JPH0558431B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention provides a group of novel compounds belonging to phenacyl derivatives of substituted anilino-2-pyrroline compounds. The compounds of this invention are useful as drugs that act on the circulatory system, and are particularly useful as preventive or therapeutic agents for heart failure, coronary artery disease, and cardiac arrhythmia. It can also be used as an anti-inflammatory, analgesic, and central stimulant. (Prior Art) 1-carbonyl-2-phenylimii)pyrrolidine, which has a carbonyl group attached to the 1-position of the pyrroline ring, is well known as a compound that acts as an antihypertensive agent (eg, US Pat. No. 3,706,766). Furthermore, ortho-substituted anilino-2-pyrroline compounds, which are compounds with various substituents including alkyl groups at the 2 and 6 positions of the phenyl group, exhibit remarkable physiological activity in the circulatory system, central nervous system, and digestive system. Although this is well known (for example, Japanese Patent Publication No. 46-32176), phenacyl derivatives of substituted anilino-2-pyrroline compounds such as the one disclosed in the present invention were not known at all. (Object of the invention) The present invention provides novel substituted anilino-2-pyrroline derivatives, and these compounds exhibit physiological activity, anti-inflammatory effect, analgesic effect, central stimulant effect, etc. particularly on the circulatory system. The present invention provides a pharmaceutical composition comprising: (Structure of the Invention) The compound targeted by this invention has the general formula (): (wherein R means an optionally substituted benzoyl group) These are substituted anilino-2-pyrroline derivatives and pharmaceutically acceptable salts thereof. Further, the optionally substituted benzoyl group in R of the general formula () is represented by the general formula (): (In the formula, R ₁ and R ₂ are hydrogen atoms, halogen atoms,
It is preferably a group represented by the following (meaning a lower alkyl group, hydroxy group or lower alkoxy group). Here, the halogen atom includes a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom. The lower alkyl group has 1 to 6 carbon atoms and includes straight chain or branched ones. Preferred lower alkyl groups are methyl, ethyl or propyl groups. The lower alkyl moiety in the lower alkoxy group includes the same as the lower alkyl group described above. Examples of phenacyl groups composed of R-CH ₂ - in the compound of general formula () include the following groups. Phenacyl, 2-bromophenacyl, 3-bromophenacyl, 4-bromophenacyl, 2-chlorophenacyl, 3-chlorophenacyl, 4-chlorophenacyl, 2,4-dichlorophenacyl,
2,5-dichlorophenacyl, 3,4-dichlorophenacyl, 2-fluorofenacyl, 3-fluorofenacyl, 4-fluorofenacyl, 2-
Methylphenacyl, 3-methylphenacyl, 4-
Methylphenacyl, 2,4-dimethylphenacyl, 2,5-dimethylphenacyl, 3,4-dimethylphenacyl, 2-hydroxyphenacyl,
3-hydroxyphenacyl, 4-hydroxyphenacyl, 2,4-dihydroxyphenacyl, 2,
5-dihydroxyphenacyl, 2,6-dihydroxyphenacyl, 3,4-dihydroxyphenacyl, 2-methoxyphenacyl, 3-methoxyphenacyl, 4-methoxyphenacyl, 2,4-dimethoxyphenacyl, 2, 5-dimethoxyphenacyl, 3,4-dimethoxyphenacyl, 3,5-dimethoxyphenacyl, 2-hydroxy-4-methoxyphenacyl, 2-hydroxy-5-methylphenacyl, 4-hydroxy-2-methylphenacyl, 4- Hydroxy-3-methylphenacyl, 4
-Hydroxy-3-methylphenacyl. The compound of the present invention represented by the general formula () comprises 2-(2,6-dichloroanilino)-2-pyrroline or its acid addition salt and a substituted phenacyl derivative represented by the following general formula () in a suitable manner. It can be obtained by reacting in a solvent according to a conventional method. X-CH ₂ -R () (R in the formula () is the same as the definition in the formula (),
X represents a halogen atom such as a chlorine atom or a bromine atom, or a leaving group such as a paratoluenesulfonylioxy group or a methanesulfonyloxy group. ) The reaction solvent in the above reaction is 2-(2,
A solvent capable of dissolving the acid addition salt of 6-dichloroanilino)-2-pyrroline is desirable, and is preferably selected from the group generally referred to as polar solvents. Specific examples include alcohols, tetrahydrofuran, dioxane, and methyl ethyl ketone. Although the above reaction can be carried out at around room temperature, it takes approximately one day and night for the reaction to proceed completely. More importantly, when using the raw material 2-(2,6-dichloroanilino)-2-pyrroline in the form of a salt, it is necessary to add an organic or inorganic base, especially in order to make the reaction proceed smoothly. Needless to say. 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. Suitable acids for salt formation include mineral acids such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid or nitric acid, or mineral acids such as, for example, oxalic acid, malonic acid,
Succinic acid, glutaric acid, maleic acid, fumaric acid,
Organic acids such as lactic acid, tartaric acid, citric acid, malic acid, gluconic acid, benzoic acid, phthalic acid, cinnamic acid or ascorbic acid. In addition, if the product of the above reaction is collected in the form of a hydrohalide salt, it can be used without desalting this salt.
Other salts can be derived by reaction with appropriate acids among those listed above. The compound of this invention has the effect of continuously reducing heart rate in dogs anesthetized with pentobarbital, and therefore, as mentioned above, it is useful as a drug that acts on the circulatory system, particularly in patients with heart failure or coronary artery disease. It is useful as a prophylactic and therapeutic agent.
Furthermore, since it has anti-inflammatory and analgesic effects in rats, it can also be used as an anti-inflammatory agent and analgesic. Furthermore, since thiopental antagonized sleep in mice, it can be used as a central stimulant. The compounds of this invention can be administered to animals and humans neat or together with conventionally known pharmaceutically acceptable excipients or carriers. The dosage unit form is not particularly limited and may be appropriately selected and used as required. Such dosage forms include tablets,
Examples include oral preparations such as 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 0.002 to 30 mg per kg of body weight per day. It is also preferable that the dosage unit form contains 0.05 to 500 mg of the active ingredient. 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 excipients (lactose,
white sugar, glucose, starch, microcrystalline cellulose, etc.), binders (starch paste solution, gum arabic solution,
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 preparation, filler, or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. When molding into the form of a suppository, a wide variety 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 customary in this field can be used, such as water, ethyl alcohol, propylene glycol,
Examples include ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan acid fatty acid esters. 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. 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-[N-(4-chlorophenacyl)-N-(2,
6-dichlorophenyl)amino]-2-pyrroline hydrobromide 1.00 g (4.36 mmol) of 2-(2,6-dichloroalinino)-2-pyrroline and 1.00 g (4.28 mmol) of 4-chlorophenacyl bromide 10ml of ethanol
and stirred at room temperature for 24 hours. After distilling off the solvent from the reaction mixture under reduced pressure, the residue was recrystallized from ether-methanol to obtain 1.33 g (2.88 mmol) of the title compound. Yield 68.0% The obtained compound was confirmed to be homogeneous by thin layer chromatography. The melting point, elemental analysis values, and spectral data are described below. Melting point 188.0℃-190.0℃ NMR spectrum (CD ₃ OD, ppm) 7.73 (multiplet,

【formula】

【formula】) 5.58 (multiplet,

【formula】) 4.73, 3.88, 2.77 (multiplet,

[Formula]) Elemental analysis value (%) Calculated value C: 46.7, H: 3.5, N: 6.1 Analysis value C: 46.7, H: 3.0, N: 5.9 Example 2 2-[N-(2,6-dichloro phenyl)-N-
(4-Methylphenacil)amino]-2-pyrroline hydrobromide 2-(2,6-dichloroanilino)-2-pyrroline 0.98 g (4.29 mmol) in the same manner as in Example 2
and 4-methylphenacyl bromide 0.98g (4.59m
mol) to obtain 1.88 g (4.26 mmol) of the title compound. Yield 92.7% Melting point 98.0-100.0℃ NMR spectrum (CD ₃ OD, ppm) 7.60 (multiplet,

【formula】

【formula】) 5.43 (multiple lines,

【formula】) 4.67, 3.86, 2.73 (multiline,

[Formula]) 2.40 (Single line, -CH ₃ ) Elemental analysis value (%) Calculated value C: 51.6, H: 4.3, N: 6.3 Analysis value C: 50.6, H: 4.2, N: 5.9 Example 3 2 -[N-(2,6-dichlorophenyl)-N-
(4-Methoxyphenacil)amino]-2-pyrroline hydrobromide 0.78 g (3.42 m
mol) and 4-methoxyphenacyl bromide 0.74
g (3.24 mmol), the title compound 1.26 g (2.74 m
mol) was obtained. Yield 80.2% Melting point 94.0-97.0℃ NMR spectrum (CD ₃ OD, ppm) 7.60 (multiplet,

【formula】

【formula】) 5.43 (multiple lines,

[Formula]) 4.76 (singlet, −OCH ₃ ) 3.90, 3.33, 2.80 (multiplet,

〔experimental method〕

An adult male and female mixed breed dog (weighing approximately 10 kg) was anesthetized with sodium pentobarbital (30 mg/Kg iv).
A cannula was inserted into the right femoral artery and blood pressure was measured according to the standard method. 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 artery. [Results] Capacity to sustainably reduce heart rate by 25% (ED ₂₅
values) are shown in Table 1.

〔experimental method〕

Test drug was administered at 5 mg per group to 5-week-old male mice (10 mice per group).
Kg was administered intraperitoneally. Thirty minutes later, 40 mg/Kg of thiopental sodium was administered through the tail vein at a rate of 0.1 ml/10 seconds, and the time from the start of thiopental sodium administration until recovery of the righting reflex was measured. [Results] Compared with the control group without drug administration, those that statistically significantly shortened the righting reflex recovery time were marked +, and those that had no effect were marked -. The results are shown in Table 2.

【table】

Claims (1)

[Claims] 1 General formula (): (wherein R means an optionally substituted benzoyl group) A substituted anilino-2-pyrroline derivative and a pharmaceutically acceptable salt thereof. 2 The optionally substituted benzoyl group of R in formula () is represented by the general formula (): (In the formula, R ₁ and R ₂ are hydrogen atoms, halogen atoms,
The compound according to claim 1, which is a lower alkyl group, a hydroxy group or a lower alkoxy group. 3. The compound according to claim ₂ , wherein the halogen atom in R ₁ and R 2 of formula () is a chlorine atom. 4. The compound according to claim ₂ , wherein the lower alkyl group in R ₁ and R 2 of formula () is a methyl group. 5. The compound according to claim ₂ , wherein the lower alkoxy group in R ₁ and R 2 of formula () is a methoxy group.