JPS60184065A - 2-methylene-1,3-propanediamine compound - Google Patents

Abstract

NEW MATERIAL:A 2-methylene-1,3-propanediamine compound shown by the formula I (R<1> is halogen; R<2> is halogen, or H) and its acid addition salt. EXAMPLE:N,N'-Bis(2,6-dichlorophenyl)-N-N'-bis( 2-imidazolin-2-yl )-2-methylene-1, 3-propanediamine. USE:A drug acting on circulatory organs useful as a preventive and remedy especially for cardiac incompetence, diseases of coronary artery, and cardiac arrhythmia. Further as an anti-inflammatory drug, analgesic, and hypotensor. PREPARATION:A 2-substituted phenylaminoimidazoline compound shown by the formula II is reacted with a dihalide compound shown by the formula III (X is Cl, Br, or I), to give a compound shown by the formula I .

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a new compound belonging to the 2-methylene-1,3-propanediamine compound. It is particularly useful as a drug for preventing heart failure, coronary artery disease, and cardiac arrhythmia.
-C is useful as a therapeutic agent. It can also be used as an anti-inflammatory agent, analgesic, and antihypertensive agent.

(Prior art) Conventionally, 2-methylene-1,3-propanediamine derivatives having a phenyl group on the nitrogen atom include N, N
'-Diphenyl-2-methylene-1,3-propanediamine is the only known component of its phenylurea adduct (Chem, Abstr, 8
7 (13) 102295P), a compound having a halogen substituent on the phenyl group and a 2-methylene-1,3-propanediamine compound having an imidazolyl substituent on the nitrogen atom were not known.

(Object of the Invention) The present invention provides a group of useful new compounds belonging to the 2-methylene-1,3-propanediamine 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 that is the subject of this invention is 2-methylene-1,3 represented by the general formula (■): (wherein R1 represents a halogen atom and R2 represents a halogen atom or a hydrogen atom) -propanediamine compounds and acid addition salts thereof.

The phenyl group "of the compound of formula (I>) has at least one substituent R1, and R1 is a halogen atom. The halogen atom includes chlorine, bromine or fluorine atom.

A particularly preferred halogen atom is a chlorine atom.

If the phenyl group has a second substituent R2, this is also selected from the same group as R1, 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-cyclonoenylamino, 2,6-dibromophenylamino, 2,6-cyfluorophenylamino, 2
-Bromo-6-chlorophenylamino, 2-chlorophenylamino, /, 2-bromophenylamino, 2-fluorophenylamino.

The compounds of this invention may also be in the form of physiologically acceptable addition salts with formic acid.

(Production method) Compound (i) of the present invention can be produced by the method shown below. Hereinafter, R1 and R2 are represented by the above formula
), and X represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom.

It can be obtained by reacting the 2-substituted phenylaminoidazoline (2) compound (2) of the general formula (■) (n) with the cybaride compound represented by the general formula (■).

To explain the above reaction in more detail, as a reaction solvent,
Alcohols such as methanol or ethanol, non-aqueous polar solvents such as tetrahydrofuran or dioxane, and chlorinated hydrocarbon solvents such as dichloromethane or chloroform are suitable.

The concentration of the substrate in the solvent should be as high as possible; therefore, it is better to use as little solvent as the solubility of the compounds of formula (II) and formula (I) allows. A temperature of 10°C to 100°C is suitable, but considering the by-products of colored substances, it is best to maintain a range of 20°C to 50°C.The reaction time is determined by the reaction temperature, the type of raw materials used (i.e.,
If) and the compound of formula (Iff), it takes several hours to several days.

Through the above reaction, the target compound of formula (I) is obtained, but in addition, as a by-product, the general formula (J
V): An imitazobilimicin compound of CH2 is also produced at the same time.

At this time, the separation of the compounds of formula (I) and formula (IV) is as follows:
This can be easily carried out by utilizing the difference in solubility in hydrocarbon solvents. For example, formula (I) and formula (rV)
(
Only the compound of formula (IV) can be selectively extracted into 0-hexane, and the compound of formula ('I) thus separated can be purified by known methods such as recrystallization. You can get it.

(Acid addition salt) Any compound of formula (I> obtained by the above method can be converted into a physiologically acceptable acid addition salt by a conventional method. Examples of the acid used in the salt formation include hydrochloric acid , hydrobromic acid, hydrogen iodide, hydrofluoric acid, sulfuric acid, phosphoric acid or nitric acid, or mineral acids such as 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 organisms produced by the above reaction are collected in the form of hydrohalides, this salt is not desalted, but is reacted with an appropriate acid among the above to convert it into 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 (it can be selected and used as necessary. Examples of dosage forms include tablets, capsules, granules, oral preparations such as various oral liquid preparations, injections, etc.
Examples include parenteral agents such as suppositories. The amount of the active ingredient to be administered is not particularly limited and is appropriately selected from a wide range, but in order to achieve the desired effect, it is necessary to administer 0.01 to 10 g per 1 ka of body weight per day. Good. Also, the amount of active ingredient in the dosage unit form is 0.1~
5001+1 (II It is preferable to use gold-containing drugs.) The therapeutic effects of the active ingredient of the present invention can be improved by coadministering other drugs as necessary depending on the type of disease and patient's condition. It is also possible to avoid increasing.

In this invention, tablets, capsules, oral liquid preparations, and other light-tasting 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 (de/υpun paste liquid, gum arabic liquid, gelatin liquid, glucose liquid, tragan 1). liquid, CMC liquid, sodium alginate liquid, etc., disintegrants (starch, calcium carbonate, etc.), lubricants (
Magnesium stearate, purified talc, etc.) may be appropriately selected, mixed, tableted, and then coded. Capsules are prepared by mixing the compound of the present invention with an inert preparation, filler, or diluent, forming a hard capsule b), and filling the mixture into soft capsules or the like. When molding into a suppository, a wide range of conventionally known carriers can be used for -C, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin,
There are many examples of semi-synthetic glycerinoid. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood;
For forming emulsions and suspensions, all diluents customary in this field can be used, such as water, ethyl alcohol, propylene glycol, mono-oxylated isostearyl alcohol, polyoxylated isostearyl Examples include 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 isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavoring agents, sweetening agents, and the like may also be included in the formulation.

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 1 251! 5.0 g of 2-(2,6-dichlorophenyl)aminoimidacillin (I) and 3.0 g
2-methylene-1,3-dichloropropane is dissolved,
The reaction was carried out by keeping the temperature at 30°C and stirring for 2 days.

The precipitated l(2,6-dichlorophenyl)aminoimidacillin hydrochloride was filtered off, and the solvent was thermally distilled off from the filtrate. Add 30xl of saturated saline solution to the residue, filter out the insoluble portion, and add 100ν! Extracted with ether. 10 to the extraction residue
% of sodium hydroxide was added dropwise to bring the pH to around 7, and the mixture was extracted again with ether. Furthermore, the pH of the extraction residue was adjusted to around 12, and extraction was performed with 100 if of ethyl acetate. After drying the ethyl acetate extract with anhydrous sulfuric acid,
Removal of the solvent gave 4.5 g of pale yellow crystals.

The operation of adding 150 xi of n-hexane to the crystals and extracting the dissolved portion was repeated three times. When the remaining crystal part was recrystallized from a mixture of n-hexane and ethyl acetate, the result was 0.8
9 of the title compound was obtained. The crystals were confirmed to be pure by thin layer chromatography.

Melting point and spectral data for this material are shown above.

Melting point ('C): 179-183 NMR spectrum (CDCρ3. Cape): 3.65 (1
11E) 4.34 (Singlet, ;CH2) 4.75 (Singlet, -CH2) 1.15-7.44 (Multiplet, =N) IR spectrum (KBr, an-'): 1600, 780 MaSS spectrum (CI/CH,): 511 (M+1
)◆ Experimental Example 2 N N'-bis 6-dibromophenyl-N N'-bis-imi 1 phosphorus-2-yl)-2-methylene-1,
3-propanediamine 6.9 g of 2-(2,,6-dibromophenyl)aminoimidacillin (2) and 3.09 g of 2-methylene-1,3-dichloropropane were added in the same manner as in Example 1. The title compound of 0.65(I was obtained.

The physical properties were as shown below.

Melting point ('C): 206-209 (decomposed) NMR spectrum (CDCQ3.pl): 3.64 (singlet, S) 4.33 < I WIiaWA, , CH2) 4.
47 (Singlet, CH2) 6.18-7.59 (Multiplet, NuD) IR spectrum (K[31', cm-'): 1610.780 Test example-1 Bradycardia activated Experiment method 1 Anesthetize an adult male dog (approximately 10 kg) with Ventopardotar Su1-lium (30111! J/kg, V), insert a cannula into the C6 femoral artery and measure blood pressure according to the standard method. did. Heart rate was recorded by driving a tachometer based on blood pressure pulse waves. The test substance was dissolved in DMF or coralline saline and administered through the stone vein.

[Results] IIi (E D
25 values) are shown in Table 1.

Table 1

Claims (1)

[Claims] 1. A 2-methylene-1,3-propanediamine compound represented by the general formula (■): (wherein R1 represents a halogen atom and R2 represents a halogen atom or a hydrogen atom) and its Acid addition salts. 2. The compound according to claim 1, wherein the halogen atom of R1 or R2 is chlorine or bromine atom C. 3. The compound according to claim 1 or 2, wherein the halogen atom of R1 or R2 is a chlorine atom. 4. The compound according to claim 1, wherein the acid addition salt is a pharmaceutically acceptable salt.