EP0538262A1 - N-dimethoxy phenyl alkyl-n'-imidazolyl phenyl amidine derivatives and process thereof - Google Patents

N-dimethoxy phenyl alkyl-n'-imidazolyl phenyl amidine derivatives and process thereof

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Publication number
EP0538262A1
EP0538262A1 EP91907721A EP91907721A EP0538262A1 EP 0538262 A1 EP0538262 A1 EP 0538262A1 EP 91907721 A EP91907721 A EP 91907721A EP 91907721 A EP91907721 A EP 91907721A EP 0538262 A1 EP0538262 A1 EP 0538262A1
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European Patent Office
Prior art keywords
phenyl
general formula
alkyl
dimethoxy
dimethoxy phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91907721A
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German (de)
French (fr)
Inventor
Young Il 565 Sindaebang-Dong Kim
Dong Yeon 22-1402 Hyundai Apartment Kim
Ki Ju 03 Ra-Dong Sungwoo Apartment Chung
Myung Seck 460-24 Mia-Dong Han
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Il Yang Pharmaceutical Co Ltd
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Il Yang Pharmaceutical Co Ltd
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Publication of EP0538262A1 publication Critical patent/EP0538262A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • 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.
  • 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.
  • drugs for decreasing the activity of gastric acic 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 + /K + - ATPase inhibitors such as omeprazole, picartamide and picoprazole.
  • antacids such as aluminium hydroxide, aluminium magnesium silicate, aluminium phosphate and magnesium hydroxide etc.
  • H 2 - receptor antagonists such as cimetidine, ranitidine, famotidine, zaltidine and nizatidine etc.
  • 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 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.
  • histamine H 2 - receptor antagonists classify the compounds of 5 species as the followings;
  • 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.
  • 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.
  • R, R 1 and R 3 which may be the same or different, represent a hydrogen atom or a lower alkyl group
  • 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.
  • 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.
  • 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.
  • An object of this invention is to provide novel compounds of N-d1methoxy phenyl alkyl-N'-imidazolyl phenyl amidine derivatives useful as gastric acid secretion inhibitors, the process for preparing them and the pharmaceutical compositions containing them.
  • 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.
  • R represents a hydrogen atom or C 1-3 lower alkyl group
  • R 1 represents a hydrogen atom, C 1-3 lower alkyl group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents C 1-3 lower alkyl), and the acid addition salts thereof capable of being supplied for pharmaceutical purposes.
  • 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.
  • 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 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 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 by the process of this invention include the following :
  • 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.
  • Cimetidine 10 5 3.61 ⁇ 0.30 ⁇ 22
  • 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.
  • Test method Rats were deprived of food for 24 hours but allowed free access to water. After drug 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 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 glan ⁇ by a micrography as to the erosion index.
  • Cimetidine 10 6 7.70 ⁇ 1.59 29
  • 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 compound(1) with 1% CMC solution.
  • 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 mg per Kg, orally in mice.
  • N-dimethoxy phenylalkyl-N'-imidazolyl phenyl amidine derivatives of this invention shown by the general formula (i) can be produced by the following processes.
  • 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), then 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).
  • solvents for example water, alcohol such as methanol or ethanol or a mixed solvent of alcohol and water, preferably methanol
  • 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.
  • 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 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 the amidine crystals at normal temperature.
  • the compound was dissolved in acetone and added maleic acid t obtain maleic acid addition salt of the entitled compound.

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Abstract

Nouveaux dérivés d'amidine de N-diméthoxy phényle alkyle-N'-imidazolyle phényle correspondant à la formule générale (I), dans laquelle m représente un entier situé entre 1 et 5, R représente un atome d'hydrogène, un groupe alkyle inférieur C1-3 et R1 représente un atome d'hydrogène, un alkyle inférieur C1-3, un groupe aryle, un groupe alkyle mono ou diméthoxy phényle (dans lequel alkyle représente alkyle inférieur C1-3) et leurs sels d'addition d'acide acceptables sur le plan pharmaceutique. Ces composés sont efficaces comme agents anti-ulcère. L'invention décrit également les procédés de préparation desdits composés.New amidine derivatives of N-dimethoxy phenyl alkyl-N'-imidazolyl phenyl corresponding to the general formula (I), in which m represents an integer between 1 and 5, R represents a hydrogen atom, a lower alkyl group C1-3 and R1 represents a hydrogen atom, a C1-3 lower alkyl, an aryl group, a mono or dimethoxy phenyl alkyl group (in which alkyl represents C1-3 lower alkyl) and their acid addition salts pharmaceutically acceptable. These compounds are effective as anti-ulcer agents. The invention also describes the processes for the preparation of said compounds.

Description

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 acic are, a) antacids such as aluminium hydroxide, aluminium magnesium silicate, 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) H+/K + - 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 carbenoxoione for 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 H2 - receptor 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 H2 - receptor antagonists have an excellent activity for inhibiting gastric secretion through a histamine H2 _ 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 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 in 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, R1 and R3 , which may be the same or different, represent a hydrogen atom or a lower alkyl group, and R2 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. 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 of N-d1methoxy 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)
wherein m represents an integer of 1-5, R represents a hydrogen atom or 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 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 "C1-3 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 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 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 by the process of this invention Include the following :
We conducted trials on the effects of the inhibition of the gastric secretion, the inhibition of the add output and the inhibition of Indomethacin-induced gastric ulcer on the compounds of this invention compared with the known compounds and the 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 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)
Compound Dose No. of Volume * Inhiibition rate
(mg/kg) rats (ml) (%)
Control - 5 4.62±0.40 -
Mifentidlne 10 5 2.34±0.23 Λ 50
30 5 2.04±0.36 Λ 56
100 6 2.18±0.25 Λ 52
Famotidine 10 .6 2.50±0.22 A 46
30 5 2.74±0.20 Λ 41
100 6 2.62±0.38 Λ 43
Cimetidine 10 5 3.61±0.30 Λ 22
30 6 3.33±0.86 28
100 5 2.20±0.36 Λ 52
Ranitidine 10 5 4.16±0.41 10
30 6 3.72±0.71 19
100 6 3.17±0.30 Λ Λ 31 150 5 3.82±0.48 17
200 5 5.05±0.76 -9
Compound(1) 10 6 3.74±0.40 ΛΛ 19 of this 30 6 3.88±0.31 Λ 16 invention 50 5 2.28±0.47 Λ 51
70 6 1.95±0.16 Λ 58
100 6 1.84±0.51 Λ 70
150 5 1.06±0.15 Λ 77
200 6 0.71±0.15 Λ 85
* : Mean ± S. E.
Λ: Significantly different from the control. (P<0.01)
Λ Λ: 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-NaOH)
Compound Dose No. of Acid output* Inhibition rate
(mg/kg) rats (μEq/hr) (%)
Control 5 77.25±7.37 -
Mifentidine 10 5 29.50±5.20 Λ 62
30 5 26.24±5.05 Λ 66 100 6 21.66±5.40 Λ 72
Famotidine 10 6 27.23±3.14 Λ 65
30 5 28.70±1.45 Λ 63
100 6 24.22±3.29 Λ 69
Cimetidine 10 5 48.61±5.66 Λ 37
30 6 47.68±7.56 Λ 38
100 5 31.75+6.75 Λ 59
Ranltidine 10 5 52.34±5.49 32
30 6 47.06±12.37 39
100 6 20.49±3.60 Λ 73
150 5 33.04±8.81 Λ Λ 57
200 5 58.25±11.44 25
Compoundd) 10 6 54.90±6.65 Λ 29 of this 30 6 51.50±8.18 Λ 33 invention 50 5 30.82+6.62 Λ 60
70 6 26.57±3.00 Λ 66
100 6 12.69±5.12 Λ 84
150 5 6.48±1.58 Λ 92
200 2 1.96±1.40 Λ 97 ± : Mean ± S.E.
Λ : Significantly different from the control. (P<0.01)
Λ Λ : 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 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 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 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
Compound Dose No. of erosion* Inhibition rate
(mg/kg) rats index(mm) (%)
Control - 6 10.38±2.21 -
Famotidine 1 6 8.95±5.20 14
3 6 2.20±1.09 Λ 79
10 5 0.67±0.22 Λ 94
30 5 0.56±0.22 Λ 95
100 5 1.01±0.14 Λ 90
Cimetidine 10 6 7.70±1.59 29
30 6 1.09±0.37 Λ 89
100 5 2.92±0.78 Λ 72
Compound(1) 1 6 8.80±2.94 15 of this 3 6 5.01+1.92 52 invention 10 6 2.19+0.37 Λ Λ 79
30 6 2.45+0.32 Λ Λ 76
50 6 0.51+0.26 Λ 95
70 6 0.44+0.16 Λ 96
100 6 0.58+0.51 Λ 94 ± : Mean ± S.E.
Λ: Significantly different from the control. (P<0.01)
ΛΛ : 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 compound(1) with 1% CMC solution.
Food and water freely provided for two weeks and observed mice. The LD50 values are then calculated by the method of Litchfield - Wilcoxon. As the result the LD50 value of the compound(l) 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 (i) can be produced by the following processes. H
In the above formulae, m, R and R1 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), then 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.
In the above formulae, m, R and R1 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 presence of phosphorus penta chloride at a temperature of 80º to 100ºC. 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 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 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 : 60%
* Property and melting point : white crystal, 120°C-130°C
* 1H NMR (DMSO-d6)
δ2.72 (2H, t, -CH2-)
δ3.35 (2H, q, -CH2-)
δ3.5 (1H, br.S, -NH-)
δ3.68, S 3.71 (6H, S, -OCH3)
δ6.82 (2H, S, imidazole -H)
δ 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) imidazole 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 (CDCl3)
δ1.8 (3H, S, -CH3)
δ3.05 (6H, m, -CH2CH2-)
δ3.86, δ4.0 (14H, S, -OCH3 , - CH2-) 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.
N - [2 - (3,4 - dimethoxy phenyl) ethyl] - N' - [4 - imidazol -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 1.5grams 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 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 undnr 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 (DMSO-d6)
δ2.35 (S, 3H, CH3)
δ2.84 (t, 2H, CH2)
δ3.55 (t, 2H, CH2)
δ3.80 (S, 6H, -OCH3)
δ 6.85 (S, 2H, aromat.)
δ6.84, δ7.0 (s, 2H, aromat.)
δ 7.22 (S, 1H, imidazole -H)
δ 7.52 - 7.68 (m, 4H, aromat.) 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 chrormatograph .(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 : 155ºC
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 (CDC13)
δ1.85 (s, 3H, CH3)
δ2.84 (t, 2H, CH2)
53.55 (t, 2H, CH2)
δ3.80 (s, 6H, -OCH3)
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

WHAT IS CLAIM IS :
1. A compound of the general formula (I) and pharmacologically acceptable acid addition salt thereof.
wherein m represents an integer of 1 to 5, R represents a hydrogen atom or C1-3lower alkyl group, and R1 represents a hydrogen atom, C1-3lower alkyl. group, aryl group, mono or dimethoxy phenyl alkyl group (wherein alkyl represents C1-3 lower alkyl).
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] - 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) 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.
wherein m, R and R1 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 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 R1 are as defined in claim 1.
EP91907721A 1990-07-12 1991-04-06 N-dimethoxy phenyl alkyl-n'-imidazolyl phenyl amidine derivatives and process thereof Withdrawn EP0538262A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR9010522 1990-07-12
KR1019900010522A KR920004935B1 (en) 1990-07-12 1990-07-12 Method of producing for n-dimethoxy phenyl alkyl-n'-imidazolyl-phenyl amidine

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KR (1) KR920004935B1 (en)
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WO (1) WO1992000966A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4225724A (en) * 1977-01-07 1980-09-30 Westwood Pharmaceuticals, Inc. 1-(2-Phenylureylene)imidazoles
IT1209431B (en) * 1980-11-28 1989-07-16 Angeli Inst Spa IMIDAZOLYLPHENYL AMIDINE, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL USE, AND INTERMEDIATE PREPARATION.

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* Cited by examiner, † Cited by third party
Title
See references of WO9200966A1 *

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JPH06104660B2 (en) 1994-12-21
AU646040B2 (en) 1994-02-03
KR920004935B1 (en) 1992-06-22
KR920002551A (en) 1992-02-28
JPH06501676A (en) 1994-02-24
WO1992000966A1 (en) 1992-01-23

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