KR920004935B1 - Method of producing for n-dimethoxy phenyl alkyl-n'-imidazolyl-phenyl amidine - Google Patents

Abstract

N-Dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivs. of formula (I) are new. Also claimed is the prepn. of (I) which comprises reacting N-cyano-N'-[4-(imidazol-4-yl)phynyl amidine and 3,4-dimethoxy phenyl alkyl amine. In the formula (I), m = 1-5; R=H or C1-3 lower alkyl; R1=H, C1-3 lower alkyl, aryl, mono- or dimethoxy phenyl alkyl (C1-3 alkyl). Pref. the cpd. (I) is N- [2-(3,4-dimethoxyphenyl)ethyl -N'-[4-(imidazol-4-yl) phenyl formamidine or yl)phenyl-3,4-dimethoxy phenyl acetamidine.

Description

N-dimectoxy phenylalkyl-N'-imidazolylphenyl amidine derivative and preparation method thereof

The present invention relates to an N-dimethoxy phenylalkyl-N'-imidazolylphenyl amidine derivative having an antiulcer action as a compound represented by the following general formula (I) and a method for producing the same.

Wherein m is an integer from 1 to 5, R is hydrogen, a lower alkyl group of C _1-3 , R ₁ is hydrogen, a lower alkyl group of C _1-3 , an aryl group, mono or dimethoxyphenylalkyl ( Alkyl is a lower alkyl) group of C _1-3 .

Drugs with anti-ulcer activity are divided into drugs that greatly reduce gastric acid activity or increase mucosal defenses against gastric acid. Firstly, a class of drugs that reduce gastric acid activity includes: a) neutralizing secreted gastric acid. antacids, which was (as a representative drug Aluminium hydroxide, magnesium silicate, Aluminium phosphate , there is Magnesium hydroxide, etc.), b) the histamine H ₂ - that in combination with the receptor to inhibit gastric acid secretion, H ₂ - receptor antagonists (Cimetidine, Ranitidine, Famotidine , Zaltidine, Nizatidine, etc.) c) anti-anhydrin drugs that selectively bind to the M1-muscarine receptor of the gastric mucosa to inhibit gastric acid secretion (Pirenzepine, Darenzepine, Telenzepine, etc.), d) gastrin receptor antagonists ( Proglumide) and, e) and the like to H ⁺ / K ⁺ -ATPase inhibitors (Omeprazole, Picartamide, Picoprazole) to block the enzyme H ⁺ / K ⁺ -ATPase function of participating in the secretion of gastric juice, more than As a drug that can cure ulcers by strengthening the defense of gastric mucosa, the agent stimulates the production of protective mucosa of gastric mucosa (Carbenoxolone), forms a protein complex with bile, and protects against gastric acid by binding to ulcer sites By obtaining a therapeutic effect (Sucralfate, Tripotassium dicitrato bismuth) and the like are known.

Of these, the H ₂ -receptor antagonists known to date can be classified into compounds having five basic nucleus structures.

1) a compound having a simple heterocyclic side chain, such as cimetidine,

2) compounds having aminomethyl-substituted aryl-side chains, such as ranitidine,

3) compounds with guanido-substituted heterocyclic side chains, such as Tiotidine,

4) Phenylformamidine derivative

5) can be divided into Bihteroyclic derivatives,

While these known H ₂ -receptor antagonists have excellent effects, some side effects (diarrhea, myalgia, dizziness, gynecomastia, liver disorders, impotence, etc.) are known and cause problems such as hypoxia with longer action time. This requires the development of new derivatives.

Representative compounds of the present invention are novel compounds having a Phenylformamidine structure as the parent nucleus, belonging to the H ₂ -receptor antagonist, and have the advantages of excellent anti-ulcer effect, low side effects, and appropriate action time.

Materials having structures similar to those of the compounds of the present invention known to date include substituted imidazolylphenyl aminos having the following structural formulas described in US Pat. No. 4,386,099, European Patent No. 131,973 and Korean Patent Publication No. 88-1317. Compounds of the dean derivatives are already known,

Wherein R, R ₁ and R ₃ are the same or different and are a hydrogen atom or a lower alkyl group, R ₂ is a straight or branched alkyl, alkenyl or alkyl group, cyano group, hydroxyl group, substituted or unsubstituted Substituted or unsubstituted cycloalkyl or substituted alkyl, bicyclic, aralkyl or aryl groups (optionally substituted by halogen, methyl, methoxy or methylenedioxy groups) or heteroatoms which may further contain heteroatoms Ring heterocyclealkyl or heterocycle group.

In the above-mentioned patents, when R ₂ is aralkyl in the specification, it is limited to benzyl group, and thus, only imidazolylphenyl amidine derivative substituted with monomethoxybenzyl is known, and the compound of the present invention is N- It is a dimethoxy phenylalkyl-N'-imidazolylphenyl amidine derivative which is different in structure from the known compound and has a superior pharmacological effect compared to the known compound.

In the present invention, "lower alkyl group of C _1-3 " means methyl, ethyl, and fluoro groups, and "aryl" means phenyl, toryl, naphthyl groups.

The compounds of the present invention may be administered orally or parenterally, with oral administration being more preferred. The compounds of the present invention are used as free bases or pharmaceutically acceptable salts thereof, which are administered as medical or pharmaceutical compositions with carriers or diluents which can be used in the manufacture of a medicament. Acceptable salts include inorganic acid salts and organic acid salts such as salt trichloride and the like.

The pharmaceutical composition of the present invention is preferably administered in capsule form or tablet form, but may be formulated and administered as a conventional pharmaceutically acceptable preparation such as a continuously released preparation, dragee, syrup, or injection. The daily allowable dose is 10 mg to 2000 mg, and the dosage unit of each dosage form is 10 mg to 1000 mg, and preferably 30 mg to 200 mg.

Among the compounds represented by the general formula (I) according to the present invention, particularly preferred compounds are as follows.

The gastric secretion inhibitory effect and acid excretion effect and the ulcer inhibitory effect induced by indomethacin were tested for the compound according to the present invention.

1) The inhibition rate on the gastric seoretion:

* Experimental Animals: Spraque-Dowly male rats were purchased at the Tertiary Experimental Animal Research Center and used for the experiment to weigh about 170-220g after preliminary breeding for about 1 week.

* Experimental Method: The rats are fasted for 24 hours (water is freely supplied), and then anesthetized with ether to perform laparotomy. Take out the stomach and ligation the pyloric part to the duodenum from the stomach with sutures and then administer the drug into the duodenum. The drug should be dissolved in distilled water in principle, otherwise it was used after suspension. After 6 hours of ligation of the pyloric region, the stomach was extracted, gastric juice was collected, centrifuged at 3,500 rpm for 10 minutes, and the number of ml was measured to compensate for individual differences in body weight. Calculated. Table 1

* Laboratory equipment: HIMAC Centrifuge SCR 20 BB (HITACHI, Japan)

TABLE 1

*: Mean ± Standard error (S.E.)

: P〈0.01에서 대조군과 유의성 있음.

: Significant difference with control at P <0.01.

: P〈0.05에서 대조군과 유의성 있음.

: Significant difference with control at P <0.05.

2) Acid output action (Acid output):

* The method is the same as 1), and 2 ml of the collected gastric juice was taken and titrated to pH 7.0 with 0.02N-NaOH to give an acidity per hour per 100g of body weight (Table 2).

TABLE 2

3) The inhibition rate indomethacin induced gastric ulcer:

* Experimental Method: After fasting the rats for 24 hours (freely supplying water), the drug was first administered orally, and 10 minutes later, indomethacin 25mg / kg (suspended in 1% CMC) was administered subcutaneously. After 6 hours, the lot is lethal and the stomach is removed, gastric juice is extracted, and about 13 ml of 2% formalin liquid is injected into the stomach, and it is immersed in 2% formalin liquid for about 10 minutes, and then incision is made long in the stomach area under a microscope. The length of the ulceration site in the gastric gland was measured and set as the erosion index (Table 3). Pamotidine upon oral administration of the drug. Cimetidine and Compound (1) of Example 1 of the present invention were both poorly soluble in water and suspended in 1% CMC.

TABLE 3

4) Acute Toxicity Test

* Experimental Method: After pre-breeding ICR type male and female mice with 20-25g body weight in the breeding room, 10 females each of 5 females and males were fasted for 3-4 hours before the experiment and orally administered with the drug. . Compound (1) of Example 1 of the present invention is poorly soluble in water, suspended in 1% CMC, orally administered by dose, and freely supplied with feed and water for 2 weeks to check the general condition. LD 50 was taken as the dose at which half of the animals die and was calculated by the Litchfield-Wilcoxon method.

Results: LD 50 of Compound (1) of Example 1 of the present invention was 5092 mg / kg. (Compound (1) LD 50 = 5092 mg / kg mouse, oral).

N-dimethoxy phenylalkyl-N'-imidazolylphenyl amidine derivative of this invention represented by general formula (I) is manufactured by the following method.

[Method 1]

(Wherein the definitions of m, R and R ₁ are as described above).

N-cyano-N '-[4- (imidazol-4-yl) phenyl] amidine of formula (III) is suspended in water or alcohol or a mixed solvent of water and alcohol, followed by 3,4-dimethoxyphenyl alkylamine of formula (II) is added and stirring is continued at room temperature until the amidine crystal is dissolved. After the reaction type, the resulting solution was treated with activated carbon, filtered, and the solvent was removed. The oily residue was dissolved in an alcohol such as methanol and ethyl ether was added to obtain a nodule of the compound of formula (I). If necessary, the obtained crystals are dissolved in anhydrous ethanol or acetone, and then passed through hydrochloric acid gas to obtain hydrochloride.

[Method 2]

(In the above formula, the definitions of m, R and R ₁ are as described above.)

3,4-dimethoxyphenylalkylamide of the general formula (IV) was reacted with an equimolar amount of imidazolylphenylamine of the general formula (V) at 80-100 ° C using phosphorus pentachloride in anhydrous benzene or xylene solution. The resulting solid is neutralized with an alkaline solution, extracted with an organic solvent such as chloroform, and the oily residue is crystallized with ethyl ether, chloroform and the like to obtain a compound of formula (I).

The method of the present invention will be described in more detail by the following examples, which do not limit the scope of protection to these examples.

Example 1

Method for preparing N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] formamidine.

8.36 grams (0.04 mol) of N-cyano-N '-[4- (imidazol-4-yl) phenyl] formamidine are suspended in 100 milliliters of methanol. 7.33 grams (0.04 mol) of 2- (3,4-dimethoxyphenyl) ethylamine was added dropwise at room temperature, followed by continued stirring at room temperature until the amidine crystals dissolved. After completion of the reaction, activated carbon was added to the resulting solution, stirred for several minutes, filtered, and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in methanol and ethyl ether was added to give 8.4 grams of the title compound.

The resulting crystals are dissolved in anhydrous ethanol or acetone and passed through a hydrochloric acid gas dried under cooling to obtain the hydrochloride of the title compound.

* Yield: 60%

* Appearance and melting point: White crystal, 120 ℃ -130 ℃

* 1 H NMR (DMSO-d ₆ ) δ2.72 (2H, t, -CH _2- ), δ3.35 (2H, q, -CH _2- ), δ3.5 (1H, br.S, -NH- ), δ 3.68, δ3.71 (6H, S, -OCH ₃ ), δ6.82 (2H, S, imidazole-H), δ6.7, δ7.5 (7H, aromat.-H).

* IR (KBr) -C = N- (1640cm -1), -NH- (3200cm -1)

Example 2

Preparation of N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[5-methyl-4- (imidazol-4-yl) phenyl] -3,4-dimethoxyphenyl acetamidine Way.

5.8 grams (0.028 mol) of phosphorus pentachloride was dissolved in 50 milliliters of dry xylene, and then 10.2 grams (0.028 mol) of N- [2- (3,4-dimethoxyphenyl) ethyl] -3,4-dimethoxyphenylacetamide was added. Stir at 50 ° C. for 1 hour. 4.7 grams (0.027 mol) of 5-methyl-4- (4-aminophenyl) imidazole was slowly added to the solution, followed by stirring at 90-100 ° C. for 3 hours. After cooling to room temperature to remove xylene, the remaining crystals are completely dissolved in ammonia water and extracted with a large amount of chloroform. The chloroform is washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The oily residue was crystallized from ethyl ether and chloroform to give 4.2 grams of the title compound.

* Yield: 30%

* Appearance and melting point: White crystal, 170 ℃

* 1 H NMR (CDCl ₃ ), δ 1.8 (3H, S, -CH ₃ ), δ3.05 (6H, m, -CH ₂ CH _2- ), δ3.86, δ4.0 (14H, S,- OCH ₃ , -CH _2- ), δ4.65 (1H, S, -NH-), δ6.85 (1H, S, imidazole-H), δ6.95, δ7.3 (10H, aromat.-H) .

* IR (KBr) -NH- (3500cm ^-1 ), -C = N- (1600cm ^-1 )

Example 3

A process for preparing N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[4-imidazol-4-yl) phenyl] propion amidine.

Dissolve 3.5 grams of phosphorus pentachloride in 50 milliliters of dry benzene, add 4 grams of N- [2- (3,4-dimethoxyphenyl) ethyl] propionamide, and stir at 50 ° C for 1 hour. 2.8 grams of 4- (4-aminophenyl) -1H-imidazole was slowly added to the solution, followed by stirring for 3 hours under reflux. After cooling to room temperature to remove benzene, the remaining crystals are completely dissolved in 20% ammonia water and extracted with a large amount of coloform. The chloroform layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallize with chloroform to obtain 1.5 grams of the title compound.

Example 4

Method for preparing N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[(imidazol-4-yl) phenyl] -benzamidine.

Dissolve 3.5 grams of phosphorus pentachloride in 50 milliliters of dry benzene, add 5 grams of N- [2- (3,4-dimethoxy phenyl) ethyl] benzamide, and stir at 50 ° C for one hour. 2.9 grams of 4- (4-aminophenyl) -1H-imidazole was slowly added to this solution, followed by refluxing and stirring for 3 hours. After cooling to room temperature to remove benzene, the remaining crystals are completely dissolved in 20% ammonia and extracted with a large amount of chloroform. The chloroform layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was crystallized from ethyl ether and chloroform to obtain 1.9 grams of the title compound.

Example 5

Process for the preparation of N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[5-methyl-4- (imidazol-4-yl) phenyl] formamidine.

Four grams (0.0177 mol) of N-cyano-N '-[5-methyl-4- (imidazol-4-yl) phenyl] formamidine are suspended in 20 milliliters of water. 6.3 grams (0.035 mole) of 2- (3,4-dimethoxyphenyl) ethylamine was added dropwise at room temperature, followed by continued stirring at room temperature until the amidine crystals dissolved. The resulting oil layer was extracted with an appropriate amount of ethyl acetate, washed several times with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a residue. The resulting residue is crystallized n-hexane and acetone, filtered and dried at room temperature to give 3.8 grams of the title compound.

* Yield: 60%

* Appearance and melting point: White crystal, 170 ℃

* 1 H NMR (DMSO-d ₆ ) δ2.35 (S, 3H, CH ₃ ), δ2.84 (t, 2H, CH ₂ ), δ3.55 (t, 2H, CH ₂ ), δ3.80 (S , 6H, -OCH ₃ ), δ6.85 (S, 2H, aromat.), Δ6.84, δ7.0 (s, 2H, arom a t.). Δ7.22 (S, 1H, imidazole-H) , δ 7.52-7.68 (m, 4H, aromat.)

Example 6

A process for preparing N- [2- (3,4-dimethoxy phenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] butyramidine.

One gram (0.004 mol) of N-cyano-N '-[4- (imidazol-4-yl) phenyl] butyramidine was suspended in 20 milliliters of methanol, followed by 2- (3,4-dimethoxyphenyl) 0.87 grams (0.0048 mol) of ethylamine were added dropwise. The mixture was refluxed for 10 hours to terminate the reaction (confirmed by TLC), the solvent was removed, and the residue was passed through a column chromatograph (dichloromethane; methanol = 9: 1) to obtain 0.627 grams of the title compound.

* Yield: 40%

* Melting Point: 70 ℃

The title compound is dissolved in acetone and maleic acid is added to form a salt.

* Melting Point: 155 ℃

Example 7

Process for the preparation of N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] acetamidine.

4.5 grams (0.02 mol) of N-cyano-N '-[4- (imidazol-4-yl) phenyl] acetamidine is suspended in 25 milliliters of methanol, and 2- (3,4-dimethoxyphenyl) 7.25 grams (0.04 mol) of ethylamine is added dropwise. The suspension is refluxed overnight, cooled to room temperature and the solvent is evaporated off. The residue is passed through a column chromatograph (solvent: ethyl acetate: methanol = 3: 1) to give 2.9 grams of the title compound.

* Yield: 40%

* Melting Point: 70 ℃ -75 ℃

* 1 H NMR (CDCl ₃ ) δ 1.85 (s, 3H, CH ₃ ), δ2.84 (t, 2H, CH ₂ ), δ3.55 (t, 2H, CH ₂ ), δ3.80 (S, 6H , -OCH ₃ ), δ6.85 (S, 2H, aromat.), Δ6.84, δ7.0 (s, 2H, aromat.). Δ7.22 (S, 1H, imidazole-H), δ7.52 -7.7 (m, 4H, aromat.)

Claims (5)

Compound of formula (I) and salts thereof

Wherein m is an integer from 1 to 5, R is hydrogen, a lower alkyl group of C _1-3 , R ₁ is hydrogen, a lower alkyl group of C _1-3 , an aryl group, mono or dimethoxyphenylalkyl ( Alkyl is a lower alkyl) group of C _1-3 . The compound of formula (I) according to claim 1, wherein the compound of formula (I) is N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] formamidine Phosphorus compounds. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is N- [2- (3,4-dimethoxyphenyl) ethyl] -N '-[5-methyl-4- (imidazol-4-yl) phenyl ] -3,4-dimethoxyphenyl acetamidine. N-cyano-N '-[4- (imidazol-4-yl) phenyl] amidine of formula (III) and 3,4-dimethoxy phenyl alkylamine of formula (II) were reacted at room temperature A process for preparing the compound of formula (I).

Wherein m, R and R ₁ are as defined above. A process for preparing a compound of formula (I) by reacting 3,4-dimethoxy phenylalkyl amide of formula (IV) with imidazolylphenylamine of formula (V) at 80-100 ° C. which is contaminated.

The definitions of m, R and R ₁ are as described above.