JPH0125749B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel dibenzo[b,e]oxepin derivatives and acid addition salts thereof. More specifically, the present invention relates to the general formula () [In the formula, R ₁ represents an alkyl group having 1 to 5 carbon atoms, and R ₂ is

[Formula] or

Represents [formula]. Or R ₁ represents a cyclohexyl group, and R ₂ is -NH-(CH ₂ )n
-Y (wherein Y represents an alkylamino group or a heterocycle having 1 to 5 carbon atoms; n is 0 or 1
Represents an integer of -3. ] and its acid addition salts. The compound of the present invention has anticholinergic, antihistamine, and antiplatelet aggregation effects, and is a useful compound as an antispasmodic agent, an antihistamine agent, a cerebral circulation improving agent, and the like. The present inventors have already discovered a new dibenzo[b,e]oxepin derivative having anticholinergic and antihistamine effects, and have filed an application (Japanese Patent Application No. 52262/1989).
However, they have further discovered a new dibenzo[b,e]oxepin derivative having anticholinergic and antihistamine effects, and have completed the present invention. The present invention will be explained in detail below. In the target compound represented by the general formula (), the alkyl group having 1 to 5 carbon atoms is methyl,
Examples include ethyl, propyl, butyl, and amino groups. Examples of the alkyl group having 1 to 5 carbon atoms in Y include methylamino, ethylamino, dimethylamino, and diethylamino groups. Examples of the heterocycle include quinuclidine, piperazine, piperidine, morpholine, indole, and the like. Acid addition salts of the present invention include inorganic salts such as hydrochlorides, sulfates, hydrobromides, phosphates, organic acid salts such as acetates, maleates, fumarates, tartrates, etc. Examples include salts such as citrate, oxalate, and benzoate. The target compound of the present invention has the general formula () (In the formula, R ₁ has the same meaning as above.) Using a known compound represented by the formula as an intermediate, it can be produced by the method described below, which is well known as a method of organic synthetic chemistry. The method for producing the known compound is described in, for example, J.Med.
Pharm.Chem., 5, 1207 (1962), Monatsh.
Chem., 93, 889 (1962), Angew.Chem., 74, 31
(1962), Belgian Patent No. 623, 259, etc. For example, known compounds are manufactured as follows. Next, a typical method for producing the target compound of the present invention will be shown. (In the formula, R ₁ and R ₂ have the same meanings as above, and Z represents a halogen atom.) A compound is reduced to a compound, and the compound is further reacted with a halogenating agent to obtain a compound. Then, the compound and the amine [

[Formula]: Compound or

[Formula]: Compound or Y- (CH ₂ ) n-NH ₂ : Compound (wherein Y and n
has the same meaning as above. )] to obtain the target compound. Furthermore, the manufacturing method will be explained in detail. The compound is usually obtained by reducing the compound by a method using a metal hydride such as lithium aluminum hydride or sodium borohydride, a catalytic hydrogenation method, or the like. That is, when reducing a compound using lithium aluminum hydride, the compound is dissolved in an anhydrous solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, diethylene glycol dimethyl ether, etc., and then 0.3 to 2.0 equivalents of the compound are hydrogenated. The reduction is completed by adding lithium aluminum and stirring at an appropriate 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 in a solvent such as water, methanol, ethanol, isopropanol, diethylene glycol dimethyl ether, dimethyl formamide, dimethyl sulfoxide, etc. The reduction is completed by adding 1.0 equivalent of sodium borohydride and stirring at an appropriate temperature of 0 to 40°C for 1 to 8 hours. Thereafter, the compound is obtained by post-treatment according to a conventional method. On the other hand, when reducing a compound by the catalytic hydrogenation method, the compound is hydrogenated at room temperature and pressure in a solvent such as methanol, ethanol, dioxane, etc. using platinum oxide, palladium on carbon, Raney-nickel, etc. as a catalyst. The compound is obtained in 2 to 7 hours. In this case, care must be taken as increasing the temperature may also cause hydrogenolysis. The thus obtained compound is converted into a compound using various halogenating agents. In this case, the halogenation reaction can be easily carried out using a method using hydrogen halide, a method using phosphorus halide, a method using thionyl halide, etc. as a halogenating agent. That is, concentrated hydrochloric acid, concentrated hydrobromic acid, or hydrogen bromide gas can be used as the hydrogen halide, and these can be used as they are or, if necessary, in the presence of concentrated sulfuric acid, zinc chloride, pyridine, triethylamine, etc., to form a compound. The compound is obtained by reacting with the compound at an appropriate temperature of 0 to 60°C for 30 minutes to 3 hours. Further, as the phosphorus halide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, etc. can be used, and these may be used in excess as they are, or Alternatively, benzene, toluene, xylene, dichloromethane, chloroform,
The compound is heated at 0 to 70°C in a solvent such as carbon tetrachloride, dimethylformamide, or diethyl ether, if necessary in the presence of a tertiary amine such as pyridine, quinoline, dimethylaniline, or triethylamine.
The compound is obtained by reacting at an appropriate temperature for 1 to 5 hours. Further, as the thionyl halide, thionyl chloride or thionyl bromide can be used, and the compound can be obtained under the same conditions as in the case of using the above-mentioned phosphorus halide. The target compound can be obtained by reacting the compound thus obtained with another compound or other compounds. That is, use the compound or the compound in an amount of 2 to 10 equivalents based on the compound, and if necessary dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, n-hexane, cyclohexane, acetonitrile. , carbon disulfide, ethyl acetate, dimethylformamide, or the like at an appropriate temperature of -10 to 120°C for 30 minutes to 3 hours, the target compound is produced. 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, etc. as a scavenger for hydrogen halide produced as a by-product, It is also possible to use only 1 equivalent of the compound or compound. Since the target compound is obtained as a free base in the form of crystals or oil, the target compound can be purified to a higher purity by column chromatography or recrystallization, if necessary. Furthermore, 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,
Acid addition salts of the target compound can be easily produced by reacting with citric acid, oxalic acid, benzoic acid, etc. in a conventional manner. Next, the names and structural formulas of representative compounds of the present invention are shown in Table 1 using the substituents R ₁ and R ₂ in the general formula (). Furthermore, the substitution position for R ₁ is also shown.

[Table] In the following explanation, compound numbers 1, 2,
The compounds of ... are called compounds 1, 2, .... Compounds 1, 2, 3 and 4 are patent application No. 55-52262.
This is a new compound that is not disclosed in the specification of JP-A-56-150083. Next, tests of acute toxicity, anticholinergic effect, antihistamine effect, and antiplatelet aggregation effect of the compound of the present invention will be shown. 1. Acute toxicity test Using 5 DD male mice weighing 20±1g per group,
The compounds of the present invention 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, and the results are shown in Table 2. 2. Anticholinergic effect test (In vitro experiment) A male Hartly guinea pig weighing around 250 g was beaten to death, the abdomen was incised, and the ileum, which extends approximately 10 cm from the cecum to the stomach, was cut to a length of 2 to 3 cm. It was used as an ileum specimen. This specimen was suspended in a Magnus bath containing Tyrode nutrient solution at a temperature of 32 ± 1°C under aeration using a self-injection method, and 10 ^-5 g/ml of acetylcholine (final concentration) and acetylcholine were added 3 minutes after administration of the compound of the present invention. The ileal contractile force when the same amount of was administered was recorded on a kymograph using a Hebel pen. The effectiveness of the compound of the present invention is determined by determining that it has an anti-acetylcholine effect if it suppresses the ileal contraction of acetylcholine alone by 80% or more, and by lowering the final concentration of the compound of the present invention until it exhibits an inhibition of 80% or less. The minimum effective concentration (MED) of acetylcholine was determined. 3 Antihistamine effect test (In vitro experiment) Using histamine 5 x 10 ^-5 g/ml (final concentration), the minimum effective concentration (MED) of antihistamine effect was determined using the same procedure and effect evaluation as the anticholinergic effect test. I asked for it. 4 Platelet aggregation test (In vitro experiment) Nine volumes of blood were collected from the common carotid artery of a white, mixed breed, male rabbit (2-2.5 kg) into a silicone-treated flask containing 1 volume of 3.8% sodium citrate.
The obtained blood was centrifuged at 1000 rpm for 15 minutes to obtain platelet-rich plasma. In this platelet-rich plasma, the appropriate concentration (final concentration) of collagen (collagen concentration that causes 50% platelet aggregation with aspirin 100γ/ml) and the platelet aggregation effect when the same concentration of collagen is administered 3 minutes after administration of the compound of the present invention. of
The light transmittance was observed by turbidimetry using an aggregometer. The effectiveness of the compound of the present invention is determined by determining that it has an antiplatelet aggregation effect when it inhibits the aggregation of collagen alone by 50%, and by changing the final concentration of the compound of the present invention until it exhibits an inhibition rate of 50% or less. The minimum effective concentration (MED) for antiplatelet aggregation effect was determined.

[Table] As can be seen from Table 2, the compounds of the present invention have low toxicity and have anticholinergic, antihistamine, and antiplatelet aggregation effects. Examples and reference examples are shown below. Example 1: Production of Compound 1 2-Cyclohexyl- obtained in Reference Example 1 described later
2.9 g of 6,11-dihydrodibenzo[be]oxepinone-11 was dissolved in 20 ml of ethanol, 0.2 g of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, 20 ml of water and 20 ml of chloroform were added to the residue, and after shaking, the aqueous layer was separated and discarded. The chloroform layer was dehydrated and concentrated under reduced pressure to obtain 2-cyclohexyl-11. −
Hydroxy-6,11-dihydrodibenzo [b,
e] 2.9 g of crude crystals of oxepin are obtained. Dissolve this in 20 ml of dichloromethane and add 2.6 thionyl chloride.
g dropwise over 15 minutes. After the addition is complete, stir at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to remove dichloromethane and excess thionyl chloride, and the concentrated residue was 2-cyclohexyl-11-chloro-6,
3.1 g of crude crystals of 11-dihydrodibenzo[b,e]oxepin are obtained. Dissolve this in 20 ml of toluene and add 2.3 N,N-diethylethylenediamine.
g was dissolved in 30 ml of toluene, and then
Stir at 80°C for 2 hours. After the reaction is complete, add 40 ml of water and lower the pH to 2.0 with concentrated hydrochloric acid. Discard the toluene layer, add 30 ml of ethyl ether to the aqueous layer,
Raise the pH to 10.5 with 10N sodium hydroxide solution.
The aqueous layer is discarded, and the ethyl ether layer is dehydrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the main fraction was concentrated, resulting in 2-
Cyclohexyl-11-{2-(diethylamino)ethyl}amino-6,11-dihydrodibenzo[b,
e] 2.8 g of oxepine [compound 1] are obtained as an oily free base with a yield of 71.9%. Dissolve this in 150 ml of ethyl ether and blow in hydrogen chloride gas to obtain 3.2 g of dihydrochloride as crystals. Melting point (℃): (dihydrochloride) 128-130 Infrared absorption spectrum: (NaCl cell, cm ^-1 ) 2930, 1500, 1455, 1260, 1230, 1020 Nuclear magnetic resonance spectrum: (CDCl ₃ , δ value, ppm) 0.93 (t, 6H), 0.63-2.07 (m, 10H), 2.07
-2.80 (m, 10H), 4.50 (5, 1H), 4.77 (d,
1H), 6.13 (d, 1H), 6.63-7.36 (m, 7H) Elemental analysis value: (as dihydrochloride C ₂₆ H ₃₈ Cl ₂ N ₂ O)
(%) C H N Theoretical value: 67.08 8.23 6.02 Actual value: 67.06 8.26 5.99 Example 2-4 Compound 2-4 having the physical property values shown in Table 3 below is obtained in the same manner as in Example 1.

[Table] Reference example 1 17.6 g of p-cyclohexylphenol and 19.3 g of 28% sodium methylate solution were mixed with 20 g of methanol.
Dissolve in ml. After dissolving, methanol was distilled off under reduced pressure, 13.4 g of phthalide was added to the residue, and the mixture was heated at 200°C.
Heat for 2 hours. After the reaction is completed, the reaction solution is cooled, 1.3 g of water is added, and the pH is lowered to 1.4 with concentrated hydrochloric acid. After crystallization, the crystals are collected and dried to give crystals of 2-(4-cyclohexylphenoxymethyl)benzoic acid.
28.8 g are obtained with a yield of 92%. Melting point (℃): 176-178 Infrared absorption spectrum: (KBr tablet, cm ^-1 ) 2920, 2850, 1690, 1510, 1275, 1250 Nuclear magnetic resonance spectrum (CDCl ₃ + d ₆ -DMSO,
δ value, ppm) 0.55-2.79 (m, 11H), 5.49 (s, 2H), 6.57
-8.23 (m, 8H), 10.28 (broad, 1H) 24.8 g of 2-(4-cyclohexylphenoxymethyl)benzoic acid obtained above was added to 72 g of thionyl chloride.
ml and reflux for 1.5 hours. After refluxing, excess thionyl chloride is distilled off, leaving 2-(4
29.1 g of crude crystals of -cyclohexylphenoxymethyl)benzoic acid chloride are obtained. The obtained compound is dissolved in 50 ml of 1,1,2,2-tetrachloroethane. Then, the solution was added dropwise under ice-cooling to 100 ml of 1,1,2,2-tetrachloroethane in which 12.6 g of aluminum chloride was suspended. After the dropwise addition was completed, the reaction was carried out at 5° C. for 2 hours. After the reaction is complete, add ice water
After adding 60 ml of concentrated hydrochloric acid, extract with 450 ml of ethyl ether. The extracted organic layer was washed with 5N sodium hydroxide solution, further washed with water, dried, and concentrated under reduced pressure to yield 18.6 g of 2-cyclohexyl-6,11-dihydrodibenzo[b,e]oxepinone-11. Obtained at 79.5%. Infrared absorption spectrum: (NaCl cell, cm ^-1 ) 2920, 1645, 1485, 1300, 1280, 760 Nuclear magnetic resonance spectrum: (CDCl ₃ , δ value, ppm) 0.80-2.90 (m, 11H), 5.11 (s, 2H), 6.79
−7.99 (m, 6H), 8.02 (d, 1H)

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ represents an alkyl group having 1 to 5 carbon atoms, and R ₂ represents [formula] or [formula]. Alternatively, R ₁ represents a cyclohexyl group, and R ₂ represents -NH-(CH ₂ )n-Y (wherein, Y has 1 to 5 carbon atoms.
represents an alkylamino group or an aliphatic nitrogen-containing heterocycle. n represents 0 or an integer from 1 to 3. However, when n is 0, it is limited to those in which -NH-Y does not form a nitrogen-nitrogen bond. )] and its acid addition salt.