Patent Application
20080004348
(7-Methoxy-naphth-1-yl)acetonitrile (20 g) is dissolved in 150 ml of anhydrous tetrahydrofuran. Sodium hydride (202.8 mmol) is added at ambient temperature, and the mixture is refluxed for 30 minutes. Dimethyl carbonate (12 ml) is added with caution, and the reaction mixture is refluxed for 30 minutes. The mixture is poured into ice-cold water, and the aqueous phase is acidified with 21 ml of 37% hydrochloric acid solution and then extracted twice with 100 ml of ether. The organic phase is washed with water, dried, decoloured and evaporated. The oil obtained is precipitated from ether, and the precipitate formed is filtered off under suction and then recrystallised to yield the title compound in the form of a white solid.
Melting Point: 80-82° C.
Aluminium chloride (80 mmol), dissolved in 200 ml of anhydrous ether, is added to a suspension of lithium aluminium hydride at 0° C. in 300 ml of anhydrous ether. After stirring for 10 minutes, the compound obtained in Step A (20 mmol), dissolved in 200 ml of anhydrous ether, is added. After 30 minutes, the mixture is hydrolysed, with caution and in the cold state, using sodium hydroxide solution (10 g; 40 ml). The precipitate formed is then filtered off and washed with copious amounts of ether. The residue obtained after evaporation is taken up in water and the aqueous phase is extracted with dichloromethane. The organic phase is then washed with water, dried and decoloured, and is then treated with gaseous hydrogen chloride and evaporated. The oil obtained is precipitated from ethyl acetate, and the precipitate formed is filtered off under suction and then recrystallised to yield the title compound in the form of a white solid.
Melting Point: 164-166° C.
The compound obtained in Step B (3.73 mmol) is dissolved in 100 ml of a mixture of water/ethyl acetate (50/50). Potassium carbonate (11.2 mmol) is added and the reaction mixture is cooled to 0° C. using an ice bath. Cyclopropanoyl chloride (4.4 mmol) is added dropwise and the mixture is stirred for 15 minutes in the cold state. When the reaction is complete, the organic phase is washed with hydrochloric acid solution (1M), washed with water, dried and evaporated under reduced pressure. The solid obtained is recrystallised from toluene to yield the title compound in the form of a white solid.
Melting Point: 153-154° C.
Elemental Microanalysis:
The procedure is as in Step C of Example 1, replacing cyclopropanoyl chloride by acryloyl chloride.
Melting Point: 150-152° C.
Elemental Microanalysis:
Vinylacetic acid (5 mmol) is dissolved in 40 ml of dichloromethane and the solution is cooled to 0° C. EDCI (6 mmol) is added in small portions and the mixture is stirred at 0° C. for 30 minutes. The compound obtained in Step B of Example 1, in the form of the base and dissolved in 20 ml of dichloromethane, is added to the mixture. After stirring for 30 minutes at 0° C., the reaction mixture is poured into water. The organic phase is washed with hydrochloric acid solution (1M) and then with sodium hydrogen carbonate solution (1M) and with water. The organic phase is then dried and evaporated. The oil obtained is precipitated from ether, and the solid obtained is filtered off under suction and then recrystallised from toluene to yield the title compound in the form of a white solid.
Melting Point: 86-88° C.
The compound obtained in Step B of Example 1 (5.6 mmol) is dissolved in 40 ml of tetrahydrofuran in the presence of triethylamine (11.2 mmol), and trifluoroacetic anhydride (5 mmol) is added. The mixture is stirred at ambient temperature for 10 minutes, concentrated under reduced pressure and then poured into water. The aqueous phase is extracted twice with 60 ml of ether, and the organic phase is washed with hydrochloric acid solution (1M) and is then washed with water, dried and evaporated. The oil obtained is precipitated from a mixture of ether/petroleum ether (50/50), and the precipitate formed is filtered off under suction and then recrystallised from toluene to yield the title compound in the form of a white solid.
Melting Point: 138-140° C.
The procedure is as in Step C of Example 1, replacing the cyclopropanoyl chloride by 4-chlorobutanoyl chloride.
Whitish Oil
The title compound is obtained by alkylation of the compound obtained in Step B of Example 1.
The procedure is as in Step C of Example 1, starting from the compound obtained in Step A and replacing the cyclopropanoyl chloride by acetyl chloride.
Melting Point: 82-84° C.
Elemental Microanalysis
The compound obtained in Step A of Example 1 (19.6 mmol) is dissolved in 80 ml of acetone in the presence of tetrabutylammonium bromide (200 mg) and potassium carbonate (58.8 mmol). The mixture is refluxed for 20 minutes and methyl bromoacetate (23.5 mmol) is added dropwise. The mixture is held at reflux for 10 minutes and filtered when the reaction is complete. The potassium carbonate is washed with acetone and the filtrate is evaporated. The solid obtained is filtered off from ether under suction and is then recrystallised from a mixture of toluene/cyclohexane (3/2) to yield the title compound in the form of a beige solid.
Melting Point: 119-121° C.
The compound obtained in Step A (16 mmol) is dissolved in 15 ml of dimethylformamide, and then lithium bromide (16 mmol) and water (16 mmol) are added to the solution. The reaction mixture is then refluxed for 16 hours and poured into 30 ml of water when the reaction is complete. The precipitate formed is dried and then recrystallised from a mixture of toluene/cyclohexane (1/3) to yield the title compound in the form of a beige solid.
Melting Point: 113-114° C.
The compound obtained in Step B (18.5 mmol) is dissolved in 200 ml of acetic anhydride, and Raney nickel (2 g) is added to the solution. The reaction mixture is placed under a pressure of 30 bar of hydrogen and heated at 60° C. for 3 hours, and is then filtered and evaporated to dryness. The residue obtained is taken up in 100 ml of water and the aqueous phase is extracted twice with 100 ml of ether. The organic phase is washed with sodium hydrogen carbonate solution (1M), washed with water, dried and evaporated. The oil obtained is precipitated from ether, and the precipitate formed is filtered off under suction and then recrystallised from diisopropyl ether to yield the title compound in the form of a white solid.
Melting Point: 94-95° C.
The compound obtained in Step C (6.3 mmol) is dissolved in 200 ml of anhydrous ether, and lithium aluminium hydride (9.45 mmol) is added in small portions. The mixture is stirred at ambient temperature for 6 hours and is neutralised using 2 ml of water. The ether phase is washed with water, dried and evaporated. The oil obtained is purified on silica gel using a mixture of acetone/ethyl acetate (40/60) as eluant to yield the title compound in the form of a white solid.
Melting Point: 143-145° C.
The title compound is obtained by mesylation of the compound obtained in Step B of Example 1.
The procedure is as in Step C of Example 1, starting from the compound obtained in Step A and replacing the cyclopropanoyl chloride by acetyl chloride. The title compound is obtained in the form of a white solid.
Melting Point: 104-106° C.
The procedure is as in Example 8, replacing the acetyl chloride in Step B by propanoyl chloride. The title compound is obtained in the form of a white solid.
Melting Point: 118-120° C.
The compound obtained in Example 8 (4.26 mmol) and morpholine (42.3 mmol) are dissolved in 40 ml of anhydrous tetrahydrofuran, and the reaction mixture is refluxed under a current of argon for 24 hours. When the reaction is complete, the mixture is concentrated in vacuo and then poured into water. The aqueous phase is extracted twice with 50 ml of ether, and the organic phase is washed with water and then washed with hydrochloric acid solution (1M). The aqueous phase is then rendered alkaline with 15 % sodium hydroxide solution and is then extracted twice with 50 ml of ether. The organic phase is washed with water, dried, decoloured and then treated with ether saturated with HCl. The precipitate formed is filtered off under suction and is then recrystallised from acetonitrile to yield the title compound in the form of a white solid.
Melting point: 125-126° C.
Elemental Microanalysis:
Sodium azide (25.6 mmol) is suspended in 10 ml of dimethylformamide; tetrabutyl-ammonium bromide (a spatula tip) is added and the mixture is heated to 70° C. The compound obtained in Example 8 (8.53 mmol), dissolved in 20 ml of dimethylformamide, is then added and the mixture is stirred at 70° C. for two hours. When the reaction is complete, 40 ml of water are added and the aqueous phase is extracted three times with 60 ml of ether. The organic phase is then washed with hydrochloric acid solution (2M) and then with water. After having been dried, the organic phase is evaporated to yield the title compound in the form of an orange-coloured oil.
Orange-coloured oil
The procedure is as in Example 11, starting from the compound obtained in Example 9.
Whitish oil
The compound obtained in Example 11 (6.48 mmol) is dissolved in 50 ml of methanol, and palladium-on-carbon (200 mg) is added to the solution. The mixture is then placed under hydrogen at atmospheric pressure and stirred at ambient temperature for 2 hours. When the reaction is complete, the catalyst is filtered off and the methanol is evaporated off. The residue obtained is taken up in ether and the resulting insoluble material is filtered off. The filtrate is then treated with ether saturated with HCl and the hydrochloride formed is filtered off under suction and then recrystallised from a mixture of acetonitrile/methanol (8/2) to yield the title compound in the form of a white solid.
Melting Point: 230-231 ° C.
The procedure is as in Example 13, starting from the compound obtained in Example 12.
Melting Point: 198-200° C.
The procedure is as in Step C of Example 1, starting from the compound obtained in Example 13 and replacing the cyclopropanoyl chloride by acetyl chloride. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 199-200° C.
Elemental Microanalysis:
The procedure is as in Example 15, starting from the compound obtained in Example 13 and replacing the acetyl chloride by propanoyl chloride. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 148-150° C.
Elemental Microanalysis:
The procedure is as in Example 15, starting from the compound obtained in Example 13 and replacing the acetyl chloride by butanoyl chloride. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 150-152° C.
Elemental Microanalysis:
The procedure is as in Step C of Example 1, starting from the compound obtained in Example 13. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 175-1 76° C.
Elemental Microanalysis:
The compound obtained in Example 8 (10 mmol) and N-methylbenzylamine (30 mmol) are dissolved in 60 ml of anhydrous tetrahydrofuran. The reaction mixture is placed under a current of argon and refluxed for 24 hours. When the reaction is complete, the mixture is concentrated in vacuo and then poured into water. The aqueous phase is extracted twice with 50 ml of ether, and the organic phase is washed with hydrochloric acid solution (2M). The aqueous phase is then rendered alkaline using sodium hydroxide solution (2M) and is then extracted twice with 50 ml of ether. The ether phase is washed with water, dried and evaporated under reduced pressure. The oil obtained is purified on silica gel using a mixture of acetone/cyclohexane (50/50) as eluant. The solid obtained after evaporation of the pure fractions is filtered off from a mixture of ether/petroleum ether under suction and is then recrystallised from diisopropyl ether.
Melting Point: 100-102° C.
The compound obtained in Example 19 (2.6 mmol) is dissolved in 40 ml of methanol, and palladium-on-carbon (a spatula tip) is added to the solution. The reaction mixture is stirred under hydrogen at atmospheric pressure at ambient temperature for 24 hours. When the reaction is complete, the mixture is filtered and then concentrated under reduced pressure and poured into water. The aqueous phase is then extracted twice with 40 ml of ether, and the organic phase is washed with water, dried and then treated with ether saturated with HCl. The precipitate formed is filtered off from ether under suction and recrystallised from acetone to yield the title compound in the form of a white solid.
Melting Point: 126-128° C.
The procedure is as in Step C of Example 1, starting from the compound obtained in Example 14 and replacing the cyclopropanoyl chloride by mesyl chloride. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 140-142° C.
Elemental Microanalysis:
The compound obtained in Step B of Example 1 (5.6 mmol) is dissolved in 40 ml of tetrahydrofuran in the presence of triethylamine (1.56 mmol), and ethyl isocyanate (2.5 mmol) is added. The mixture is stirred at ambient temperature for 10 minutes, concentrated under reduced pressure and poured into water. The aqueous phase is extracted twice with 60 ml of ether; the organic phase is washed with hydrochloric acid solution (1M) and is then washed with water, dried and evaporated. The oil obtained is precipitated from a mixture of ether/petroleum ether (50/50); the precipitate formed is filtered off under suction and then recrystallised from acetonitrile to yield the title compound in the form of a white solid.
Melting Point: 120-122° C.
Elemental Microanalysis:
The procedure is as in Example 1, replacing the (7-methoxy-naphth-1-yl)acetonitrile in Step A by (3-bromo-7-methoxy-naphth-1-yl)acetonitrile, and the cyclopropanoyl chloride in Step C by acetyl chloride. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 129-131° C.
The procedure is as in Example 23, replacing the (7-methoxy-naphth-1-yl)acetonitrile in Step A by (3-allyl-7-methoxy-naphth-1-yl)acetonitrile. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 142-144° C.
The procedure is as in Example 23, replacing the (7-methoxy-naphth-1-yl)acetonitrile in Step A by (7-methoxy-3-vinyl-naphth-1-yl)acetonitrile. The title compound is recrystallised from acetonitrile and obtained in the form of a white solid.
Melting Point: 109-111° C.
Aluminium chloride (80 mmol), dissolved in 200 ml of anhydrous ether, is added to a suspension of lithium aluminium hydride (80 mmol) at 0° C. in 300 ml of anhydrous ether. After stirring for 10 minutes, the compound obtained in Step B of Example 7 (20 mmol), dissolved in 200 ml of anhydrous ether, is added. After 30 minutes, the mixture is hydrolysed, in the cold state and with caution, using sodium hydroxide solution (250 mmol). The inorganic precipitate formed is then filtered off and washed with copious amounts of ether. The residue obtained after evaporation is taken up in water, and the aqueous phase is extracted with dichloromethane. The organic phase is then washed with water, dried and decoloured and is then treated with gaseous hydrogen chloride and evaporated. The oil obtained is precipitated from ethyl acetate, and the precipitate formed is filtered off under suction and then recrystallised to yield the title compound in the form of a white solid.
Melting Point: 164-166° C.
The compound obtained in Step A (20 mmol) is dissolved in a mixture of water/ethyl acetate (25 ml/75 ml) cooled to 0° C. Potassium carbonate (60 mmol) is added, and then cyclopropanecarboxylic acid chloride (26 mmol) is added dropwise to the reaction mixture. The batch is stirred vigorously at ambient temperature for 30 minutes. The two phases are separated and the organic phase is washed with 0.1M aqueous hydrochloric acid solution and then with water. After drying over magnesium sulphate, the organic phase is evaporated under reduced pressure. The residue obtained is recrystallised to yield the title compound in the form of a white solid.
Melting Point: 158-160° C.
The procedure is as in Example 26, replacing the cyclopropanecarboxylic acid chloride in Step B by propionic acid chloride. The title compound is obtained in the form of a white solid.
Melting Point: 123-125° C.
The procedure is as in Example 26, replacing the cyclopropanecarboxylic acid chloride in Step B by fluoroacetic acid chloride.
Melting Point: 96-98° C.
The procedure is as in Example 26, replacing the cyclopropanecarboxylic acid chloride in Step B by cyclobutanecarboxylic acid chloride. The title compound is obtained in the form of a white solid.
Melting Point: 113-115° C.
The acute toxicity was evaluated after oral administration to groups each comprising 8 mice (26±2 g). The animals were observed at regular intervals during the course of the first day, and daily for the two weeks following treatment. The LD50 (dose that causes the death of 50% of the animals) was evaluated and demonstrated the low toxicity of the compounds of the invention.
The compounds of the invention are tested in a behavioral model, the forced swimming test.
The apparatus is composed of a plexiglass cylinder filled with water. The animals are tested individually for a session of 6 minutes. At the start of each test, the animal is placed in the center of the cylinder. The time spent immobile is recorded. The animal is considered to be immobile when it stops struggling and remains immobile on the surface of the water, making only those movements which allow it to keep its head above water.
Following administration 40 minutes before the start of the test, the compounds of the invention significantly reduce the time spent immobile, which indicates their antidepressive activity.
The MT1 or MT2 receptor binding experiments are carried out using 2-[125I]-iodomelatonin as reference radioligand. The radioactivity retained is determined using a liquid scintillation counter.
Competitive binding experiments are then carried out in triplicate using the various test compounds. A range of different concentrations is tested for each compound. The results enable the binding affinities of the compounds tested (Ki) to be determined.
The Ki values found for the compounds of the invention accordingly demonstrate binding to one or other of the melatoninergic binding sites, those values being ≦10 μM.
As way of example, compound of Example 6 exhibits a Ki (MT1) of 4.9 nM and a Ki (MT2) of 8.9 nM.
The affinity of the compounds for the human 5-HT2C receptor is evaluated on membrane preparations from CHO cells stably expressing that receptor.
Incubation is carried out in 50mM TRIS buffer, pH 7.4 containing 10 mM MgCl2 and 0.1% BSA, in the presence of [3H]-mesulergine (InM) and 25 fmol/ml of receptor. Non-specific binding is determined in the presence of 10 μM mianserin.
The reaction is stopped by the addition of 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: the radioactivity bound to the membranes remaining on the filters (GF/B pretreated with 0.1% PEI) is determined by liquid scintillation counting.
The results obtained show that the compounds of the invention have affinity for the 5-HT2C receptor, with Ki values <100μM.
As way of example, compound of Example 6 exhibits a Ki (5-HT2C) of 26 μM.
The involvement of melatonin in influencing, by day/night alternation, the majority of physiological, biochemical and behavioral circadian rhythms has made it possible to establish a pharmacological model for use in the search for melatoninergic ligands.
The effects of the compounds are tested on numerous parameters and, in particular, on the circadian rhythms of locomotive activity, which constitute a reliable indicator of the activity of the endogenous circadian clock.
In this study, the effects of such compounds on a particular experimental model, namely the rat placed in temporal isolation (permanent darkness), is evaluated.
Experimental Protocol
One-month-old male rats are subjected, as soon as they arrive at the laboratory, to a light cycle of 12 hours' light per 24 hours (LD 12: 12).
After 2 to 3 weeks' adaptation, they are placed in cages fitted with a wheel connected to a recording system, in order to detect the phases of locomotive activity and thus monitor the nychthemeral rhythms (LD) or circadian rhythms (DD).
As soon as the rhythms recorded show a stable pattern during the light cycle LD 12: 12, the rats are placed in permanent darkness (DD).
Two to three weeks later, when the free course (rhythm reflecting that of the endogenous clock) is clearly established, the rats are given a daily administration of the compound to be tested.
The observations are made by means of visualisation of the rhythms of activity:
A Software Package Makes it Possible:
Results
The compounds of the invention clearly appear to allow powerful action on the circadian rhythm via the melatoninergic system.
The compounds of the invention are tested in a behavioral model, the light/dark cages test, which allows the anxiolytic activity of the compounds to be demonstrated.
The apparatus consists of two polyvinyl boxes covered with plexiglass. One of the boxes is in darkness. A lamp is placed above the other box, yielding a light intensity of approximately 4000 lux in the center of the box. An opaque plastic tunnel separates the light box from the dark box. The animals are tested individually for a session of 5 minutes. The floor of each box is cleaned between each session. At the start of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the illuminated box and the number of passages through the tunnel are recorded after the first entry into the dark box.
Following administration of the compounds 30 minutes before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of passages through the tunnel, which demonstrates the anxiolytic activity of the compounds of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0605916 | Jun 2006 | FR | national |
