AU646040B2 - N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives and process thereof - Google Patents

Description

OPT DATE 04/02/92 AOJP DATE 12/03/92 INTERl.___ APPLN. TD 76522 91, r'L NUMBER PCT/KR91/00olO N TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WVO 92/00966 C07 D 233/64 A61IK 31/415 Al (43) International Publication Date: 23 January 1992 (23.01.92) (21) International Application Number: PCT/KR9I/000I0 (74) Agent: KIM. Jae. Cheon: Suite 304. Changlim Building.

816-3, Yoksam-dong. Kanignam-ku, Seoul 135-081 (KR).

(22) International Filing Date: 6 April 1991 (06.04,9 1) (81) Designated States: AT (European patent), AU, BE (Euro.

Priority data: pean patent), CH (European patent), DE (European pa- 90-10522 12 July 1990 (12.07.90) KR tent), DK (European paten,). ES (European patent), FR jrZ ,,qAG PA eW /7*P(European patent), GB3 (European patent), GR (Euro- 2L Y'A/ P/9e~z Cpean patent), IT (European patent), JP, LU (European (71) Applicant (for all designated States except US): 1hpatent), NL (European patent), SE (European patent), P14,*MHE?-~ [KR/KR]; 24-5, Hawolgog- us.

dong, Sungbug-gu, Seoul 136-132 (KR).

(72) Inventors; and Published Inventors/Applicants (for US only) KIM, Young. 11 [KR/ With international search report, KR]; 565, Sind aebang-dong, Dongjak-gu, Seoul 156-010 (KiR). KIM, Dong, Yeon [KR/KR]; 22-1402, Hyundai Apartment, Ohgeum-dong, Songpa-gu, Seoul 138-130 CHUNG, Ki, Ju tKR/KR): 503, Ra-dong, Sung- 0A woo Apartment, Yokkok 3-dong, Nam-gu, Puchun, Kyungki-do 422-100 B-AN, Myung, Seck [KR/KR]; 460-24, Mia-dong, Dobong-gu, Seoul 132-100 f\PA7 0C, (54) Title: N-DIMETHOXY PHENYL ALKYL-N'-IMIDAZOLY. PHENYL AMI DINE DERIVATIVES AND PROCESS

THEREOF

C H C HO N

CH

3 0 CN)-H N

R

N NH (57) Abstract Novel N-dirnethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives of general formula wherein the in represents an integer of I to 5, R represents a hydrogen atom, C lower alkyl group, and Rt represents a hydrogen atom, C1.

3 lower alkyl group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents CtA lower alkyl) and pharmaceutically acceptable acid addition salts thereof. These compounds are useful as antiulcer agents. Also disclosed are processes for preparing the compounds.

WO 92/00966 PCT/KR91/00010 1 N-DIMETHOXY PHENYL ALKYL-N'-IMIDAZOLYL PHENYL AMIDINE DERIVATIVES AND PROCESS THEREOF FIELD OF INVENTION The present invention relates to novel N-dimethoxy phenyl alkyl N' imidazolyl phenyl amidine derivatives which are useful as antiulcer agents such as gastric ulcer and duodenal ulcer and the process for preparing them.

BACKGROUND OF INVENTION 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 acid are, a) antacids such as aluminium'hydroxide, aluminium magnesium silicate, aluminium phosphate and magnesium hydroxide etc., b) H 2 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) H ATPase inhibitors such as omeprazole, picartamide and picoprazole.

Secondly, drugs for increasing the defensive activity in mucous membrane against gastric acid are, agents such as carbenoxolone for WO 92/00966 PCT/KR91/00010 2 promoting the formation of the gastric mucous membrane, and agents such as sucralfate, tripotassium dicitrato bismuth for the treatment of gastric ulcer by preventing from the gastric acid upon forming a protein complex with bile juice and combining with a region caused ulcer.

According to the compound formula histamine H 2 receptor antagonists classify the compounds of 5 species as the followings; 1) compounds such as cimetidine which has a formula of simple heterocyclic side chain, 2) compounds such as ranitidine 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 histamine

H

2 receptor, but the side effects such as diarrhea, muscle pain, 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 H2 receptor antagonist, having an excellant effect on the treatment of 17 ulcer and decreasing the side effects than the known compounds.

WO 92/00966 PCT/KR91/00010 3 DESCRIPTION OF THE PRIOR ART Hitherto, as the materials possessing the feature analogues to the compounds of the present invention, the following compounds in U.S.Pat.No.4,336,099, E.P.Pat.No.131,973 and K.R.Pat.Publication No.1317/1988,etc., are disclosed.

R2 N C N N NH

R

3 R1 Wherein R, R 1 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-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidines. Tht 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.

WO 92/00966 PCT/KR91/00010 4 SUMMARY OF THE INVENTION An object of this invention is to provide novel compounds of N-dlmethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives useful as gastric acid secretion inhibitors, the process for preparing 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 as antiulcer agents, process for preparing them and the pharmaceutical compositions containing them.

Thus, according to this invention, there are provided novel N-dimethoxy phenyl' alkyl-N'-imidazolyl phenyl amidine derivatives of the general formula (I)

(CH

2 )m NH C N I N NH

R

1

(I)

wherein m represents an integer of 1-5, R represents a hydrogen atom or C1- 3 lower alkyl group, and R 1 represents a hydrogen atom, 0 1 -3 lower alkyl group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents 01-3 lower alkyl), and the acid addition salts thereof capable of being supplied for pharmaceutical purposes.

Furthermore, according to other embodiments of this invention there is provided a process for preparing the novel N-dimethoxy phenyl alkyl N' imidazolyl phenyl amidine derivatives of the general formula and the medical compositions containing the said compounds.

Accordingly, there is provided according to another form of the invention a process for preparing a compound of the general formula and acid additional salts thereof which comprises reacting N-cyano-N'- [4-(imidazol-4-yl) phenyl] amidine of the general formula (III) with 3,4-dimethoxy phenyl alkyl amine of the general formula (II) at normal temperature

CH

3 0

CH

3 O- (CH 2 )m-NH-C=N- R, N, NH (I)

CH

3 0

(CH

2 )m-NH 2

(II)

(III)

wherein m, R and R 1 are as hereinabove defined.

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 easily form acid addition salts thereof. Therefore, this invention includes also the acid addition salts. These salts of the N-dimethoxy phenyl alkyl N' imidazolyl phenyl amidine derivatives formed with inorganic acid 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 compounds 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 10ng to 2000mg, a unit dose depending on the formulation of preparation is from 10mg to 1000mg, preferably from 30mg to 200mg, li) IN\LIBFF100OO91:ER 5 o( 2 WO 92/00966 PCT/K R911/0001 0 6 Particularly desired compounds of the general formula prepared by the process of this invention Include the following compound R R 1 m remark 5(1) H H 2 Example 1 -CH3 OCH 3 2 Example 2

-CH

2

-OCH

3 H CH 2 CH3 2 Example 3 H 2 Example 4 -CH3 H 2 Example H CH 2

CH

2

CH

3 2 Example 6 H CH 3 2 Example 7 We conducted trials on the effects of the inhibition of the gastric secretion, the inhibition of the acid output and the inhibition of indomethacin-induced gastric ulcer on the compounds of this invention compared with the known compounds and th, method and 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 WO 92/00966 PCT/KR91/00010 there are provided a process for preparing the novel N-di ethoxy phenyl alkyl N' imidazolyl phenyl amidine derivative of the general formula and the medical compositions containi g the said compounds.

The term "C 1 3 lower alkyl group" in the above definition means methyl group, ethyl group and propyl group, "ary/r means phenyl group, tolyl group and naphthyl group.

Furthermore, the compounds of the gen ral formula easily form acid addition salts thereof. Therefore, this invention includes also the acid addition salts. These salt of the N-dimethoxy phenyl alkyl N' imidazolyl phenyl amidine derivatives formed with inorganic acid or organic acids are, for example, hydrochlorides, hydrobromides, sulfates, etc.

The compounds of t s invention can be administered orally or parenterally but the ral administration is preferred. The compoundc of this invention re used as the free bases or the pharmacological acceptable sal s thereof. In general, they are used as medical or pharmaceuti al compositions with carriers or diluents which can be used gen rally for preparing medicaments. The compositions of this inven ion are most convenient to use in the form of capsules or t lets 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 0mg to -200mg.

1 1

V**'J

WO 92/00966 PCT/KR91/00010 7 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. Tne 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 1009, and results are shown in table 1.

An instrument HIMAC Centrifuge SCR 20 BB (Hitachi, Japan) Table 1.

Volume of gastric juice (ml/100g) Compound Dose No.of Volume Inhibition rate (mg/kg) rats (ml) Control 5 4.6210.40 Mifentidine 10 5 2.34±0.23 A 5 2.04±0.36 A 56 100 6 2.18±0.25 A 52 Famotidine 10 6 2.50±0.22 46 5 .2.74+-0.20 41 100 6 2.62+0.38 43 Cimetidine 10 5 3.61±0.30 22 6 3.3310.86 28 100 t 2.20+0.36 A 52 Ranitidine 10 5 4.16±0.41 6 3.72+0.71 19 100 6 3.17±0.30 31 WO 92/00966 PCT/KR91/00010 Compound(1) of this invention 3.82±0.48 5.05±0.76 3.74i0.40 3.88±0.31 2.28±0.47 1.95±0.16 1.84±0.51 1.06±0.15 0.71±0.15

A

A

A

A

A

A

A/\

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 and of collected gastric juice was titrated with O.C?N-NaOH pH 7.0 and measured the acidity per 100g of weight a:.

hour. Results are shown in table 2.

1 Acid output per 1 Compound Dose No.of (mg/kg) rats Control 5 Mifentidine 10 5 5 Table hour 2.

(Titration with 0.02N-NaOH) Acid output" Inhibition rate (CEq/hr) 77.25±7.37 29.50:5.20 62 26.24±5.05 66 WO 92/00966 WO 9200966PCr/KR9J /00010 Famot id ine Cimetidine Ranitidine 100 10 100 10 100 1fJ 100 150 200 10 30 50 100 150 200 21. 66±5. 40 27. 23±3.14 28.70+-1.45 2 4. 22±3. 29 48.61±5.66 47. 68±7.56 31.75±6.7 5 52. 34±5. 49 47. 06±12. 37 20. 49±3. 60 33. 04±8. 81 58. 25±11. 44 54. 90±6. 65 51. 50±8. 18 30. 82±6. 62 2 6. 57±3. 00 12. 69±5. 12 6. 48±1 .58 1.96±1.40

A

A

A

A

A

A

A

A

AA

A

A

Compound (1) of this invention :Mean S. E.

A :Significantly A A :Significantly different different from the control.

from the control.

(P<0.01) (P<0.05) 3) The inhibition rate indorethacin-induced gastric ulcer: Test method :Rats were deprived of food for 24 hours but allowed free access to water. After drug WO 92/00966 PCT/KR91/00010( administration orally, suspensions of 25mg/Kg of indomethacin with 1% CMC were injected subcutaneously.

After 6 hotrs rats were killed, and picked up stomachs and "emL/ed gastric juice. After 13ml of 2% formalin solution was perfused in 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 gland by a micrography as to the erosion index.

Drugs were non-soluble i, water and administered.

orally in the form of suspensions, with 1% CMC solution.

Results are shown in table 3.

The effects on the Compound Dose (mg/kg) Control Famotidine 1 Table 3 indomethacin-induced gastric ulcers in rats No.of erosion Inhibition rate rats index(mm) A -0 n+ 21 6 6 6 6 6 8.9565.20 2.20±1.09 0,67±0.22 0.56±0.22 1.01±0.14 7.70±1.59 1.09±0.37 2.9210.78 8.80±2.94 Cimetidine Compound(1) 1 WO 92/00966 PCT/KR91/00010 i of this 3 6 5.01+1.92 52 invention 10 6 2.19+0.37 79 6 2.45+0.32 /A 76 6 0.51-..5 A 70 6 0.44+0.16 A 96 100 6 0.58+0.51 94 Mean S.E.

Significantly different from tne control. (P<0.01) /A Significantly different from the control. (P<0.05) 4) Acute toxicity in mice Male and female ICR mice weighing 20 to 259 were pre bred and test carried out with groups of total 10 mice of 5 mice each cf the male and female. The compound(1) according to this invention was non-soluble in water and therefore administered orally in the form of suspension of the compound(1) with 1% CMC solution.

Food and water freely provided for two weeks and observed mice. The LDso values are then calculated by the method of Litchfield -Wilcoxon. As the result the LD 50 value of the compound(1) of this invention was 5092 mg per Kg, orally in mice.

The N-dimethoxy phenylalkyl-N'-imidazolyl phenyl amidine derivatives of this invention shown by the general formula can be produced by the following process.

WO 92/00966 PCT/KR91/00010 12 Process 1

CH

3 0

(CH

2 )m NH 2 NC N C NH

R

R1 N NH (II)

(III)

-(CH

2 )m NH N Ri N NH

(I)

In the above formulae, m, R and R, have the same significance as above.

N-cyano-N'-[4-(imidazol-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), t"enr stirred in order to dissolve amidines(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.

WO 92/00966 WO 9200966PCT/KR91/0)001O 1 3 P eeecss 2

CH

3 0 0

CH

3 0 (CH 2 )m C NH -R1+ H 2 N 1\ (IV) (V

CH

3 0 (CH 2 )m NH N I N N Ri

N

In the above formulae, m, /W /ad R, have the same significance as above.

3,4-dimethoxy phe I alkyl amides of general formula (IV) were reacted with pequim ar amounts of imidazolyl phenyl amines of general formula i solvents such as anhydrous benzene or xylene in the presence phosphorus penta chloride at a temperature of 80 to 100 C.

Afte preacted, the obtained solids were neutralized with an alkaline olution, and extracted with organic solvents such as chloroform etc.

and the oily residuals were crystallized from ethyl ether and Ielzrferrn to ebtain th l ce -eeRus-e-f---e-ne-r-a-1---o ffrul (-2.T The process ofl this invention will further be ex~plained by the following examples and should not be construed as limiting the invention thereto.

EXAMPLES

Example 1 N-i:2-(3,4-dimethoxy phenyl) ethyl]-N'-I:4-(imidazol-4- yl) phenyll formamidine.

WO 92/00966 PCT/K R91/00010 14 8.36 grams (0.04mole) of N-cyano-N'-[(4-imidazol-4-yl) phenyl] formamidine were suspended in 100 ml of methanol and after added hereto 7.33 grams (0.04mole) of 2-(3,4-dimethoxy phenyl) ethyl amine at normal temperature, and continuously stirred in order to dissolve S the amidine crystals at normal temperature. After reacted, the obtained solution was treated with active carbon, and stirred it for a few minutes and filtered, and then the. remaining solution was evaporated under the reduced pressure. The oily residuals were dissolved in methanol, and added ethylether to obtain 8.4 grams of the entitled compound.

yield Property and melting point white crystal, 120 0 C-130 0

C

1H NMR (DMSO-d 6 a 2.72 (2H, t, -CH 2 S3.35 (2H, q, -CH 2 (1H, br.S, -NH-) &3.68, S 3.71 (6H, S, -OCH 3 g6.82 (2H, S, imidazole -H) S6.7, 87.5 (7H, aromat. -H) IR (KBr) C= N (1640cm-1), -NH 3200cm 1 Example 2.

N [2 (3,4 dimethoxy phenyl) ethyl] methyl (imidazol 4 yl) phenyl] 3,4 dimethoxy phenyl acetamidine.

5.8grams (0.028mole) of phosphorus pentachloride were dissolved in 50m1 of xylene and after added hereto 10.2 grams (0.028mole) of WO 92/00966 PCT/KR91/00010 N-[2-(3,4-dimethoxy phenyl) ethyl]-3,4 dimethoxy phenyl acetamide, and stirred at 50 0 C for 1 hour. In this solution 4.7grams (0.027mole) of 5-methyl-4-(4-aminophenyl) imidazole were slowly added and stirred at 900 to 1000C for 3 hours. It cooled at normal temperature to remove xylene.

The remaining crystals were completely dissolved in 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 !0 residuals were cyrstallized from ethylether and chloroform to obtain 4.2grams of the entitled compound.

yield Sproperty and melting point white crystal, 170°C 1H NMR (CDC13) S 1.8 (3H, S, -CH3) '3.05 (6H, m, -CH 2

CH

2 3.86, S4.0 (14H, S, -OCHe CH2-) S4.65 (1H, S, -NH-) S6.85 (1H, S, imidazole H) &6.95 S7.3 (10H, aromat H) IR (KBr) NH (3500cm -C N (1600cm 1 _fp 9\ Example 3.

N [2 (3,4 dimethoxy phenyl) ethyl] N' [4 -(imidazol 4 yl) phenyl] propionamidine.

3.5 grams of phosphorus pentachloride were dissolved in 50m1 of WO 92/00966 PCT/KR91/00010 16 dry benzene and after added hereto 4 grams of N [2 (3,4 dimethoxy phenyl) ethyl] propion amide, and stirred at 50 OC 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 1.5grams of the entitled.

compound.

Example 4.

N (3,4 dimethoxy phenyl) ethyl] N' [4 -(imidazol 4 yl) phenyl benzamidine.

of phosphorus pentachloride were dissolved in 50ml of dry benzene and after added hereto 5grams of N-[2-(3,4-dimethoxy phenyl) ethyl] benzamide, 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 under reduced pressure. The oily residuals were crystallized from ethyl ether and chloroform to obtain 1.9grams of the entitled compound.

i WO 92/00966 PCT/KR91/00010 17 Example N [2 (3,4 dimethoxy phenyl) ethyl] methyl imidazol 4 yl) phenyl] formamidine.

4grams (0.0177 mole) of N cyano N' [5 methyl 4 (imidazol 4 yl) phenyl] form amidine were suspended In 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 Property and melting point white crystal, 170 C 1H NMR (DMSO-d 6 &2.35 3H, CH3) 82.84 2H, CH2) S3.55 2H, CH2) E3.80 6H, -OCH 3 S6.85 2H, aromat.) S6.84, S7.0 2H, aromat.) S7.22 1H, imidazole -H) S7.52 7.68 4H, aromat.)

S/

'ii," WO 92/00966 PCT/KR91/00010 18 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 after added hereto 0.87grams (0.0048mole) of 2 (3,4 dimethoxy phenyl) ethyl amine. The mixed solution was refluxed for 10 hours and the end of the reaction was confirmed by TLC, and removed the solvent. The remained residuals were passed through column chrormatograph .(the rate of dichloro methane VS methanol is 9:1) to obtain 0.627 grams of the entitled compound.

Yield Melting point 7000C The compound was dissolved in acetone and added maleic acid to obtain maleic acid addition salt of the entitled compound.

Melting point 155°C Example 7 N-[2-(3,4-dimethoxy phenyl) ethyl] N'-[4-(imidazol 4 y phenyl] acetamidine.

grams (0.02 mole) of N-cyano-N'-[4-(imidazol-4-yl) phenyl] acetamidine were suspended in 25ml of methanol and after added hereto 7.25 grams (0.04 mole) of 2-(3,4-dimethoxy phenyl) ethylamine. The suspension was refluxed overnight and cooled to room temperature and evaporated the solvent.

The residuals were passed through column chromatograph (solvent; WO 92/00966 WO 9200966PCT/KR9]/00010 19 ethyl acetate :methanol to obtain 2.9 grams of the entitled compound.

Yield :401.

Melting point 70'C 7500 1H NMR (00013) 3H, O-H 3 E"2.84 2H, CH 2 83.55 2H, OH 2 3.80 6H, -OC H 3 E6.85 2H, aromat.) 6.84, 3 7. 0 2H, aromat.) .7.22 1H, imidazole H) 7.7 (in, 4H, aromat.)

Claims (9)

1. A compound of the general formula and pharmacologically acceptable acid addition salt thereof. CH 30 (CH 2 NH C N R N NH I R1 (I) wherein m represents an integer of 1 to 5, R represents a hydrogen atom or C1-31ower alkyl group, and Ri represents a hydrogen atom, C1_3lower alkyl group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents C1.3 lower alIyl).

2. A compound as claimed in claim 1 which is N [2 (3,4 -dimethoxy phenyl) ethyl] N' [4 (imidazol 4 yl)phenyl] formamidine.

3. A compound as claimed in claim 1 which is N [2 (3,4 -dimethoxy phenyl) ethyl] methyl imidazol 4 yl) phenyl] 3,4 dimethoxy phenyl acetamidine.

4. A process for oreparing a compound of the general formula(I) and acid additional salts thereof which comprises of reacting N-cyano-N'- [4-(imidazol-4-yl) phenyl] amidine of the general formula(III) with 3,4-dimethoxy phenyl alkyl amine of the general formula (II) at normal temperature A. CH 3 0 CH 3 O 0 (CH 2 )m-NH 2 (I NC-N=C-NH N NH (111) wherein m, R and R, are as defined in claim 1.

5. A N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivative, substantially as herein described with reference to any one of Examples 1 to 7.

6. A process for preparing a N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivative, which process is substantially as herein described with reference to any one of Examples 1 to 7. Dated 12 November, 1993 11 Yang Pharm. Co., Ltd Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON INAIM1100091tlER21o2 21 o12 INTERNATIONAL SEARCH REPORT International Application No PCT/'R 91/00010 I, CLASSIFICATION OF SUBJECT MATTER (II sev.ral classific3tion symools aooy locale alll) According to International Patent Classification (IPC) or to both National Classification and IPC Int.Cl. 5 C 07 D 233/64 A 61 K 31/415 II, FIELDS SEARCHED Minimum Documentation Searched 7 Classificaton System Classification Symools Int.Cl." C 07 D 233/64 A 61 K 31/415 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In tne Fields Searched S AT III. DOCUMENTS CONSIDERED TO BE RELEVANT' Category I Citation of Document, i" with indication, where appropriate, of the relevant passages "i Relevant to Claim No A EP, A2/A3, 0 053 407 (ISTITUTO DE ANGELI 1,4,5 09 June 1982 (09.06.82), see claims 1,22,50-52. A US, A, 4 225 724 (WARNER, JR. et al.) 30 September 1,4,5 1980 (30.09.80), see claim 1; column 1, lines

9-20. Decial categories of cited documents to later document published aher the international fiing date document defining the general state of the at which is not or priority date and not in confic' with the aoticatlon but considered to be of particular relevance citeon to understand the principlo or t;.orfy underlying the invention earier document but published on or atter the international document o particular relevance: the claimeo invention hilng date cannot be considered novel or cannot be conosdered to document which may throw doubts on priority claim(t) or involve an Inventive step which cited to establish the publicaton date of another document o particular relevance; the claimed inventon ciation or other special reason (as specifieol cannot be considered to involve an inventive steo when the document referring to an oral discloiure, use. exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skiled document oublished prior to the International filing date but In the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion ol the International Search I Date of Mailing of this International Search Report 17 May 1991 (17.05.91) 11 June 1991/ ll.c. 1) International Searching Authority Signature of Authorize Officer, AUSTRIAN PATENT OFFICE Form PCT/ISAI210 isecond sheet) (January 1985) Anhang zum internatio- nalen Recherchenbcricht Liber die internationale Patentanmelduna Nr. In diesem Anhang sind die Mitglieder der Patentfamilien der- im obengenannten interna- tionalen Recherch!!nbe-- r'icht angefUhrten Patentdokumente ange- geben. Diese Angaben diene~ n' a r Lhta-rich- twig und erfolgen ohne Gew~hr. Annex to the International Search Report on Interna- tional Patent Application No. PCT/KP 91/00010 This Annex lists the patent family members relating to the patent documei.ts cited in the above-mentioned Inter- national search report. The Austrian Patent Office is in no way liable for these par- ticulars which are merely given f/ E purpose of in- formation. Annexe au rapport de recherche internationale relatif i la demande de brevet international n* La prhsente annexe indique les mermbres de la famille de brevets relatifs aux docu- ments de brevets cit~s dans le rapport de recherche inter- nationa~evis6 ci-dessus. Les renseignements fournis sont donn~s i titre indicatif et n'engagent pas la responsa- bilit& de l'Office autr~ichien des brevets. Im Recherchenbericht Datum der Mitglied(er) der Datum der angefUhrtes Patent- Verdffentlichung Patentfamilie Verbffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date in search report Date de Membre(s) de la Date de Document de brevet cite' publication famille de publication dans le rapport brevets de recherche EF-A2- 53.407 0 9 C)6-2 HU-E4 187478 28-01-86 AR-Al- '228a4 68 15 -1 )3 -8a3 AT-E 244+95 15-01-87 AU-A-77947/81 03'-06-82 AU-Ei2- 554592 29-0~8-86 CA-Al- 1 171092 17-07-934 CA-A2- I118 10809 15-01-85 CS-B2- 249115 12-03-B7 CS-B2- 249544 12-03-97 201:el893 17-09863 DE-CCO- 3.175754 C05 87 DK-A 5255/81 2-9-05-82 DK'-B 157862 .26-0290 D C 1 57862 06-09-90 EF-TD- 53407 20-01-93 53,407 2 7 r)7- EP-81- 53.407 _10-12-86 ES9-Al- 50750 1 01-09-82 ES-Al- 507505 0)1 -09-8'2 ES-Al- 507506 0 1-09-82 ES-Al- S07507 ()11-0C9 -82 ES-Al- 507508 C01i-0(9-682 ES-Al- 507509 01-0t9-82 ES-AS- 507501i 01 -82 ES-AS- 307505 0-10 -8 2 ES-AS- 507506 0 1 -10-82 ES-AS- 507507 0-0-92 ES-AS- 507508 01-10)-82 ES-AS- 507509 01-10-82 ES-Al- 8207147 0~1-12-82 see page 2 PCT/KR JI/ 310 page 2 im Recherchenbericht Datum der Mitglied(er) der Datum der angef~ihrtes Patent- Verdffentlichung Patentfamilie Verdffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date in search report Date de Membre(s) de la Date de Document de brevet cith publication famille de publication dans le rapport brevets de recherche- ES-Al- 8207148 ES-Al-- 8207149 ES-Al- 820:7150) ES-Al- 8207151 ES-Al- 8207152 Fl-A e 13794 Fl-E;- 7320:9 Fl-C .3209 GB-Al- 20883.75 G9-92- 2088B375 HK-A 681/86 IE-B 51946 IL-AC)- 64738B IL-Al- 643.88 3F- A2-57 120575 3F'--E14- 207-3031 KR-S I- 88C)1317 MY-A -146/87 NO-A e 814065 NO-A (3 74353 NO-ACO- 874353 NO-S 156183 N O-C -158163 NO-S 160)578 NO-C -160578 NZ-A 199093 PH-A 17390 PH-A 1.9032 FL-AlI- 234007 FL-Al- 23.8422 FL--Si- 15 74 9 PL--8i- 13L6-015O FrT-A 74048 FT-B 74048 1I1038 1 SU-A3- I I C)3*82 US-A 43,860)99 US-A 4465841 YU--A 1759/83 YU--A 2760)/81 YU-B 42447 YU-B 42076 ZA-A 8- 108240) AT-E 24495 CA--A2- 1181090 k R-U 8202056 NO-A 7,5 NO-AC:)- 87-47353: 160576 C) I 12-82 0l 1 82 01-12-82 01-12-82

29-05-82 29-05-87 1 0-09-B7 09-06-82 C)9-C01 28- 11-86 29-C)4-8B7

283--)2-82 27-0C)7-832 25-C)7--90C 27-07-98 3 12-437 01 -06-82 01 -06-82 19-1C.),-e7 18G-0()4- 8 '27- C%7 89 23-01-09 037-051-89 1-05-85 08-08-84 06- 12-85 1 4-03-83 30-06-84 :1-08-88 027--83 115-01-85 02-- 1C)8-84 0 6-84J 19-0-88 23-01-89 see page 3 PCT/KB 91/Ou~lO page 3 Im Recherchenbei-icht Datum der Mitglied(er) der- Datum der- angefUhrtes Patent- Verbffentlichung Patentfamilie Verbffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date in search report Daite de Membre(s) de la Date de Document de brevet citi publication famille de Publication dans le rapport brevets de recherche UJS-A 4225724 30-o)9-80(: NO-c 160578 US-A 4465841 AU-A1-32331/78 AU-B2- 521807 B-E-Al- 862608 CA-Al- 1149385 CA-A2- 1164877 CH-A 636102 CH-A 640229 CS- 200232 DE-Al- 2900480) DE-C2- 2859766 DE-C2- 280 C C)49C) DI-A 42/78 DlK-B -157024 DXK-C -157024 Fl-A -780023 Fl-,A B 21308 F I-AC)- 8321308 64374 FI-B 64375 Fl-C 643-74 Fl-C 64375 FR-Al- 2376e58 FR-FU-- 23,76858 GB-A 1579496 GB--A 1579499 IE-R 46191 IE-9 46192 3 A2-53087 398 JF'-A2-61 171 470 JP-B4- 1030825 LUJ-A 793 NL-A -7800 114 SE-A -780)138::, SE-A -8300)c945 SE-AC)-- 8300945 SE--B 436359 SE-C 436359 SE-B 4-60477 SE-C *-460477 YU-A 21/72 ZA-A 780C))027 US-A -4160097 US-A -4172947 US-A -4191767 14-08-84 19-o7-79 29-04-832 03-07-78 C:)5-0:7-83Z 03-C)4-84 1 3-05-fl3 30-12-83 29-08)-3C) 13-07-78 0)5-04-90 12-0:4-9) 08-07-729 30-.-10:-89 02-C)4-90C 14-04-82 14-04-G2 29-0C7 -83 29-C)7-83 10- 10- 11-83 C)4-0C8 -78 24-1 0-8C0 29-1 1-SC) 83 01-01-78 02-08-86 1 a-0)9-78 11-C-7-70 C)E?-C)7.-78 2 1-0)2-83 21 0:3- 12-84 1 4-03-85 16-10)-9 C) 8-0)2-9 C.) 70 -0'4-90 71-01-71:- see page 4 PCT/KR 91/00010 page 4 Im Recherchenbericht Datum dIer Mitglied(er) der Datum der angefUhrtes Patent- Verbffentlichung Patentfamilie Verbffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date in search report Date de Membre(s) de la Date de Document de brevet cit& publication famille de publication dans l~e rapport brevets de recherche US-A US-A US-A US-A US-A FI-B 4197403 4198508 4200750 4229452 4236015 64375 15-04-80 29-0:4-80"- 25-11-C0 29-o7-83