JPH0374234B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) This invention relates to a novel compound belonging to imidazopyrimidine compounds. The compounds of this invention are useful as drugs that act on the circulatory system, and are sometimes useful as preventive and therapeutic agents for heart failure, coronary artery disease, and cardiac arrhythmia. It can also be used as an anti-inflammatory, analgesic, and antihypertensive agent. (Prior Art) Tetrahydro or hexahydroimidazo[1,2-a]pyrimidine derivatives having a substituted phenyl group at the 8-position are known (Japanese Patent Laid-Open No. 58-4784, US Pat. No. 3,769,288). Among these compounds, 8-substituted phenyltetrahydroimidazo[1,2-a]pyrimidine derivatives have a double bond within the pyrimidine core, but it is unknown whether there are substituents that extend outside the pyrimidine core. It has not been done. Furthermore, among the 8-substituted phenylhexahydroimidazo[1,2-a]pyrimidine derivatives having a substituent in the pyrimidine core, the only known one is one having a hydroxy group. Thus, no 8-substituted phenylimidazo[1,2-a]pyrimidine derivatives having a methylene group (exo-type double bond) protruding from the pyrimidine bone core have been known. OBJECTS OF THE INVENTION The present invention provides a group of useful new compounds belonging to the imidazopyrimidine compounds. These compounds are expected to be useful in the pharmaceutical field due to their physiological activity, anti-inflammatory, analgesic, and antihypertensive effects, particularly on the circulatory system. (Structure of the Invention) The compound targeted by this invention has the general formula (): (In the formula, R ¹ represents a halogen atom or a lower alkyl group.
R ² represents a halogen atom, a lower alkyl group, or a hydrogen atom) 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. The phenyl group of the compound of formula () has at least one substituent R ¹ , and R ¹ is a halogen atom or a lower alkyl group. Halogen atoms include chlorine, bromine or fluorine atoms. A particularly preferred halogen atom is a chlorine atom. Lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl or 2
-Includes ethylbutyl group, etc. A particularly preferred lower alkyl group is a methyl group. If the phenyl group has a second substituent R ² , this is also selected from the same group as R ¹ but contains a hydrogen atom. (Examples of Phenylamino Groups) Examples of substituted phenylamino groups constituting the moiety of the compound of this invention are as follows. 2,6-dichlorophenylamino, 2,6-dibromophenylamino, 2-bromo-6-chlorophenylamino, 2-chloro-6-methylphenylamino, 2-bromo-6-methylphenylamino, 2,6-dimethylphenylamino, 2,6-
Difluorophenylamino, 2-fluoro-6-
Methylphenylamino, 2-chlorophenylamino, 2-bromophenylamino, 2-fluorophenylamino, 2-methylphenylamino, 2-
Chloro-6-ethylphenylamino, 2-bromo-6-ethylphenylamino, 2-chloro-6-
Propylphenylamino, 2-bromo-6-butylphenylamino, 2-fluoro-6-isopropylphenylamino. 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. Hereinafter, R ¹ and R ² in the formula are:
The formula is the same as described above for formula (), and X represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom. General formula (): 2-substituted phenylaminoimidazoline compound () and general formula: It can be obtained by reacting the dihalide compound represented by 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 dehydrohalogenating agent, alkali metal carbonates, bicarbonates, etc. can be used. These may be anhydrous salts or hydrated salts. Further, the reaction temperature is preferably 10°C to 100°C, but in consideration of by-products of colored substances, it is preferable to maintain the reaction temperature in the range of 20°C to 50°C. The reaction time varies depending on the reaction temperature, the presence or absence of a dehydrohalogenating agent, and the type used, and takes from several hours to several days. Then, precipitated by-products are filtered off, and the target product is separated and purified by conventional methods such as solvent evaporation and extraction with a solvent from the filtrate containing the target product. (Acid addition salt) The compound of formula () obtained by the above method is:
Any of these can be converted into physiologically acceptable acid addition salts according to conventional methods. Acids suitable for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
Mineral acids such as hydrofluoric acid, sulfuric acid, phosphoric acid or nitric acid, or for example oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid,
Organic acids such as tartaric acid, citric acid, malic acid, gluconic acid, benzoic acid, phthalic acid, cinnamic acid or ascorbic acid. If the product of the above reaction is collected in the form of a hydrohalide salt, this salt can be reacted with an appropriate acid among the above without desalting to form other salts. can lead. 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 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, 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, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan 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 solubilizers, 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 8-(2,6-dichlorophenyl)-2,3,
5,6,7,8-Hexahydro-6-methylene-imidazo[1,2-a]pyrimidine In 25 ml of ethanol, 5.0 g of 2-(2,6-dichlorophenyl)aminoimidazoline () and
3.0 g of 3-chloro-2-chloromethyl-1-propene was dissolved, and the mixture was kept at 30°C and stirred for 2 days to conduct a reaction and precipitate. 2-(2,6-dichlorophenyl)aminoimidazoline hydrochloride was filtered off,
The solvent was evaporated from the filtrate. 30 ml of saturated brine was added to the residue, and the insoluble portion was filtered off, followed by extraction with 100 ml of ether. 10% sodium hydroxide was added dropwise to the extraction residue to bring the pH to around 7, and the mixture was extracted again with ether. Furthermore, the extraction residue was adjusted to pH around 12, and extracted with 100 ml of ethyl acetate. After drying the ethyl acetate extract over anhydrous sodium sulfate and removing the solvent, 4.5 g of pale yellow crystals were obtained. The operation of adding 150 ml of n-hexane to the crystals and extracting the dissolved portion was repeated three times, and when the n-hexane was distilled off, 2.8 g of colorless crystals were obtained. When this was recrystallized from hexane-ethyl acetate, 2.1 g of the title compound was obtained as pure by thin layer chromatography. In addition, in the above reaction, when sodium carbonate decahydrate was added as a scavenger for hydrogen chloride, 3.0 g of the title compound was obtained. The melting point and spectral data of this new substance are shown below. Melting point (℃): 98-101 NMR spectrum ( _CDCl3 , ppm) 3.20-3.72 (multiplet,

[Formula]) 3.80 (Singlet, CH ₂ -N-Ar) 4.09 (Singlet, CH ₂ -) 5.12 (Multiplet, CH ₂ =) 7.08-7.42 (〃, Ar) IR spectrum (KBr・cm ^-1 ) 1600, 785 Mass spectrum (CI/ _CH4 , m/e) 310 (M+29) ⁺ , 282 (M+1) ⁺ , 246 (M-35) ⁺ Mass spectrum, CI indicates the spectrum due to chemical ionization . Example 2 8-(2,6-dibromophenyl)-2,3,
5,6,7,8-hexahydro-6-methylene-imidazo[1,2-a]pyrimidine 6.9 g of 2-(2,6-
dibromophenyl) aminoimidazoline () and
From 3.0 g of 3-chloro-2-chloromethyl-1-propene, 3.2 g of thin layer chromatographically pure title compound were obtained. Melting point (℃): 103.5-105 NMR spectrum ( _CDCl3 , ppm) 3.30-3.87 (multiplet,

[Formula]) 3.93 (Singlet, CH ₂ ) 4.25 (Singlet, CH ₂ ) 5.25 (Multiplet, = CH ₂ ) 6.97-7.83 (Multiplet, Ar) IR spectrum (KBr cm ^-1 ) 1570 , 780 mass spectrum (CI/CH ₄ , m/e) 370 (M+1) ⁺ , 290 (M-79) ⁺ Example 3 8-(2-chloro-6-methylphenyl)-2,
3,5,6,7,8-Hexahydro-6-methylene-imidazo[1,2-a]pyrimidine 5.0 g of 2-(2-chloro-
6-methylphenyl)-aminoimidazoline ()
and 3.22 g of 3-chloro-2-chloromethyl-1-
When propene was dissolved and the same treatment as in Example 1 was carried out, 2.8 g of the title compound pure by thin layer chromatography was obtained. Melting point (°C): 55-57°C NMR spectrum ( _CDCl3 , ppm) 2.46 (singlet, _CH3 ) 3.26-3.90 (multiplet,

〔experimental method〕

An adult male and female mixed breed dog (body weight 9-15 kg) was anesthetized with 30 mg/kg (intravenous injection) of pentobarbital sodium, a cannula was inserted into the right femoral artery according to a conventional method, and blood pressure was measured. 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] Capacity to sustainably reduce heart rate by 25% (ED ₂₅
values) are shown in Table 1. Table 1 Compound ED mg/Kg (iv) Example 1 0.3 〃 2 0.3 〃 3 0.3 Propranolol 0.2 Test Example 2 Acute toxicity test by intravenous administration [Test method] DDY male mice, 5 mice per group were used. The test drug was dissolved in 0.1N hydrochloric acid and administered intravenously at 0.1ml/10g for 10 seconds.The progress was observed for 7 days and estimated.
The _LD50 value was determined. [Results] The LD ₅₀ value of the compound of Example 1 was 15 mg/Kg.

Claims (1)

[Claims] 1 General formula (): (In the formula, R ¹ is a halogen atom or a lower alkyl group,
R ² represents a halogen atom, a lower alkyl group, or a hydrogen atom) and an acid addition salt 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 any one of claims 1 to 2, wherein the lower alkyl group of R ¹ or R ² is a methyl group. 4. The compound according to claim 1, wherein the halogen atom of R ¹ or R ² is a chlorine or bromine atom. 5. The compound according to claim 1 or 4, wherein the halogen atom of R ¹ or R ² is a chlorine atom. 6. The compound according to claim 1, wherein the acid addition salt is a pharmaceutically acceptable salt.