Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines

Definitions

• R 1 , R 2 and R 3 each represent, independently of one another, a hydrogen or halogen atom or a hydroxy group, (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy,
• R 4 represents a hydrogen or halogen atom or a (C 1 -C 4 ) alkyl, 2-methoxyethoxy, (C 1 -C 6 ) alkoxy, (C 3 -C 6 ) cycloalkylmethoxy or phenylmethoxy group,
• Z represents an oxygen atom or two hydrogen atoms
• R represents an ethoxy group when Z represents an oxygen atom, or else represents a phenyl group optionally substituted by one or more halogen atoms or (C 1 -C 4 ) alkyl, (C 1 -C 4 )) alkoxy groups or amino.
• the compounds of the invention may exist in two forms of non-equivalent geometric isomeries, namely the ⁇ isomer form, or endo, in which the CH 2 group connecting the two heterocycles is in the axial position, and the ⁇ isomer form, or exo, in which the said CH 2 group is in an equatorial position in a so-called "chair" conformation of the piperidine cycle.
• the compounds of the invention may also exist in the form of bases or of addition salts with acids.
• An epoxide of formula (III) is obtained, which is converted into an aldehyde of formula (IV) by the action of a Lewis acid, for example boron trifluoride etherate, in an inert solvent, for example toluene , at a temperature of 0 to 40 ° C.
• a Lewis acid for example boron trifluoride etherate
• an inert solvent for example toluene
• the aldehyde of formula (IV) is then reduced to the alcohol of formula (V) by the action of a mixed alkaline hydride, for example sodium borohydride, in an aliphatic alcohol, for example methanol, at a temperature of 0 to 20 ° C.
• a mixed alkaline hydride for example sodium borohydride
• an aliphatic alcohol for example methanol
• the hydroxyl group of the alcohol of formula (V) is then transformed into a labile group W, for example into a tosylate, trifluoroacetate or halide group, to obtain a compound of general formula (VI), which is reacted with a 1,2,3,4-tetrahydroisoquinoline of general formula (VII), in which R 1 , R 2 , R 3 and R 4 are as defined above, in an aprotic solvent, for example N, N-di - methylformamide, in the presence of a base, for example potassium carbonate, at a temperature of 20 to 100 ° C, to result in a compound of general formula (la), which corresponds to the general formula (I) when Z represents an oxygen atom and R represents an ethoxy group.
• a aprotic solvent for example N, N-di - methylformamide
• the compound of general formula (la) is deprotected according to a known method, for example by the action of concentrated sulfuric acid, to obtain the amine of general formula (VIII), which is reacted with an acid chloride of general formula (IX), in which R is as defined above, in a chlorinated solvent, for example dichloromethane, in the presence of a base, for example triethylamine, at a temperature of 20 to 40 ° C.
• a chlorinated solvent for example dichloromethane
• a base for example triethylamine
• a compound of general formula (Ib) is obtained which corresponds to general formula (I) when Z represents an oxygen atom and R represents an optionally substituted phenyl group.
• the compound of general formula (Ib) can be reduced by the action of a mixed alkaline hydride, for example aluminum and lithium hydride, in an ethereal solvent, for example tetrahydrofuran, at a temperature from 0 to 60 ° C, to obtain a compound of general formula (Ie) where Z represents two hydrogen atoms.
• the reduced compound of general formula (Ib) can be obtained directly by reacting the amine of general formula (VIII) with a halide of general formula (X), in which R is as defined above, in an aprotic solvent, for example N, N-dimethylformamide, in the presence of a base such as potassium carbonate, at a temperature of 20 to 100 ° C.
• the substituted 1,2,3,4-tetraisoquinolines of general formula (VII) can be prepared by methods analogous to that described in J. Med. Chem. (1987) 30 2208.
• the compound of general formula (XII) is obtained, which is reduced by the action of a mixed alkaline hydride, for example aluminum and lithium hydride, in an ethereal solvent, for example tetrahydrofuran, at a temperature of 0 to 60 ° C, to obtain a compound of general formula (Id), which corresponds to the general formula (I) when Z represents two hydrogen atoms and R represents an unsubstituted phenyl group.
• a mixed alkaline hydride for example aluminum and lithium hydride
• an ethereal solvent for example tetrahydrofuran
• this compound can then be debenzylated, for example by catalytic hydrogenation, to obtain the amine of general formula (VIII), and treat the latter as described in connection with scheme 1.
• Ethyl 8- (phenylmethyl) -8-azab ⁇ cyclo [3.2.1] octane-3-carboxylate of formula (XI) can be prepared by a method analogous to that described in J. Med. Chem. (1994) 37 2831.
• the dash "-” is part of the word, and the dash “_” is only used for the break at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.
• the mixture is poured into 1 l of water, and a
• the mixture is poured into 200 ml of ice water, the organic phase is separated by decantation, and the aqueous phase is extracted twice with dichloromethane.
• the organic phases are combined, dried over sodium sulfate, filtered and the solvents are evaporated off under reduced pressure.
• the mixture is poured into 600 ml of water, it is extracted with three times 200 ml of ethyl acetate, the organic phase is washed twice with 100 ml of 1N hydrochloric acid and then with water, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.
• a crude product is obtained which is purified by chromatography on a silica gel column, eluting with a dichloromethane / methanol mixture 100/0 to 97/3, and 20.3 g of tosylate are obtained, which is used as it is in the next step.
• the mixture is poured into 50 ml of water, extracted with dichloromethane, the organic phase is separated, washed with water, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure .
• the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture 100/0 to 95/5, which gives 1.26 g of base.
• the hydrochloride is prepared by adding 35 ml of hydrochloric acid in 0.1N solution in propan-2-ol in a solution of the 1.26 g (0.0035 mol) of base in 20 ml of acetate d 'ethyl. The solvents are evaporated off under reduced pressure, the residue is recrystallized from a mixture of propan-2-ol and ethyl acetate, and 0.9 g of compound is obtained in the form of a white solid.
• the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture.
• the crystallization mother liquors of the preceding example are concentrated under reduced pressure, 100 ml of water are added to the residue, then 30% sodium hydroxide solution to basic pH, the mixture is extracted with dichloromethane, the organic phase with water, dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol 100 / 0 to 98/2, to separate the ⁇ (less polar) isomer from the ⁇ (more polar) isomer.
• Example 2.2 Using the method described in Example 2.2, from 0.41 g (0.00129 mole) of (endo) -3 - [(5,8-dimethoxy-1,2,3,4- tetrahydroisoquinoline-2 -yl) methyl] -8-azabicyclo [3.2.1] octane and 0.48 g (0.00258 mole) of 3-ethoxybenzoyl chloride, 0.5 g of compound at l is obtained, after purification by chromatography 'basic condition.
• the excess hydride is hydrolyzed with 1 ml of 10% sodium hydroxide, the mixture is diluted with 30 ml of tetrahydrofuran, a few grams of sodium sulfate are added, the insoluble material is filtered off, the solvent is evaporated under pressure reduced, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol 98/2 to 90/10, and 0.1 g (0.000246 mole) of compound is isolated. basic condition.
• the mixture is cooled to 0 ° C., the excess hydride is hydrolyzed with water and 30% aqueous sodium hydroxide, the mineral is filtered off, washing with tetrahydro furan, the mixture is concentrated. filtrate under reduced pressure, and 10.5 g of product are obtained in the form of a yellow oil.
• This compound is suspended in 100 ml of ethanol, 1 g of 10% palladium on carbon is added, and the mixture is subjected to hydrogenation in a Parr apparatus, at a pressure of about 0.32 MPa, at about 40 ° C, for 10 h.
• the catalyst is filtered off, the fitrat is concentrated under reduced pressure, and 2.35 g of compound are obtained, which is used as it is in the next step.
• the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 to 85/15 mixture of dichloromethane and methanol, and 0.9 g of compound is obtained in the form of the base.
• 0.6 g of difumarate is isolated in the form of a white solid.
• the mixture is cooled to room temperature, it is poured into 100 ml of water and ice, it is extracted with three times 100 ml of ethyl acetate, the organic phase is washed with water, it is dried over sodium sulfate, it is filtered and the solvent is evaporated off under reduced pressure.
• the residue is purified by chromatography on a column of silica gel, eluting with a 97/3 to 85/15 mixture of dichloromethane and methanol.
• the mixture is hydrolyzed with 100 ml of water, the precipitate is removed by filtration, rinsing with ethyl acetate, the organic phase is dried over magnesium sulfate, and the solvent is evaporated off under reduced pressure.
• the catalyst is filtered off, the solvent is evaporated off under reduced pressure and 1.71 g of compound are obtained in the form of a yellow oil, which is used as it is in the following step.
• the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their advantage as substances with therapeutic activities. Study of the affinity for dopaminergic receptors of type D 2.
• the compounds displace the binding of a specific labeled ligand, spiperone (hereinafter referred to as "[ 3 H] spiperone” and described by Briley and Langer., Eur. J. Pharmacol. (1978) 50 283) on receptors D 2 present in the rat striatum.
• the animals used are male Sprague-Dawley rats weighing 150 to 250 g. After decapitation, the brain is removed and the striatum is excised. The tissue is ground using a Polytron TM mill in 50 volumes of 50 mM Tris-HCl buffer containing sodium chloride (120 mM), potassium chloride (5 mM) and the pH of which is adjusted to 7 , 4 (i.e. 100 mg of fresh tissue per 5 ml). The homogenized tissues are washed twice at 4 ° C., centrifuging them each time for 10 min at 40,000 ⁇ g and resuspending the pellet in fresh cooled buffer. Finally the last pellet is suspended in the same volume of buffer and added ascorbic acid (0.1% in final concentration) and pargyline (10 ⁇ M in final concentration). Then allowed to incubate at 37 ° C for 10 min.
• [ 3 H] spiperone (New England Nuclear, specific activity 20-40 mCi / mmol) is determined by incubating 100 ⁇ l of the membrane suspension with the radioligand (0.25 nM) in a final volume of 1 ml, for
• the membranes are recovered by filtration on Whatman GF / B TM filters which are washed with two 5 ml volumes of ice-cold buffer. The filters are extracted into the scintillation liquid and the radioactivity is measured by liquid scintigraphy with an efficiency of 50 to 60%. For each compound tested, the results are expressed by the IC 50 , that is to say by the concentration which inhibits 50% of the binding of the [ 3 H] spiperone, calculated by a graphical method or
• IC 50 values are between 0.01 and 10 ⁇ M.
• the compounds were the subject of an in vi tro study as to their affinity for the dopaminergic receptors D 3 obtained from a membrane preparation of the caudate nucleus of beef, essentially as described by Schoemaker H. in Eur. J. Pharmacol. (1993) 242 R1-R2.
• the caudate beef kernels (Collect Organe, Paris, France), stored at -80 ° C, are thawed and homogenized at 4 ° C in 10 volumes of buffer (10 mM Tris, 1 mM EDTA, pH 7.5 at 25 ° C) using a Polytron TM (position 5, 30 s).
• the homogenate is centrifuged at 2500 g for 1 min (Sorvall TM centrifuge equipped with an SS34 rotor).
• the homogenate is centrifuged at 35,000 g for 15 min, the pellet is resuspended in the incubation buffer, (HEPES 50 mM, EDTA 1 mM, 8-hydroxyquinoline 50 ⁇ M, ascorbic acid 0.005%, pH 7.5 to 25 ° C), at a rate of 100 mh of initial tissue per ml.
• HEPES 50 mM, EDTA 1 mM, 8-hydroxyquinoline 50 ⁇ M, ascorbic acid 0.005%, pH 7.5 to 25 ° C at a rate of 100 mh of initial tissue per ml.
• the membrane suspension (150 ⁇ l) is incubated at 23 ° C for 60 min in tubes, in the presence of 0.8 nM of [ 3 H] 7-OH-DPAT (specific activity 120-160 Ci / mmol, Amersham TM) in a final volume of 1 ml of incubation buffer containing 0.2 ⁇ M of zolpidem hydrochloride and 1 mg of bovine serum albumin, in the presence or in the absence of compound to be tested.
• the filters are cut and then dried in an oven at 120 ° C for 10 min and the radioactivity retained on the filters is determined by liquid scintillation spectrometry. The non-specific binding is determined in the presence of 1 ⁇ M of dopamine.
• IC 50 values of the compounds of the invention are of the order of
• the compounds displace the binding of a specific labeled ligand, [ 3 H] -8-hydroxy-di-n-propylamino-2 tetralin (hereinafter referred to as "[ 3 H] -8-OH-DPAT" and described by Gozlan et al., Nature (1983) 305 140) on the 5-HT 1A receptors present in the hippocampus of the rat.
• the animals used are male Sprague-Dawley rats weighing 160 to 200 g. After decapitation, the brain is removed and the hippocampus is excised. The tissue is ground in an Ultra-Turrax Polytron TM device for 30 s at half the maximum speed in 10 volumes of 50 mM Tris buffer, pH adjusted to 7.4 with hydrochloric acid (i.e. 100 mg of fresh tissue per ml). The homogenized tissues are washed twice at 4 ° C., centrifuging them each time for 10 min at 48000 ⁇ g and resuspending the pellet in fresh cooled buffer. Finally, the last pellet is suspended in the buffer to arrive at a concentration of 50 mg of starting tissue per ml of 50 mM buffer. Then allowed to incubate at 37 ° C for 10 min.
• the binding with [ 3 H] 8-OH-DPAT (1 nM) is determined by incubation of 50 ⁇ l of membrane suspension in a final volume of 250 ⁇ l of buffer containing 10 ⁇ M of pargyline and 3 ⁇ M of paroxetine. After an incubation of 15 min at 37 ° C., the membranes are recovered by filtration on Whatman filters. GF / B TM which is washed three times with aliquots of 5 ml of ice-cold buffer. The filters are extracted into the scintillation liquid and the radioactivity is measured by liquid scintigraphy. We define the specific bond of the
• [ 3 H] 8-OH-DPAT as the amount of radioactivity retained on the filters and which can be inhibited by co-incubation with 5-hydroxytryptamine at 10 ⁇ M.
• the specific bond represents 90% of the total radioactivity recovered on the filter.
• the percentage of inhibition of the binding with [ 3 H] 8-OH-DPAT is determined, then the concentration IC 50 , a concentration which inhibits 50% of the binding.
• the IC 50 values are between 0.001 and 10 ⁇ M.
• the compounds of the invention were also the subject of an in vi tro test for displacement of the binding of spiperone to the serotonergic receptors (5-HT 2 ) of the cerebral cortex of the rat.
• the homogeneous mixture is centrifuged at 40,000 ⁇ g for 10 min then, twice, the pellet is recovered, it is washed by suspending it in the same buffer mixture, it is homogenized again and it is centrifuged. Finally, the final pellet is diluted in the same buffer mixture at the rate of 100 mg of wet tissue for 1 ml of buffer.
• tissue is then subjected to a 10 min preliminary incubation at 37 ° C in the presence of 10 micromoles / l of pargyline, then to a 20 min incubation at 37 ° C in the presence of [ 3 H] spiperone (specific activity: 15 at 30 Ci per millimole) at the
• the membranes are then recovered by filtration through filters Whatman GF5B TM, which is washed twice with 5 ml of cold buffer. The radioactivity retained by the filter is measured by liquid scintigraphy.
• the curve of the percentage inhibition of the specific binding of [3 H] spiperone as a function of the concentration of displacing drug is established.
• the IC 50 concentration is determined graphically, a concentration which inhibits 50% of the specific binding.
• the specific bond is defined as being the bond displaced by 100 micromoles / l of 5-HT.
• the IC 50 concentrations of the compounds of the invention are between 0.030 and 10 ⁇ M.
• results of the tests carried out in vitro on the compounds of the invention show that some of them have a strong affinity for the dopaminergic receptors of type D 2 and D 3 and for the serotonergic receptors of type 5-HT 1A and 5- HT 2 , and are mixed ligands.
• CI 50 (D 2 ) / CI 50 (D 3 ) is between 1 and 60, and the specificity, represented by the ratio CI 50 (5-HT 1A ) / CI 50 (D 3 ) is between 1 and 30.
• the compounds of the invention have, on the other hand, been subjected to in vivo pharmacological tests.
• the hyperactivity is recorded for 20 min, 30 min after the injection of d-amphetamine (2 mg / kg), immediately after introduction of the animals into the activity cages crossed by two light beams perpendicular to 2 cm above the floor .
• the beam cuts are recorded automatically.
• the compounds are injected intraperitoneally, 30 min before d-amphetamine, at doses of 0.3, 1, 3 and 6 mg / kg, and the effective doses of DE 50 , doses which reduce hyperactivity by 50%, are determined.
• the ED 50 of the most active compounds are of the order of 1 mg / kg.
• Each leg of the rat is placed on a plug 2.5 cm high and 1.2 cm in diameter, the distance between two contralateral plugs being 8 cm, and the distance between two ipsilateral plugs being 13 cm.
• the rat is considered to be in catalepsy if it keeps its four legs on the plugs for more than 10 s.
• the duration of catalepsy is measured for a maximum of 2 min to 1 h, 2 h and 4 h after intraperitoneal administration of the test compounds, at doses of 1, 3, 10, 30 and 60 mg / kg.
• the compounds either have a weak cataleptigene activity or are totally devoid of it at the doses tested.
• the compounds of the invention can be used for the treatment of psychoses, in particular schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics, for the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorder, for the treatment of various forms of depression, including psychotic depression, for the treatment of disorders due to alcohol abuse or withdrawal, sexual behavior disorders, eating disorders, and for the treatment of migraine.

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