JPH032124B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel [1] benzepino[3,4
-b] An antiulcer agent containing a pyridine derivative and an acid addition salt thereof as an active ingredient. More specifically, the present invention relates to the general formula () [In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, or a halogen atom, X represents an oxygen atom or a sulfur atom, and R ² represents

[Formula] (In the formula, Y represents an amino group, substituted amino group, heterocycle or substituted heterocycle, Z represents a hydrogen atom, alkyl group or acyl group, and n represents an integer from 1 to 3.)
or

[Formula] (where m represents 0, 1 or 2, and Z has the same meaning as above). The present invention relates to an anti-ulcer agent containing a novel [1] benzepino[3,4-b]pyridine derivative represented by the following formula and its acid addition salt as an active ingredient. The present invention will be explained in detail below. The target compound represented by general formula (I) (hereinafter,
Referred to as Compound I. ), examples of the alkyl group in R ¹ include alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, and pentyl groups. Examples of the halogenated alkyl group include halogenated alkyl groups having 1 to 3 carbon atoms, such as trifluoromethyl, trichloromethyl, and tribromomethyl groups. As an alkoxy group,
Alkoxy groups having 1-5 carbon atoms, such as methoxy,
Examples include ethoxy, propoxy, butoxy, and pentyloxy groups. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. The substituent of the substituted amino group in Y may be a mono- or di-substituent, and includes an alkyl group having 1 to 5 carbon atoms, such as a methyl, ethyl, propyl, butyl, and pentyl group. Examples of the heterocycle include pepyrazine, pepyridine, morpholine, pyrrolidine, pyridine, quinuclidine, imidazole, indole, quinoline, pyrrolitidine, and the like. Examples of substituents on the heterocycle include methyl,
Examples include alkyl groups having 1 to 5 carbon atoms such as ethyl, propyl, butyl, and pentyl groups, and halogen atoms such as fluorine, chlorine, bromine, and iodine. The alkyl group in Z has 1-5 carbon atoms.
alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl groups. Examples of the acyl group include acyl groups having 1 to 5 carbon atoms, such as formyl, acetyl, propionyl, butyryl, valeryl, fluoroacetyl, difluoroacetyl,
Examples include trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl, and tribromoacetyl groups. Acid addition salts of the compound include salts with pharmacologically acceptable inorganic acids, such as hydrochloride, hydrobromide, sulfate, and phosphate; salts with organic acids, such as acetate and maleic acid; acid salts, fumarates, tartrates,
Examples include citrate, oxalate, and benzoate salts. Next, the acute toxicity test and anti-ulcer effect test of the compound are shown. Acute toxicity test A group of 5 DD male mice weighing 20 ± 1 g were used.
Compounds were administered orally (po: 0.3 mg/g) or intraperitoneally (ip: 0.1 mg/g). The mortality status was observed 7 days after administration, and the MLD (minimum mortality dose) value was determined.
The results for representative compounds are shown first.
Shown in the table. Anti-ulcer effect test For the experiment, male Donryu rats (weight 190-210 g) that had been fasted for 17 hours were used. Immediately after oral administration of Compound I (po: 30 mg/Kg), they were placed in a restraint cage devised by Takagi et al. [Jap. J.Pharmacol., 18 , 9
(1968)], the rats were immersed up to the xiphoid process in water at 23 ± 1°C. After 7 hours, the rats were killed with carbon dioxide gas, the stomachs of each rat were removed, and the length of the gastric damage caused to the glandular stomach was measured. were observed and measured using a stereomicroscope, and the sum of these values was used as the damage index for each rat. 4-5 rats were used per group. The test compound was used either dissolved in physiological saline or dissolved or suspended in physiological saline to which an appropriate amount of polyethylene glycol 400 was added. The damage index was compared with that of the vehicle (physiological saline or physiological saline-polyethylene glycol 400 mixture) administration group, and the inhibition rate was calculated from the following formula. Table 1 shows the results for representative compounds. Inhibition rate (%) = vehicle administration group - test compound administration group / vehicle administration group x 10
0

[Table] In view of its pharmacological action, the compound can be used in various pharmaceutical forms for administration purposes.
The pharmaceutical compositions of the present invention can be prepared by uniformly admixing an effective amount of a particular compound as the active ingredient, free or in the form of an acid addition salt, with a pharmaceutically acceptable carrier. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form suitable for administration orally or by injection. Any useful pharmaceutically acceptable carrier can be used in preparing compositions in oral dosage forms. For example, oral liquid preparations such as suspensions and syrups may contain water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, alkyl para It can be manufactured using preservatives such as hydroxybenzoate and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets contain excipients such as lactose, glucose, sucrose and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl cellulose, and gelatin. binders such as
It can be manufactured using surfactants such as fatty acid esters, plasticizers such as glycerin, etc. Tablets and capsules are the most useful oral dosage units because of their ease of administration. Solid pharmaceutical carriers are used in the manufacture of tablets and capsules. Injectable solutions can also be prepared with carriers consisting of saline solutions, glucose solutions, or mixtures of saline and glucose solutions. The effective dose of the compound is 10-50 mg/person (approximately 60
Kg)/day, and the administration frequency is preferably about 3 times a day. Next, a manufacturing example of the compound will be explained. The compound has the general formula () (wherein R ¹ and Among the above-mentioned compounds, methods for producing some of the compounds are known, for example, in JP-A-49-117496, Chem.
Pharm. Bull., 29 , 3515 (1981), etc., and compounds not described can also be produced by the same method as described. (In the formula, R ¹ , R ² and acid addition salt of Then, the compound or the acid addition salt of the compound and the amine [Z′-NH-(CH ₂ )
n-Y: compound or

[Formula] (In the formula, Y, Z, m and n have the same meanings as above, and Z' represents a hydrogen atom or an alkyl group having 1-5 carbon atoms.)]
A compound can be obtained by reacting with. Furthermore, manufacturing method A will be explained in detail. The compound is obtained by reducing the compound, usually by a method using a metal hydride complex such as lithium aluminum hydride or sodium borohydride. That is, when reducing a compound using lithium aluminum hydride, the compound is dissolved or suspended in a dry solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, etc., and then 0.3-2.0 The reduction is completed by adding an equivalent amount of lithium aluminum hydride and stirring at a suitable temperature between 0° C. and the boiling point of the solvent for 30 minutes to 3 hours. Thereafter, the compound is obtained by post-treatment according to a conventional method. In addition, when reducing a compound using sodium borohydride, the compound is dissolved or suspended in a solvent such as water, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, dimethyl formamide, dimethyl sulfoxide, etc. 0.3−1.0 against
Add equivalent amount of sodium borohydride and heat to 0-60℃
The reduction is completed by stirring for 1-8 hours at a suitable temperature. Thereafter, the compound is obtained by post-treatment according to a conventional method. In addition, by using the catalytic hydrogenation method,
It is also possible to obtain compounds by reducing them. The compound thus obtained is converted into a compound or an acid addition salt of the compound using various halogenating agents. In this case, this halogenation can be easily carried out by a method using thionyl halide or a method using phosphorus halide as a halogenating agent. That is, thionyl chloride, thionyl bromide, etc. can be used as the thionyl halide, and these can be used in excess as they are, or benzene,
The compound and the 0- By reacting at an appropriate temperature of 70° C. for 1 to 5 hours, the compound or the acid addition salt of the compound can be obtained. In addition, phosphorus halides include phosphorus trichloride, phosphorus pentachloride,
Phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, etc. can be used, and the compound or the acid addition salt of the compound can be obtained under the same conditions as when using thionyl halide described above. In addition, it is also possible to halogenate a compound by a method using hydrogen halide to obtain a compound or an oxidized salt of the compound. A compound is obtained by reacting the compound or acid addition salt of the compound thus obtained with the compound or the compound. That is, using 2 to 10 equivalents of the compound or the acid addition salt of the compound,
If necessary, in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, cyclohexane, acetonitrile, carbon disulfide, ethyl acetate, dimethylformamide, etc., from -10 to A compound is produced by reacting at an appropriate temperature of 120°C for 30 minutes to 3 hours. In addition, during this reaction, by coexisting a base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, pyridine, quinoline, dimethylaniline, triethylamine, diisopropylethylamine as a scavenger for hydrogen halide, It is possible to use as little as 1 equivalent of the compound or compounds. (wherein,
NH ₂ :compound (in the formula, Z' has the same meaning as above)] to form a compound, and further, the compound and Y
-( _CH2 )n-W: Compound (wherein, W is chlorine,
Halogen atoms such as bromine and iodine, methylsulfonyloxy, phenylsulfonyloxy, p
The compound 'can be obtained by reacting a sulfonyloxy group such as -toluenesulfonyloxy group) or an acid addition salt of the compound. Furthermore, manufacturing method B will be explained in detail. Either use the compound in excess as it is, or use it in an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, ethyl acetate, etc. at -78 to 50 °C. The compound can be obtained by reacting with the compound or an acid addition salt of the compound for 30 minutes to 3 hours at an appropriate temperature. The compound thus obtained is mixed with 1 to 5 equivalents of the compound or an acid addition salt of the compound and dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane. , hexane, cyclohexane, methanol, ethanol, propanol, acetonitrile, carbon disulfide, ethyl acetate,
In a solvent such as dimethylformamide, if necessary, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, pyridine, quinoline,
In the presence of a base such as dimethylaniline, triethylamine, diisopropylethylamine, etc., and if necessary, in the presence of a catalytic amount of iodide such as sodium iodide, potassium iodide, etc., at an appropriate temperature of 0 to 120°C for 30 minutes to 6 hours. Upon reaction, compound 1' is produced. The compounds obtained in Production Methods A and B in this way are obtained as free bases in the form of crystals or oils, so if necessary, column chromatography or recrystallization may be performed to obtain the target compound with even higher purity. It can be a refined product. Additionally, physiologically usable inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or organic acids such as acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, oxalic acid, benzoic acid, etc. An acid addition salt of a compound can be easily produced by acting according to the following method. The names, structures, and physical and chemical properties of specific examples of compounds are shown in Tables 2, 3, and 4, respectively. In addition, compounds 1, 2..., 26 are the same as Reference Example 1 below.
2,...26 corresponds to compounds 1,2,...26.

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[Table] Examples and reference examples are shown below. The melting points, infrared absorption spectra, nuclear magnetic resonance spectra, and elemental analysis values of the compounds obtained in each reference example are shown in Table 4. Example 1: Tablet Tablets were prepared according to the following composition using a conventional method. 5-[2-(diethylamino)ethyl]amino-
5,11-dihydro[1]benzoxepino[3,
4-b] Pyridine trihydrochloride monohydrate (compound 1 trihydrochloride monohydrate) 20 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearyl phosphate 1 mg Tar pigment Trace amount Example 2: Powder The following was prepared by the conventional method. Powders were prepared according to the composition. 5-[2-(dimethylamino)ethyl]amino-
5,11-dihydro[1]benzoxepino[3,
4-b] Pyridine trihydrochloride 1/2 hydrate (compound 5
trihydrochloride (1/2 hydrate) 20 mg Lactose 280 mg Example 3: Syrup A syrup was prepared according to the following composition by a conventional method. 5-[2-(diisopropylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine trihydrochloride 1/2 hydrate (compound 24 trihydrochloride 1/2 hydrate) 300mg refined white sugar 40g methyl paraoxybenzoate 10mg propyl paraoxybenzoate 0.1ml strawberry flavor Add water to make a total volume of 100ml. Reference example 1 5-oxo-5,11-dihydro[1]benzoxepino[3] , 4-b] Dissolve 11.1 g of pyridine in 160 ml of ethanol, and dissolve 1.3 g of sodium borohydride.
g and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, 50 ml of water and 100 ml of ethyl acetate were added to the residue, and after shaking, the aqueous layer was separated and discarded. The ethyl acetate layer was dried and concentrated under reduced pressure to obtain 5-
10.5 g of crude crystals of hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine are obtained. The crude crystals are purified by recrystallization from isopropanol to obtain 9.5 g of purified crystals. Melting point: 143-144℃ Infrared absorption spectrum: (KBr tablet, cm ^-1 ) 3200, 1590, 1485, 1215, 1040, 800 Nuclear magnetic resonance spectrum: (CDCl ₃ , δ value, ppm) 5.19 and 5.42 (ABq, 2H ), 5.78 (s, 1H),
6.95−7.60 (m, 5H), 7.80 (dd, 1H), 8.33
(dd, 1H) Elemental analysis value: (as C ₁₃ H ₁₁ NO ₂ ) (%) C H N Theoretical value: 73.23 5.20 6.57 Actual value: 73.01 5.04 6.48 The 5-hydroxy-5 thus obtained,
11-dihydro[1]benzoxepino[3,4-
b] 1.5 g of pyridine is suspended in 15 ml of dichloromethane, and under ice cooling, a solution of 1.7 g of thionyl chloride dissolved in 5 ml of dichloromethane is added dropwise over 10 minutes. After completion of the dropwise addition, the homogeneous reaction solution was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride, and a hydrochloric acid addition salt of 5-chloro-5,11-dihydro[1]benzoxepino[3,4-b]pyridine is obtained as a concentrated residue. Dissolve this in 10 ml of dichloromethane and
4.2 g of diethylethylenediamine dissolved in 20 ml of dichloromethane was added dropwise to the solution, followed by stirring at room temperature for 3 hours. After the reaction is completed, 20 ml of water and 20 ml of dichloromethane are added, and after shaking, the aqueous layer is separated and discarded, and the dichloromethane layer is dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography and the main fraction was concentrated to give 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine (compound 1 ) 2.0 g are obtained as oily free base with a yield of 91%. When this is dissolved in isopropanol and a solution of hydrogen chloride in isopropanol is added, 2.6 g of trihydrochloride monohydrate is obtained. Alternatively, the oily free base is dissolved in isopropanol, concentrated hydrochloric acid is added thereto, and then acetone is added while heating under reflux. Then, when the mixture is stirred at room temperature, white crystals are precipitated. After crystallization, filter
After thorough washing with acetone and drying, the trihydrochloride is obtained. Reference Example 2 23 In Reference Example 1, the raw material 5-hydroxy-5,11
-dihydro[1]benzoxepino[3,4-
b] Compound 2-23 shown in Table 4 was obtained in the same manner as in Reference Example 1, except that the raw materials shown in Table 4 were used in place of 1.5 g of pyridine and 4.2 g of N,N-diethylethylenediamine.

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[Table] Reference Example 24 5-chloro-, obtained from 4.3 g of 5-hydroxy, 5,11-dihydro[1]benzoxepino[3,4-b]pyridine in the same manner as Reference Example 1.
5,11-dihydro[1]benzoxepino[3,
4-b] Pyridine hydrochloric acid addition salt in dichloromethane
Dissolved ammonia in 50ml dillolomethane solution
The mixture was added dropwise to 200 ml under ice-cooling, and then stirred at room temperature for 2 hours. After the reaction was completed, 50 ml of water was added, the aqueous layer was separated and discarded after shaking, and the dichloromethane layer was dried and concentrated under reduced pressure to obtain 5-amino-5,11-dihydro[1].
4.2 g of crude crystals of benzoxepino[3,4-b]pyridine are obtained. When this crude crystal is purified by recrystallization from diisopropyl ether, the purified crystal 3.6
g is obtained. Melting point: 72-73℃ Infrared absorption spectrum: (KBr tablet, cm ^-1 ) 3280, 1590, 1490, 1430, 1220, 1050, 770 Nuclear magnetic resonance spectrum: (CDCl ₃ , δ value, ppm) 4.92 (s, 1H ), 5.11and5.52(q, 2H, AB,
type), 6.90−7.47 (m, 5H), 7.65 (dd, 1H),
8.37 (dd, 1H) Elemental analysis value: (as C ₁₃ H ₁₂ N ₂ O) (%) C H N Theoretical value 73.56 5.70 13.20 Actual value 73.56 5.54 13.33 5-Amino-5,11 thus obtained −
Dihydro[1]benzoxepino[3,4-b]
2.0g of pyridine, 2.8g of hydrochloride of 2-diisopropylaminoethyl chloride and triethylamine
Dissolve 3.9 ml in 35 ml of toluene, add 0.2 g of sodium iodide, and reflux for 3 hours. After the reaction is complete, 35 ml of toluene and 20 ml of water are added, and after shaking, the aqueous layer is separated and discarded, and the toluene layer is dried and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography and the main fraction was concentrated to yield 5-[2-(diisopropylamino)ethyl]amino-5,11-
Dihydro[1]benzoxepino[3,4-b]
2.2 g of pyridine (compound 24) are obtained as an oily free base with a yield of 69%. Reference example 25 2.1 g of 5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 8.3 g of 3-aminoquinuclidine were dissolved in 50 ml of dry benzene, and 1.1 g of titanium tetrachloride was dissolved in this solution. A solution of g dissolved in 20 ml of dry benzene was added dropwise under ice cooling. After completion of the dropwise addition, the mixture was stirred for 3 hours under ice cooling and then stirred at room temperature for 2 days. After the reaction is completed, the precipitate is filtered off and the filtrate is concentrated. Add 150 ml of ethyl acetate and 30 ml of water to the residue,
After shaking, the aqueous layer is separated and discarded, and the ethyl acetate layer is dried and concentrated. The residue was purified by silica gel chromatography and the main fraction was concentrated to give 1.35 g of 5-(3-quinuclidinyl)imino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crystals. It will be done. Dissolve this in 20ml of methanol, adjust the pH to 5 using hydrochloric acid, add 1.0g of sodium cyanoborohydride, and heat to 80°C at 40-50℃.
Time reacts. After the reaction is complete, add 30 ml of water, and then adjust the pH using 1N aqueous sodium hydroxide solution.
After adjusting the volume to 12, extract twice with 100 ml of ethyl acetate. The ethyl acetate layer is dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography and the main fraction was concentrated to yield 5-(3-quinuclidinyl)
1.0 g of amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine (compound 25) is obtained as a diastereomeric mixture. Reference Example 26 2.1 g of 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine [Compound 1] obtained in Reference Example 1 and 1.0 ml of triethylamine Dissolve in 50ml of dichloromethane and add 0.6g of acetyl chloride in this.
Drop on ice. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 20 ml was added, shaken, the aqueous layer was separated, and the dichloromethane layer was dried and concentrated under reduced pressure to obtain 5{N-acetyl-N-[2-(diethylamino)ethyl]}amino-5. , 2.1 g of 11-dihydro[1]benzoxepino[3,4-b]pyridine (compound 26) as an oily free base.
Obtained at 91%.

Claims (1)

[Claims] 1 General formula () [In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, or a halogen atom, X represents an oxygen atom or a sulfur atom, and R ² represents [Formula] (wherein, Y represents an amino group , represents a substituted amino group, heterocycle or substituted heterocycle, Z represents a hydrogen atom, an alkyl group or an acyl group, and n represents an integer of 1-3),
or [Formula] (in the formula, m represents 0, 1 or 2, and Z has the same meaning as above). An anti-ulcer agent containing a novel [1] benzepino[3,4-b]pyridine derivative represented by the following formula and its acid addition salt as an active ingredient.