FR2754261A1 - QUINUCLIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The invention concerns compounds of formula (I) in which: R1 represents one hydrogen atom, one halogen such as fluorine, chlorine, bromine or iodine, one C1-6 alkyl group, linear or branched, one C1-2 perfluoroalkyl group or one nitro group, and R2 and R3 represent, independently of each other, one hydrogen atom, one halogen such as fluorine, chlorine, bromine or iodine, one C1-6 alkyl group, linear or branched, or a C1-6 alkoxy group, in the form of enantiomers, of diastereoisomers, or mixtures of these different forms, including racemic mixtures as well as their N-oxide derivative, their methiodide or their additive salts to pharmaceutically acceptable acids. The invention is applicable in therapeutics.

Description

The present invention relates to quinuclidine derivatives, their preparation and their therapeutic application.

dans laquelle
R1 représente un atome d'hydrogène, un halogène tel que fluor, chlore, brome ou iode, un groupe C16 alkyle, linéaire ou ramifié, un groupe C12 perfluoroalkyle ou un groupe nitro, et,
R2 et R3 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un halogène tel que fluor, chlore, brome ou iode, un groupe C16 alkyle, linéaire ou ramifié, ou un groupe C16 alcoxy.The compounds correspond to the general formula (I)

in which
R1 represents a hydrogen atom, a halogen such as fluorine, chlorine, bromine or iodine, a linear or branched C16 alkyl group, a C12 perfluoroalkyl group or a nitro group, and
R2 and R3 represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine, bromine or iodine, a linear or branched C16 alkyl group or a C16 alkoxy group.

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

The compounds of the invention can be prepared according to the following general scheme 1
Diagram 1

According to this scheme, an orthofluoronitrobenzene of formula (II), in which R 1 is as defined in formula (I), is reacted with an aniline of formula (III) in which
R2 and R3 are as defined in formula (I), at temperatures between 20 and 1800 C, and, if necessary, with a copper-based catalyst and / or hexamethylphosphotriamide, to yield the compound of formula (IV).

The nitro function of the compound of formula (IV) thus obtained can be reduced in a conventional manner for a person skilled in the art, for example: by catalytic hydrogenation, or reduction using tin halide hydrate or sodium sulphide. sodium, to give the orthophenylenediamine of formula (V).

The orthophenylenediamine of formula (V) thus obtained may be cyclized to benzimidazolone of formula (VI) by reaction with urea at temperatures of the order of 170 to 1800 ° C. or by the action of a phosgene derivative, in a solvent such as dichloromethane, at a temperature between 0 and 400C.

The benzimidazolone of formula (VI) is then converted into halobenzimidazole of formula (VII), in which halo represents chlorine or bromine.

For example, the benzimidazolone of formula (VI) is reacted in phosphoryl chloride and heated at reflux of the latter to yield a chlorobenzimidazole of formula (VII).

Finally, the chlorobenzimidazole of formula (VII) is coupled with the sodium hydroxide of quinuclidinol, chiral or racemic, of formula (VIII) in a solvent such as dimethylformamide or tetrahydrofuran, at temperatures of between 0 and 800 ° C. in order to lead to compounds of formula (I).

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

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

The following examples illustrate the methods and techniques suitable 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 N- (2-methoxyphenyl) -2-nitrobenzenamine
17.2 ml of 2-methoxyaniline and 8 ml of 2-fluoro-nitrobenzene, 0.1 ml of hexamethylphosphotriamide and a few mg of copper (II) chloride are introduced into a flask. It is brought to 1600 ° C. for 20 hours, then, after returning to ambient temperature, it is taken up in 200 ml of a 1/1 water / ethyl ether mixture. The aqueous phase is extracted twice with 50 ml of ether and the combined organic phases are washed with 100 ml of a 9/1 mixture of a saturated aqueous solution of ammonium chloride and a solution of aqueous ammonia. 25%. It is dried over magnesium sulphate, filtered through Celite and concentrated. Purified by flash chromatography on silica gel eluting with a 9/1 mixture of cyclohexane and ethyl acetate. 16 g of product are obtained.

Example 2 N- (2-methoxyphenyl) benzene-1,2-diamine
16 g of N- (2-methoxyphenyl) -2-nitrobenzenamine and 74 g of tin chloride dihydrate are mixed in 120 ml of ethyl acetate and refluxed for 3 h. After returning to room temperature, it is poured on ice and basified with sodium carbonate. It is extracted with ethyl acetate and dried over sodium sulphate. After concentration, 13 g of product are obtained.

This is used as is and immediately for the preparation of the compounds of formula (VI).

Example 3 1- (2-methoxyphenyl) -1,3-dihydro-2H-benzimidazol-2-one
13 g of N- (2-methoxyphenyl) benzene-1,2-diamine and 11 g of freshly recrystallized urea are mixed and heated at 1800 ° C. for 5 hours. Once returned to a temperature below 1000 C, the reaction mixture is triturated in water. The gum obtained is decanted and then triturated in ethyl ether to give, after drying under vacuum over phosphorus pentoxide, 11.5 g of product.

Example 4: 2-Chloro-1- (2-methoxyphenyl) -1H-benzimidazole
11.5 g of 1- (2-methoxyphenyl) -1,3-dihydro-2H-benzimidazol-2-one and 160 ml of phosphoryl chloride are refluxed for 3 hours and then the latter is distilled off and the residue is discarded. on ice. It is basified with sodium hydroxide and extracted with ethyl ether. After concentration, purify on silica gel eluting with methylene chloride. 6.6 g of product are thus obtained.

Example 5 1- (2-Methoxyphenyl) -2- (quinuclidin-3-yloxy) -1H-benzimidazole
A mixture of 81 mg of sodium hydride and 353 mg of quinuclidinol gradually heated to 700 ° C. in 10 ml of dimethylformamide until completion of the evolution of hydrogen. It is then cooled to 0 ° C. and 702 mg of 2-chloro-1- (2-methoxyphenyl) -1H-benzimidazole, in solution in 7 ml of dimethylformamide, are added. The mixture is allowed to warm slowly to room temperature and 20 ml of water are added. Extracted with ethyl acetate and pre-purified by acid-base treatment. After concentration, chromatography on silica gel eluting with a 92/8 / 0.8 mixture of chloroform / methanol / ammonia. 550 mg of product is recovered.

By reproducing the processes described in Examples 1, 2, 3, 4 and 5, with the appropriate starting materials (II) and (III), other compounds of general formula (I) according to the invention are prepared. .

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> Salt <SEP> PF
<tb> 1 <SEP> H <SEP> H <SEP> H <SEP> s (-] <SEP> Fumarate <SEP> 169
<tb><SEP>%<SEP> basis <SEP> = <SEP> -21.6
<tb><SEP> (c <SEP> = <SEP> 1, <SEP> CH2Cl2)
<tb> 2 <SEP> H <SEP> H <SEP> H <SEP> R (+) <SEP> Fumarate <SEP> 158
<tb><SEP>%<SEP> base <SEP> = <SEP> +20.2 <SEP>
<tb><SEP> (c <SEP> = <SEP> 1, <SEP> CH2Cl2) <SEP>
<tb> 3 <SEP> H <SEP> H <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 179
<tb> 4 <SEP> H <SEP> 2-CH3 <SEP> H <SEP> Racemic <SEP> Oil
<tb> 5 <SEP> H <SEP> 2-CH2CH3 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> Decomp <SEP>
<tb> 6 <SEP> H <SEP> 2-iCH3CH7 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> Decomp <SEP>
<tb> 7 <SEP> H <SEP> 2-C1 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 195
<tb> 8 <SEP> H <SEP> 2-oCH, <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 205
<tb> 9 <SEP> H <SEP> 3-Cl <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 182
<tb> 10 <SEP> H <SEP> 4-Cl <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 207
<tb> 11 <SEP> H <SEP> 2-CH3 <SEP> 4-OCH, <SEP> Racemic <SEP> Fumarate <SEP> 204
<tb> 12 <SEP> 5-CF3 <SEP> 2-CH3 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 185
<tb> 13 <SEP> 5-No2 <SEP> 2-CH3 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> Decomp <SEP>
<tb> 14 <SEP> 5-CH3 <SEP> 2-CH3 <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 188
<tb> 15 <SEP> 5-C1 <SEP> H <SEP> H <SEP> Racemic <SEP> Fumarate <SEP> 212
<Tb>
In this table iC3H7 represents an isopropyl and "Decomp" means that the product decomposes before melting.

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 [3Hi-N-methyl-scopolamine binding with human M1, M2 and M3 muscarinic receptors transfected into CHO (Chinese hamster ovarian cells) cells (Buckley et al. al., Mol Pharmacol 35: 469-476, 1989).

CHO cell membranes expressing the 3 human muscarinic receptor subtypes M1, M2 and M3 were provided by Receptor Biology (Baltimore, USA).

10 to 30 μg of membranes were incubated in a phosphate buffer, pH 7.4 (Sigma, St. Louis, MO) in the presence of [3 H] nmethylscopolamine (NEN-Dupont, Les Ullis, France), 0.49 nM for M1 and 0.5 nM for M2 and M3, and a compound of the invention, in a total volume of 1 ml. The non-specificity of the binding was determined by 1 μM atropine (Sigma, St
Louis, Mo) for the M1, M2 and 0.5 μM receptors for M3.

Incubation (60 min at 250 C) was stopped by rapid filtration on Whatmann GF / B filters 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). Compound concentration displacing 50% specific binding (IC50) was used to calculate Ki values according to Cheng's equation
Prusoff. The efficiency 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
M1 and M3 are between 1 and 800 nM.

The IC 50's of the compounds of the invention vis-à-vis the receptors
M2 are higher by a factor of 1 to 50.

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; CaCl2: 2.5; MgSO4: 1.2; KH2PO4: 1.2
NaHCO3: 25; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1 μM), methysergide (1 AM), ondasetron (1 bed), GR113808 (1 WM) were added to Krebs to inhibit the adrenergic receptors and the different subtypes of Serotoninergic 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.

The voltage was measured via isometric gauges (Hugo Sacks, type 351) connected to couplers (Gould) that transform and amplify the responses that will be plotted on 4-track potentiometric recorders (Gould) and connected to a control system. data acquisition (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 WM), 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 Achieving a carbachol concentration-response range at intervals of half a log unit.

The concentrations producing half of the maximal effect (ECSo tWM)) 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. the affinity of the antagonist (apparent pKB or pA2) according to the method of Furchgott (Handbook of
Experimental Pharmacology, 1972, 283-335).

The pKb of the compounds of the invention are between 6 and 9.

The results of the biological tests show that the compounds of the invention are muscarinic receptor antagonists. These compounds can therefore be used in the treatment of diseases associated with impaired motility or tone of smooth muscles such as those of the intestine, trachea or bladder. These diseases include: emergency urinary incontinence, irritable bowel syndrome, chronic airway obstruction, diverticulosis, ptyalism or oesophageal achalasia.

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, dragees, capsules, capsules, suspensions or oral or injectable solutions, and dosed to allow administration of 0.1 to 50 mg / kg per day.

Claims (4)

claims 1. Compounds of general formula (I)

 in which: R1 represents a hydrogen atom, a halogen such as fluorine, chlorine, bromine or iodine, a linear or branched C16 alkyl group, a perfluoroalkyl C12 group or a nitro group, and R2 and R3 represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine, bromine or iodine, a C16 alkyl group, linear or branched, or a C16 alkoxy group, in the form of enantiomers, diastereoisomers, or mixtures of these different forms, including racemic mixtures and their Noxide derivative, their methiodide or their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that a halobenzimidazole of formula <VII) is reacted.

 wherein R1, R2 and R3 are as defined in claim 1, with quinuclidinol. 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.