JPH0547536B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel azulene derivative sulfonate, a method for producing the same, and the application of this compound for pharmaceutical use. Conventionally, azulene derivatives, mainly sodium guaiazulene sulfonate, have been used as pharmaceutical drugs, mainly for the treatment of gastric ulcers, gastritis, and inflammation. However, since this compound is unstable to light and heat, there are many difficulties in formulation and handling.Therefore, a more stable compound with excellent medicinal efficacy has been desired. In order to improve these shortcomings, the inventor has
As a result of synthesizing a new azulene derivative and studying its pharmacological action, the present invention was completed. Furthermore, the inventors of the present application have focused on the fact that aluminum sulfate ester compounds of various sugars have gastroprotective effects, and have synthesized the aluminum salts of the novel azulene derivatives in addition to the sodium sulfonate salts to improve their pharmacology. After examining their effects, we found that these aluminum salts also have a strong ulcer-inhibiting effect, and we also succeeded in producing aluminum sulfonate salts of these azulene derivatives in good yield. The sulfonate of the novel azulene derivative of the present application has the general formula (1): [[In the formula, R ₁ is a C _1-6 alkyl group or a benzyl group, R ₂ is a hydrogen atom or a C _1-5 alkyl group, R ₃ is a hydrogen atom or a lower alkyloxy group, X represents Na or Al(OH) ₂ , respectively, and R ₁ is an alkyl group, when R ₃ is a hydrogen atom, R ₂ is an alkyl group, and when R ₁ is a benzyl group, R ₂ is an alkyl group. In the group, R ₃ represents a hydrogen atom or an alkoxy group, respectively.
However, compounds in which R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ is a hydrogen atom, and X is Na are excluded. same as below. ] In the compound represented by, the alkyl group of R ₁ is
It means an alkyl group having 1 to 6 carbon atoms. or,
The alkyl group for R ₂ is a branched alkyl group having 1 to 5 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl butyl, isobutyl, and other groups. Furthermore, the lower alkyloxy group of R ₃ means a lower alkyloxy group such as a methoxy group, an ethoxy group, or a propoxy group. The main examples of the compound of the present invention represented by the above general formula (1) are as follows. (1) Sodium 7-isopropyl-3-benzyl azulene sulfonate (2) Sodium 4-methoxy-3-methyl azulene sulfonate (3) Sodium 4-methoxy-3-ethyl azulene sulfonate (4) 4-methoxy-3 - Sodium propyl azulene sulfonate (5) Sodium 4-methoxy-3-butyl azulene sulfonate (6) Sodium 4-methoxy-3-bentylazulene sulfonate (7) Sodium 4-methoxy-3-hexyl azulene sulfonate ( 8) Sodium 7-isopropyl-4-methoxy-3-methylazulene sulfonate (9) Sodium 7-isopropyl-4-methoxy-3-ethyl azulene sulfonate (10) 7-isopropyl-4-methoxy-3-propylazulene Sodium sulfonate (11) Sodium 7-isopropyl-4-methoxy-3-butyl azulene sulfonate (12) Aluminum 7-isopropyl-3-methyl azulene sulfonate (13) Aluminum 7-isopropyl-3-ethyl azulene sulfonate Above In the following, compounds (1) to (13) are
(1) - Cited as compounds (13). The compound of the present application represented by general formula (1) is superior in terms of medicinal efficacy and chemical stability compared to guaiazulene-3-sulfonic acid sodium currently used for treatment, and has a remarkable anti-pepsin effect. Due to its action and anti-ulcer effect, it is useful as an anti-inflammatory agent, especially an anti-gastritis agent, or as an anti-ulcer agent. The compound represented by general formula (1) can be produced by the method of Yasunami et al., one of the inventors of the present invention (Chemistry Letters
1980 p.579), general formula (2): (However, R' represents a methyl group or an ethyl group. R ₂ ,
R ₃ is the same as above. ) The compound represented by the general formula (3): R ₁ −CH ₂ CHO ...(3) and the aldehyde represented by the general formula (4): (however

[Formula] represents an imino residue. The same applies hereinafter) General formula (5) obtained by reaction with an imino compound represented by: The general formula obtained by reacting the enamine shown by
(6)： The compound represented by is decarboxylated using 100% phosphoric acid etc. to obtain the general formula (7): An azulene derivative is obtained. In the above reaction, examples of the imino residue include a dimethylamino group, a diethylamino group, a morpholino group, and a pyrrolidinyl group. The purpose of sulfonation of the azulene derivative of general formula (7) can be achieved by any method, such as reacting sulfuric acid in acetic anhydride, using sulfuric anhydride, or using a pyridine sulfate complex. . Conversion to an aluminum salt can be easily obtained by reacting an aqueous solution of each of the sulfonic acid sodium salts of the azulene derivatives obtained by the above method with aluminum ions to precipitate the aluminum salt. The aluminum ion used here generally includes metallic aluminum, aluminum hydroxide,
Aluminum chloride, aluminum propoxide, etc. can be used. The compounds of the present invention have the effects required for anti-ulcer agents and are particularly useful for the prevention and treatment of gastric ulcers and gastritis. In the novel method of the present invention for preventing and treating gastric ulcers, the novel compound is administered at 6 to 600 doses per day.
mg/person in 2 to 4 divided doses per day. The novel compounds of the present invention can be administered as the sole active ingredient or in combination with other anti-ulcer agents or other anti-inflammatory agents. The compounds of the invention are administered orally or sublingually at the dosages indicated. These are preferably administered orally;
For example, the drug may be administered in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, etc. prepared according to conventional methods in medical manufacturing. The amount of active compound in such therapeutically useful compositions or formulations is such that a suitable dosage will be obtained. Below, pharmacological test examples and manufacturing examples of the compound of the present invention are listed. [Pharmacological test] According to Shay's method (Gastroenterology 26906), rats weighing 180 to 200 g were fasted for 24 hours, the pylorus was ligated, and 16 hours later, the rats were sacrificed and opened, and the area of the ulcer formed was measured. The results are shown in Table 1. Shown below. The substance of the present application was suspended in 1% methylcellulose and orally administered immediately after ligation. The results were expressed as an incidence control rate (%) based on the incidence rate of the control group.

[Table] [Toxicity test] The table below shows the LD ₅₀ values determined by oral administration to CD rats for acute toxicity test of the compounds of the present invention.

[Table] Formulation example 1 Tablet preparation The active ingredients were 1.0, 5.0, 15.0, 20.0, 30.0, respectively.
Tablets containing 50.0 mg are prepared as illustrated below.

[Table] Umu

[Table] Um Mix all of the active compounds, cellulose and part of the cornstarch and granulate into a 10% cornstarch paste. The resulting granules are sieved, dried and mixed with the remaining cornstarch and magnesium stearate. Then, the obtained granules were mixed with 1.0 active ingredient per tablet.
Compress into tablets containing 5.0, 15.0, 20.0, 30.0, 50.0 mg. Formulation example 2 Granule preparation

[Table] After thoroughly mixing the active compound with all of the methylcellulose, crystalline cellulose, lactose, and a portion of corn starch, add the remaining crystalline cellulose, lactose, and corn starch, mix thoroughly, and prepare granules using a conventional method. shall be. Reference Example 1 Production of sodium 3-propylazulene sulfonate 1-propylazulene in a 100 ml three-necked flask
Add 7.6g and dissolve in 50ml of benzene. Add 12.43 g of pyridine sulfuric acid while stirring thoroughly, and reflux for 6 hours. After the reaction is completed, the benzene layer is filtered off, the remaining solid is thoroughly washed with benzene, and then the solid is dissolved in methanol. Sodium methylate is added dropwise to this methanol solution to raise the pH to 8, the precipitated crystals are filtered off, and the methanol layer is evaporated under reduced pressure to obtain a solid. This fixation is washed once with ether and then recrystallized with ethanol to obtain the target compound. Yield 42%. MP: 210~215℃ IR: 3400, 2940, 2850, 1580, 1420, 1400,
1200, 1090, 1020, 960, 880, 750, 740, 670
(cm ^-1 ) Reference Example 2 Production of sodium 7-isopropyl-3-n-pentylazulene sulfonate In a 500 ml eggplant-shaped flask, add 5-isopropyl-
Add 22.0 g of 3-methoxycarbonyl-2H-cyclopenta[b]furan-2-one and add 75
Add _200ml of % _H2SO4 and heat to dissolve in water. (95～
98℃). After 30 minutes, the reaction solution was poured into 2 portions of water, extracted with chloroform, and the chloroform layer was washed with water, dried, and concentrated to obtain 15.0 g of a yellow liquid. Separately dl-citronellal 20g, pyrrolidine 11.0
Dissolve g in 200ml of benzene and heat under reflux for 2 hours.
After removing the produced water, the reaction solution was concentrated and distilled under reduced pressure to obtain 21 g of enamine. Next, 15 g of the above yellow liquid and 16.5 g of enamine were dissolved in 200 ml of absolute ethanol and heated under reflux for 12 hours. The reaction solution was concentrated and extracted with benzene. The benzene layer is washed with water, dehydrated, concentrated, and purified by silica gel column chromatography using benzene. 6 g of dark purple liquid are obtained. This is sulfonated according to Reference Example 1, and then converted into a sodium salt. mp: 113-116°C ir: 3450, 2950, 1640, 1380, 1240, 1180 (cm ^-1 ) Example 1 Compound (1) is obtained by a method according to Reference Example 2. Compound (1) mp: 250℃ ir: 3450, 2950, 1640, 1560, 1530, 1460, 1420
(cm ^-1 ) Example 2 Compound (2) 7 g of 8-methoxy-3-ethoxycarbonyl-oxazulene is dissolved in ethanol, 6.19 g of diethylamine and 4.19 g of propionaldehyde are added, and the mixture is refluxed for 8 hours. After the reaction, ethanol is distilled off and the residue is dissolved in benzene. The benzene layer was washed with a saturated NaHCO ₃ aqueous solution, 5% HCl, and saturated brine, dried over Glauber's salt, and the benzene was distilled off to obtain a reddish-purple solid. This was purified by silica gel column chromatography using benzene as an eluent, and 8-
5.348 g of methoxy-3-ethoxycarbonyl-1-methylazulene are obtained. Furthermore, add 5 g of this compound to 50 ml of 100% phosphoric acid,
Heat the solution over an aqueous solution (90-95°C) until no carbon dioxide gas is generated (approximately 1.5 hours). After cooling, pour the reaction mixture into water and extract the aqueous layer with benzene. The benzene layer is washed with saturated NaHCO ₃ water and saturated NaCl water, respectively, and after drying, the benzene is distilled off to obtain a dark blue viscous liquid. This compound was purified by silica gel column chromatography using n-hexane as the eluent, and a purple viscous liquid was obtained.
Methoxy-1-methylazulene (IR spectrum:
2950, 1600, 1560, 1540, 1510, 1460 (cm ^-1 ))
Obtain 2.7g. This compound was converted into sulfonic acid sodium salt according to the sulfonation method of Reference Example 1 to obtain 2.7 g of the desired product. mp: 186-188°C (decomposition) ir: 3400, 1600, 1570, 1540, 1460, 1370, 1270 The compounds listed in Examples 3-13 were prepared from the respective corresponding starting materials according to the method of Example 2 ( 3) to (13) are obtained. Example 3 Compound (3) The target compound is obtained by using butyraldehyde in place of propionaldehyde in Example 2. MP: 60℃ IR: 3400, 2950, 1600, 1570, 1540, 1450,
1370, 1270 (cm ^-1 ) Example 4 Compound (4) mp: 108-110℃ ir: 3450, 2910, 2850, 1600, 1570, 1530 (cm
^-1 ) Example 5 Compound (5) mp: 188-190℃ (decomposition) ir: 3450, 2950, 1600, 1570, 1530, 1460 (cm
^-1 ) Example 6 Compound (6) mp: 189-192℃ (decomposition) ir: 3450, 2950, 1600, 1560, 1530, 1450 (cm ^-1 ) Example 7 Compound (7) mp: 225-228℃ (Decomposition) ir: 3450, 2900, 1650, 1560, 1520, 1460 (cm ^-1 ) Example 8 Compound (8) mp: 95-97℃ ir: 3450, 2950, 1650, 1540, 1280, 1180 (cm ^{- 1} ) Example 9 Compound (9) mp: 108-110℃ ir: 3450, 2950, 1650, 1540, 1260, 1180 (cm ^-1 ) Example 10 Compound (10) mp: 188-190℃ ir: 3450, 2950, 1640, 1560, 1530 (cm ^-1 ) Example 11 Compound (11) mp: 166-168℃ ir: 3450, 2950, 1640, 1560, 1530, 1470 (cm ^-1 ) Reference example 3 3-methylazulene Production of aluminum sulfonate Using 5 g of 1-methyl azulene, sodium 3-methyl azulene sulfonate was prepared according to Reference Example 1. Dissolve 5 g of the obtained sodium 3-methylazulene sulfonate in 60 ml of water and remove insoluble materials by filtration to make a liquid. Separately, 2.727 g of AlCl ₃ is dissolved in 40 ml of water and insoluble materials are removed by filtration. and stir for 30 minutes. Add 10% NaOH dropwise to this reaction solution,
Adjust the pH to 4-4.5. Filter the precipitated crystals,
Wash thoroughly with water and dry. MP: 250℃ or above IR: 3400, 1630, 1580, 1395, 1140, 1040, 740
(cm ^-1 ) Al content: 13.96% According to Reference Example 3, compounds (12) and (13) are obtained from the azulene derivative sulfonic acid sodium salts corresponding to Examples 12 and 13, respectively. Example 12 Compound (12) mp: 250℃ or higher IR: 3400, 2950, 1420, 1150, 1040 (cm ^-1 ) Al content: 9.46% Example 13 Compound (13) mp: 250℃ or higher IR: 3400, 2950 , 1580, 1420, 1390, 1150 (cm ^-1 ) Al content: 10.58%

Claims (1)

[Claims] 1. General formula: [However, in the formula, R ₁ is a C _1-6 alkyl group or a benzyl group, R ₂ is a hydrogen atom or a C _1-5 alkyl group, R ₃ is a hydrogen atom or a lower alkyloxy group, represents Na or Al(OH) ₂ , respectively, and when R ₁ is an alkyl group and R ₃ is a hydrogen atom, R ₂ is an alkyl group, and when R ₁ is a benzyl group, R ₂ is an alkyl group. In, R ₃ represents a hydrogen atom or an alkoxy group, respectively.
However, compounds in which R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ is a hydrogen atom, and X is Na are excluded. ] An azulene derivative sulfonate represented by: 2 General formula: [However, in the formula, R ₁ is a C _1-6 alkyl group or a benzyl group, R ₂ is a hydrogen atom or a C _1-5 alkyl group, R ₃ is a hydrogen atom or a lower alkyloxy group, represents Na or Al(OH) ₂ , respectively, and when R ₁ is an alkyl group and R ₃ is a hydrogen atom, R ₂
is an alkyl group, when R ₁ is a benzyl group, R ₂ is an alkyl group,
R ₃ represents a hydrogen atom or an alkoxy group, respectively.
However, compounds in which R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ is a hydrogen atom, and X is Na are excluded. ] An anti-ulcer agent containing an azulene derivative sulfonate as an active ingredient. 3 General formula: [However, in the formula, R ₁ is a C _1-6 alkyl group or a benzyl group, R ₂ is a hydrogen atom or a C _1-5 alkyl group, R ₃ is a hydrogen atom or a lower alkyloxy group, represents Na or Al(OH) ₂ , respectively, and when R ₁ is an alkyl group and R ₃ is a hydrogen atom, R ₂ is an alkyl group, and when R ₁ is a benzyl group, R ₂ is an alkyl group. In, R ₃ represents a hydrogen atom or an alkoxy group, respectively.
However, compounds in which R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, R ₃ is a hydrogen atom, and X is Na are excluded. ] An anti-inflammatory agent containing an azulene derivative sulfonate as an active ingredient. 4. The anti-inflammatory agent according to claim 3, which is an anti-gastritis agent. 5 General formula: [However, in the formula, R ₁ is a C _1-6 alkyl group or a benzyl group, R ₂ is a hydrogen atom or a C _1-5 alkyl group, R ₃ is a hydrogen atom or a lower alkyloxy group, and X is Na or Al(OH) ₂ respectively, and when R ₁ is an alkyl group and R ₃ is a hydrogen atom, R ₂ is a lower alkyl group, and when R ₁ is a benzyl group, R ₂ is an alkyl group. ,
R ₃ represents a hydrogen atom or an alkoxy group, respectively. The same shall apply hereinafter in this section. ] After sulfonating the azulene derivative represented by
General formula: [In the above formula, X represents Na or Al(OH) ₂ . however,
When R ₁ is a lower alkyl group, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom, X is Al
(OH) represents ₂ . ] A method for producing an azulene derivative sulfonate salt.