FR2634205A2 - 4-Methyl-2-[(4-piperidyl)methyl]-1,2,3,4-tetrahydroisoquinoline derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds of general formula I: in which R represents a group of general formula -Z-R' in which Z represents a -CO- group or a -CH2- group and R' represents a phenyl group optionally carrying from 1 to 3 substituents chosen from halogen atoms and linear or branched (C1-C3)alkyl and linear or branched (C1-C3)alkoxy groups. Application in therapeutics.

Description

The present application for a fifth certificate of addition to the main patent application N08711288 of August 7, 1988 relates to derivatives of methyl-4 [(piperidinyl-4) methyl] -2-tetrahydro-l, 2,3,4 isoquinoline , their preparation and their application in therapeutics.

dans laquelle R représente soit un atome d'hydrogène, soit un groupe méthyle, soit un groupe benzyle éventuellement substitué par un atome de chlore ou un groupe méthyle ou méthoxy, soit encore un groupe phénéthyle.The compounds of the main patent application correspond to the following general formula

wherein R represents either a hydrogen atom, a methyl group, a benzyl group optionally substituted by a chlorine atom or a methyl or methoxy group, or a phenethyl group.

dans laquelle
R représente un groupe de formule générale -Z-R' dans laquelle Z représente un groupe -CH2- ou un groupe -CO- et R' représente un groupe phényle portant éventuellement de un à trois substituants choisis parmi les atomes d'halogènes et les groupes (C1-C3)alkyle linéaires ou ramifiés et (C1-C3)alcoxy linéaires ou ramifiés.The compounds of the present application correspond to the general formula (I)

in which
R represents a group of general formula -ZR 'in which Z represents a group -CH2- or a group -CO- and R' represents a phenyl group optionally carrying from one to three substituents chosen from halogen atoms and groups ( C1-C3) linear or branched alkyl and (C1-C3) alkoxy linear or branched.

They can be in the form of free bases or addition salts with acids.

According to the invention, the compounds of general formula (I) can be prepared by a process illustrated by Scheme 1 given below.

A compound of general formula (I) in which Z represents a -CO- group is first prepared by reacting 4-methyl-1,2,3,4-tetrahydro-isoquinoline of formula (II) with a tosylate of general formula ( III) (in which Tos represents a tosyl group and R 'is as defined above), either in the absenze or in the presence of an inert solvent such as dimethylformamide, toluene or xylene, a temperature of 20 to 1500C, and optionally in the presence of an organic base, such as a tertiary amine, or mineral, such as an alkali carbonate or hydrogencarbonate.

There is thus obtained a compound of general formula (Ia) which corresponds to the general formula (I) when Z represents a group -CO-.

If it is desired to prepare a compound of the general formula (I)
Z represents a -CH 2 - group, the compound of general formula (Ia) is then reduced by means of a simple hydride or complex of boron or aluminum, for example lithium aluminum hydride, hydride aluminum, the diborane / tetrahydrofuran complex or the diborane / methyl sulfide complex, or any equivalent means, in an ethereal solvent such as diethyl ether, tetrahydrofuran or dioxane, at a temperature of 20 to 1000C.

There is thus obtained a compound of general formula (Ib) which corresponds to the general formula (I) when Z represents a -CH 2 - group.

The 4-methyl-1,2,3,4-tetrahydro-isoquinoline of formula (II) can be obtained by a process such as that described by
G. L-. Grunewald et al. in J. Med. Chem., 1988, 31, 433.
Diagram 1

Figure 2

The tosylates of general formula (III) can be prepared according to a method illustrated by the above scheme 2.

Piperidine-4-methanol of formula (IV) is reacted with an acid chloride of general formula R'COCl (in which
R 'is as defined above), in an inert solvent such as a chlorinated solvent, at a temperature of 20 to 800c. An ester-amide of general formula (V) is thus obtained, which is saponified, for example by means of sodium or potassium hydroxide, in a lower aliphatic alcoholic solvent, preferably ethanol, to obtain the alcohol. of general formula (VI), the tosylate is finally prepared by means of tosyl chloride, in a basic medium such as pyridine.

Piperidine-4-methanol of formula (Iy) can be obtained for example by reduction of ethyl piperidine-4-carboxylate by means of lithium aluminum hydride, or by such a reduction of benzyl-1 piperidine-4 ethylcarboxylate followed by catalytic hydrogenolysis under pressure.

Furthermore, the main patent application and the applications for first and second certificates of addition Nos. 8718342 and 8805129 describe various processes for the preparation of compounds of general formula (I) which do not carry a methyl group at 4; Such methods, in principle, are equally applicable to the preparation of the compounds of the present invention.

The following examples illustrate in detail the preparation of some compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the products obtained.

The numbers given in parentheses in the titles of the examples correspond to those in the table given below.

Example 1 (Compound N05)
Methyl-4 [[(3-methyl-phenyl) carbonyl-1-piperidinyl-4-methyl] -2-tetrahydro-1,2,3,4-isoquinoline, fumarate.

1.1. Pipérldine-4-methanol.

In a four-necked flask equipped with a mechanical stirring system and a condenser 28.5 g (0.75 mol) of lithium aluminum hydride and 1.2 l of tetrahydrofuran are introduced. 117.9 g (0.75 mole) of ethyl piperidine-4-carboxylate in solution in 1.2 l of tetrahydrofuran are added to the suspension obtained, and the mixture is stirred for 6 h at 20 ° C. It is cooled to OOC and then hydrolyzed by successively adding 22 ml of water, 22 ml of 1N sodium hydroxide and 46 ml of water, the mixture is stirred at 200 ° C., filtered and the tetrahydrofuran precipitate is washed. The solvent is then evaporated under reduced pressure and 84.4 g of an oil are obtained which is used as it is in the next step.

1.2. 3-Methyl-3-benzoyl-1-piperidinyl-4-methyl] benzoate

In a 3-liter three-neck flask, 42.25 g (0.367 mole) of piperidine-4-methanol, 430 ml of 1,2-1,2-dichloroethane are introduced under an argon atmosphere, and 82 g (0.81 g) are added. mole) of triethylamine and then 125.2 g (0.81 mole) of 3-methyl-benzoyl chloride. The mixture is refluxed for 4 hours, 8.2 g (0.08 mol) of triethylamine and 12.5 g (0.08 mol) of 3-methyl-benzoyl chloride are added and the mixture is heated for a further 3h.

It is filtered, the salts are washed with 1,2-dichloroethane, the filtrate is evaporated under reduced pressure, the residue is dissolved in ethyl acetate, and the solution is washed with saturated aqueous sodium chloride solution. the solvent is evaporated under reduced pressure and the residue is recrystallized from a 1/1 mixture of isopropyl alcohol / ethyl acetate. 80 g of a white solid are obtained. Melting point: 80-830C.

1.3. (3-Methylbenzoyl) -1-piperidine-4-methanol.

To a solution of 80 g (0.23 moles) of [(3-methyl-benzoyl) -1-piperidinyl] methyl 3-methylbenzoate in 400 ml of ethanol, a solution of 12.76 g (0 g) was added. 23 moles) of potassium hydroxide in 75 ml of ethanol and 75 ml of water.

The mixture is stirred at 20 ° C. for 3 h, the solvent is evaporated off under reduced pressure and the aqueous phase is extracted with ethyl acetate The organic phase is washed with water and then with a saturated aqueous solution of chloride of sodium, and dried over magnesium sulfate, the solvent is evaporated off under reduced pressure and 53 g of alcohol are obtained, which is used as it is in the next step.

1.4. Methyl 4-benzenesulfonate t (3-methylbenzoyl) -1-piperidinyl-4] methyl.

52 g (0.22 mol) of (3-methylbenzoyl) -1-piperidine-4-methanol in 100 ml of pyridine are added to a solution and 53.3 g (0.28 mol) of methyl-4-benzenesulphonyl chloride are added to a solution. in 60 ml of pyridine. The mixture is stirred at 20.degree. C. for 4 hours and then poured into ice, the phase is extracted with dichloromethane, the organic phase is washed with 1N aqueous hydrochloric acid and dried over magnesium sulphate. The solvents are evaporated under reduced pressure to give 70 g of white solid, m.p. 68-700C.

1.5. Methyl-4 [[(3-methyl-phenyl) carbonyl-1-piperidinyl] -4-methyl] -2,2,3,4-tetrahydro-isoquinoline, fumarate.

Under argon atmosphere, 3 g (0.02 mol) of 4-methyl-1,2,3,4-tetrahydro-isoquinoline and 7.6 g of methyl (4-methylbenzoyl) methyl 4-benzenesulfonate are introduced into a flask. piperyl dinyl-4] methyl, 2.8 g (0.02 mol) of potassium carbonate and 20 ml of dimethylformamide. The mixture is stirred for 9 hours at 900 ° C., cooled and poured into water. The mixture is extracted with dichloromethane, the organic phase is washed with water, dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. 6.5 g of residue are obtained, which is purified by chromatography on a silica column, eluting with ether, which gives 2.5 g of pure base. 1 g of this is dissolved in the minimum amount of ethanol. 0.35 g of fumaric acid is added, the mixture is stirred for 20 minutes at room temperature, the solvent is evaporated under reduced pressure and the residue is recrystallized from isopropyl alcohol. Finally, 0.7 g of fumarate is finally isolated. Melting point: 126-1270C.

Example 2 (Compound N06)
Methyl-4 [[(3-methyl-phenyl) methyl-1-piperidinyl] methyl] -2,2,3,4-tetrahydro-isoquinoline, difumarate.

To a solution of 1.38 g (0.038 mol) of methyl-4 [[(methyl-3-phenyl) carbonyl-1-piperidinyl-4-methyl] -2-tetrahydro-1,2,3,4 isoquinoline in 50 ml of tetrahydrofuran is added under argon atmosphere, 12 ml (0.0114 mol) of borane / tetrahydrofuran complex, and the mixture is stirred under reflux for 6 hours. The excess complex is decomposed by addition of 20 ml of methanol, 5 ml of hydrochloric acid and refluxing for 1 h, then the solvents are evaporated under reduced pressure. The aqueous phase is neutralized with ammonia, extracted with dichloromethane, the organic phase is washed with water and then with saturated sodium chloride solution, dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. 1 g of base is obtained which is dissolved in ethanol, 0.76 g of fumaric acid in solution in ethanol are added, the mixture is stirred for 15 minutes, the solvent is evaporated under pressure. reduced and the residue is recrystallized from isopropyl alcohol. Finally, 1 g of difumarate is obtained. Melting point: 147-1480C.

The following table illustrates the chemical structures and the physical properties of some compounds according to the invention.
Board

<tb> N <SEP> Z <SEP> R <SEP> Sel <SEP> F (C) <SEP>
<tb><SEP> 1 <SEP> CO <SEP> C6H5- <SEP> fum. <SEP> 156-157
<tb><SEP> 2 <SEP> CH2 <SEP> C6H5- <SEP> difum. <SEP> 163-164
<tb><SEP> 3 <SEP> CO <SEP> Cl-3-C6H4- <SEP> fum. <SEP> 147-149
<tb><SEP> 4 <SEP> CH2 <SEP> C1-3-C6H4 <SEP> difum. <SEP> 174-176
<tb><SEP> 5 <SEP> CO <SEP> CH3-3-C6H4- <SEP> fum. <SEP> 126-127
<tb><SEP> 6 <SEP> CH2 <SEP> CH3-3-C6H4 <SEP> difum. <SEP> 147-148
<tb><SEP> 7 <SEP> CO <SEP> C2H50-3-C6H4- <SEP> fum. <SEP> 97-99
<tb><SEP> 8 <SEP> CH2 <SEP> C2H5O-3-C6H4- <SEP> difum. <SEP> 145-150
<Tb>
Note
In the column "Salt""fum." refers to fumarate and "difum" refers to difumarate.

The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Thus, they have been studied for their affinity for serotoninergic receptors of the 5-HT1A type.

The compounds move in the rat hippocampus a labeled specific ligand, [3H) -8-hydroxy-2-dipropylamino-tetralin (hereinafter referred to as "3H) -8-OH-DPAT") described by
Gozlan et al., Nature, (1983), 305, 140-142.

The animals used are male Sprague-Dawley rats - from 160 to 200 g. After decapitation, the brain is removed and the hippocampus excised. The fabric is ground in a machine
Ultra-Turrax Polytron for 30 s at half the maximum speed in 10 volumes of 50 mM Tris buffer pH adjusted to 7.4 with hydrochloric acid (ie 100 mg of fresh tissue per ml). The homogenized tissues were washed three times at 40C, centrifuging them each time at 48000xg and resuspending the pellet for 10 min in fresh cooled buffer. Finally, the last pellet is suspended in the buffer to give a concentration of 100 mg of starting tissue per ml of 50 mM buffer.

It is then allowed to incubate at 37 ° C. for 10 minutes.

The binding of [3H] -8-OH-DPAT is determined by incubating 10 μl of the membrane suspension in a final volume of 1 ml of buffer containing 10 μg of pargylline.

After incubation the membranes are recovered by filtration on Whatman GF / B filters which are washed three times with 5 ml aliquots of ice-cold buffer. The filters are extracted into the scintillation fluid and the radioactivity is measured by liquid scintigraphy. The specific binding of E3h1-8-OH-DPAT is defined as the radioactive amount retained on the filters and can be inhibited by co-incubation in 10-hydroxy-5-tryptamine. At a concentration of 1 nM [3H] -8-OH-DPAT the specific binding represents from 7% to 80% of the total radioactivity recovered on the filter.

For each concentration of compounds studied, the percentage inhibition of binding with [3H) -8-OH-
DPAT, then the IC50 concentration, a concentration that inhibits 50% of the binding.

For the compounds of the invention, the IC50s are between 0.001 and 0.3 μM.

The central activity of the compounds of the invention was evaluated by their effects on the "pgo-geniculo-occipital spikes" induced by reserpine (PGO-R test) in the cat, according to the method described by H. Depoortere, Sleep 1976, 3rd
Europ. Cong. Sleep Res., Montpellier 1976, 358-361 (marger,
Basel 1977).

Cumulative doses of test compounds (0.003 to 3 mg / kg intravenously) are administered at 39 min intervals, 4 hours after intraperitoneal injection of a 0.75 mg / kg dose of reserpine, at curarized cats, under artificial ventilation. The electroencephalographic and phasic activities (PGO-R points) are collected using cortical and deep electrodes (lateral knee).

For each dose of compound studied, the percentage of decrease in the number of PGO spikes is determined, then the DA50 active dose which reduces by 50% this number of spikes.

For the compounds of the invention, the ED50 values are between 0.003 and 3 mg / kg intravenously.

The results of the tests show that the compounds of general formula (I) possess, in vitro, a high affinity and a selectivity for serotoninergic receptors of 5-HT1A type. In vivo they show an agonist activity, partial agonist, or antagonist at these receptors.

The compounds of the invention can therefore be used for the treatment of diseases and conditions involving serotoninergic receptors of the 5-HT1A type, directly or indirectly, in particular for the treatment of depressive states, states of anxiety, sleep disorders , for the regulation of food intake, and for vascular, cardiovascular or cerebrovascular treatment such as hypertension or migraine.

For this purpose they may be presented in any form suitable for their oral or parenteral administration, combined with any suitable excipients, and dosed to allow a daily dosage of 1 to 1000 mg.

Claims (3)

claims 1. Compounds of general formula (I)

 in which R is a group of the general formula -ZR 'wherein Z is -CO- or -CH2- and R' is phenyl optionally having one to three substituents selected from halogen atoms and groups (C1-C3) linear or branched alkyl and linear or branched (C1-C3) alkoxy, and their addition salts with acids. 2. Process for the preparation of compounds according to claim 1, characterized in that the 4-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with a tosylate of general formula (III)

 (wherein Tos represents a tosyl group and R 'is as defined in claim 1), either in the absence or in the presence of an inert solvent such as dimethylformamide, toluene or xylene, at a temperature from 20 to 1500C, and optionally in the presence of an organic base, such as a tertiary amine, or mineral, such as an alkaline carbonate or hydrogen carbonate, thus obtaining a compound of general formula (Ia)

 then, if it is desired to prepare a compound of general formula (I) in which Z represents a -CH 2 - group, the compound of general formula (Ia) is then reduced by means of a simple hydride or complex of boron or aluminum , such as lithium aluminum hydride, aluminum hydride, diborane / tetrahydrofuran complex or diborane / methylsulfide complex, in an ethereal solvent such as diethyl ether, tetrahydrofuran or dloxane at a temperature of 20 to 1000C. 3. Pharmaceutical composition characterized in that it is suitable a compound according to claim 1 associated with a pharmaceutical excipient.