Method for producing imidazolylphenyl amidine derivatives or acid-additive salts thereof

专利摘要:
Object of the present invention are new pharmacologically active amidine derivatives of 2-substituted 4-phenylimidazole of formula …<CHEM>… in which R representa a linear or branched alkyl group, a hydroxy group, a C1-3 alkoxy group, a mercapto group, C1-3 alkylthio group, a halogen atom, a C1-3 alkylsulfinyl or alkylsulfonyl group, a sulfamoyl group, an amino group which may be substituted by one or two alkyl groups having 1 to 3 carbon atoms, an acylamino group or a phenyl group; R1 and R2, which may be the same or different, represent a hydrogen atom or an alkyl group; R3 represents a linear or branched alkyl group containing optionally one heteroatom such as an oxygen, a sulphur or a nitrogen atom, an alkenyl group, an alkynyl group, a cyano group, an aryl or an aralkyl group optionally substituted, a cycloalkyl or cycloaliphatic alkyl group, a substituted or unsubstituted heterocyclilalkyl or heterocyclic group; R4 represents a hydrogen atom, a C1-3 alkyl or alkoxy group, a halogen atom, a cyano or carbamoyl group, tautomeric forms thereof and acid addition salts thereof. …<??>Processes for the preparation of the compounds of formula (1) and their intermediates as well as the pharmaceutical compositions containing them are also object of this invention. …<??>The new compounds are H2-receptor blocking agents which inhibit the gastric acid secretion and are useful antiulcer agents.
公开号:SU1313345A3
申请号:SU853844125
申请日:1985-01-29
公开日:1987-05-23
发明作者:Бьетти Джузеппе；Череда Энцо；Донетти Артуро；Джакетти Антонио；Пагани Фердинандо
申请人:Институто Де Анджели С.П.А. (Фирма)；
IPC主号:

专利说明:

one
The invention relates to a process for the preparation of new imidazole-containing compounds having valuable pharmacological properties, in particular, to a process for the preparation of imidazolylphenylamidine derivatives of the general formula
 C- iH-Bi H
Found,%: C 56.17; H 5.00; N 12.08.
where R is hydroxyl, C, -C-alkyl;
R, -C, -C-alkyl, allyl,
or their acid addition salts, which are a agent blocking the receptor and are suitable as an inhibitor of the secretion of gastric acid and antifungal 4-yl) -phenyl-formamidine (compound Cj, H, 4N40g.
Calculated,%: C 55.93; H 5.12; N 11.86.
Nn-hexyl-N (2-methyl-imidaz
facilities,
The aim of the invention is to obtain new imidazole-containing compounds having better properties than cimetidine, a compound of a similar structure, having the same type of activity.
Example. Creeping N-methyl-N (2-methyl-imidazol-4-yl-phenyl - formamidine (compound 1).
2.25 g of N-cyano-K-4- (2-methyl-imidazol-4-yl) -phenyl-formamidine are added in one portion to 22.5 ml of a 33% aqueous solution of methylamine. After 10 minutes, the separated solid is filtered, washed with water and dried. 1.2 g of the title compound are obtained.
Maleate (ethanol). T. pl. 173-174 C (decomposition).
Found,%: C 54.07; H 4.79; N 12.31.
 .
Calculated,%: C 53.81; H 4.97;
N 12.55.
The following compounds are prepared analogously. N-Ethyl-M - 4- (2-methyl-imidazol-4-yl-phenyl-formamidine (compound 2).
Maleate (ethanol). M.p. 166-168 C (decomposition).
Found,%: C 54.49; H 5.21; N 12.38.
C2, Hj, N403.
Calculated,%: C 54.78; H 5.25; N 12.17. .
N-Haonponkn-N (2-methyl-imidazol-4-yl) -phenyl 3 Formamidine (compound 3).
5).
Maleate (acetone). M.p. 127-130 С (decomposition).
Found,%: C 57.87; H 6.24; 25 N 10.62-.
,, n, og,
Calculated,%: C 58.13; H 6.24; N 10.85.
30 N-ethyl-N (2-ethyl-imidazol-4-yl) -phenyl-formamidine (compound
Maleate (ethanol). M.p. 165-167 (decomposition).
Found,%: C 55.78; H 5.51;
35
N 11.59.
.N.Og.
Calculated N 11.81.
%: C 55.69; H 5.52;
40
45
50
55
N-isopropyl-N (2-ethyl-imidazol-4-yl) -phen formate -formamidine (compound 7).
Maleate (ethanol). M.p. 180-181 C (decomposition).
Found %: C, 56.95; H 5.79; N 11.30.
.aN.Og.
Calculated,%: C 56.55; H 5.78; N 11.47. ,
M-Ethyl-H (2-isopropap-imide-ZOL-4-IL) -phenyl-formamidine (compound 8).
Maleate (ethanol). M.p. 174-175 (expansion).
Found,%: C 56.73; H 5.87; N 11.60.
Ci HjgN Og Calculated,%: C 56.55; H 5.78; N 11.47.
Maleate ethanol Etc. 192-193 ° C (decomposition).
Found,%: C 55.84; H 5.59; N 11, 63.
CiiH.gN.Og.
Calculated,%: C 55.69; H 5.52; N 11.81.
M-Allyl-H (2-methyl-imidazol-4-yl) -phenyl 1-formamidine (compound 4).
Maleate (ethanol). M.p. 170-171 C (decomposition).
Found,%: C 56.17; H 5.00; N 12.08.
4-yl) -phenyl-formamidine (compound Cj, H, 4N40g.
Calculated,%: C 55.93; H 5.12; N 11.86.
Nn-hexyl-N (2-methyl-imidazol4-yl) -phenyl-formamidine (compound 5).
Maleate (acetone). M.p. 127-130 С (decomposition).
Found,%: C 57.87; H 6.24; N 10.62-.
,, n, og,
Calculated,%: C 58.13; H 6.24; N 10.85.
N-Ethyl-N (2-ethyl-imidazol-4-yl) -phenyl-formamidine (compound 6).
Maleate (ethanol). M.p. 165-167 C (decomposition).
Found,%: C 55.78; H 5.51;
N 11.59.
.N.Og.
Calculated N 11.81.
%: C 55.69; H 5.52;
N-isopropyl-N (2-ethyl-imidazol-4-yl) -phen formate -formamidine (compound 7).
Maleate (ethanol). M.p. 180-181 C (decomposition).
Found %: C, 56.95; H 5.79; N 11.30.
.aN.Og.
Calculated,%: C 56.55; H 5.78; N 11.47. ,
M-Ethyl-H (2-isopropap-imide-ZOL-4-IL) -phenyl-formamidine (compound 8).
Maleate (ethanol). M.p. 174-175 C (expansion).
Found,%: C 56.73; H 5.87; N 11.60.
Ci HjgN Og Calculated,%: C 56.55; H 5.78; N 11.47.
31
N-isopropyl-M (2-Igupropyl-imidazol-4-yl) -phenyl-formamidine (compound 9).
Maleate (ethanol). M.p. 168-170 ° C (decomposition).
Found,%: C 57.02; H 6.10; N 11.28.
C, 4H, oN, Og.
Calculated,%: C 57.36; H 6.02; N 11.13.
M-Isopropyl-H - 4- (2-methyl-imide sol-4-yl) phenyl-J-acetamidine (compound 1).
Maleate (ethanol). M.p. 106-108 C (decomposition).
Found,%: C 56.67; H 5.76; N 11, 55.
23 H e v - e
Calculated,%: C 56.55; H 5.78;
N 11.47. ,
M-Ethyl-M (2-methyl-imidazole-4 -) - phenyl formamidine (compound M
Maleate (acetone). M.p. 171-173 C (decomposition).
Found,%: C 54.61; H 5.19; N 11.98.
Cj, H.N.Og.
Calculated,%: C 54.78; H 5.25; N 12.17.
N-Hsonponmi-N-3- (2-methyl-imide ZOL-4-IL) -phenyl-formamidine (compound 12).
Maleate (acetone). T. Il. 168-171 ° (decomposition).
Found,%: C 55.44; H 5.48; N And 69.
 Cj H 6N408.
Calculated,%: C 55.69; H 5.52; N 11.81.
M-Isopropyl-M (2-hydroxy-imidazol-4-yl) -phenyl-formamidine (compound 13).
Maleate (acetone). M.p. 2 1-213 ° C (decomposition).
Found,%: With 56.47; H 5.69; N 15.58.
€, N, „N, 05.
Calculated,%: C 56.66; H 5.59; N 15.55.
N-tert-Butyl-N (2-methyl-imidazol-4-yl) -phenyl-formamidine (Compound 14).
Sulfate (methanol), mp, 276-278 ° C (decomposition).
Found,%: C 50.79; H 6.31; N 15.77,
c, N „N4045.
0
five
0
five
0
five
0
Calculated} 1o,%: C 50.84; H 6.26; N 15.81,
Biological experiments.
The antagonistic activity of new compounds in experiments (in vitro) and on H, histamine receptors is confirmed (in vivo) by inhibiting H-dependent biological effects including histamine-induced positive chronotropic effect and histamine-induced secretion of gastric acid.
A positive chronotropic effect is examined in isolated atria of guinea pigs suspended in a 50 ml bath containing an oxidized (O. 95%; CO 5%) Krebs-Genseleit solution, having a pH of 7.4 and a temperature of 32 ° C. A myocardial drug with an isometric tension of 1 g is stabilized for 60 minutes and the myocardial contraction is recorded through an isometric lever connected to a strain gauge, the heartbeat is recorded with a cardiotachometer. After a two-fold control reaction to histamine (10 gml), the test compounds are added to the bath at the desired concentration and after 30 minutes the atria are again treated with histamine. The chronotropic reaction that is obtained in the presence of an antagonist is compared with the control reaction to histamine, and the percentage reduction in the reaction that is caused by histamine is determined from the data obtained. In addition, the average effective concentration (EC50) of the antagonist H is determined by the usual method.
Inhibition of histamine-induced tachycardia is given in Table 1.
Table I
45
50
five
14
7
5.1
4.0 12.0
13
Cimetidine
1.94 34.0
The ability of the test compounds to inhibit the secretion of gastric acid, caused by hista-) mines, is investigated after an intravenous or intraduodenal administration to rats in which perfusion is performed through the stomach. At the same time, a polyethylene tube is introduced into the aerophageal and pyrolysis-antral zone of anesthetized animals (1 g kg of urethane, intraperitoneally). After washing the stomach to remove food debris, a continuous gastric perfusion is started using 0.5 ml f min of saline at 37 ° C. After 30 minutes from the start of perfusion, samples are collected every 30 minutes, which are titrated for acid content, expressed as µeq 1N. NaOH. After a constant acid content is reached, intravenous histamine perfusion (1 mg-kg, h) begins and continues until the end of the experiment. After achieving a consistently high degree of acid secretion, the test compounds are injected intravenously in increasing doses, with a further detection of the dose-response ratio. The effective dose is then determined (). The antisecretory activity in the isolation of gastric acid, caused by histamine in vivo, is given in Table 2.
table 2
0.032 0.067 0.025 0.219 0.080
Cimetidine
0.187 0.065 0.560
Compounds were given as base.
LDjo cimetidine is 150 mg / kg (intravenously, in mice). In biological experiments, the LD5Q of the new compounds is 85-120 mg / kg.
Table 3 shows the toxicity data.
Table 3
50

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining imidazolylphenylamidine derivatives of the general formula
w () N with l
55 Ifl
where R is hydroxyl, C, -C-alkyl;
  f-1 Sat-alkyl,
allyl
or their acid addition salts, characterized in that the compound of the general formula
 //
N C- 3H-CN I
n
-x
where R has the specified value, is subjected to interaction with the compound of the General formula
HjN R,
where R, has the specified value, followed by separation of the target product in free form or in the form of a salt.
Compiled by G.Zhukova Editor L.Gratillo Tehred I.Popovich Corrector M.Sharoshi
1983/58
Circulation 372Subscribe
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, Projecto st., 4

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法律状态:

优先权:

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