inhibitory activity is equivalent to or greater than that of omeprazole. Means for Solving the Problems According to the present invention, the following general formula [] (In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a methyl group, and R ³ represents hydrogen an atom, a methyl group or a propoxy group, and R ⁴ represents a hydrogen atom or a methyl group (except when R ² , R ³ and R ⁴ are all hydrogen atoms). provided. Examples of the halogen atom represented by R ¹ in the general formula [] include fluorine atom, chlorine atom, bromine atom, and iodine atom. Similarly, the alkyl group having 1 to 4 carbon atoms includes linear or branched ones, such as methyl group, ethyl group, n-
Propyl group, isopropyl group, n-butyl group or
Examples include tert-butyl group. Also, carbon number is 1
~4 alkoxy groups include straight chain or branched ones, such as methoxy group, ethoxy group, n
-propoxy group, isopropoxy group, sec-butoxy group, etc. Benzoxazole derivative represented by the above general formula [] (hereinafter simply referred to as the compound of the present invention [])
is the following general formula [] (In the formula, R ¹ , R ² , R ³ or R ⁴ have the same meanings as above.) A 2-(substituted pyridylmethylthio)benzoxazole derivative represented by the formula is oxidized using an oxidizing agent in the presence of an appropriate reaction solvent. It can be manufactured by The reaction ratio is such that the amount of the oxidizing agent is 1.0 to 1.3 times the molar amount of the 2-(substituted pyridylmethylthio)benzoxazole derivative []. Examples of oxidizing agents that can be used include m-chloroperbenzoic acid,
Perbenzoic acids such as perbenzoic acid or benzoyl peroxide, fatty acid peroxides such as peracetic acid, or tert
Examples include peroxides such as -butylhydroperoxide and hydrogen peroxide, but m-chloroperbenzoic acid is preferred in terms of high stability. Suitable reaction solvents include, for example, dichloromethane,
Consisting of halogenated hydrocarbons such as chloroform, tetrachloromethane or tetrachloroethane, alcohols such as methanol, ethanol, propanol or butanol, aromatic hydrocarbons such as benzene, toluene or xylene, or water, or two or more of these A mixed liquid may be mentioned. However, in terms of selectivity and yield in the oxidation reaction, chloroform is particularly preferred. The reaction temperature is -70~80℃, preferably -
The temperature is within the range of 10 to 30°C, and the reaction time is about 1 minute to 72 hours, preferably about 30 minutes to 3 hours. The 2-(substituted pyridylmethylthio)benzoxazole derivative [] has the following general formula [] (In the formula, R ¹ has the same meaning as above.) A 2-mercaptobenzoxazole derivative represented by the following general formula [] (In the formula, X represents a chlorine atom or a bromine atom,
R ² , R ³ and R ⁴ have the same meanings as above. be able to. The reaction ratio is such that the pyridine derivative [] is used in an equimolar amount to the 2-mercaptobenzoxazole derivative [], and the base is used in a 2.0 to 2.3 times molar amount. Examples of bases that can be used include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Reaction solvents include, for example, aromatic hydrocarbons such as benzene, triene or xylene, alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol, diethylene glycol or triethylene glycol, aprotic solvents such as dimethylformamide or dimethylsulfoxide. Examples include a polar solvent, water, or a mixture of two or more thereof. The reaction is carried out at a temperature of 10 to 200°C, preferably 70 to 110°C, and the reaction time is about 1 minute to 120 hours, preferably about 20 minutes to 6 hours. This condensation reaction
The reaction proceeds favorably in the presence of crown ethers such as 18-crown-6 or 15-crown-5, and good results such as shortened reaction time and improved yield can be obtained. The starting material 2-mercaptobenzoxazole derivative [] can be prepared by a known method, for example, Chemische Berichte, Vol. 16, p. 1825.
1883 or Organic Synthesis;
It can be produced by a method similar to that described in Organic Syntheses, Vol. 30, p. 56, 1950. Actions and Effects of the Invention The inhibitory action on (H ⁺ +K ⁺ )ATPase activity and gastric acid secretion suppressing action of the compound of the present invention [] produced as described above will be described in detail below.
The test was conducted using a representative compound (hereinafter abbreviated as test compound) of the compounds of the present invention. <(H ⁺ +K ⁺ )ATPase activity inhibition effect> The inhibitory effect of the compound of the present invention [ ] on (H ⁺ +K ⁺ )ATPase was tested using a solution containing 300 to 500 μg of the enzyme in terms of protein amount. The test compound was added to the solution, and the mixture was allowed to react for 5 to 30 minutes at 35 to 37°C, followed by measuring the activity of (H ⁺ +K ⁺ )ATPase in the reaction solution. (H ⁺ +K ⁺ )
ATPase was obtained from fresh fundic glands of pigs using the method of Saccomani et al. (The Journal).
Of Biological Chemistry;The
Journal of Biological Chemistry Volume 251 No. 23 7690
(1976) was used. The test compound was dissolved in an appropriate alcohol in advance and added so that the concentration of the compound in the reaction system was 1×10 ⁻³ mol. (H ⁺ +
The activity of K ⁺ ) ATPase is determined by mixing magnesium chloride and potassium chloride with the resulting reaction solution, adding adenosine triphosphate to this, and carrying out an enzymatic reaction at 37°C for 5 to 15 minutes. Phosphoric acid was determined by colorimetric determination using ammonium molybdate reagent. The initial concentrations of magnesium chloride, potassium chloride, and adenosine triphosphate were 2 mmolar, 20 mmolar, and 2 mmolar, respectively. Colorimetry was performed at wavelengths of 360-400 nm. In addition, the activity without the addition of the test compound was also measured using the same procedure as described above, and this was used as a control test. The results were as shown in Table 1. In the table, the inhibitory effect was determined by calculating the difference between the measured value obtained in the control test and the measured value for the test compound, and expressed as a percentage of the measured value in the control test. The table also shows the (H ⁺ +K ⁺ ) ATPase activity inhibitory effects of omeprazole and Compound A, which were measured in the same manner as described above, for comparison.

【table】

[Table] <Suppression of gastric acid secretion> Body weight after overnight fasting and ligation of the pylorus
Using a group of 5 male Wistar rats weighing approximately 200 g, the inhibitory effect of the compound of the present invention on gastric acid secretion was tested. The test was conducted by intraduodenally administering the test compound to each rat at a rate of 25 mg per 1 kg of body weight, and after 4 hours, each rat was sacrificed and opened, and the total acidity of the collected gastric fluid was measured. The test compound was administered by suspending it in a 0.5% carboxymethyl cellulose aqueous solution. The total acidity of the gastric juice was determined by titrating the gastric juice with a 0.1N aqueous sodium hydroxide solution until the pH value of the gastric juice reached 7.0. In addition, the total acidity of gastric fluid in the non-administration group was also measured in the same manner as described above. The results were as shown in Table 2. In the table, the inhibitory effect was determined by calculating the difference in total acidity between the non-administration group and the administration group, and expressed as a percentage of the total acidity of the non-administration group. For comparison, the table also shows the gastric acid secretion suppressing effect of omeprazole, which was measured in the same manner as above.

[Table] As is clear from Tables 1 and 2, the compound of the present invention [] exhibits an inhibitory effect on gastric acid secretion derived from an inhibitory effect on (H ⁺ +K ⁺ )ATPase activity that is equivalent to or greater than that of omeprazole. have Therefore, the compound of the present invention [] is recognized to be a useful drug as an anti-ulcer agent. The present invention will be further explained with examples. Example 1 (a) 5-fluoro-
2-Mercaptobenzoxazole 1.69g
(0.01 mol) and 2-chloromethyl-3,5-
1.92 g (0.01 mol) of dimethylpyridine hydrochloride was added, and the mixture was heated under reflux for 2 hours, and then the reaction solvent was distilled off under reduced pressure. The obtained residue was dissolved in 150 ml of chloroform, washed with a 5% aqueous sodium hydroxide solution, and then dried over anhydrous sodium sulfate. This chloroform solution was concentrated under reduced pressure to an appropriate volume, and the resulting concentrated solution was purified by silica gel column chromatography using chloroform as a developing solvent.
-[2-(3,5-dimethyl)pyridylmethylthio]-5-fluorobenzoxazole 2.39g
(yield 83.0%). (b) 2-[2-(3,5
-dimethyl)pyridylmethylthio]-5-fluorobenzoxazole 1.15g (0.004mol)
was dissolved in 50 ml of chloroform, and 0.86 g (0.005 mol) of m-chloroperbenzoic acid was added at 5 to 10°C.
The mixture was gradually added thereto and stirred at the same temperature for 1 hour. 100 ml of chloroform was poured into this reaction solution, and the resulting solution was washed at 15°C with 70 ml of 10% aqueous sodium carbonate solution, and then dried over anhydrous sodium sulfate. This chloroform solution was concentrated under reduced pressure to an appropriate volume and subjected to silica gel column chromatography using chloroform as a developing solvent to collect a fraction containing the target product. This fraction was dried under reduced pressure, and the resulting solid residue was recrystallized from an ethyl ether-petroleum ether mixture. 0.30 g of colorless crystals of fluorobenzoxazole (yield 24.6
%) was obtained. The melting point of this crystal was 103-104°C. IR spectrum (KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (as C ₁₅ H ₁₃ FN ₂ O ₂ S): Theoretical value (%); C, 59.19 H, 4.31 N, 9.21 Actual value ( %); C, 59.29 H, 4.27 N, 9.28 5-fluoro-2-mercaptobenzoxazole (0.01 mol) and 2-chloromethyl-3,5
-dimethylpyridine hydrochloride (0.01 mol), the corresponding 2-mercaptobenzoxazole derivative [] (0.01 mol) and the pyridine derivative []
The following compounds of Examples 2 to 13 were produced in substantially the same manner as in Example 1 above, except that the amount of each compound was changed to (0.01 mol). Example 2 2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]benzoxazole. Colorless crystals; yield 0.31g (yield 27.1%) Melting point: 95-97°C (ethyl acetate-petroleum ether) IR spectrum (KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (C ₁₅ H ₁₄ N ₂ O ₂ S): Theoretical value (%); C, 62.91 H, 4.93 N, 9.79 Actual value (%); 63.20 H, 5.18 N, 9.87 Example 3 2-[2-(3,5-dimethyl) Pyridylmethylsulfinyl]-5-bromobenzoxazole. Pale yellow crystal; yield 0.28g (yield 19.2%) Melting point: 115-118℃ (ethyl ether - petroleum ether) IR spectrum ((KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (C ₁₅ H ₁₃ BrN ₂ O ₂ S): Theoretical value (%); C, 49.32 H, 3.59 N, 7.67 Actual value (%); 49.57 H, 3.81 N, 7.77 Example 4 2-[2-(3,5- Dimethyl)pyridylmethylsulfinyl]-5-methoxybenzoxazole. Colorless crystals; yield 0.36g (yield 28.4%) Melting point: 103-105°C (ethyl ether - petroleum ether) IR spectrum (KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (as C ₁₆ H ₁₆ N ₂ O ₂ S): Theoretical value (%); C, 60.74 H, 5.10 N, 8.86 Actual value (%); 60.68 H, 5.03 N, 8.92 Example 5 2-[2-(4-methyl)pyridylmethylsulfinyl]-5-fluorobenzoxazole. Colorless crystals; yield 0.31 g (yield 26.7%) Melting point: 97-99°C (ethyl ether-petroleum ether) ) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₄ H ₁₁ FN ₂ O ₂ S): Theoretical value (%); C, 57.92 H, 3.82 N, 9.65 Actual value (%); 58.09 H, 3.91 N, 9.57 Example 6 2-[2-(4-methyl)pyridylmethylsulfinyl]benzoxazole. Colorless crystals; yield 0.35 g (yield 32.1%) Melting point; 93-95 °C (ethyl ether - petroleum ether) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₄ H ₁₂ N ₂ O ₂ S): Theoretical value (%); C, 61.74 H , 4.44 N, 10.29 Actual value (%); 61.88 H, 4.63 N, 10.17 Example 7 2-[2-(4-methyl)pyridylmethylsulfinyl]-6-chlorobenzoxazole. Colorless crystals; yield 0.37 g (Yield 30.2%) Melting point: 96-98°C (ethyl acetate-cyclohexane) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₄ H ₁₁ ClN ₂ O ₂ S): Theoretical value (%); C, 54.81 H, 3.61 N, 9.13 Actual value (%); 55.05 H, 3.85 N, 9.01 Example 8 2-[2-(4-methyl)pyridylmethylsulfinyl]-5- Iodobenzoxazole. Pale yellow crystal; yield 0.23g (yield 14.4%) Melting point: 101-103℃ (ethyl acetate-petroleum ether) IR spectrum ((KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (C ₁₄ H ₁₁ IN ₂ O ₂ S): Theoretical value (%); C, 42.22 H, 2.78 N, 7.04 Actual value (%); 42.42 H, 3.01 N, 7.11 Example 9 2-[2-(4-methyl) Pyridylmethylsulfinyl]-6-sec-butoxybenzoxazole. Pale yellow glassy substance; yield 0.33 g (yield 23.9
%) IR spectrum (KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (as C ₁₈ H ₂₁ N ₂ O ₃ S): Theoretical value (%); C, 62.58 H, 6.13 N, 8.11 Actual measurement Value (%): 62.79 H, 6.34 N, 8.02 Example 10 2-[2-(4-methyl)pyridylmethylsulfinyl]-4-fluorobenzoxazole. Pale yellow crystal; yield 0.28g (yield 24.1%) Melting point: 98-101℃ (ethyl acetate-n-hexane) IR spectrum ((KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (C ₁₄ H ₁₁ FN ₂ O ₂ S): Theoretical value (%); C, 57.92 H, 3.82 N, 9.65 Actual value (%); 58.19 H, 3.96 N, 9.59 Example 11 2-[2-(3-methyl ) Pyridylmethylsulfinyl]-5-fluorobenzoxazole. Colorless crystals; yield 0.33 g (yield 28.4%) Melting point: 117-119°C (ethyl ether - petroleum ether) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₄ H ₁₁ FN ₂ O ₂ S): Theoretical value (%); C, 57.92 H, 3.82 N, 9.65 Actual value (%); 57.84 H, 3.91 N, 9.74 Implemented Example 12 2-[2-(3,4,5-trimethyl)pyridylmethylsulfinyl]-5-fluorobenzoxazole. Colorless crystals; yield 0.35 g (yield 27.5%) Melting point: 114-116°C (ethyl ether ) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₆ H ₁₅ FN ₂ O ₂ S): Theoretical value (%); C, 60.36 H, 4.75 N, 8.80 Actual value (%); 60.56 H, 4.89 N, 8.75 Example 13 2-[2-(3,5-dimethyl-4-n-propoxy)pyridylmethylsulfinyl]-5-fluorobenzoxazole. Colorless crystals; Yield 0.29 g (yield 20.0%) Melting point: 82-84℃ (ethyl ether-petroleum ether) IR spectrum (KBr, cm ^-1 ): 1070 (S=O) Elemental analysis value (as C ₁₈ H ₁₉ FN ₂ O ₃ S ): Theoretical value (%); C, 59.65 H, 5.28 N, 7.73 Actual value (%); 59.77 H, 5.11 N, 7.69 Example 14 (a) 5-n-butyl-2-mercaptobenz in 50 ml of toluene Oxazole 2.07g (0.01mol),
1.12 g (0.02 mol) of potassium hydroxide and 0.1 g of 18-crown-6 were added and mixed under heating, and the resulting water was removed by azeotropic distillation. 1.78 g (0.01 mol) of 2-chloromethyl-4-methylpyridine hydrochloride was added to this mixed solution, and the mixture was heated under reflux for 30 minutes. The resulting reaction solution was cooled and poured into ice water, and then the reaction product was extracted with 300 ml of chloroform. This extract was washed with a 5% aqueous potassium carbonate solution, dried over anhydrous potassium carbonate, and concentrated to an appropriate amount. When this concentrated solution was purified by silica gel column chromatography using chloroform as a developing solvent, 2.77 g of 2-[2-(4-methyl)pyridylmethylthio]-5-n-butylbenzoxazole (yield: 88.7%). (b) 1.25 g (0.004 mol) of 2-[2-(4-methyl)pyridylmethylthio]-5-n-butylbenzoxazole obtained as described above was dissolved in 50 ml of chloroform, and m-chloro 0.86 g (0.005 mol) of perbenzoic acid was gradually added at 10 to 15°C, and the mixture was stirred at the same temperature for 30 minutes. 100 ml of chloroform was poured into this reaction solution, and the resulting solution was diluted with 50 ml of 5% potassium carbonate aqueous solution.
After washing at ℃, it was dried with anhydrous potassium carbonate. This chloroform solution was concentrated under reduced pressure to an appropriate volume and subjected to silica gel column chromatography using chloroform as a developing solvent to collect a fraction containing the target product. This fraction was then dried under reduced pressure to give 2-[2-(4-methyl)pyridylmethylsulfinyl]-5-n-
0.20 g (yield 15.2%) of a pale yellow glassy substance of butylbenzoxazole was obtained. IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (as C ₁₈ H ₂₀ N ₂ O ₃ S): Theoretical value (%); C, 65.82 H, 6.14 N, 8.53 Actual value ( %); 65.99 H, 6.01 N, 8.60 5-n-butyl-2-mercaptobenzoxazole (0.01 mol) and 2-chloromethyl-4-
Methylpyridine hydrochloride (0.01 mol) was added to the corresponding 2-mercaptobenzoxazole derivative []
(0.01 mol) and the pyridine derivative [] (0.01 mol), the following treatments were carried out in substantially the same manner as in Example 14 to produce the compounds of Examples 15 and 16 below. Example 15 2-[2-(3-methyl)pyridylmethylsulfinyl]-7-n-propylbenzoxazole. Pale yellow glassy substance; yield 0.28g (yield 22.3
%) IR spectrum (KBr, cm ^-1 ): 1060 (S=O) Elemental analysis value (as C ₁₇ H ₁₈ N ₂ O ₂ S): Theoretical value (%); C, 64.94 H, 5.77 N, 8.91 Actual measurement Value (%); 64.88 H, 5.85 N, 9.00 Example 16 2-[2-(4-methyl)pyridylmethylsulfinyl]-4-methylbenzoxazole. Colorless crystals; yield 0.31g (yield 27.1%) Melting point: 96-98°C (ethyl acetate-n-hexane) IR spectrum (KBr, cm ^-1 ): 1080 (S=O) Elemental analysis value (C ₁₅ H ₁₄ (as N ₂ O ₂ S): Theoretical value (%); C, 62.91 H, 4.93 N, 9.79 Actual value (%); 63.18 H, 4.70 N, 9.61 Listed below in almost the same way as each example described above Compounds were also prepared with yields of 5.3-37.8%. 2-[2-(4-methyl)pyridylmethylsulfinyl]-7-methoxybenzoxazole. 2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-7-ethylbenzoxazole. 2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-5-n-propoxybenzoxazole. 2-[2-(3-methyl)pyridylmethylsulfinyl]-6-isopropoxybenzoxazole. 2-[2-(3,4,5-trimethyl)pyridylmethylsulfinyl]-5-methylbenzoxazole. 2-[2-(3,5-dimethyl-4-n-propoxy)pyridylmethylsulfinyl]-6-ethoxybenzoxazole. 2-[2-(3-methyl)pyridylmethylsulfinyl]benzoxazole. 2-[2-(3,4,5-trimethyl)pyridylmethylsulfinyl]benzoxazole. 2-[2-(3,5-dimethyl-4-propoxy)pyridylmethylsulfinyl]benzoxazole. 2-[2-(5-methyl)pyridylmethylsulfinyl]-5-isopropylbenzoxazole. 2-[2-(3,4-dimethyl)pyridylmethylsulfinyl]-5-tertbutylbenzoxazole.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a methyl group, and R ³ represents hydrogen a benzoxazole derivative represented by the following formula: an atom, a methyl group, or a propoxy group, and R ⁴ represents a hydrogen atom or a methyl group, except when R ² , R ³ and R ⁴ are all hydrogen atoms.