N-DIMETHOXY PHENYL ALKYL-N'-IMIDAZOLYL PHENYL AMIDINE DERIVATIVES AND PROCESS THEREOF

Abstract: Novel N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives of general formula (I), wherein the m represents an integer of 1 to 5, R represents a hydrogen atom, C1-3 lower alkyl group, and R1 represents a hydrogen atom, C1-3 lower alkyl group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents C1-3 lower alkyl) and pharmaceutically acceptable acid addition salts thereof. These compounds are useful as antiulcer agents. Also disclosed are processes for preparing the compounds.

Description: N-DIMETHOXY PHENYL ALKYL-N'-IMIDAZOLYL PHENYL AMIDINE DERIVATIVES AND PROCESS THEREOF 5 FIELD OF INVENTION The present invention relates to novel N-dimethoxy phenyl alkyl - N' - i idazolyl phenyl amidine derivatives which are useful as antiulcer agents such as gastric ulcer and duodenal . ulcer and the • j Q process for preparing them. BACKGROUND OF INVENTION 5 Antiulcer agents have an. antiulcer activity classify into drugs for decreasing the activity of gastric acid and drugs for increasing the defensive activity in mucous membrane against gastric acid. Firstly, drugs for decreasing the activity of gastric acic are, a) antacids such as aluminium hydroxide, aluminium magnesium silicate, 0 aluminium phosphate and magnesium hydroxide etc., b) H2 - receptor antagonists such as cimetidine, ranitidine, famotidine, zaltidine and nizatidine etc., c) anti-muscarinic agents such as pirenzepine, darenzepine and telenzepine etc., d) gastrin-receptor antagonist such as proglumide and e) + - ATPase inhibitors such as omeprazole, 5 picartamide and picoprazole. Secondly, drugs for increasing the defensive activity in mucous membrane against gastric acid are, agents such as carbenoxoione for promoting the formation of the gastric mucous membrane, and agent such as sucralfate, tripotassium dicitrato bismuth for the treatmen of gastric ulcer by preventing from the gastric acid upon forming protein complex with bile juice and combining with a region cause ulcer. According to the compound formula histamine H 2 - recepto antagonists classify the compounds of 5 species as the followings; 1) compounds such as dmetidlne which has a formula of simple heterocyclic side chain, 2) compounds such as ranltidina which has a formula of aminomethyl - substituted aryl side chains, 3) compounds such as tiotidine which has a formulae of guanido - substituted. heterocyclic side chains, 4) phenyl formamidine derivatives, 5) biheterocyclic derivatives. The above - identified known H 2 - receptor antagonists have an excellent activity for inhibiting gastric secretion through a histamin H 2 _ receptor, but the side effects such as diarrhea, muscle pair., dizziness, gynecomatism, hepatic disorders, impotence and hypoacidity cause. Therefore it desires to develope a new compound for the treatment of gastric and duodenal ulcer. Thus, according to the present invention, there are provided novel compounds whicn has a formula of phenyl formamidine, as a H 2 - receptor antagonist, having an excellant effect on the treatment of ulcer and decreasing the side effects than the known compounds. DESCRIPTION OF THE PRIOR ART Hitherto, as the materials possessing the feature analogues to the compounds of the present invention, the following compounds 1n U.S.Pat.No.4,386,099, E.P.Pat.No.131,973 and K.R.Pat.Publication No.1317/1988,etc. , are disclosed. Wherein R, R-| and R 3 , which may be the same or different, represent a hydrogen atom or a lower alkyl group, and R 2 represents a linear or branched alkyl, alkenyl or alkynyl group, a cyano group, a hydroxyl group, a substituted or unsubstituted cycloalkyl or cyclo aliphatic alkyl group, a bicyclic group, an aralkyl or aryl group optionally substituted by halogen, methyl, methoxy or methylene dioxy groups, or a substituted or unsubstituted hetero cyclylalkyl or heterocyclic group which may contain a further hetero atom. In the above-cited inventions, it was described that R only represents a benzyl group in case of an aralkyl in the description thereof, that is, it may be assumed that imidazolylphenyl amidines substituted by mono methoxy benzyl are disclosed from the cited invention, but the compounds of the present invention are derivatives of N-d1methoxy phenyl alkyl-N'-i idazolyl phenyl amidines. The compounds prepared according to the present invention are all novel compounds having different structures and more superior pharmacological effects compared with those of the known compounds. SUMMARY OF THE INVENTION An object of this invention is to provide novel compounds o N-d1methoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivative useful as gastric acid secretion inhibitors, the process for preparin them and the pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives which are useful a antiulcer agents, process for preparing them and the pharmaceutical compositions containing them. Thus, according to this Invention, there are provided nov N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives o the general formula (I) ( I ) wherein m represents an integer of 1-5, R represents a hydrogen atom or C- | _ 3 lower alkyl group, and R 1 represents a hydrogen atom, Cτ- 3 lower alkyl group, aryl group, mono or di ethoxy phenyl alkyl group (wherein alkyl represents C-ι_ 3 lower alkyl), and the acid addition salts thereof capable of being supplied for pharmaceutical purposes. Furthermore, according to other embodiments of this invention there are provided a process for preparing the novel N-dimethoxy phenyl alkyl - N' - imidazolyl phenyl amidine derivatives of the- general formula (I) and the medical compositions containing the said compounds. The term "C-1-3 lower alkyl group" in the above definition means methyl group, ethyl group and propyl group, "aryl" means phenyl group, tolyl group and naphthyl group. Furthermore, the compounds of the general formula (I) easily form acid addition salts thereof. Therefore, this invention includes also the add addition salts. These salts of the N-dimethoxy phenyl alkyl - N' - imidazolyl phenyl amidine derivatives formed with inorganic add or organic acids are, for example, hydrochlorides, hydrobromides, sulfates, etc. The compounds of this invention can be administered orally or parenterally but the oral administration is preferred. The compoundε of this invention are used as the free bases or the pharmacological acceptable salts thereof. In general, they are used as medical or pharmaceutical compositions with carriers or diluents which can be used generally for preparing medicaments. The compositions of this invention are most convenient to use in the form of capsules or tablets but they may be used as sustained release preparations, sugar-coated preparations, syrups or injections. An administrable daily dose is from 10mg to 2000mg, a unit dose depending on the formulation of preparation is from 10mg to 1000mg, preferably from 30mg to 200mg. Particularly desired compounds of the general formula (I) prepared b the process of this invention Include the following : We conducted trials on the effects of the inhibition of th gastric secretion, the inhibition of the add output and th inhibition of Indomethacin-induced gastric ulcer on the compounds o this invention compared with the known compounds and the method an results of trials are described in the below. 1) The Inhibition rate on the gastric secretion : Spraque-Dowly male rats provided from Sam-Yuk Experimental Animals Research Center were pre-bred for one week and rats weighing, from 170g to 220g were used on test. Rats were deprived of food for 24hours but allowed free access to water. The pylorus was ligated under ether anesthesia. Test compounds were intraduodenally given immediately after the ligation of pylorus. The drugs can be administered in the form of solutions dissolved with distilled water and it can be administered in the form of suspensions. The animals were sacrificed 6hrs. after drug administration and gastric juice was collected. The gastric juice was centrifuged at 3,500 rpm for 10 minutes and measured the volume(ml) thereof. For the amendment of the weight differences of the Individuals the gastric volumes were measured the number of ml per 100g, and results are shown in table 1. An instrument : HIMAC Centrifuge SCR 20 BB (Hitachi, Japan) Table 1. Volume of gastric juice (ml/100g) * : Mean ± S. E. /\ : Significantly different from the control. (P<0.01) / / : Significantly different from the control. (P<0.05) 2) Acid output : Test method is the same with the method of 1), and 2m of collected gastric juice was titrated with 0.02N-NaOH t pH 7.0 and measured the acidity per 100g of weight and on hour. Results are shown in table 2. Table 2. Acid output per 1 hour (Titration with 0.02N-Na0H) * : Mean ± S.E. A : Significantly different from the control. (P<0.01) AA : Significantly different from the control. (P<0.05) 3) The inhibition rate indomethacin-induced gastric ulcer : Test method : Rats were deprived of food for 24 hours but allowed free access to water. After drug 10 administration orally, suspensions of 25mg/Kg of indomethacin with 1% CMC were injected subcutaneously. After 6 hours rats were killed, and picked up stomachs and removed gastric juice. After 13ml of 2% formalin solution was perfused 1:ι the stomach and deposited in 2% formalin solution for 10 minutes. Great curvature of stomach was incised in length, and then measured the length of indomethacin - induced gastric ulcers at the gastric glanα by a micrography as to the erosion index. Drugs were non-soluble in water and administered , orally in the form of suspensions, with 1% CMC solution. Results are shown in table 3. Table 3 The effects on the indomethacin-induced gastric ulcers in rats * : Mean ± S.E. A: Significantly different from the control. (P<0.01) V : Significantly different from the control. (P<0.05) 4) Acute toxicity in mice : Male and female ICR mice weighing 20 to 25g were pre - bred and test carried out with groups of total 10 mice of 5 mice each of the male and female. The compound(l) according to this Invention was non-soluble in water and therefore administered orally in the form of suspension of the compoundO) with 1% CMC solution. Food and water freely provided for two weeks and observed mice. The LD 50 values are then calculated by the method of Litchfield - Wilcoxon. As the result the LD 50 value of the compound(l) of this invention was 5092 g per Kg, orally in mice. The N-dimethoxy phenylalkyl-N'-imidazolyl phenyl amidine derivatives of this invention shown by the general formula (i) can be produced by the following processes. Process 1 (I) In the above formulae, m, R and R-] have the same significance as above. N-cyano-N'-[4-(1midazol-4-yl)phenyl] amidines of the general formula(III) were suspended in solvents, for example water, alcohol such as methanol or ethanol or a mixed solvent of alcohol and water, preferably methanol, and added hereto equimolar amounts of 3,4-dimethoxy phenyl alkyl amines of the general formula(II), then stirred in order to dissolve a idines(III) at normal temperature. After reacted, the obtained solution was treated with active carbon and filtered them. The solvents were then removed and the oily residuals were dissolved in alcohol such as methanol and added ethylether to obtain the compounds of general formula(I). If necessary, the obtained crystals were dissolved in absolute alcohol or acetone, and converted with inorganic or organic acids into non-toxic acid addition salts. Particularly preferred acids include hydrochloric acid, hydrobromic acid, maleic acid and fumaric acid. Process 2 ( I ) In the above formulae, m, R and R< have the same .significance as above. 3,4-dimethoxy phenyl alkyl amides of general formula (IV) were reacted with equimolar amounts of Imidazolyl .phenyl amines of general formula (V) in solvents such as anhydrous benzene or xylene in the _. c presence of phosphorus penta chloride at a temperature of 80 to 100 C. After reacted, the obtained solids were neutralized with an alkaline solution, and extracted with organic solvents such as chloroform etc. and the oily residuals were crystallized from ethyl ether and chloroform to obtain the compounds of general formula (I). The processes of this invention will further be explained by the following examples and should not be construed as limiting the invention thereto. EXAMPLES Example 1 N-[2-(3,4-dimethoxy phenyl) ethyl]-N'-[4-(imidazol-4- yl) phenyl] formamidine. 8.36 grams (0.04mole) of N-cyano-N'-[(4-imidazol-4-yl) phenyl formamidine were suspended in 100 ml of methanol and after adde hereto 7.33 grams (0.04mole) of 2-(3,4-dimethoxy phenyl) ethyl amin at normal temperature, and continuously stirred in order to dissolv c the amidine crystals at normal temperature. After reacted, th obtained solution was treated with active carbon, and stirred it for few minutes and filtered, and then the- remaining solution wa evaporated under the reduced pressure. The oily residuals wer dissolved in methanol, and added ethylether to obtain 8.4 grams o the entitled compound. * yield : 60% * Property and melting point : white crystal , 120°C-130°C * 1H NMR (D.MS0-d 6 ) £ 2.72 (2H, t, -CH 2 -) £3.35 (2H, q, -CH 2 ~) £3.5 (1H, br. S, -NH-) £3.68 , S 3.71 (6H, S , -0CH 3 ) £ 6.82 (2H, S , imidazole -H) S 6.7 , 87.5 (7H, aromat. -H) * IR (KBr) - C= N - ( 1640cm ~ 1 ) , -NH - ( 3200cm~ 1 ) Example 2. N - [2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [5 - methyl - 4 - (imidazol - 4 - yl) phenyl] - 3,4 - dimethoxy phenyl acetamidine. 5.8grams (0.028mole) of phosphorus pentachloride were dissolved in 50ml of xylene and after added hereto. 10.2 grams (0.028mole) of N-[2-(3,4-dimethoxy phenyl) ethyl]-3,4 - dimethoxy phenyl acetamide, and stirred at 50°C for 1 hour. In this solution 4.7grams (0.027mole) of 5-methyl-4-(4-aminophenyl) i idazole were slowly added and stirreα at 90° to 100 C for 3 hours. It cooled at normal temperature to remove xylene. The remaining crystals were completely dissolved 1n ammonia water and extracted with chloroform. After washed chloroform layer with water and saturated sodium chloride solution and dried by anhydrous magnesiun sulfate, then concentrated under reduced pressure. The oily residuals were cyrstdllized from ethylether and chloroform to obtain 4.2grams of the entitled compound. * yield : 30% * property and melting point : white crystal, 170 C * 1H NMR (CDC1 3 ) 51.8 (3H, S, -CH 3 ) £3.05 (6H, m, -CH2CH 2 -) £3.86, £4.0 (14H, S, -OCH 3 , - CH 2 -) £4.65 (1H, S, -NH-) £6.85 (1H, S, imidazole - H) £6.95, £7.3 (10H, aromat - H) * IR (KBr) - NH - (3500cm _1 ) , -C = N - (1600cm ~ 1 ) Example 3. N - [2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [4 - i idazol - 4 - yl) phenyl] propionamidlne. 3.5 grams of phosphorus pentachloride were dissolved in 50ml of dry benzene and after added hereto 4 grams of N - [2 - (3,4 dimethoxy phenyl) ethyl] propion amide, and stirred at 50 °C for 1 hour. In this solution 2.8 grams of 4 - (4 - amino phenyl) - 1H imidazole were slowly added and stirred for 3 hours under refluxing. It cooled at normal temperature to remove benzene. The remaining crystals were completely dissolved in 20% ammonia water and extracted with chloroform. After washed chloroform layer with water and saturated sodium chloride solution and dried by anhydrous magnesium sulfate, then concentrated under reduced pressure. The oily residuals were crystallized from chloroform to obtain l.δgrams of the entitled compound. Example 4. N - [ 2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [4 - imidazol - 4 - yl) phenyl ] benzamidine. 3.5grams of phosphorus pentachloride were dissolved in 50ml of dry benzene and after added hereto δgrams of N-[2-(3,4-dimethoxy phenyl) ethyl] benza ide, and stirred at 50°C for 1 hour. In this solution 2.9grams of 4-(4-amino phenyl)-1H-imidazole were slowly added and stirred for 3 hours under refluxing. It cooled at normal temperature to remove benzene. The remaining crystals were completely dissolved in 20% ammonia water and extracted with chloroform. After washed chloroform layer with water and saturated sodium chloride solution and dried by anhydrous magnesium sulfate, then concentrated und r reduced pressure. The oily residuals were crystallized from ethyl ether and chloroform to obtain 1.9grams of the entitled compound. Example 5. N - [2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [5 - methyl - 4 - (imidazol - 4 - yl) phenyl] formamidine. 4grams (0.0177 mole) of N - cyano - N' - [5 - methyl - 4 - (imidazol - 4 - yl) phenyl] form amidine were suspended 1n 20ml of water and after added hereto 6.3 grams (0.035mole) of 2 - (3,4 - dimethoxy phenyl) ethylamine at normal temperature, and continuously stirred in order to dissolve the amidine crystals at normal temperature. The obtained oil layer was extracted with ethyl acetate and washed with water several times. It was dried by anhydrous magnesium sulfate, then distilled under reduced pressure to obtain the residuals. The remaining residuals were crystallized with n-hexane and acetone, and then fitered and dried at normal temperature to obtain 3.8grams of the entitled compound. * yield : 60% * Property and melting point : white crystal, 170 C * 1H NMR (DMS0-d 6 ) £2.35 (S, 3H, CH 3 ) §2.84 (t, 2H, CH 2 ) £3.55 (t, 2H, CH 2 ) £3.80 (S, 6H, -0CH 3 ) £ 6.85 (S, 2H, aromat.) £6.84, £7.0 (s, 2H, aromat.) $ 7.22 (S, 1H, imidazole -H) δ 7.52 - 7.68 (m, 4H, aromat.) 1 8 Example 6. N - [2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [4 - (imidazol 4 - yl) phenyl] butyramidine. 1 gram (0.004 mole) of N-cyano - N' - [4 - (imidazol - 4 - yl phenyl] butyramidine were suspended in 20ml of methanol and afte added hereto 0.87grams (0.0048mole) of 2 - (3,4 - dimethoxy phenyl ethyl amine. The mixed solution was refluxed for 10 hours and the en of the reaction was confirmed by TLC, and removed the solvent. Th remained residuals were passed through column chror atograph .(the rat of dichloro methane VS methanol is 9:1) to obtain 0.627 grams of th entitled compound. * Yield : 40% * Melting point : 70°C The compound was dissolved in acetone and added maleic acid t obtain maleic acid addition salt of the entitled compound. * Melting point : 155 C Example 7 N-[2-(3,4-dimethoxy phenyl) ethyl] - N'-[4-(1midazol - 4 - yl phenyl] acetamidine. 4.5 grams (0.02 mole) of N-cyano-N'-[4-(imidazol-4-yl) phenyl] acetamidine were suspended in 25ml of methanol and after added heret 7.25 grams (0.04 mole) of 2-(3,4-dimethoxy phenyl) ethylamine. Th suspension was refluxed overnight and cooled to room temperature and evaporated the solvent. The residuals were passed through column chromatograph (solvent; ethyl acetate : methanol = 3:1) to obtain 2.9 grams of the entitled compound. * Yield : 40% * Melting point : 70 °C - 75 °C * 1H NMR (CDC1 3 ) 1.85 (s, 3H, CH 3 ) §2.84 (t, 2H, CH 2 ) 53.55 (t, 2H, CH 2 ) 3.80 (s, 6H, -OCH3) £6.85 (s, 2H, aromat.) 6.84, $7.0 (s, 2H, aromat.) §7.22 (s, 1H, imidazole - H) £7.52 - 7.7 (m, 4H, aromat.)

Claims: WHAT IS CLAIM IS : 1. A compound of the general formula (I) and pharmacologicall acceptable acid addition salt thereof. ( I ) wherein m represents an integer of 1 to 5, R represents a hydroge atom or C-i_ 3 lower alkyl group, and Ri represents a hydrogen atom C^s lower alkyl. group, aryl group, mono or dimethoxy phenyl alky group (wherein alkyl represents C1-3 lower alkyl). 2. A compound as claimed in claim 1 which is N - [2 - (3,4 -dimethox phenyl) ethyl] - N' - [4 - (imidazol - 4 - yDphenyl] formamidine 3. A compound as claimed in claim 1 which is N - [2 - (3,4 -dimethox phenyl) ethyl] - N' - [5 - methyl - 4 - (imidazol - 4 - yl phenyl] - 3,4 - dimethoxy phenyl acetamidine. 4. A process for oreparing a compound of the general formula(I) an acid additional salts thereof which comprises of reactin N-cyano-N'- [4-(imidazol-4-yl) phenyl] amidine of the genera formula(III) with 3,4-dimethoxy phenyl alkyl amine of the genera formula (II) at normal temperature. CH 3 0 CH 3 0 // (CH 2 )m - NH - C // W / ( I ) N NH wherein , R and R-| are as defined in claim 1. 5. A process for preparing a compound of the general formula(I) and acid additional salts thereof which comprises of reacting 5 3,4-dimethoxy phenyl alkyl amide of the general formula (IV) with Imidazolyl phenyl amine of the general formula(V) in the presence of phosphorus pentachlorlde at 80 to 100 C. wherein m, R and R-j are as defined in claim 1

Inventors: CHUNG KI JU, HAN MYUNG SECK, KIM DONG YEON, KIM YOUNG IL, CHUNG, KI, JU, HAN, MYUNG, SECK, KIM, DONG, YEON, KIM, YOUNG, IL
Applicants: IL YANG PHARM CO LTD, IL YANG PHARM. IND. CO., LTD.
Application year: 1991
Main classification: C07D233
IPC codes: A61K31, A61P1, A61P43, C07D233