FR2772378A1 - DERIVATIVES OF IMIDAZOLE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The invention concerns a compound of formula (I) in which: R1 and R2 represent, independently of each other, a hydrogen, a C1-6 alkyl group, linear or branched, or together form a polymethylene -(CH)n- group, n ranging between 3 and 6; and R3 represents a hydrogen or halogen atom or a C1-C4 alkyl group, linear or branched, in the form of enantiomer, diastereoisomer or a mixture of those different forms including racemic mixture and its N-oxide derivatives and its additive salts to pharmaceutically acceptable acids. The invention is applicable in therapeutics.

Description

dans laquelle
R1 et R2 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe C16 alkyle, linéaire ou ramifié, ou ensemble forment un groupe polyméthylène -(CH2)n-, n pouvant prendre les valeurs de 3 à 6, et,
R3 représente un atome d'hydrogène, d'halogène ou un groupe C14 alkyle, linéaire ou ramifié.The present invention relates to imidazole derivatives of general formula (I)

in which
R1 and R2 represent, independently of each other, a hydrogen atom, a C16 alkyl group, linear or branched, or together form a polymethylene group - (CH2) n-, n can take the values of 3 to 6, and,
R3 represents a hydrogen atom, a halogen atom or a linear or branched C14 alkyl group.

The halogen atoms can be fluorine, chlorine, bromine or iodine.

In the context of the present invention, the term C16 alkyl is understood to mean a saturated, linear or branched, aliphatic group comprising from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl or isopropyl, n butyl, isobutyl, t-butyl, n-pentyl etc.

The compounds of general formula (I) may be in the form of free base, N-oxide or addition salts with pharmaceutically acceptable acids, which are also part of the invention.

The compounds of general formula (I) contain one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers.

These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

The compounds of the invention can be prepared by
processes illustrated in the following diagrams, including the
operating conditions are conventional for the man from
job.

et l'alcoolate de 3-quinuclidinol

In Scheme 1, R and A0 respectively represent

and 3-quinuclidinol alkoxide

An epoxide of formula (II) is reacted successively with triflic acid in dimethylsulfoxide and then with diisopropylethylamine to yield hydroxyketone (III) according to the method described by BM Trost in
Tetrahedron letters 29 (1988), 18, 2163-66.

The hydroxyketone (III) II) is opposed to an arylurea (RNHCONH2) at 1800C in hexanol, optionally in the presence of molecular sieve (4A), to give the imidazolone (IV).

This imidazolone (IV) can also be obtained from the α-haloketone (V), by successive reactions of potassium phthalimide and then concentrated hydrobromic acid and acetic acid, to lead first to the hydrobromide of the aminoketone (VI) which by treatment with phenyl isocyanate (RNCO) in pyridine or dimethylformamide results in the compound (IV).

Alternatively, when R2 represents a linear or branched C16 alkyl group, the compound of formula (IV) may be prepared as shown in scheme 2, according to the method described in patent US 3432520, R2 'representing a hydrogen atom or a hydrogen atom. C15 alkyl group.

Figure 2

According to this scheme 2, a propargylamine of formula (XV) is reacted with phenyl isocyanate (R 3 -C 6 H 6 -NCO) in toluene to yield urea (XVI) which, by treatment with an alkaline alkoxide, such as that sodium methoxide or ethoxide or potassium tert-butoxide in the corresponding alcohol causes a rearrangement followed by a cyclization to lead to imidazolone (IV).

The imidazolone (IV) is then refluxed with phosphorus oxychloride, optionally in the presence of phosphorus pentachloride or gaseous hydrochloric acid, to yield chloroimidazole (VII).

The condensation of chloroimidazole (VII) with an alcoholate of formula AO-, formed by the action of a non-nucleophilic base such as sodium hydride on a 3-quinuclidinol (AOH), is carried out in dimethylformamide at temperatures between 20 and 1200C (oil bath or microwave oven) to give the compounds of formula (I).

Alternatively, the compounds of formula (I) can be obtained from alphahaloketone of formula (V) which is thermally condensed at a temperature ranging from 1600C to 1800C, with formamide, to give imidazole (VIII).

This imidazole (VIII) is then subjected to the triphenyl action of bismuth ((R) 3Bi) in the presence of copper acetate and triethylamine in dichloromethane to give imidazole (IX).

The proton in position 2 of this imidazole (IX) is then torn off with butyllithium in tetrahydrofuran at temperatures between -78 and -100C. The anion thus formed is trapped by means of dimethyl disulphide to yield the sulphide (X).

The sulphide (X) is oxidized to sulphone (XI) by the action of loxoxons (potassium peroxymonosulphate) in the presence of wet alumina.

The condensation of the sulfone (XI) with an alcoholate of formula AO-, formed by the action of a non-nucleophilic base such as sodium hydride on a 3-quinuclidinol (AOH), is carried out in dimethylformamide at temperatures between 20 and 1200C, to yield compounds of formula (I).

The racemic 3-quinuclidinol (HA) as well as the enantiomer (R) are commercially available. The (S) -enantiomer is obtained from G. Lambrecht, Arch. Pharm (1976), 309 (3), 235 and Eur. J. Med. Chem (1979), 14 (2), 111.

The other raw materials are directly commercially available, are known in the literature or can be synthesized by methods known to those skilled in the art.

The following examples illustrate the methods and techniques used for the preparation of this invention, without, however, limiting the scope of the claim. The elemental microanalyses and the NMR and IR spectra confirm the structures of the compounds obtained.

Example 1: 2-Hydroxycyclohexanone
9.8 g (0.1 mol) of cyclohexene oxide in 75 ml of dimethylsulfoxide are cooled in an ice bath and a solution of 9 ml (0.1 mol) of triflic acid in 25 ml of dimethylsulfoxide is added. minutes. Allowed to warm to room temperature and stirred again for 2 hours.

150 ml of dichloromethane are added, cooled to -780C and added over 30 minutes, 87 ml (0.5 mol) of diisopropylethylamine. Allowed to warm to room temperature, stirred again for 1 hour and poured into 1500 ml of a solution of 10% sodium bisulfate. It is extracted with dichloromethane, dried over magnesium sulphate and then evaporated.

The residual oil is purified by flash chromatography on silica gel, eluting with methylene chloride and recovering 4.5 g of product.

Example 2: 1-Phenyl-1,3,4,5,6,7-hexahydro-2H-benzimidazol-2-one
A mixture of 4.5 g (39.4 mmol) of 2-hydroxycyclohexanone, 7.5 g (55 mmol) of phenylurea and 7 ml of hexanol is stirred under reflux for 20 hours. It is concentrated under vacuum and the solid residue is recrystallized in acetone and 2.5 g of product are recovered. melting point: 2200C)
Example 3: 2-Aminocyclohexanone hydrobromide
A mixture of 50 g (0.27 mol) of potassium phthalimide, 50 g (0.27 mol) of 2-chlorocyclohexanone and 200 ml of dimethylformamide is stirred at 950 ° C. for 8 hours. It is poured into ice water, ether is added and the mixture is stirred until crystallization of the product. It is drained, washed with water and with ether, dried under vacuum. 40 g of 2- (2-oxycyclohexyl) -1H-isoindole-1,3 (2H) -dione (curtion DY, J. Am.Chem.Sc. (1955), 77, 1105-10) are obtained.

(melting point: 155 C)
A 40 g mixture is stirred under reflux for 4 hours.
<0.16 mol) of the above product in 200 ml of acetic acid and 200 ml of 48% hydrobromic acid. It is cooled in an ice bath, filtered phthalic acid and concentrated under vacuum.

The evaporation residue is taken up in 100 ml of ethanol and 100 ml of toluene and then concentrated in vacuo. This operation is repeated until a well crystallized residue is obtained.

It is taken up with an alcohol / ether mixture 50:50, filtered, dried under vacuum. 20 g of product are obtained.

(melting point: 1530C)
Example 4: 1-Phenyl-1,3,4,5,6,7-hexahydro-2H-benzimidazol-2-one
A mixture of 1.94 g (0.01 mol) of 2-aminocyclohexanone hydrobromide, 1.19 g (0.01 mol) of phenyl isocyanate and 4 ml of pyridine is stirred at 125 ° C. for 4 hours.

Water is added, stirred until crystallization, drained, washed with water and dried. The compound is purified by flash chromatography on silica gel, eluting with a 95: 5 dichloromethane / methanol mixture. 0.7 g of product is recovered.

 (melting point: 224 ° C).

Example 5: 2-Chloro-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole
A mixture of 2.3 g is stirred under reflux for 6 hours.
(0.0107 mol) 1-phenyl-1,3,4,5,6,7-hexahydro-2H-benzimidazol-2-one and 30 ml of phosphorus oxychloride
(POCl 3) The excess phosphorus oxychloride is evaporated under vacuum and the residue is hydrolyzed with water and concentrated ammonia. Extracted with dichloromethane twice, the residue is evaporated and purified by flash chromatography on silica gel with a heptane / ethyl acetate 80:20 eluent. 0.8 g of product is recovered.

Example 6 4,5,6,7-Tetrahydro-1H-benzimidazole
To 50 g (0.377 mol) of 2-chlorocyclohexanone placed in a 1 liter tricolor is added 400 ml of formamide and then the mixture is heated at 180 ° C. for 2 hours and 30 minutes The medium which has returned to ambient temperature is poured onto a solution 1 N sodium hydroxide (380 ml) This medium is then placed in a continuous liquid-liquid extractor and extracted with 400 ml of ethyl acetate for 6 hours The organic phase is dried over magnesium sulfate, concentrated under vacuum then purified by chromatography on silica gel using a gradient (5 to 10% methanol in dichloromethane).

10.2 g of product are obtained in gum form.

Example 7: 1-Phenyl-4,5,6,7-tetrahydro-1H-benzimidazole 250 mg (2 mmol) 4,5,6,7-tetrahydro-1H-benzimidazole, 1.1 g
(2.5 mmol) of triphenyl bismuth, 363 mg (2 mmol) of copper acetate and 203 mg (2 mmol) of triethylamine are stirred in 5 ml of dichloromethane at room temperature for 24 hours. 2 grams of silica are then added and the medium is concentrated under reduced pressure. The powder obtained is purified by chromatography on silica gel, eluting with a 95: 5: 0.5 dichloromethane / methanol / ammonia mixture. 315 mg of product is obtained.

Example 8: 2-Methylthio-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole
In a three-necked 100 ml under nitrogen, 2.36 g (12 mmol) of 1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole are added, 20 ml of tetrahydrofuran are added, and then the mixture is cooled to -78 ° C. C. 9 ml (14.3 mmol) of a 1.6 N solution of buthyllithium in hexane are then slowly added, stirred at -800 ° C. for 5 minutes and allowed to rise to -20 ° C. and stir again. minutes at this temperature. The reaction medium is then cooled to -80 ° C. and a solution of dimethyl disulphide (2.24 g, 24 mmol) diluted in 10 ml of tetrahydrofuran is introduced dropwise. at room temperature, then cooled to 0 ° C., 15 ml of water and then 15 ml of ethyl acetate are slowly introduced in. The phases are separated and then the aqueous phase is extracted twice with 10 ml of ethyl acetate. The combined organic phases are washed twice with 10 ml of water, once with 5 ml of brine and then dried over magnesium sulphate and concentrated in vacuo The crude reaction product is purified by chromatography on silica gel using as a solution eluting a gradient of 1 to 2% of methanol in dichloromethane, giving 2.17 g of product.

(melting point: 112)
Example 9: 2-Methylsulfonyl-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole 3.8 g of pre-moistened alumina, 7.07 g (11.5 mmol) of oxone and 10 ml of chloroform are vigorously agitated.

To this medium is added a solution of 2-methylthio-1-phenyl 4,5,6,7-tetrahydro-1H-benzimidazole solubilized in 10 ml of chloroform and further stirring under reflux for 2 hours. Cool to 00C then filter the mixture, rinse the solid with 10 ml of chloroform and 10 ml of a mixture of tetrahydrofuran / methanol: 9/1. The filtrate is concentrated under reduced pressure and then purified by chromatography on silica gel using a dichloromethane / methanol mixture 99/1 and 98/2. 0.65 g of product is obtained.

Example 10: (S) -3 - [(1-Phenyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl) oxy] quinuclidine 0.42 g (3.26 mmol) from (S) - quinuclidinol and 0.09 g (3.9 mmol) of 95% sodium hydride are gradually heated to 800C in 6 ml of anhydrous dimethylformamide for 30 minutes. After cooling to 5 ° C., 0.6 g are added
(2, 17 mmol) 2-methylsulfonyl-1-phenyl-4,5,6,7-tetrahydro-1H-benzimidazole, dissolved in 4 ml of anhydrous dimethylformamide. It is heated at 100 ° C. for 30 minutes, then left for 30 minutes at 700 ° C. It is cooled and poured on ice, the aqueous phase is extracted with ethyl acetate, washed with brine and dried over sodium sulphate. purified, after concentration, by chromatography on silica gel, eluting with a gradient of methanol in chloroform to give 0.21 g of product The difumarate is crystallized in acetone (aD = +16.9, c = 1.0025 (methanol))
Example 11 N-Phenyl-N'-prop-2-ynylurea
To a suspension of 50 ml (0.45 mol) of phenyl isocyanate in 160 ml of toluene, 25 g are added dropwise.
(0.45 mol) of propargylamine dissolved in 80 ml of toluene. The mixture is stirred for 1 hour 30 minutes, the precipitate is filtered off, washed with a little toluene and then dried in an oven under vacuum at 40 ° C. 70.7 g of product are obtained.

(melting point: 133 ° C)
Example 12: 5-Methyl-1-phenyl-1,3-dihydro-2H-imidazol-2-one
To a suspension of 10 g (0.062 mol) of N-phenyl-N'-prop-2-ynylurea in 140 ml of toluene is added 0.8 ml of 5.35 N sodium methoxide. The temperature is brought to reflux. for 4 hours. The solvent is evaporated and the solid residue is taken up with acetone. The product precipitates, filtered, washed with a little acetone, dried under vacuum at 500C.

6 g of product are obtained.

(melting point: 2070C)
The following table illustrates the chemical structures and the physical properties of certain compounds of formula (I) according to the invention.

Board

<tb> N <SEP> R1 <SEP> R2 <SEP> R3 <SEP> chirality <SEP> PF <SEP> Salt
<tb><SEP> (C)
<tb><SEP> 1 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> S (+) <SEP> 155 <SEQ> fumarate
<tb><SEP>&alpha; D = + 23.2
<tb><SEP> c = 1.002, <SEP> methanol
<tb><SEP> 2 <SEP> (CH2) 4 <SEP> H <SEP> Racemic <SEP> 180 <SEP> Fumarate
<tb><SEP> 3 <SEP> (CH2) 4 <SEP> H <SEP> R (-) <SEQ> 181 <SEP> Fumarate
<tb>&alpha; D = -18.9
<tb><SEP> c = 1.006, <SEP> methanol
<tb><SEP> 4 <SEP> (CH2) 4 <SEP> H <SEP> S (+) <SEP> 177 <SEP> Fumarate
<tb>&alpha; D = + 16.9
<tb><SEP> c = 1.0025, <SEP> methanol
<tb><SEP> 5 <SEP> C2H5 <SEP> C2H5 <SEP> H <SEP> Racemic <SEP> 170 <SEP> Fumarate
<tb><SEP> 6 <SEP> H <SEP> H <SEP> H <SEP> Racemic <SEP> 198 <SEP> Fumarate
<Tb>
The compounds of the invention have been the subject of pharmacological tests which have shown their interest as active substances in therapeutics.

In particular, they have been tested for their inhibitory effects on the binding of [3H] -N-methyl-scopolamine with human M3 muscarinic receptors transfected into CHO (Chinese hamster ovarian cells) cells (Buckley et al., Mol, Pharmacol 35: 469-476, 1989).

CHO cell membranes, in solution in a buffer
10 mM TRIS-HC1, 2 mM EDTA pH 7.2, expressing the human M3 muscarinic receptor subtype were provided by Receptor Biology (Baltimore, USA).

10 to 30 μg of membranes were incubated in phosphate buffer, pH 7.4 (Sigma, St. Louis, MO) in the presence of 0.5 nM [3 H] -N-methyl scopolamine (NEN-Dupont, Les Ulis). , France), and a compound of the invention, in a total volume of 1 ml.

The non-specificity of the binding was determined by 0.5 ux of atropine (Sigma, St. Louis, MO). Incubation (60 min at 25 ° C) was stopped by rapid filtration on filters
Whatmann GF / B by a Brandel filtration device. The filters were washed three times with 4 ml cold phosphate buffer, dried and the radioactivity was measured by liquid scintillation (scintillating Ultima Gold). The concentration of compound displacing 50% specific binding (IC50) was used to calculate the values of
Ki according to the Cheng-Prusoff equation. The effectiveness of each product studied is expressed by the negative logarithm of their
Ki (pKi).

The IC 50's of the compounds of the invention vis-à-vis the receptors
M3 are between 1 and 350 nM.

The compounds of the invention have also been studied as to their antagonistic effects against contractions of the female rabbit detrusor, mediated by M3 receptors.

Female rabbits (New Zealanders, 3-4 kg, ESD provider) approximately 20 weeks old were sacrificed by cervical dislocation and then exsanguinated. After opening the abdomen, the bladders were removed and then quickly placed in a solution of Krebs bicarbonated composition (mM): NaCl 114; KCl: 4.7; Cocoa2: 2.5; MgSO4: 1.2; KH2PO4: 1.2;
NaHCO3: 25; ascorbic acid: 1.1; glucose: 11.7. Propranol (1M), methylsergide (1M), ondansetron (1M), GR113808 (1M) were added to Krebs to inhibit ß-adrenergic receptors and the different subtypes, respectively. of serotonergic receptors 5-
HT1 / 5-HT2, 5-HT3 and 5-HT4. The bladders were cleaned, degreased then each face was cut into two longitudinal flaps about 4 mm wide and 15 mm long.

The tissues were then placed in 20 ml vats thermostatically controlled at 370 ° C. under carbogenic aeration (95% O 2, 5%).
CO2) and were subjected to a basal tension of 1 g.

Voltage was measured via isometric gauges (Hugo Sacks, type 351) connected to couplers
(Gould) which transforms and amplifies the answers that will be plotted on 4-track potentiometric recorders (Gould) and connected to a data acquisition system (Jad, Notocord). An equilibration time of about 45 minutes was observed during which the Krebs is renewed and the basal tension rectified.

After an equilibration period of 30 minutes, an initial contraction to carbachol (1 AM), a potent muscarinic agonist, was achieved. The tissues were then rinsed abundantly and after a further equilibration period of 30 minutes, the tissues were incubated for 30 minutes in the presence or absence of a compound of the invention to be studied (concentration 0.1 or 1 AM) before the realization of a concentration-response range to carbachol at intervals of half a log unit.

Concentrations producing half of the maximum effect
(EC50 (M)) were calculated for each range (absence or presence of the compound to be studied), then the power of the compound to shift the carbachol response curve was determined by a calculation of the affinity of the antagonist ( pKb or apparent pA2) according to the method of Furchgott (Handbook of
Experimental Pharmacology, 1972, 283-335)
The pKb of the compounds of the invention are between 7 and 9.5.

The results of the biological tests show that the compounds of the invention are muscarinic M3 receptor antagonists.

They can therefore be used in the treatment of irritable bowel syndrome, airway obstruction and bladder instability, especially urinary incontinence.

The compounds of the invention, in combination with suitable pharmaceutically acceptable excipients, may be presented in any form suitable for oral or parenteral administration, such as tablets, lozenges, capsules, capsules, suspension or oral or injectable solutions, and dosed to allow administration of 0.1 to 50 mg / kg per day.

Claims (4)

R3 represents a hydrogen atom, a halogen atom or a linear or branched C1-alkyl group, in the form of an enantiomer, a diastereoisomer, or a mixture of these different forms, including racemic mixture and its N-derivatives; oxide and its addition salts with pharmaceutically acceptable acids. R1 and R2 represent, independently of each other, a hydrogen atom, a C16 alkyl group, linear or branched, or together form a polymethylene group - (CH2) n-, n can take the values of 3 to 6, and,  in which

 1. Compound of formula (I) 2. Process for the preparation of a compound according to claim 1, characterized in that a chloroimidazole of formula (VII) is reacted.

 or a sulfone of formula (XI)

 in which R has formula

R 1, R 2 and R 3 are as defined in claim 1, with a 3-quinuclidinol alkoxide. 3. Medicinal product characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.