WO1999031097A1

WO1999031097A1 - Imidazol derivatives as muscarinic m3 receptor antagonists

Info

Publication number: WO1999031097A1
Application number: PCT/FR1998/002678
Authority: WO
Inventors: Gilles Courtemanche; Gérard Defosse; Olivier Crespin; Philippe R. Bovy
Original assignee: Sanofi-Synthelabo
Priority date: 1997-12-12
Filing date: 1998-12-10
Publication date: 1999-06-24
Also published as: AU1566499A; FR2772378B1; FR2772378A1

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

IMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION

THERAPEUTIC

The subject of the present invention is imidazole derivatives of general formula (I)

in which :

R _x and R ₂ represent, independently of each other, a hydrogen atom, a C- ^ g alkyl group, linear or branched, or together form a polymethylene group - (CH ₂ ) _n -, n being able take the values from 3 to 6, and, R ₃ represents a hydrogen atom, a halogen atom or a group

Ci. ₄ alkyl, linear or branched.

The halogen atoms can be fluorine, chlorine, bromine or iodine. In the context of the present invention, the term C ₁ is understood. ₆ alkyl, a saturated, linear or branched aliphatic group, comprising from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or etc ...., preferably a C _ ₂ alkyl group.

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

The compounds of general formula (I) have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, are part of the invention.

The preferred compounds according to the invention are the compounds for which R _x and R ₂ represent, independently of one another, a hydrogen atom, a group. ₃ alkyl, linear or branched, or together form a polymethylene group - (CH ₂ ) _n -, n being able to take the values of 3 or 4. Among these, the compounds for which R ₁ and R ₂ together represent a polymethylene group - (CH ₂ ) _n -, n being able to take the values of 3 or 4 are particularly preferred.

On the other hand, the compounds for which R ₃ represents a hydrogen are also preferred.

The compounds of the invention can be prepared by methods illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.

In diagram 1, R represents: - (7

R ₃ being as defined above and AO ^" represents the 3-quinuclidinol alcoholate

According to this scheme, an epoxide of formula (II), in which R and R ₂ are as defined above, is reacted successively with triflic acid in dimethyl sulfoxide then with diisopropylethylamine to yield the hydroxyketone (III ) according to the method described by BM Trost in Tetrahedron letters 29 (1988), JL8., 2163-66. Diagram 1

RNHCO

N OA

NOT

Hydroxyketone (III) is opposite to an arylurea (RNHCONH ₂ ), in which R is as defined above, at 180 ° C. in hexanol, possibly in the presence of molecular sieve (4A), to lead to imidazolone (IV).

This imidazolone (IV) can also be obtained from -haloketone (V), in which _R1 and R ₂ are such that defined above, by successive reactions of potassium phthalimide then of concentrated hydrobromic acid and acetic acid, to lead first of all to aminoketone hydrobromide (VI) which by treatment with phenyl isocyanate (RNCO) , in which R is as defined above, in pyridine or dimethylformamide leads to compound (IV).

Alternatively, when R ₂ represents a linear or branched alkyl group C ^ g, the compound of formula (IV) can be prepared as indicated in scheme 2, according to the method described in patent US3432520, R ₂ 'representing an atom d hydrogen or a group C ₁ . ₅ alkyl.

Diagram 2

According to this scheme 2, a propargylamine of formula (XV) is reacted, in which R ₂ and R ₂ . are as defined above, with phenyl isocyanate (R ₃ -C ₆ H ₅ -NCO), in which R ₃ is as defined above, in toluene to yield urea (XVI) which, by treatment by an alkaline alcoholate, such as sodium methylate or ethylate or potassium tert-butoxide, in the corresponding alcohol, causes an allene rearrangement followed by cyclization to result in imidazolone (IV), in which R ₂ represents a C ₁ _ ₆ alkyl group. The imidazolone (IV) is then heated to reflux of the phosphorus oxychloride, optionally in the presence of phosphorus pentachloride or gaseous hydrochloric acid, to lead to 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 or potassium ter-butoxide, on a 3-quinuclidinol (AOH), s 'carried out in an aprotic solvent such as dimethylformamide or N-methylpyrrolidinone, at temperatures between 20 and 120 ° C (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), as defined above, which is thermally condensed at a temperature varying from 160 ° C to 180 ° C, with formamide , to give imidazole (VIII).

This imidazole (VIII) is then subjected to the action of bismuth triphenyl ((R) ₃ Bi), in which R is as defined above, in the presence of copper acetate and triethylamine in dichloromethane to lead to l 'imidazole (IX).

The proton in position 2 of this imidazole (IX) is then torn off by means of butyllithium in tetrahydrofuran at temperatures between -78 and -10 ° C. The anion thus formed is trapped by means of dimethyldisulfide to lead to the sulfide (X).

Sulfide (X) is oxidized to sulfone (XI) for example, by the action of oxone ^® (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), takes place in dimethylfor amide at temperatures between 20 and 120 ° C, to lead to the compounds of formula (I).

Racemic 3-quinuclidinol (AOH) and the (R) enantiomer 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. Elementary microanalyses and NMR and IR spectra confirm the structures of the compounds obtained.

Example 1: 2-Hydroxycyclohexanone

Cooled in an ice bath 9.8 g (0.1 mol) of cyclohexene oxide in 75 ml of dimethyl sulfoxide and added a solution of 9 ml (0.1 mol) of triflic acid in 25 ml of dimethyl sulfoxide in 30 minutes. The mixture is left to return to ambient temperature and is stirred again for 2 hours. 150 ml of dichloromethane are added, the mixture is cooled to -78 ° C. and 87 ml (0.5 mol) of diisopropylethylamine are added over 30 minutes. The mixture is allowed to return to ambient temperature, is stirred again for 1 hour and poured onto 1500 ml of a 10% sodium bisulfate solution. Extracted with dichloromethane, dried over magnesium sulfate and then evaporated. The residual oil is purified by flash chromatography on silica gel, eluting with methylene chloride and 4.5 g of product are recovered. Example 2: 1-Phenyl-1,3,4,5,6,7-hexahydro-2H-benzimidazol-2-one

The mixture is stirred under reflux for 20 hours, a mixture of 4.5 g (39.4 mmol) of 2-hydroxycyclohexanone, 7.5 g (55 mmol) of phenylurea and 7 ml of hexanol. It is concentrated under vacuum and the solid residue is recrystallized from acetone, 2.5 g of product are recovered (melting point: 220 ° C.)

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 95 ° C. for 8 hours. Poured onto ice water, add ether and stir until the product crystallizes. It is filtered, washed with water and ether, dried under vacuum. 40 g of 2- (2-oxycyclohexyl) -1H-isoindole-1, 3 (2H) -dione are obtained (Curtin D.Y., J.Am.Chem. Soc. (1955), 21, 1105-10). (melting point: 155 ° C)

A mixture of 40 g (0.16 mol) of the above product in 200 ml of acetic acid and 200 ml of 48% hydrobromic acid is stirred at reflux for 4 hours. Cooled in an ice bath, phthalic acid filtered and concentrated in vacuo. 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. The residue is taken up with an alcohol / ether mixture 50:50, filter, dried under vacuum. 20 g of product are obtained (melting point: 153 ° C.)

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. o

Water is added, stirred until crystallization, wrung, 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 (0.0107 mol) of 1-phenyl-1,3,4,5,6,7,7-hexahydro-2H-benzimidazol-2-one and 30 ml of is stirred under reflux for 6 hours. phosphorus oxychloride (POCl ₃ ) The excess phosphorus oxychloride is evaporated in vacuo and the residue is hydrolyzed with water and concentrated ammonia. Extracted with dichloromethane twice, evaporated and purified the residue by flash chromatography on silica gel with an eluent heptane / ethyl acetate 80:20. 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 three-liter three-necked flask, 400 ml of formamide are added and then the mixture is heated to 180 ° C. for 2 hours and 30 minutes. The medium returned to room temperature is poured onto a 1N sodium hydroxide solution (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 sulphate, concentrated under vacuum and then purified by chromatography on silica gel using a gradient (5 to 10% methanol in dichloromethane). 10.2 g of product are obtained in the form of a gum.

Example 7: 1-Phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole

250 mg (2 mmol) of 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 agitated in 5 ml of dichloromethane at room temperature for 24 hours. 2 grams of silica are then added and the medium is then concentrated under reduced pressure. The powder obtained is purified by chromatography on silica gel, eluting with a dichloromethane / methanol / ammonia mixture 95: 5: 0.5. 315 mg of product are obtained.

Example 8: 2-Methylthio-1-phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole

2.36 g (12 mmol) of l-phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole are added to a 100 ml three-necked flask under nitrogen, 20 ml of tetrahydrofuran are added, then the mixture is cooled to -78 ° C. 9 ml (14.3 mmol) of a 1.6 N buthyllithium solution in hexane are then added slowly. Stirred at -80 ° C for 5 minutes then allowed to rise to -20 ° C and stirred another 45 minutes at this temperature. The reaction medium is then cooled to -80 ° C. and a solution of 2.24 g (24 mmol) of dimethyldisulfide diluted in 10 ml of tetrahydrofuran is introduced therein dropwise. When the addition is complete, the mixture is left to return to ambient temperature. Then cooled to 0 ° C before gently introducing 15 ml of water and then 15 ml of ethyl acetate. 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 then dried over magnesium sulphate and concentrated in vacuo. The crude reaction product is purified by chromatography on silica gel using a gradient of 1 to 2% of methanol in dichloromethane as the eluting solution. 2.17 g of product are obtained.

(melting point: 112 °)

Example 9: 2-Methylsulfonyl-1-phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole

3.8 g of previously moistened alumina, 7.07 g (11.5 mmol) of oxone and 10 ml of chloroform are vigorously stirred. To this medium is added a solution of 2-methylthio-1-phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole dissolved in 10 ml of chloroform then continues stirring, bringing to reflux for 2 hours. Cool to 0 ° C and then filter the mixture, rinse the solid with 10 ml of chloroform and 10 ml of a tetrahydrofuran / methanol: 9/1 mixture. The filtrate is concentrated under reduced pressure and then purified by chromatography on silica gel using a dichloromethane / methanol mixture 99/1 then 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) of (S) -quinuclidinol and 0.09 g (3.9 mmol) of 95% sodium hydride are gradually heated to 80 ° C in 6 ml of anhydrous dimethylformamide, for 30 minutes. After cooling to 5 ° C., 0.6 g (2.17 mmol) of 2-methylsulfonyl-1-phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazole, dissolved in 4 ml of anhydrous dimethylformamide, is added. . It is heated to 100 ° C for 30 minutes, then left for 30 minutes at 70 ° C. Cool and pour onto ice, exhaust the aqueous phase with ethyl acetate, wash with brine and dry over sodium sulfate. It is purified, after concentration, by chromatography on silica gel, eluting with a gradient of methanol in chloroform. 0.21 g of product is thus obtained. Difumarate is crystallized from acetone. (α _D = +16.9; c = 1.0025 (methanol))

Example 11: N-Phenyl -N '-prop-2-ynyl rée

To a suspension of 50 ml (0.45 mol) of phenyl isocyanate in 160 ml of toluene, 25 g (0.45 mol) of propargylamine dissolved in 80 ml of toluene are added dropwise. The mixture is stirred for 1 hour 30 minutes, the precipitate is filtered, washed with a little toluene and then dried in an oven under vacuum at 40 °. 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, 0.8 ml of 5.35 Ν sodium methylate is added. The mixture is brought to reflux temperature for 4 hours. The solvent is evaporated and then the solid residue is taken up with acetone. The product precipitates, it is filtered, washed with a little acetone, dried under vacuum at 50 ° C. 6 g of product are obtained. (melting point: 207 ° C)

The table which follows illustrates the chemical structures and the physical properties of certain compounds of formula (I) according to the invention, obtained in a manner analogous to that described in the examples.

Board

The compounds of the invention have been the subject of pharmacological tests which have shown their interest as active substances in therapy.

They have in particular been tested for their inhibitory effects on the binding of [ ³ H] -N-methyl-scopolamine with human muscarinic type M ₃ receptors transfected into CHO (chinese hamster ovarian cells) cells (Buckley et al ., Mol. Pharmacol. 35: 469-476, 1989). Membranes of CHO cells, in solution in 10 m TRIS-HC1 buffer, 2 mM EDTA pH 7.2, expressing the human muscarinic receptor subtype M ₃ were supplied by the company 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 0.5 nM of [ ³ H] -N-methyl-scopolamine (NEN-Dupont, 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 μM of atropine (Sigma, St Louis, MO). Incubation (60 min at 25 ° C) was stopped by rapid filtration on hatmann GF / B filters by a Brandel filtration device. The filters were washed three times with 4 ml of cold phosphate buffer, dried and the radioactivity was measured by liquid scintillation (scintillant Ultima Gold). The concentration of compound displacing 50% the specific bond (IC ₅₀ ) was used to calculate the Ki values 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 values of the compounds of the invention vis-à-vis the M ₃ receptors are between 1 and 350 nM.

The compounds of the invention have also been studied as to their antagonistic effects with respect to the contractions of the female rabbit detrusor, mediated by the M ₃ receptors. Female rabbits (New Zealanders, 3-4 kg; ESD supplier) aged around 20 weeks were sacrificed by cervical dislocation and then bloodless. After opening the abdomen, the bladders were removed and then quickly placed in a bicarbonate solution of Krebs of composition (mM): NaCl: 114; KC1: 4.7; CaCl ₂ : 2.5; MgSO ₄ : 1.2; KH ₂ P0 ₄ : 1.2; NaHCO ₃ : 25,; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1 μM), methylsergide (1 μM), 1 ondansetron (1 μM), GR113808 (1 μM) were added to Krebs in order to inhibit the β-adrenergic receptors and the various serotoninergic receptor subtypes 5 respectively - HT- _L / 5-HT ₂ , 5-HT ₃ and 5-HT ₄ . The bladders were cleaned, degreased and each side was cut into two longitudinal flaps about 4 mm wide and 15 mm long. The tissues were then placed in 20 ml tanks thermostated at 37 ° C under carbogenic aeration (95% 0 ₂ , 5% C0 ₂ ) and were subjected to a basal tension of 1 g. The voltage was measured using isometric gauges (Hugo Sacks, type 351) connected to couplers (Gould) which transform and amplify the responses which will be traced on 4-track potentiometric recorders (Gould) and connected to a system of data acquisition (Jad, Notocord). A balancing time of approximately 45 minutes was observed during which the Krebs is renewed and the basal tension rectified.

After a 30-minute equilibration period, an initial contraction with carbachol (1 μM), a powerful muscarinic agonist, was performed. The tissues were then rinsed thoroughly and then after a new equilibration period of 30 minutes, the tissues were incubated for 30 minutes in the presence or not of a compound of the invention to be studied (concentration 0.1 or 1 μM) before achieving a concentration-response range for carbachol at intervals of half a logarithm. The concentrations producing half of the maximum effect (EC ₅₀ (μM)) were calculated for each range (absence or presence of the compound to be studied), then the power of the compound to shift the response curve to carbachol was determined by a calculation of the affinity of the antagonist (pK _b or apparent pA ₂ ) according to the method of Furchgott (Handbook of Experimental Pharmacology, 1972, 283-335). The pK _b 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 antagonists of the muscarinic M ₃ receptors.

They can therefore be used in the treatment of irritable bowel syndrome, obstruction of the airways and bladder instabilities, in particular emergency urinary incontinence.

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

Claims

Compound of formula (I)

in which

R _x and R ₂ represent, independently of one another, a hydrogen atom, a group C ₁ . ₆ alkyl, linear or branched, or together form a polymethylene group - (CH ₂ ) _n -, n can take the values from 3 to 6, and, R ₃ represents a hydrogen, halogen atom or a group C _{1 -4} alkyl, linear or branched, in the form of an enantiomer, a diastereoisomer, or a mixture of these different forms, including a racemic mixture as well as its N-oxide derivatives and its addition salts with pharmaceutically acceptable acids .

2. Compound of formula (I) according to claim 1, characterized in that it consists of:

- 3- [(1-Phenyl-4, 5-dimethyl-1H-imidazol-2-yl) oxy] - quinuclidine;

- 3- [(1-Phenyl-4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-yl-oxy] quinuclidine; - 3- [(1-Phenyl-4, 5-diethyl-1H-imidazol- 2-yl) oxy] quinuclidine; or

- 3- [(1-Phenyl-1H-imidazol-2-yl) oxy] quinuclidine.

3. 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 the formula and,

R _x , R and R ₃ are as defined in claim 1, with a 3-quinuclidinol alcoholate.

4. Medicament characterized in that it consists of a compound according to claim 1.

5. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.