CS244150B2 - 2-substituted 4-phenylimidazole's new amidine derivatives production - Google Patents

Description

(1) where.

R represents a straight or branched (C1 -C4) alkyl group, a hydroxy group, a C1 -C3 alkoxy group, a mercapto group, a C1 -C3 alkylthio group, a halogen atom, a C1 -C3 alkylleulfinyl group, a sulfamoyl group a group or amino group which may be substituted by an alkyl group having 1 to 3 carbon atoms, an oetamido group or a phenyl group,

R 6 and R 8, which may be the same or different, represent a hydrogen atom or a C 1 -C 3 alkyl group, a straight or branched C 1 -C 3 alkyl group, a hydroxyl-substituted C 1 -C 3 alkyl group, an alkoxyalkyl group , alkylthioalkyl or cyanalkyl, wherein each alkyl moiety contains 1 to 3 carbon atoms, 3 to 5 carbon alkenyl, 3 and 4 carbon alkynyl, cyano, phenyl, halophenyl, benzyl, 3-cycloalkyl up to 3 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety, a furfuryl group or a pyridyl group,

R @ 1 represents a hydrogen atom, a C1 -C3 alkyl group, a C1 -C3 alkoxy group, a halogen atom, a cyano group or a carbamoyl group, the tautomeric forms and their acid addition salts.

Acid addition salts for pharmaceutical use are physiologically tolerable acid addition salts. The term acid addition salts includes salts with inorganic or organic acids. Suitable physiologically compatible acid addition salts include, for example, salts formed with acetic acid, maleic acid, fumaric acid, citric acid, hydrochloric acid, tartaric acid, hydrobromic acid, nitric acid or sulfuric acid.

It is to be understood that for the sake of simplicity, the description of the invention will refer to either the base or the corresponding salt form.

It should further be pointed out that although in the general formula I the double bond in the amidine group and in the imidazolyl ring has been added to a certain position, other different tautomeric forms are possible. In addition, the compounds in which R is hydroxy or mercapto may be in the form of the corresponding imidazolinone or imidazolithione. The present invention encompasses such tautomeric forms in relation to the compounds as well as the process for their preparation.

In the compounds of formula I, when R is a straight or branched alkyl group, it may be an alkyl group having 1 to 4 carbon atoms, and when R R and Rg are an alkyl group it may be an alkyl group having 1 to 3 carbon atoms if Rj is an alkyl group. a linear or branched alkyl group, the group may contain 1 to 3 carbon atoms, and preferably may contain oxygen atoms such as a hydroxypropyl or methoxyethyl group, a sulfur atom such as a methylthioethyl or ethylthioethyl group, a nitrogen atom such as for example, in a cyanoethyl group, when R ^ represents an alkenyl group, it may contain 3 to 5 carbon atoms, if the 3® alkynyl group may be in the form of an alkynyl group containing 3 or 4 carbon atoms, if Rj represents a cycloalkyl or cycloalkylalkyl containing 3 to 6 carbon atoms, R1 may also represent a phenyl group, preferably substituted by chlorine and R1 may also be a benzyl group, the aromatic portion of which may be substituted and R1 may also represent a furfuryl or pyridyl group.

In the general formula, the amidine group may be at the ortho, meta or para position of the benzene ring relative to the imidazolyl group and at any position in the benzene ring.

244,50

The compounds of formula (Ie) according to the invention are prepared by leaving a compound of formula (IV)

(IN)

R where

R, Rp, Hg, and R6 are as defined above and

B denotes a suitably unsubstituted group, e with an amine of the formula VI ^Η 2 ^Ν - ^Η 3 (VI) where

R ₃ is as defined above.

In the compound of formula (VB), it is preferably a leaving group such as an oxy group, an acetyl group, an ethoxycarbonyl group or a carbamoyl group.

The reaction according to the invention is usually carried out in the presence of water or an inert organic solvent, for example an alcohol such as methanol or ethanol, formamide, dioxane or acetonitrile. This reaction can be carried out, for example, at a temperature of from 10 to 50 ° C, preferably at room temperature. .

The compounds of formula (V) used as starting materials in the above process may be prepared by methods known in the literature, for example by reaction with a compound of formula (II).

where

R, R, and R R are as defined above, with the N-substituted ethylimidate of formula VII

EtO kde

R 1 and B are as defined above, and Et is ethyl, or optionally when B is cyano in the formula (V), the reaction may also be carried out in one step by reacting a compound of formula II with cyanamide in the presence of a compound of formula VIIIa.

R ₂ -C

(Vlil) where

R ₂ výěe my abovementioned meaning and

I denotes a lower alkyl group such as a methyl or ethyl group.

The reaction is generally carried out in the presence of a suitable inert organic solvent, such as an alcohol, ethers, ethyl acetate, acetonitrile or dioxane, or is carried out without solvent at a temperature of from 20 to 80 ° C. The compound of formula (VII) may be prepared by conventional methods.

The compounds of the formula I prepared according to the invention can optionally be converted by reaction with inorganic or organoacid acids into the corresponding physiologically acceptable acid addition salts, for example by methods known per se, for example by reacting the base compounds with a solution of the corresponding acid in a suitable solvent. Suitable acids include, for example, hydrochloric acid, sulfuric acid, butyric acid and fumaric acid. The compounds of formula I and their physiologically tolerated acid addition salts block the Hg-receptor and prevent the secretion of gastric gels.

Claims (2)

Representative examples of preferred compounds of the invention, for their superior effects as antisecretory and anti-ulcer agents and for treating gastrointestinal tract disorders are: N-ethyl-N '- [4- (2-methyl-4-imideaolyl) phenyl] formemidine (compound 2), R-i-propyl-N'-Q4- (2-methyl-4-iraidazolyl) phenylformamidine (compound 3), f {-allyl-N '- [4' (2-methyl-4-imidazolyl) phenyl] formamidine (compound 4), N-tert-butyl-N '- (N- (2-methyl-4-imidazolyl) phenyl) formamidine (compound 39), N-isopropyl-N '- [1- (2-hydroxy-4-imidezolyl) phenylformamide] (compound 28). The antagonistic effect of the compounds of the invention against the H ₂ -receptors of hlamine is shown either in vitro or in vivo by inhibition of the H ₂ -dependent biological effects, which includes hiememin-induced positive ehronotropic effect and histamine-induced gastric acid secretion. The depression of the positive chronotropic effect was investigated in an isolated guinea pig heart chamber, suspended in saline (50 ml) containing oxygenated (0: 959 - CO ₂ : 59) Xrebs-Henseleit solution (pH 7.4), maintained at 32 ° C. C. The myocardial waffle, loaded with 1 g of isometric traction, was allowed to stabilize for 60 minutes, and then myocardial contractions were recorded by an isometric lever associated with a spring tensometer and the instantaneous velocity was monitored by a cardiotachorometer and a thermal tip recording device. After two control responses to histamine (10 ~ ® g.ml ^- ") were added to the bath tsstovaná compound in the desired final chitosan concentrations and allowed 30 minutes before the atria are again brought into contact with histamine. The chronotroonic responses obtained in the presence of the antagonist were compared to a control response to histamine and the percent reduction in histamine-induced response (Hg) was calculated. The average effective concentration (EC ^ g) of Hg antagonists is also calculated according to the standard procedure of Dr. Vauda, Dose-Curve Analysis, Methode in Fharmacology, Volume 3: Smooth Muscles, ed. Daniel EE, Paton. M., Plenum Press, New York (1975), Ash and Schild, Br. J. Pharmacol. Chemother. 27, 427-429 (1966). The results are shown in the following table. In vivo inhibitory effect on histamine-induced tachycardia (guinea pig atrium) Compound EC 50 g ^M 2 1.5 3 1,8 4 1,2 39 4.0 28 1.94 Cimetidine 34.0 The ability of test compounds to inhibit histamine-induced gastric acid secretion was observed after intravenous or intraduodenal administration to the stomach of perfused rats, according to Gosh and Schlud (Br. J. Pharmacol. Chemother, 13, 54, 1958). Preparation of the animals in the complete anesthesia (urethane, 1 g.kg ^- 'i.p.) and constant temperature, consisting in the introduction and attachment of polyethylene tubing (PE 50) in the esophagus and into pylorickoantrálnl area. After the stomach is washed to remove food debris was carried kontrinuální stomach perfusion with saline, 0.5 ml min ^- '(37 ° C) using Joblingova peristaltiekého pump. After 30 minutes from the start of perfusion, the stomach perfusate was collected into the samples after 30 minutes and titrated to the acid content expressed as µEkv. 1 N NaOH. As a control, constant intravenous histamine puffs (1 mg.kg ^- 'h ^- ') maintained during the experimental period were used. After the acid secretion reached a consistently higher level, increased doses of the test compound were administered by intravenous injection to obtain a dose-dependent function. Then EDgg · The results are shown in the following table. . Table II In vivo antisecretory effect on histamine-induced gastric secretion (stomach of perfused rats)