JPH0510342B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) This invention relates to a novel compound belonging to 2-aminoimidazoline compounds. The compounds of this invention are useful as drugs that act on the circulatory system, and are particularly useful as preventive/therapeutic agents for heart failure or coronary artery disease, cardiac arrhythmia, and antihypertensive agents. It can also be used as an anti-inflammatory and analgesic. (Prior Art) Hitherto, there have been no known aminoimidazoline derivatives in which an amino group substituted with an imidazoline nucleus and a benzene nucleus is further substituted with an alkyl group containing oxime or oxime ether. (Object of the Invention) The present invention provides a group of useful new compounds belonging to the class of 2-aminoimidazoline compounds containing oximes or oxime ethers. (Structure of the Invention) The compound targeted by this invention has the general formula (): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
^R2 represents a hydrogen atom, a lower alkyl group, or a benzyl group) and an acid addition salt thereof. The term "lower" as used in this invention includes from 1 to 6 carbon atoms, more usually from 1 to 4 carbon atoms. Oxime- or oxime ether-containing substituents forming part of the compounds of this invention: An example is as follows. 2-hydroxyiminoethyl group, 2-hydroxyiminopropyl group, 2-hydroxyiminobutyl group, 2-hydroxyiminopentyl group or 2-
2-hydroxyimino lower alkyl group such as hydroxyiminohexyl group; 2-methoxyiminoethyl group, 2-methoxyiminopropyl group, 2-
Methoxyiminobutyl group, 2-methoxyiminopentyl group, 2-methoxyiminohexyl group, 2-
Ethoxyiminoethyl group, 2-ethoxyiminopropyl group, 2-ethoxyiminobutyl group, 2-ethoxyiminopentyl group, 2-ethoxyiminohexyl group, 2-propoxyiminoethyl group, 2-
Propoxyiminopropyl group, 2-propoxyiminobutyl group, 2-propoxyiminopentyl group, 2-propoxyiminohexyl group, 2-butoxyiminoethyl group, 2-butoxyiminopropyl group, 2-butoxyiminobutyl group, 2-butoxy 2-lower alkoxyimino lower alkyl group such as iminopentyl group or 2-butoxyiminohexyl group; 2-benzyloxyiminoethyl group;
2-benzyloxyimino lower alkyl groups such as 2-benzyloxyiminopropyl, 2-benzyloxyiminobutyl, 2-benzyloxyiminopentyl or 2-benzyloxyiminohexyl. The compounds of this invention may be in the form of addition salts with physiologically acceptable acids. (Production method) The compound () of this invention can be produced by the method shown below. In the following formula, R ¹ and R ² are the same as those explained for the previous formula (). a General formula (): In the hydroxytetrahydroimidazoimidazole derivative represented by the general formula (): NH ₂ OR ² (), mineral salts of hydroxylamine or its ether compound (e.g., hydrochloride, sulfate, etc.)
How to react with. In this method, the compound of formula () has the general formula (): Hal-CH ₂ COR ³ () (wherein R ³ means a hydrogen atom or a methyl group,
halogenated acetaldehyde or halogenated acetone represented by (Hal means chlorine atom, bromine atom or iodine atom) and the formula (): 2-(2,6-dichlorophenyl)aminoimidazoline (2) in the presence or absence of a dehydrohalogenating agent. The inside of the reaction system in the above-mentioned reaction between the compound of formula () and the mineral acid salt of the compound of formula () is preferably kept acidic, and the solvent for this purpose is preferably an organic acid such as acetic acid. In addition, in order to obtain a free compound of formula () in the reaction system, at least an alkali metal salt such as sodium acetate, potassium acetate, potassium hydroxide, etc. of formula ( ) of mineral acid salts of 1.0
It is necessary to coexist in an amount more than double the molar amount. In addition, the reaction temperature is preferably 10°C to 80°C, and the reaction time is determined by the reaction temperature, the type of demineralizing agent, or the formula ().
It varies depending on the combination of compounds of formula () and varies from 1 hour to 50 hours. b General formula (): A method based on the reaction of a compound represented by and a compound of formula (). The compound of formula () in this method can be used, for example, in Chem.Ber., No. 29
It can be synthesized according to the method of Vol., p. 1550 (1896). This b) method can be applied, for example, to Helvetica. Himika.
This can be done by referring to Helv.Chim.Acta, Vol. 45, p. 2528 (1962). As the reaction solvent in the above reaction, ethers such as diethyl ether, alcohols such as methanol, etc. are suitable. The reaction temperature is 0℃~30℃
°C and reaction time vary depending on the reaction temperature and substrate, but vary from 3 hours to 20 hours. Further, a compound of formula () in which R ² is a hydrogen atom, general formula (a): and a halide represented by the general formula (): R ⁴ −Hal () (in the formula, R ⁴ means a lower alkyl group or a benzyl group, and Hal has the same meaning as the formula ()) By reacting these in the presence of a dehydrohalogenating agent, a compound of the general formula () (in this case, R ² in the formula means a lower alkyl group or a benzyl group) can be obtained. This O-alkylation reaction can be carried out, for example, in Helvetica. Himika. Acta, (Helv.Chim.Acta), 60th
It can be carried out according to the method of Vol. 228 (1977).
As the reaction solvent in the above reaction, dimethoxyethane is suitable, and as the dehydrohalogenating agent, for example, alkali metal hydrides such as sodium hydride and potassium hydride can be used.
The reaction temperature is 0°C to 30°C, and the reaction time varies depending on the reaction temperature, the type of dehydrohalogenation agent, or the type of substrate, and varies from 1 hour to several hours. By the above method, a compound of general formula () can be synthesized. (Acid addition salt) The compound of formula () obtained by the above method is:
Any of them can be used by converting them into a physiologically acceptable powder and water-soluble acid addition salt according to a conventional method. Suitable acids for acid formation include mineral acids, such as, for example, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, phosphoric or nitric acids, or, for example, oxalic, malonic, succinic, glutaric acids. acids, maleic acid, fumaric acid, lactic acid, tartaric acid,
Organic acids such as citric acid, malic acid, gluconic acid, benzoic acid, phthalic acid, cinnamic acid or ascorbic acid. Furthermore, as an organism that undergoes the above reaction,
If collected in the form of a hydrohalide salt, this salt can be converted into other salts by reacting with a suitable acid among those mentioned above without desalting. The compounds of this invention can be administered to animals and humans as such or together with conventionally known pharmaceutical carriers. There are no particular limitations on the dosage unit form;
They are selected and used as appropriate. Examples of such dosage forms include oral preparations such as tablets, capsules, granules, and various oral liquid preparations, and parenteral preparations such as injections and suppositories. The amount of the active ingredient to be administered is not particularly limited and can be appropriately selected from a wide range, but in order to achieve the desired effect, it is preferably 0.01 to 10 mg per kg of body weight per day. Also, the amount of active ingredient in the dosage unit form is 0.1~
It is recommended to contain 500 mg. Depending on the type of disease and the patient's condition, the therapeutic effect of the active ingredient of the present invention can be increased by using other drugs in combination with these dosages, if necessary. In this invention, oral preparations such as tablets, capsules, and oral liquid preparations are manufactured according to conventional methods. For example, tablets may contain the compound of the present invention, excipients (lactose, sucrose, glucose, starch, microcrystalline cellulose, etc.), binders (starch paste liquid, gum arabic liquid,
Gelatin solution, glucose solution, tragacanth solution, CMC
liquid, sodium alginate solution, etc.), a disintegrant (starch, calcium carbonate, etc.), and a lubricant (magnesium stearate, purified talc, etc.) are appropriately selected, mixed, tableted, and then coded. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. When molding into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc. . When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when formed into solutions, emulsions, and suspensions, a diluent is used. All those commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan acid fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the preparation to adjust the isotonicity of the solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc. may be included in the preparation, if necessary. This invention will be explained below with reference to Examples. Further, the results of pharmacological tests on the compounds of this invention are shown in Test Examples. Example 1 2-(2,6-dichlorophenyl-2-hydroxyiminoethyl)aminoimidazoline (2) 5 g of 2-(2,6-dichlorophenyl)aminoimidazoline (2) was dissolved in 40 ml of ethyl alcohol. Then, 4.6 g of 45% chloroacetaldehyde aqueous solution was added thereto. After stirring all day and night while maintaining room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in 40 ml of saturated brine. This aqueous solution was extracted with 100 ml of ether, and the extraction residue was further neutralized to around pH 7, followed by further extraction with 100 ml of ether. The extract was discarded, and the residual aqueous solution was gradually made alkaline with a 1N aqueous sodium hydroxide solution to precipitate colorless crystals. After filtering and drying, 4.9g of 1-(2,
6-dichlorophenyl)-3-hydroxy-2,
3,5,6-tetrahydroimidazo[1,2,-
a] Imidazole (R ¹ in formula () is a hydrogen atom) was obtained. 2.5 g of the above colorless crystals and 1.81 g of potassium acetate were dissolved in 30 ml of acetic acid, 1.28 g of hydroxylamine hydrochloride was added thereto, and the mixture was reacted at room temperature for 3 hours. After the precipitated crystals were filtered off, they were added to ethyl alcohol, the insoluble portion was filtered, and the ethyl alcohol was distilled off to obtain 2.8 g of colorless crystals.
When this was recrystallized from ethyl alcohol,
1.7 g of the title compound (formula () in which R ¹ and R ² are hydrogen atoms) was obtained. The crystals were confirmed to be pure by thin layer chromatography. Shows the melting point and spectral data of the substance. Melting point (°C): 233-234 (decomposition) NMR spectrum (CD ₃ OD, ppm) 3.88 (singlet, N N]) 4.46, 4.66 (double line, N-CH ₂ -) 7.50-7.80
(multiple lines,

[Formula]) IR spectrum (KBr, cm ^-1 ) 790, 1610 Mass spectrum (m/e, FD*1) 286 M ⁺ (m/e, EI*2) 268 (M-18) ⁺ *1: Ionization When using the field day soap method as a method. *2: When electron impact ionization is used as the ionization method. Example 2 2-(2,6-dichlorophenyl-2-methoxyiminoethyl)aminoimidazoline (2) 2.0 g of 1-(2,6-dichlorophenyl)-3-hydroxy obtained in Example 1 -2,3,5,
After dissolving 6-tetrahydroimidazo[1,2,-a]imidazole and 1.44 g of potassium acetate in 25 ml of acetic acid, 1.23 g of hydroxylamine-O-
Methyl ether hydrochloride was added and stirred at room temperature for 2 hours. After filtering off the precipitated crystals, the solvent was evaporated from the filtrate, and the residue was dissolved in 20 ml of saturated saline. When made alkaline with 1N sodium hydroxide solution, colorless crystals precipitated, which were filtered and recrystallized from hexane-ethyl acetate, yielding 1.90 g.
The title compound (formula () in which R ¹ is a hydrogen atom and R ² is a methyl group) was obtained. The crystals were confirmed to be pure by thin layer chromatography. The physical properties were as shown below. Melting point (°C): 120-123 NMR spectrum (CDCl ₃ , ppm) 3.38 (broad, NH) 3.61 (singlet, N N]) 3.74, 3.81 (singlet, OCH ₃ ) 4.40, 4.50 (2 Heavy line, N-CH ₂ -) 7.12 to 7.60
(multiple lines,

[Formula]) 7.70 (Triplet, -CH=) IR spectrum (KBr, cm ^-1 ) 780, 1600 Example 3 2-(2,6-dichlorophenyl-2-benzyloxyiminoethyl) aminoimidazoline ( 2) 2.5 g of 1-(2,6-dichlorophenyl)-3-hydroxy-2,3,5, obtained in Example 1
After dissolving 6-tetrahydroimidazo[1,2-a]imidazole and 1.67 g of potassium acetate in 30 ml of acetic acid, 2.0 g of hydroxylamine-O-benzyl ether hydrochloride was added, and the mixture was stirred at room temperature overnight. The solvent is evaporated from the reaction solution and the residue is
When 30 ml of saturated saline was added, an oil layer separated at the bottom. The oil layer was taken out and dried under vacuum, then ethyl acetate was added and stirred to crystallize, which was filtered to obtain 2.5 g of crude crystals. Recrystallization from an ethyl acetate-methyl alcohol mixture gave 1.95 g of the title compound (formula () in which R ¹ is a hydrogen atom and R ² is a benzyl group). The crystals were confirmed to be pure by thin layer chromatography. The physical properties were as shown below. Melting point (℃): 155-157 NMR spectrum (CD ₃ OD, ppm) 3.82 (singlet, N N]) 4.42, 4.64 (double, N-CH ₂ -) 4.98, 5.05 (single −CH ₂ −) 7.27 (multiplet,

[Formula]-CH=) 7.54 (multiplet,

[Formula]) IR spectrum (KBr, cm ^-1 ) 780, 1610 Example 4 2-(2,6-dichlorophenyl-2-hydroxyiminopropyl)aminoimidazoline (2) 8 g of 2-(2,6- Dichlorophenyl)aminoimidazoline (2) was dissolved in 45 ml of ethyl alcohol, and 6.5 g of bromoacetone was added thereto.
The temperature was kept at 15°C to 20°C and the mixture was stirred all day and night, and then the solvent was distilled off under reduced pressure at a temperature below 30°C. The residue was dissolved in 60 ml of saturated brine and extracted with ether. The extracted residue was adjusted to pH 12 with 10% sodium hydroxide solution and extracted three times with 100 ml of ether. The extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off, and 10.9 g of 1-(2,6-dichlorophenyl)-
3-Hydroxy-2,3,5,6-tetrahydro-3-methylimidazo[1,2-a]imidazole (of the formula () in which R ¹ is a methyl group) was obtained. 2.2g of the above compound and 1.23g of potassium acetate
It was dissolved in 30 ml of acetic acid, 0.87 g of hydroxylamine hydrochloride was added thereto, and the mixture was reacted at room temperature for 48 hours. When the reaction solution was distilled off and 30 ml of brine was added to the residue, colorless crystals were precipitated. Filter this and
Recrystallization from ether-methyl alcohol gave 1.8 g of the title compound (formula () in which R ¹ is a methyl group and R ² is a hydrogen atom). The crystals were confirmed to be pure by thin layer chromatography. The physical properties were as shown below. Melting point (°C): 234-235 NMR spectrum (CD ₃ OD, ppm) 1.97 (singlet, CH ₃ ) 3.90 (singlet, N N]) 4.42 (singlet, -CH ₂ -) 7.63 (multiple line,

[Formula]) IR spectrum (KBr, cm ^-1 ) 785, 1610 Example 5 2-(2,6-dichlorophenyl-2-methoxyiminopropyl)aminoimidazoline (2) fumarate obtained in Example 4 and 2.5 g of 1-(2,6-dichlorophenyl)-3-hydroxy-2,3,5,
6-tetrahydro-3-methylimidazo[1,2
-a] Add imidazole and 1.71 g of potassium acetate to 30
ml of acetic acid, 1.46 g of hydroxylamine-O-methyl ether hydrochloride was added thereto, and the mixture was stirred at room temperature overnight. Distill the solvent from the reaction solution and remove the residue.
After dissolving in 30 ml of saturated saline and making alkaline with 10% sodium hydroxide, an oil layer was separated. After extracting this with ethyl acetate, impurities were separated by column chromatography to obtain 1.5 g of crystals. When this was dissolved in ethyl acetate and an ether-ethyl alcohol mixed solution of fumaric acid was added, colorless crystals were precipitated. After filtration, it is recrystallized from an ether-methyl alcohol mixture,
1.2 g of the title compound (formula () in which R ¹ and R ² are methyl groups) was obtained. The physical properties were as shown below. Melting point (℃): 212-213 NMR spectrum (CD ₃ OD, ppm) 1.91 (singlet, CH ₃ ) 3.70 (singlet, -OCH ₃ ) 3.83 (singlet, N N]) 4.33 (singlet line, CH ₂ ) 7.54 (multiple line,

〔experimental method〕

An adult male and female mixed breed dog (weight 9 to 15 kg) was anesthetized with 30 mg/kg (iv) of sodium pentobarbital, and a cannula was inserted into the right femoral artery in a conventional manner to measure blood pressure. Heart rate was recorded by driving a tachometer based on blood pressure pulse waves. The test substance was dissolved in DMF or physiological saline and administered through the right femoral vein. [Results] Dose that sustainably reduces heart rate by 25% (ED ₂₅
values) are shown in Table 1.

【table】

Claims (1)

[Claims] 1 General formula (): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
² -aminoimidazoline compounds and acid addition salts thereof; 2 The lower alkyl group of R ¹ or R ² has 1 to 1 carbon atoms.
Claim 1 which is an alkyl group having 4
Compounds described in Section. 3. The compound according to claim 1, wherein the acid addition salt is a pharmaceutically acceptable salt.