JPH0374232B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) This invention relates to a novel compound belonging to fused heterocyclic compounds having an imidazoline nucleus as a partial structure. The compound of the present invention is useful as a drug that acts on the circulatory system, and is particularly useful as a prophylactic/therapeutic agent for heart failure or coronary artery disease or cardiac arrhythmia. It can also be used as an anti-inflammatory and analgesic. (Prior art) Among the fused heterocyclic compounds having a substituted phenyl group at the 8-position and an imidazo[1,2-a]pyrimidinone skeleton, certain types are known (West German Patent No. 2418537). , West German Patent No. 2011970). Some of these compounds have a double bond within the ring, but no compound with a double bond protruding from the ring (exo type) has been known. Also, in place of the 6-membered ring part of the fused heterocycle, 5
1 of 5,6-dihydro-1H-imidazo[1,2-a]imidazol-3(2H)-one as a membered ring
-Substituted phenyl derivatives were also unknown. Among the known imidazoimidazole-type compounds, the structure that is considered to be closest to this is a 2,3-dione-type substance (West German Patent No. 2109524). (Objective of the Invention) The present invention provides a group of useful new compounds belonging to fused heterocyclic compounds having an imidazoline nucleus as a partial structure. These compounds are expected to be useful in the pharmaceutical field due to their physiological activity, anti-inflammatory and analgesic effects, particularly on the circulatory system. (Structure of the invention) The compound targeted by the present invention has the general formula (In the formula, R represents a hydrogen atom or a lower alkyl group, and A represents a valence bond or a vinylidene group.) The compound of the present invention, when A is a vinylidene group,
It has an imidazopyrimidone skeleton with exo methylene, and if A is a valence bond, the imidazoimidazole skeleton is also a monoketone compound. In addition, the lower alkyl group in R has 1 to 1 carbon atoms.
6, more commonly 1 to 3 or 4 carbon atoms. Typical atoms or atomic groups represented by R in the general formula () include hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-
There are butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl or 2-ethylbutyl groups. The compounds of the invention may be in the form of addition salts with physiologically acceptable acids. (Manufacturing method) The compound of formula () is, for example, a compound of the general formula [However, in the formula, Hal represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, A and R have the same meaning as defined in the formula (), and R' represents a lower alkyl group] and 2- It can be obtained by reacting (2,6-dichlorophenyl)aminoimidazoline (2)() in the presence or absence of a dehydrohalogenating agent. To explain the above reaction in more detail, suitable reaction solvents include alcohols such as methanol or ethanol, non-aqueous polar solvents such as tetrahydrofuran or dioxane, and chlorinated hydrocarbon solvents such as dichloromethane or chloroform. As the agent, carbon salts, bicarbonates, etc. of alkali metals can be used. In addition, the reaction temperature is preferably 10℃ to 100℃, but considering the by-product of colored substances, etc., the reaction temperature is 20℃ to 50℃.
It is best to keep it within the range of ℃. The reaction time varies depending on the reaction temperature, the presence or absence of a dehydrohalogenating agent, and the type used, and varies from 3 hours to 50 hours. According to the above reaction method, the desired product is obtained, which is a cyclic compound in which the halogen of the haloester is substituted with the bridging nitrogen atom of (), and the ester group is amidated with the nitrogen on the imidazoline ring. Intermediates in which the ester residues were not amidated were not isolated. Any compound of general formula () of the present invention can be converted into a physiologically acceptable acid addition salt according to a conventional method. Suitable acids for salt 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. , maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, gluconic acid, benzoic acid, phthalic acid, cinnamic acid or ascorbic acid. In addition, as a product of 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 the present invention can be administered to animals and humans as such or together with conventionally known pharmaceutical carriers. The dosage unit form is not particularly limited and may be appropriately selected and used as required. 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 the present 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
A disintegrating agent (starch, calcium carbonate, etc.) and a lubricant (magnesium stearate, purified talc, etc.) may be appropriately selected, mixed, tableted, and then coated. 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, hard capsules, and the like. When forming 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, and semi-synthetic glycerides. 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 prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. In addition, coloring agents, preservatives, fragrances, flavoring agents,
Sweeteners and the like may also be included in the formulation. Further, the results of pharmacological tests on the compounds of the present invention are shown in Test Examples. The present invention will be explained below with reference to Examples. Example 1 1-(2,6-dichlorophenyl)-5,6-dihydro-1H-imidazo[1,2-a]imidazol-3-one 2.30 g of 2-(2,6-dichlorophenyl) Aminoimidazoline (2) was dissolved in 20 ml of ethanol, 1.67 g of ethyl bromoacetate and 1.06 g of sodium carbonate were added, and the mixture was heated under reflux for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added to about 100 ml of brine, and extracted twice with 100 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was removed and the residue was recrystallized from chloroform-hexane to obtain 1.6 g of the above chromatographically pure compound. Melting point and spectral data are shown below. Melting point (℃); 186-187 NMR spectrum ( _CDCl3 , ppm); 3.70, 4.17 (multiplet,

[Formula]) 4.42 (singlet, CH ₂ CO) 7.06~7.40 (multiplet,

[Formula]) IR spectrum (KBr, cm ^-1 ); 1740, 1690, 790 Example 2 1-(2,6-dichlorophenyl)-2-methyl-5,6-dihydro-1H-imidazo[1, 2
-a] Imidazol-3-one Dissolve 2.30 g of 2-(2,6-dichlorophenyl)aminoimidazoline (2) in 15 ml of methanol, add 1.81 g of ethyl α-bromopropionate, and heat for 5 hours. It refluxed. After removing the solvent of the reaction solution and washing the oily residue with ether, it was dissolved in water and extracted with chloroform while adjusting the pH stepwise. After collecting the extracts from the same spot using thin layer chromatography of the extracts and removing the solvent, the residue was recrystallized from a mixture of ethyl acetate and hexane. Obtained 1.1g. Melting point (℃); 148-150 NMR spectrum ( _CDCl3 , ppm); 1.40 (doublet, _CH3 ) 3.74, 4.16 (multiplet,

【formula】) 4.84 (quadruple line, -CH) 7.04~7.40 (multiplet,

[Formula]) IR spectrum (KBr, cm ^-1 ); 1730, 1670, 785 Example 3 6-methylene-8-(2,6-dichlorophenyl)-2,6,7,8-tetrahydro-imidazo [ 1,2-a] Pyrimidin-5(3H)-one Dissolve 5.0 g of 2-(2,6-dichlorophenyl)aminoimidazoline (2) in 10 ml of ethanol,
4.4 g of α-bromomethyl ethyl acrylate was added and reacted at room temperature for 5 hours. Add 50ml of reaction solution
After adding NaHCO ₃ aqueous solution and extracting with 50 ml of ether, the raffinate ethanol was removed.
White crystals precipitated. The crystals were filtered and recrystallized from a mixture of ethyl acetate and hexane to obtain 3.53 g of the above compound which was pure in terms of thin layer chromatography. Melting point (℃); 154-155 NMR spectrum ( _CDCl3 , ppm); 3.64-4.20 (multiplet,

[Formula]) 4.30 (singlet, CH ₂ CO) 5.51, 6.33 (singlet, = CH ₂ ) 7.05~7.48 (multiplet,

〔result〕

Dose that sustainably reduces heart rate by 25% (ED ₂₅
values) are shown in Table 1.

〔experimental method〕

After fasting overnight, the test substance was orally administered to 5-week-old DDY male mice, and 1 hour later, 0.1 ml of 0.03% phenylbenzoquinone per 10 g of body weight was administered into the membrane cavity. After 5 minutes, the number of stretches was counted for 10 minutes. [Results] Table 2 shows the dose that reduces the number of stretching by 50% (ED ₅₀ value).

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom or a lower alkyl group, and A represents a valence bond or a vinylidene group.) A fused heterocyclic compound and an acid addition salt thereof.