JP2000512620A - 3-[(1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabicyclo [3.2.1] octane derivatives, their preparation, and their application in therapy - Google Patents

Abstract

(57) [Summary] General formula (I): Wherein R ₁ , R ₂ and R ₃ each represent a hydrogen or halogen atom, or a hydroxyl, alkyl or alkoxy group; R ₄ represents a hydrogen or halogen atom, or alkyl, 2-methoxyethoxy, alkoxy, R represents a cycloalkylmethoxy or phenylmethoxy group; or R ₃ and R ₄ together form a methylenedioxy group; Z represents oxygen or two hydrogen atoms; When it represents oxygen it represents an ethoxy group, or it represents a phenyl group which may be optionally substituted by one or more halogen atoms or an alkyl, alkoxy or amino group. ] The compound of. The compounds for D ₂ and D ₃ -type dopamine receptors, and has a strong affinity for 5-HT _1A and 5-HT ₂ type of serotonin receptors, also a mixed ligand. Other compounds have a strong affinity for dopamine receptors of type ₃ D, also D ₂ type dopamine receptors, as well as sensitive to 5-HT _1A and 5-HT ₂ serotonin receptor affinity And therefore a selective and specific ligand.

Description

DETAILED DESCRIPTION OF THE INVENTION   3-[(1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-           Azabicyclo [3.2.1] octane derivatives, their preparation,                     And their application in treatment   The present invention provides a compound represented by the general formula (I): [Where,   R₁, R_Two, And R_ThreeAre each independently of the other a hydrogen or halogen atom, Or hydroxyl, (C₁-C_Four) Alkyl or (C₁-C_Four) Alkoxy group And;   R_FourIs a hydrogen or halogen atom, or (C₁-C_Four) Alkyl, 2-methoxy Siethoxy, (C₁-C₆) Alkoxy, (C_Three-C₆) Cycloalkylmethoxy or Represents a phenylmethoxy group; or   R_ThreeAnd R_FourTogether form a methylenedioxy group;   Z represents an oxygen atom or two hydrogen atoms; and   R represents an ethoxy group when Z represents an oxygen atom, or Or more halogen atoms, or (C₁-C_Four) Alkyl, (C₁-C_FourArco Represents a phenyl group optionally substituted with a xy or amino group . ] For the compound corresponding to   The compounds of the present invention have two non-equivalent geometric isomeric forms, the That is, CH connecting two heterocycles_TwoThe group is in the axial position, α or And the CH isomer form, and the CH_TwoThe group is a “chair” conformation of the so-called piperidine ring In the equatorial position, in the β or exo isomer form. Departure The named compounds may also exist in base form or in the form of addition salts to acids.   Particularly advantageous compounds are those of the general formula_FourRepresents an alkoxy group, and Wherein R represents a phenyl group which may be optionally substituted.   According to the present invention, a compound of general formula (I) is prepared by the method described in the following scheme: Can be manufactured.                               Scheme 1  According to Scheme 1, a compound of formula (II) in an inert solvent (eg, dimethyl sulfoxide) Of 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate Reacts with sulfur ylides (e.g., trimethylsulfoxonium salts) at temperatures between 0 and 40C Let it.   An epoxide of the formula (III) is obtained and is reacted with a Lewis acid (e.g. For example, by the action of a boron trifluoride etherate compound), this is heated to a temperature of 0 to 40 ° C. Converts to the aldehyde of formula (IV) in degrees.   Then, in an aliphatic alcohol (e.g., methanol), mixed alkali hydride ( For example, by the action of sodium borohydride, the aldehyde of the formula (IV) is Reduction at 0 ° C. to the alcohol of formula (V).   The hydroxyl group of the alcohol of formula (V) is then reacted with a reactive group W (eg, Tosylate, trifluoroacetate or halide groups) A compound of the formula (VI) is obtained, and an aprotic solvent (for example, N, N-dimethylformamide) is obtained. At a temperature of 20 to 100 ° C. in the presence of a base (for example, potassium carbonate). Formula (VII) [wherein R₁, R_Two, R_Three, And R_FourIs as defined above And 1,2,3,4-tetrahydroisoquinoline of the general formula (Ia) Compounds (this is the general case where Z represents an oxygen atom and R represents an ethoxy group) Corresponding to formula (I)).   If desired, at this stage of the method, for example, chromatography on a silica gel column Obtained by chromatography or by differential crystallization of the hydrochloride. The two isomers can be separated.   Wherein R represents a phenyl group which may be optionally substituted, In order to produce the compound, by a known method (for example, by the action of concentrated sulfuric acid), Deprotection of the compound of formula (Ia) affords the amine of general formula (VIII) and the chlorinated solvent ( This in the presence of a base (e.g., triethylamine) At a temperature of 20 to 40 ° C., wherein R is as defined above. With the acid chloride.   A compound of general formula (Ib) wherein Z represents an oxygen atom and R is Corresponding to general formula (I) when representing a phenyl group which may be optionally substituted To).   If desired, mixed alkaline water in an ether solvent (e.g., tetrahydrofuran) By the action of a hydride (eg, lithium aluminum hydride), the compound of the general formula (Ib) The compound is reduced at a temperature of 0 to 60 ° C. to form a compound of the general formula (Ic) wherein Z represents two hydrogen atoms. ) Can be obtained. As one variant, an aprotic solvent (e.g., For example, in N, N-dimethylformamide), the amine of the general formula (VIII) is replaced with potassium carbonate. At a temperature of 20 to 100 ° C. in the presence of a base such as As defined above] to form Certain compounds of general formula (Ib) can be obtained directly.   3-oxo-8-azabicyclo [3.2.1] octane-8-carboxyl of formula (II) Ethyl acid is commercially available.   The substituted 1,2,3,4-tetrahydroisoquinoline of the general formula (VII) is J. Med. Chem. (1987), 30, 2208. It can be manufactured by a method.                               Scheme 2  According to Scheme 2, 8- (F) of formula (XI) in an inert solvent (for example, toluene). Ethenylmethyl) -8-azabicyclo [3.2.1] octane-3-carboxylate Is prepared from dimethyl aluminum And the general formula (VII)₁, R_Two, R_Three, And R_FourIs the previously defined 1,2,3,4-tetrahydroisoquinoline and at a temperature of 0 to 100 ° C. Let react.   A compound of the general formula (XII) is obtained in an ether solvent (eg, tetrahydrofuran). By the action of mixed alkali hydrides (for example, lithium aluminum hydride), This is reduced at a temperature of 0 to 60 ° C. to give a compound of the general formula (Id), wherein Z is 2 In which R represents an unsubstituted phenyl group, and Corresponding to formula (I)).   If desired, the compound is then debenzylated, for example, by catalytic hydrogenation. To give an amine of the general formula (VIII), Processing can be performed as described for system 1.   8- (phenylmethyl) -8-azabicyclo [3.2.1] octane of the formula (XI) Ethyl 3-carboxylate is described in J. Am. Med. Chem. (1994), 37, 2831. It can be manufactured by a method similar to that which has been used.   The following examples illustrate the preparation of some compounds of the invention. Elemental trace analysis, average In addition, the IR and NMR spectra confirm the structure of the compound obtained.   In the titles of the examples, the numbers shown in parentheses are those in the first column of Table 1 described later. Corresponds to numbers.   In compound names, the hyphen "-" forms part of the word, and the line " "Simply serves as a line break; if the line is not at the Should be removed and replaced with either an ordinary hyphen or space should not do.Example 1 (Compound No. 1) (Exo) -3-[(1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] Ethyl-8-azabicyclo [3.2.1] octane-8-carboxylate hydrochloride 1.1. Spiro (8-azabicyclo [3.2.1] octane-3,2'-oxirane)-       Ethyl 8-carboxylate   Washing 20 g of sodium hydride as a suspension in 60% oil with pentane, 12 g (0.5 mol) of sodium hydride were obtained, and 400 ml of dimethyl sulfoxide was obtained. And 107 g (0.486 mol) of trimethylsulfoxonium iodide are added dropwise. The mixture is then stirred at room temperature for 2 hours.   Then, 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylic acid 60 g (0.3 mol) of ethyl are added dropwise and stirring is continued for 24 hours at room temperature. The mixture Is poured into 1 L of water and extracted with 3 × 300 ml of diethyl ether. Organic phase Dry with thorium, filter and remove the solvent by evaporation under reduced pressure to give a pale yellow 39.4 g of an oily product are obtained which can be used in the next step without further purification. To use. 1.2.3-Formyl-8-azabicyclo [3.2.1] octane-8-       Ethyl carboxylate   400 ml of toluene and 7.4 g of boron trifluoride etherate compound (0.052 m ol) was placed in a 1 L three-necked round bottom flask and subsequently dissolved in 100 ml of toluene. Spiro (8-azabicyclo [3.2.1] octane-3,2'-oxirane) -8-cal 22 g (0.104 mol) of ethyl borate are added dropwise and stirring is continued for 15 minutes at room temperature.   The mixture was poured into 200 ml of ice-water and, after sedimentation had taken place, the organic phase was separated off and extracted with water. The phases are extracted twice with dichloromethane. Combine the organic phases and dry over sodium sulfate , Filter and remove the solvent by evaporation under reduced pressure.   A mixture of two aldehydes in α and β configuration is obtained, which is Elute with a 100/0 to 98/2 mixture of tanol.   14.45 g of a 3/7 mixture of α / β isomers are obtained in the form of a colorless oily product. Is used in the next step without further purification. 1.3.3- (Hydroxymethyl) -8-azabicyclo [3.2.1] octane-8-       Ethyl carboxylate   3-formyl-8-azabicyclo [3.2.1] oct in a 500 ml round bottom flask 14.45 g of ethyl tan-8-carboxylate (3/7 mixture of α / β) (0.0683 m ol) was dissolved in 150 ml of methanol, and the solution was dissolved in a mixture of salt, water, and ice. C., and 2.59 g (0.0683 mol) of sodium borohydride were added dropwise. The mixture is stirred for 1 hour 30 minutes at 0-5 ° C.   The mixture is hydrolyzed by adding 50 ml of water and methanol is removed under reduced pressure. Is removed by evaporation, a further 50 ml of water are added and the mixture is diluted with 3 portions of dichloromethane. Extract three times with 00 ml. The organic phase is dried over sodium sulfate, filtered and the solvent is removed. Evaporated off under reduced pressure to give 14.6 g of product, which was further purified Used in the next step without doing. 1.4.3-[[[(4-Methylphenyl) sulfonyl] oxy] methyl] -8-       Ethyl azabicyclo [3.2.1] octane-8-carboxylate   3- (Hydroxymethyl) -8-azabicyclo [3.2 dissolved in 25 ml of pyridine .1] 14.6 g of ethyl octane-8-carboxylate in a 250 ml three-neck round bottom flask And the mixture is cooled to 0 ° C. with a mixture of salt, water, and ice, 14.36 g (0.0753 mol) of tosyl chloride dissolved in 45 ml was added dropwise over 45 minutes. Then, the mixture is stirred first at 0 ° C. for 15 minutes and then at room temperature for 24 hours.   The mixture was poured into 600 ml of water and extracted three times with 200 ml of ethyl acetate. Was washed with 100 ml of 1N hydrochloric acid and then twice with water, dried over sodium sulfate and Filter and remove the solvent by evaporation under reduced pressure.   Obtain the crude product, dichloromethane / methanol 100 / 0-97 / 3 mixture This was purified by chromatography on a silica gel column eluted with , 20.3 g of tosylate, this product being obtained in the next step without further purification. use. 1.5. (Exo) -3-[(1,2,3,4-tetrahydroisoquinoline-2-       Yl) methyl] -8-azabicyclo [3.2.1] octane-8-       Ethyl carboxylate hydrochloride   1.33 g (0.01 mol) of 1,2,3,4-tetrahydroisoquinoline, 3-[[[(4 -Methylphenyl) sulfonyl] oxy] methyl] -8-azabicyclo [3.2.1] o 3.67 g (0.01 mol) of octane-8-carboxylate, 1.52 g of potassium carbonate (0.011 mol) and 20 ml of N, N-dimethylformamide in an argon atmosphere. Place the mixture in a 100 ml three-necked round-bottomed flask, Heat for 2 hours 30 minutes.   The mixture was allowed to cool to room temperature, poured into 150 ml of ice water and extracted with ethyl acetate. , The organic phase is washed with water, dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure. Eject and remove, 100 / 0-98 / 2 mixture of dichloromethane and methanol The residue was purified by chromatography on a silica gel column eluted with To give 1.5 g of a 3/7 mixture of α / β isomers.   This mixture was dissolved in 30 ml of ethyl acetate and 0.1 dissolved in 2-propanol. 46 ml (0.0046 mol) of N hydrochloric acid were added and the solvent was removed by evaporation under reduced pressure. The distillate is recrystallized from a mixture of ethyl acetate and 2-propanol.   Finally, 0.7 g of the hydrochloride salt (pure β-isomer) was converted to a yellowish white solid. Get in shape. Melting point: 219-223 [deg.] C.Example 2 (Compound No. 5) (Exo) -8-benzoyl-3-[(1,2,3,4-tetrahydroisoquinoline- 2-yl) methyl] -8-azabicyclo [3.2.1] octane hydrochloride 2.1. (Exo) -3-[(1,2,3,4-tetrahydroisoquinoline-2-       Yl) methyl] -8-azabicyclo [3.2.1] octane   (Exo) -3-[(1,2,3,4-tetrahydroisoquinolin-2-yl) methyl ] -8-Azabicyclo [3.2.1] octane-8-carboxylic acid ethyl hydrochloride 1.3 5 g (0.0037 mol) was dissolved in 15 ml of water, and 15 ml of concentrated sulfuric acid was added dropwise. The thing is heated at 100 ° C. for 3 hours.   The mixture was cooled to 0 ° C. with a mixture of salt, water, and ice, and 30% sodium hydroxide was added. Lithium is added in small portions and the mixture is extracted with dichloromethane. Separate the organic phase Take, dry over sodium sulfate, filter and remove the solvent by evaporation under reduced pressure To give 0.95 g of product, which is used in the next step without further purification . 2.2. (Exo) -8-benzoyl-3-[(1,2,3,4-       Tetrahydroisoquinolin-2-yl) methyl] -8-       Azabicyclo [3.2.1] octane hydrochloride   (Exo) -3-[(1,2,3,4-tetrahydroisoquinolin-2-yl) methyl -8-azabicyclo [3.2.1] octane 0.95 g (0.0037 mol), trie 0.62 g (0.0065 mol) of tylamine and 15 ml of dichloromethane In a 100 ml three-necked round bottom flask placed under a gon atmosphere, benzoyl chloride .87 g (0.0015 mol) are added dropwise and the mixture is stirred at room temperature for 24 hours .   The mixture is poured into 50 ml of water, extracted with dichloromethane, the organic phase is separated off, Wash with water, dry over sodium sulfate, filter and evaporate the solvent under reduced pressure To remove.   Silica eluted with a 100/0 to 95/5 dichloromethane / methanol mixture The residue is purified by chromatography on a gel column, and 1.26 g of base are obtained. obtain.   0.1N 2 in a solution of 1.26 g (0.0035 mol) of the base in 20 ml of ethyl acetate The hydrochloride is then removed by adding 35 ml of hydrochloric acid as a propanol solution To manufacture. The solvent is removed by evaporation under reduced pressure and the residue is treated with 2-propanol and Recrystallisation from a mixture of ethyl acetate gives 0.9 g of the compound in the form of a white solid. You. Melting point: 251-256 [deg.] C (decomposition).Example 3 (Compound No. 2) (Exo) -3-[(5,8-dimethoxy-1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane-8-carboxylic acid ethyl hydrochloride   5,8-Dimethoxy-1,2,3,4-in 40 ml of N, N-dimethylformamide 4.2 g (0.0218 mol) of tetrahydroisoquinoline, 3-[[[(4-methylphen Nyl) sulfonyl] oxy] methyl] -8-azabicyclo [3.2.1] octane-8- 7.5 g (0.0204 mol) of ethyl carboxylate and 3.31 g (0.30 g) of potassium carbonate. 0239 mol) was placed in a three-necked round bottom flask placed under an argon atmosphere. Heat the mixture at 100 ° C. for 3 hours.   The mixture was cooled to room temperature, poured into 150 ml of ice water, extracted with ethyl acetate, The organic phase is separated off, washed with water, dried over sodium sulphate, filtered and the solvent is eliminated. Evaporate off under reduced pressure to remove.   Silica eluted with a 100/0 to 95/5 dichloromethane / methanol mixture The residue was purified by chromatography on a gel column, yielding 4.03 g of base. As a 3/7 mixture of α / β isomers.   4.03 g (0.0104 mol) of these were dissolved in 40 ml of ethyl acetate and 0.1N was added. 104 ml (0.0104 mol) of hydrochloric acid as a 2-propanol solution were added and the volume Is reduced by half and the mixture is triturated.   The solid is separated by filtration, dried and the pure hydrochloride salt of the isomer in beta configuration 1.66 g are obtained in the form of a white solid. Melting point: 195-198C.Example 4 (Compound No. 3) (Endo) -3-[(5,8-dimethoxy-1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane-8-carboxylic acid ethyl hydrochloride   The crystallization mother liquor from the previous example was concentrated under reduced pressure and 100 ml of water was added to the residue. Followed by the addition of 30% sodium hydroxide until the pH is basic. Extract the mixture with dichloromethane, wash the organic phase with water and dry over sodium sulfate And filtered, the solvent is removed by evaporation under reduced pressure, dichloromethane and Chromatography on a silica gel column eluted with a 100/0 to 98/2 mixture of tanols Purify the residue by chromatography to convert the β-isomer (which is more polar) to the α-isomer. Separates the body (less polar).   To 0.5 g (0.00129 mol) of the α (endo) isomer dissolved in 10 ml of ethyl acetate And 13 ml (0.0013 mol) of hydrochloric acid as a 0.1N 2-propanol solution were added. The volume of the solution is reduced under reduced pressure until crystallization starts.   Finally, 0.35 g of the hydrochloride salt of the pure α (endo) isomer was converted to a yellowish white Isolated in the form of a colored solid. Melting point: 197-200 <0> C.Example 5 (Compound No. 14) (Exo) -8- (3-ethoxybenzoyl) -3-[(5,8-dimethoxy- 1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane hydrochloride 5.1. (Exo) -3-[(5,8-dimethoxy-1,2,3,4-       Tetrahydroisoquinolin-2-yl) methyl] -8-       Azabicyclo [3.2.1] octane   Using the procedure described in Example 2.1, (exo) -3-[(5,8-dimethoxy -1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabizi 1 g (0.00234 mol) of ethyl [3.2.1] octane-8-carboxylate hydrochloride Starting with, 0.74 g of product was prepared, which was used in the next step without further purification. About to use. 5.2. (Exo) -8- (3-ethoxybenzoyl) -3-[(5,8-dimethoxy-       1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-       Azabicyclo [3.2.1] octane hydrochloride   Using the procedure described in Example 2.2, (exo) -3-[(5,8-dimethoxy -1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabizi 0.74 g (0.00234 mol) of black [3.2.1] octane and 3-chloroethoxy Starting with 0.86 g (0.004688 mol) of cibenzoyl, After further purification, 0.94 g of the compound is obtained in base form.   This product was dissolved in 20 ml of ethyl acetate to give a 0.1N 2-propanol solution. 21 ml (0.0021 mol) of hydrochloric acid were added and the volume of the solution was reduced by half under reduced pressure. The mixture is triturated, left to crystallize, and In this case, 0.68 g (0.00136 mol) of a yellowish white solid are isolated. Melting point: 188-190C.Example 6 (Compound No. 15) (Endo) -8- (3-ethoxybenzoyl) -3-[(5,8-dimethoxy- 1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane hydrochloride 6.1. (Endo) -3-[(5,8-dimethoxy-1,2,3,4-       Tetrahydroisoquinolin-2-yl) methyl] -8-       Azabicyclo [3.2.1] octane   Using the method described in Example 2.1, compound (endo) -3-[(5,8-dimethyl Toxi-1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-a 0.55 g (0.05 g) of ethyl zabicyclo [3.2.1] octane-8-carboxylate hydrochloride 0.13 mol) to produce 0.41 g of product, which is further purified And use it in the next step. 6.2. (Exo) -8- (3-ethoxybenzoyl) -3-[(5,8-dimethoxy-       1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-       Azabicyclo [3.2.1] octane hydrochloride   Using the procedure described in Example 2.2, (endo) -3-[(5,8-dimethoxy -1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabizi 0.41 g (0.00129 mol) of chromo [3.2.1] octane and 3-chloroethoxy Starting with 0.48 g (0.00258 mol) of cibenzoyl, After further purification, 0.5 g of compound is obtained in base form.   0.5 g (0.00108 mol) of the base was dissolved in 10 ml of ethyl acetate, and 0.1N 2- 11 ml (0.0011 mol) of hydrochloric acid as a propanol solution were added, and the volume of the solution was added. Is reduced by half under reduced pressure, the mixture is triturated and left to stand, After crystallization, 0.37 g (0.0007) of a yellowish-white solid was finally obtained. 4 mol) is isolated. Melting point: 188-190C.Example 7 (Compound No. 9) (Exo) -8-benzoyl-3-[(5,8-dimethoxy-1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane hydrochloride   Using the procedure described in Example 2.2, (exo) -3-[(5,8-dimethoxy -1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabizi 1.1 g (0.0035 mol) of chloro [3.2.1] octane and 0.8 g of benzoyl chloride Starting with 5 g (0.006 mol), after purification by chromatography, the compound 1.3 g are obtained in base form.   0.5 g (0.0012 mol) of this base was dissolved in 10 ml of ethyl acetate, and 0.1N 2 12 ml (0.0012 mol) of hydrochloric acid as a propanol solution are added and the solution Reduce the volume by half under reduced pressure, triturate the mixture and leave to stand 0.41 g of a yellowish-white solid (0.000 g) 9 mol) are isolated. Melting point: 222-227 ° C (decomposition).Example 8 (Compound No. 44) (Exo) -8- (phenylmethyl) -3-[(5,8-dimethoxy-1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane dihydrochloride   0.09 g (0.09 g) of lithium aluminum hydride in 10 ml of tetrahydrofuran (Exo) -8-benzoyl-3-[(5,8-dimethoxy) 1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabi 0.8 g (0.0019 mol) of cyclo [3.2.1] octane are added and the mixture is diluted with 0. Cool to 0 ° C. and stir at this temperature for 3 hours.   The excess hydride is hydrolyzed with 1 ml of 10% sodium hydroxide and the mixture Was diluted with 30 ml of tetrahydrofuran, several grams of sodium sulfate were added, and the mixture was insoluble. The toxic substances were filtered off and the solvent was removed by evaporation under reduced pressure to give Silica gel column eluted with a 98/2 to 90/10 mixture of toluene and methanol The residue was purified by chromatography on a system of 0.1 g of compound (0.00 g). 0246 mol) is isolated in base form.   This compound was dissolved in 10 ml of ethyl acetate to give a 0.1N 2-propanol solution. 6 ml of hydrochloric acid were added and the solvent was evaporated off under reduced pressure to give 2-propanol 1 ml and 2.5 ml of ethyl acetate. Finally, 0.06 g of dihydrochloride is yellowish. Obtained in the form of an off-white solid. Melting point: 221-224 [deg.] C.Example 9 (Compound No. 35) (Exo) -3-[(5-methoxy-1,2,3,4-tetrahydroisoquinoline- 2-yl) methyl] -8- (phenylmethyl) -8- Azabicyclo [3.2.1] octanedi- (E) -but-2-endioate 9.1. (Exo) -5-methoxy-2-[[8- (phenylmethyl) -8-       Azabicyclo [3.2.1] oct-3-yl] carbonyl] -1,2,3,4-       Tetrahydroisoquinoline   50 ml of toluene is placed in a 500 ml three-necked round bottom flask, and trimethylaluminum is added. 20.2 ml (40.35 mmol) of sodium chloride (as a 2 M solution in heptane) are added in portions. Is cooled to 0 ° C. under an argon atmosphere. 5-Methoxy dissolved in 50 ml of toluene 6.7 g (41.1 mmol) of 1,2,3,4-tetrahydroisoquinoline are added dropwise, The mixture is heated to 50 ° C. and after a few minutes at this temperature, 8- (phenylmethyl) -8 -7.8 g of ethyl azabicyclo [3.2.1] octane-3-carboxylate (28.5 mmol l) is added and the mixture is heated at reflux for 4 hours.   The mixture was cooled to 0 ° C. with a mixture of ice, salt, and water, and 30 ml of water was added. The insoluble substances are separated by filtration, and the filtrate is washed with water. Wash, dry over sodium sulfate and remove the solvent by evaporation under reduced pressure.   A column eluted with a 100/0 to 92/8 mixture of dichloromethane and methanol The residue was purified by chromatography on a Ricagel column to give compound 10 .89 g are obtained in the form of an orange-yellow oil. 9.2. (Exo) -3-[(5-methoxy-1,2,3,4-       Tetrahydroisoquinolin-2-yl) methyl] -8-       (Phenylmethyl) -8-azabicyclo [3.2.1] octane       Di- (E) -but-2-engioate   1.6 g of lithium aluminum hydride suspended in 70 ml of tetrahydrofuran ( 41.8 mmol) was placed in a 250 ml three-necked round bottom flask, and the mixture was placed in an argon atmosphere. The solution was cooled to 0 ° C. under an atmosphere, and dissolved in 30 ml of tetrahydrofuran. Methoxy-2-[[8- (phenylmethyl) -8-azabicyclo [3.2.1] oct- 10.89 g of 3-yl] carbonyl] -1,2,3,4-tetrahydroisoquinoline ( 27.9 mmol) are added, the mixture is allowed to return to room temperature and stirring is continued for 4 hours.   The mixture was cooled to 0 ° C and excess hydride was removed with water and 30% sodium hydroxide. Hydrolyzed with an aqueous solution of sodium hydroxide, and the inorganic substances were separated by filtration and washed with tetrahydrofuran. After purification, the filtrate is concentrated under reduced pressure to give 10.5 g of product in the form of a yellow oil.   This product was dissolved in 100 ml of ethanol, and the solution was dissolved in 100 ml of ethanol. 6.5 g (55.8 mmol) of malic acid are added, the mixture is concentrated to about 80 ml and left to stand And crystallize.   Finally, 13.64 g of the compound are isolated in the form of a white solid. Melting point: 197-200 <0> C.Example 10 (Compound No. 8) (Exo) -8- (4-Methylbenzoyl) -3-[(5-methoxy-1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane hydrochloride 10.1. (Exo) -3-[(5-methoxy-1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-         Azabicyclo [3.2.1] octane   (Exo) -3-[(5-methoxy-1,2,3,4-tetrahydroisoquinoline- 2-yl) methyl] -8- (phenylmethyl) -8-azabicyclo [3.2.1] octa 5 g (8.21 mmol) of di- (E) -but-2-endioate are dissolved in water, 0% aqueous sodium hydroxide solution is added and the mixture is diluted with 100 ml of dichloromethane. Times, the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure, 3.1 g of compound are obtained in base form.   This compound was suspended in 100 ml of ethanol, and the suspension was suspended in 10% carbon. Of the mixture, and the mixture is placed on a Parr apparatus under a pressure of about 0.32 MPa. Hydrogenate at 40 ° C. for 10 hours. The catalyst is separated by filtration, and the filtrate is concentrated under reduced pressure. To give 2.35 g of the compound, which is obtained in the next step without further purification. use. 10.2 (exo) -8- (4-methylbenzoyl) -3-[(5-methoxy-         1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-         Azabicyclo [3.2.1] octane hydrochloride   Using the procedure described in Example 2.2, (exo) -3-[(5-methoxy-1, 2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8-azabicyclo [ 3.2.1] octane 1.43 g (5 mmol) and 4-methylbenzoyl chloride 1.1 Starting with 6 g (7.5 mmol) by chromatography on a silica gel column After purification, 1.5 g (3.7 mmol) of the compound are obtained in base form.   0.3 g (0.74 mmol) of this base was dissolved in 10 ml of ethyl acetate, and 0.1N 7.5 ml (0.75 mmol) of hydrochloric acid as a solution of lopanol were added and the volume of the solution was reduced. Reduce the mixture by half under pressure, triturate the mixture, allow to stand, and crystallize. To   Finally, 0.21 g of the hydrochloride salt is isolated. Melting point: 237-240 ° C.Embodiment 11 (Compound No. 36) (Exo) -3-[(5-methoxy-1,2,3,4-tetrahydroisoquinoline- 2-yl) methyl] -8-[(4-methylphenyl) methyl] -8- Azabicyclo [3.2.1] octanedi- (E) -but-2-endioate   Lithium aluminum hydride 0.17 suspended in 20 ml of tetrahydrofuran g (4.45 mmol) was placed in a 100 ml three-necked round bottom flask, and the mixture was Cooled to 0 ° C. under a hydrogen atmosphere, in the form of a base dissolved in 10 ml of tetrahydrofuran. Of (exo) -8- (4-methylbenzoyl) -3-[(5-methoxy-1,2,3,4 -Tetrahydroisoquinolin-2-yl) methyl] -8-azabicyclo [3.2.1] 1.2 g (2.97 mmol) of octane are added and the mixture is heated at reflux for 4 hours. You.   The mixture was cooled to 0 ° C. and water and 30% aqueous sodium hydroxide were added. The excess hydride is destroyed and the insoluble material is separated by filtration and Wash with lahydrofuran and concentrate the residue under reduced pressure. Dichloromethane and Chromatography on a silica gel column eluted with a 98/2 to 85/15 mixture of methanol The residue is purified by chromatography to give 0.9 g of the compound in base form.   This base was dissolved in 10 ml of ethanol, and fumaric acid dissolved in 50 ml of ethanol. 0.54 g (4.6 mmol) are added, the solvent is evaporated off under reduced pressure and the residue is evaporated. Recrystallize from ethanol.   0.9 g of the fumarate are obtained in the form of a white solid. Melting point: 188-199.5C.Example 12 (Compound No. 42) (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8- (phenylmethyl) -8- Azabicyclo [3.2.1] octanedi- (E) -but-2-endioate 12.1. (Exo) -5- (1-Methylethoxy) -2-[[8-         (Phenylmethyl) -8-azabicyclo [3.2.1] oct-3-         Yl] carbonyl] -1,2,3,4-tetrahydroisoquinoline   Using the procedure described in Example 9.1, give 5- (1-methylethoxy) -1,2, 4.58 g (23.8 mmol) of 3,4-tetrahydroisoquinoline and 8- (phenylene) Ethyl) -8-azabicyclo [3.2.1] octane-3-carboxylate 4.1 Starting with 5 g (15.2 mmol), 6.2 g of compound are obtained in the form of an orange-colorless oil. 12.2. (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-         (Phenylmethyl) -8-azabicyclo [3.2.1] octane         Di- (E) -but-2-engioate   Using the procedure described in Example 9.2, lithium aluminum hydride 1.15 g (30.2 mmol) and (exo) -5- (1-methylethoxy) -2-[[8- (f Enylmethyl) -8-azabicyclo [3.2.1] oct-3-yl] carbonyl]- Starting with 6.3 g (15.1 mmol) of 1,2,3,4-tetrahydroisoquinoline, 6.05 g of the compound are obtained in the form of a yellow oil.   0.9 g (2.22 mol) of this product was dissolved in 50 ml of ethanol, and ethanol 2 0.51 g (4.44 mmol) of fumaric acid dissolved in 00 ml are added and the solvent is evaporated under reduced pressure And the residue is recrystallized from ethanol.   0.6 g of the difumarate is isolated in the form of a white solid. Melting point: 203-205.5C.Example 13 (Compound No. 43) (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4- Tetrahydroisoquinolin-2-yl) methyl] -8-[(4- Methylphenyl) methyl] -8-azabicyclo [3.2.1] octane Di- (E) -but-2-engioate 13.1. (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-         Azabicyclo [3.2.1] octane   Using the procedure described in Example 10.1, (exo) -3-[(5 -(1-methylethoxy) -1,2,3,4-tetrahydroisoquinolin-2-yl) 4.8 g of methyl] -8- (phenylmethyl) -8-azabicyclo [3.2.1] octane (11.9 mmol) and contact with 1.35 g of palladium on 10% carbon After hydrogenation, 2.7 g of compound are obtained, which product is obtained without further purification without further purification. Used in the process. 13.2. (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-[(4-         Methylphenyl) methyl] -8-azabicyclo [3.2.1] octane         Di- (E) -but-2-engioate   (Exo) -3-[(5- (1-methylethoxy) -1,2,3,4-tetrahydroi 2.6 g of soquinolin-2-yl) methyl] -8-azabicyclo [3.2.1] octane 8.27 mmol), 1.85 g (10 mmol) of benzyl bromide, 1.52 g (1 1 mmol), and 35 ml of N, N-dimethylformamide in an argon atmosphere. Heat the mixture at 50 ° C. for 1 hour in a 00 ml round bottom flask.   1.52 g (11 mmol) of potassium carbonate was further added, and the mixture was added at 50 ° C for 8 hours and 30 minutes. Keep heating.   The mixture was cooled to room temperature, poured into 100 ml of ice water and 100 ml of ethyl acetate. Extract three times, wash the organic phase with water, dry over sodium sulfate, filter and dissolve. The medium is removed by evaporation under reduced pressure.   A column eluted with a 97 / 3-85 / 15 mixture of dichloromethane and methanol The residue is purified by chromatography on a Ricagel column.   2.25 g of base are obtained, and this product is dissolved in 100 ml of ethanol. 1.25 g (10.8 mmol) of fumaric acid dissolved in 150 ml were added and the solvent was evaporated under reduced pressure. Eject and remove and recrystallize the residue from ethanol.   1.45 g of the difumarate are isolated in the form of a white solid. Melting point: 188-199.5C.Example 14 (Compound No. 18) (Exo) -8- (3,4-Dichlorobenzoyl) -3-[(5,8-dimethoxy- 1,2,3,4-tetrahydroisoquinolin-2-yl) methyl] -8- Azabicyclo [3.2.1] octane hydrochloride 14.1. (Exo) -5,8-Dimethoxy-2-[[8- (phenylmethyl) -8-         Azabicyclo [3.2.1] oct-3-yl] carbonyl]-         1,2,3,4-tetrahydroisoquinoline   15.3 ml (30.6 mmol) of a 2M solution of trimethylaluminum in hexane and 30 ml of toluene was placed in a three-necked round bottom flask under an argon atmosphere, followed by 5,8-Dimethoxy-1,2,3,4-tetrahydroisoxyl dissolved in 80 ml of ruene 4.06 g (21 mmol) of norin are added dropwise and the mixture is heated to 50 ° C. 8- (phenylmethyl) -8-azabicyclo [3.2.1] octa dissolved in 30 ml 5.2 g (20.4 mmol) of methyl 3-carboxylate are added dropwise and the mixture is refluxed. Heat at temperature for 8 hours. The mixture is hydrolyzed with 100 ml of water and the precipitate is filtered off. Rinsing it with ethyl acetate, drying the organic phase over magnesium sulfate, The solvent is removed by evaporation under reduced pressure.   9.83 g of an oily product are obtained, 98/2 mixture of dichloromethane and methanol This product was purified by chromatography on a silica gel column eluted with To make.   5.5 g of compound are obtained in the form of a yellow oil, which product is obtained without further purification. Used in the step. 14.2. (Exo) -3-[(5,8-dimethoxy-1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-         (Phenylmethyl) -8-azabicyclo [3.2.1] octane   Anhydrous tetrahydrofuran (80 ml) was placed in a 500 ml three-necked round bottom under an argon atmosphere. In a flask, 1 g (26 mmol) of lithium aluminum hydride was added, and the suspension was added. The solution was cooled to 0 ° C. and dissolved in 20 ml of tetrahydrofuran (exo) -5,8-. Dimethoxy-2-[[8- (phenylmethyl) -8-azabicyclo [3.2.1] oct -3-yl] carbonyl] -1,2,3,4-tetrahydroisoquinoline 5.5 g (1 (3 mmol) are added dropwise and the mixture is heated at reflux for 8 hours.   The mixture is cooled in an ice bath and hydrolyzed with 1N aqueous sodium hydroxide solution, The soluble material was separated by filtration, rinsed with ethyl acetate, and the filtrate was dried over magnesium sulfate. Dry, filter and remove the solvent by evaporation under reduced pressure.   5.28 g of compound are obtained in the form of a yellow oil, which product is obtained without further purification. Used in the next step. 14.3. (Exo) -3-[(5,8-dimethoxy-1,2,3,4-         Tetrahydroisoquinolin-2-yl) methyl] -8-         Azabicyclo [3.2.1] octane   (Exo) -3-[(5,8-dimethoxy-1,2,3, 4-tetrahydroisoquinolin-2-yl) methyl] -8- (phenylmethyl) -8 2.33 g (5.73 mmol) of azabicyclo [3.2.1] octane in 200 ml of Parr Placed in a tube, followed by palladium supported on 10% carbon under an argon atmosphere And hydrogenation is carried out at room temperature under a pressure of about 0.35 MPa.   The catalyst was separated by filtration and the solvent was removed by evaporation under reduced pressure to give compound 1.7. 1 g are obtained in the form of a yellow oil, which product is used without further purification in the next step I do. 14.4. (Exo) -8- (3,4-dichlorobenzoyl) -3-[(5,8-         Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-         Yl) methyl] -8-azabicyclo [3.2.1] octane hydrochloride   (Exo) -3-[(5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolyl 1.7-g (5.62 m) of 2- (2-yl) methyl] -8-azabicyclo [3.2.1] octane mol), 1 ml of triethylamine and 50 ml of dichloromethane under argon. 3,4-Dichlorochloride dissolved in 5 ml of dichloromethane 2.35 g (11.24 mmol) of benzoyl are added dropwise and the mixture is allowed to stand at room temperature for 48 hours. Stir.   Ice water is added, the mixture is extracted with dichloromethane, the organic phase is washed with water and sulfuric acid is added. Dry over sodium acid, filter and remove the solvent by evaporation under reduced pressure. The Silica eluted with a 100/0 to 95/5 mixture of chloromethane and methanol The residue is purified by chromatography on a gel column.   1.66 g of base are obtained, the product is dissolved in ethyl acetate and dissolved in 2-propanol. 32.7 ml of a 0.1N hydrochloric acid solution are added and the solvent is removed by evaporation under reduced pressure. The product is recrystallized from ethyl acetate with a few milliliters of ethanol. Hydrochloride 1.3 5 g are obtained. Melting point: 190-191C.   The following table illustrates the chemical structures and physical properties of some compounds according to the present invention. You. "R_Four”Column,“ C_ThreeH_Five"Means a cyclopropyl group and" C_Five H₉"Means a cyclopentyl group and" C₆H₁₁Is a cyclohexyl group Means   "R_Four"And" R ",₆H_Five”,“ C₆H_Four”,“ C₆H_Three" And "C₆H_TwoThe terms `` '' are each an unsubstituted phenyl group, a monosubstituted phenyl group. Phenyl, disubstituted phenyl, and trisubstituted phenyl A substituent, if applicable, is indicated before it by a substituent, The position is indicated before. In the “isomer” column, “α” represents the ene of the compound. Indicates the relative configuration and “β” indicates the exo relative configuration.   In the "Salt" column, "-" means a compound in the form of a base, and "HCl" , Hydrochloride, “2HCl” means dihydrochloride, “fum.” Means fumaric acid "2fum." Means difumarate, and "Mes." It means sulfonate hydrate. In the column of “melting point (° C.)”, “(d)” Means melting point with decomposition; (A) and (B) are two different Means crystalline form.   The compounds of the present invention have been subjected to a series of pharmacological tests to give them as therapeutically active substances. Demonstrated their value.The affinity of test for D ₂ type dopaminergic receptors   The compound has the D present in the rat striatum._TwoSpecific labeling of the receptor Spandil, a gand ("[^ThreeH] Spiperone, ”Briley and Lan ger., Eur. J. Pharmacol. (1978), 50, 283). Replace the bond.   The animals used are 150-250 g male Sprague-Dawley rats. Interruption After the head, the brain is removed and the striatum is removed. Sodium chloride (120 mM), potassium chloride 50 mM Tris-HCl buffer containing 5 mM sodium chloride (5 mM) and adjusted to pH 7.4. Polytron in 50 volumes of liquid^TMGrind the tissue using a grinder (5 ml Fresh tissue 100 mg). Wash the homogenized tissues twice at 4 ° C. and wash them The pellets were freshly chilled by centrifugation at 40,000 × g each for 10 minutes. Suspend in buffer. Finally, suspend the final pellet in the same volume of buffer, Add ascorbic acid (final concentration 0.1%) and pargyline (final concentration 10 μM) You. The mixture is then incubated at 37 ° C. for 10 minutes.   100 μl of membrane suspension in a final volume of 1 ml in the presence or absence of test compound Incubate with radioligand (0.25 nM) for 20 minutes at 37 ° C Allows [^ThreeH] Spiperone (New England Nuclear, specific activity 20-40 mCi / m mol) is measured. Nonspecific binding was determined by the presence of haloperidol at a concentration of 10 μM. Measure in the presence. After the incubation, the membrane was replaced with Whatman GF / B.^TMfilter And washed with two volumes of 5 ml of chilled buffer. That Extract the filter with scintillation fluid and convert the radioactivity to liquid scintigraphy It is measured at an efficiency of more than 50-60%. For each test compound, the results are IC calculated by graphical or mathematical method₅₀That is, [^ThreeH] Spiperone Is expressed as the concentration that inhibits the inhibition by 50%.   For compounds of the present invention, IC₅₀Values are between 0.01 and 10 μM. Exam   Essentially, Schoemaker H. By Eur. J. Pharmacol. (1993), 242 The compound was prepared from bovine caudate nucleus membrane preparation as described in D obtained_ThreeImbi on their affinity for dopaminergic receptors Tested in Toro.   On the day of the experiment, cattle caudate nuclei (Collect Organe, Paris, Fr.) stored at -80 ° C. ance) and unpack Polytron^TMBuffer (position 5, 30 seconds) using buffer (10 mM Squirrel, 1 mM EDTA, pH 7.5 at 25 ° C.) Homogenize in 10 volumes at 4 ° C. I do. Centrifuge the homogenate at 2500 g for 1 minute (removed by SS34 rotor). Sorvall attached^TMcentrifuge). Collect supernatant, 35,000 g for 15 minutes Centrifuged, resuspended in 10 volumes of buffer, homogenized and centrifuged. Wash the pellet and suspend the final pellet in 10 volumes of buffer. And incubate at 37 ° C. for 10 minutes in advance.   The homogenate is centrifuged at 35,000 g for 15 minutes and the pellet Incubation buffer (100mh of initial tissue per ml) 50 mM HEPES, 1 mM EDTA, 50 μM 8-hydroxyquinoline, Resuspend in 0.005% ascorbic acid, pH 7.5) at 25 ° C.   In a tube, in the presence or absence of a test compound, its membrane suspension (150 μl) Incubate containing 0.2 μM zolpidem hydrochloride and 1 mg of bovine serum albumin 0.8 nM in a final volume of 1 ml^ThreeH] 7-OH-DPAT (specific radiation No. 120-160 Ci / mmol, Amersham^TM) At 23 ° C for 60 minutes in the presence of Lab. Wha pre-treated with bovine serum albumin (0.1%) for 30 minutes tman GF / C^TMIncubate Brandel Harvest using filters er M-48^TMStop by filtration over. Each reaction medium was buffered (50 mM Squirrel, 120 mM NaCl, 5 mM KCl, pH 7.4 at 25 ° C.) After settling, the tubes are rinsed twice with 4 ml of this buffer.   After cutting the filter, the filter is dried at 120 ° C. for 10 minutes in an oven. Of radioactivity retained on filters by liquid scintillation spectrometry . Non-specific binding is measured in the presence of 1 μM dopamine.   For each concentration of test compound, [^ThreeH] 7-OH-DPAT specific binding After calculating the inhibition (%), the IC₅₀Ie the concentration that inhibits its binding by 50% To determine.   IC of the compound of the present invention₅₀Values are about 0.005 μM to 10 μM.Examination of affinity for 5-HT _1A type serotonergic receptor The compound is found in 5-HT present in rat hippocampus._1ASpecific labeling for the receptor Ligand^ThreeH] -8-hydroxy-2-di-n-propylaminetetraly (Hereinafter, [[^ThreeH] -8-OH-DPAT "; Gozlan et al., Nature (1983). , 305, 140).   The animals used are 160-200 g male Sprague-Dawley rats. Interruption After the head, the brain is removed and the hippocampus is removed. 50 mM pH adjusted to 7.4 with hydrochloric acid Ultra-Turrax Polytron in 10 volumes of Tris buffer^TMMachine at maximum speed Grind in half for 30 seconds (100 mg fresh tissue per ml). Homogenized pair The fabrics were washed twice at 4 ° C. and they were each centrifuged at 48,000 × g for 10 minutes. Suspend the pellet in fresh chilled buffer. Finally, the final pellet Suspension in buffer to give a concentration of 50 mg of starting tissue per ml of buffer at 50 mM You. The mixture is then incubated at 37 ° C. for 10 minutes.   Final volume of buffer containing 10 μM pargyline and 3 μM paroxetine 2 By incubating 50 μl of the membrane suspension in 50 μl,^ThreeH] 9 The binding to -OH-DPAT (1 nM) is measured. Incubate at 37 ° C for 15 minutes After that, the membrane is replaced with Whatman GF / B.^TMCollected by filtration through a filter, This is washed three times with 5 ml aliquots of chilled buffer. Thin the filter Radioactivity is measured by liquid scintigraphy by extraction with a titration solution. [^Three The specific binding of [H] 8-OH-DPAT is determined by the amount of radioactivity retained on the filter. Defined as the co-infusion with 10 μM 5-hydroxytryptamine. It can be inhibited by co-incubation. 1 nM [^ThreeH] 8 At the concentration of -OH-DPAT, its specific binding was the total collected on the filter. Represents 90% of the radioactivity.   For each concentration of test compound, [^ThreeInhibition of binding with [H] 8-OH-DPAT ( %) And then the IC₅₀Concentration, ie, the concentration that inhibits its binding by 50% To determine.   For compounds of the present invention, IC₅₀Values are 0.001-10 μM.Test for affinity for 5-HT type ₂ serotonergic receptor   The compounds of the invention may also be used in vitro to produce serotonin in rat cerebral cortex. Dynamic (5-HT_Two) We also tested displacement of spiperone binding to the receptor.   For this test, the rat brain was excised, the cortex was excised from it, and 1 liter Per milliliter of 50 mM Tris / HCl buffer (pH = 7.4), 120 mM Sodium chloride, and in 10 volumes of a mixture containing 5 mmol of potassium chloride Homogenize at 0 ° C. Centrifuge the homogeneous mixture at 40,000 xg for 10 minutes. After centrifugation, collect the pellet and suspend it in the same buffer mixture And homogenized it again, centrifuged and Perform the process twice. Finally, at a rate of 100 mg of wet tissue per ml of buffer, the final Dilute the pellet in the same buffer mixture.   The tissue was then pre-diluted at 37 ° C. for 1 μm in the presence of Incubate for 0 min, followed by [at a concentration of 0.3 nmol / L [^ThreeH] Piperon (specific activity: 15-30 Ci / mmol) and the presence of test compound Incubate at 37 ° C for 20 minutes in the presence. Then, the membrane is replaced with Whatman G F / B^TMCollect by filtration on a filter and wash it twice with 5 ml of cold buffer You. The radioactivity retained on the filter is measured by liquid scintigraphy. You.   To assess the activity of the compound,^ThreeH] Spiperone specific binding inhibition (%) A line is established as a function of the concentration of the replacement drug. IC₅₀Concentration, that is, its specific The concentration that inhibits binding by 50% is determined graphically and determined.   The specific binding is the binding exhibited by 100 micromol / L 5-HT. Is defined as   IC of the compound of the present invention₅₀The concentration is between 0.030 and 10 μM.   The results of in vitro tests performed on the compounds of the present invention show that Tsukaga D_TwoAnd D_ThreeTo dopaminergic receptors, as well as to 5-HT_1AAnd And 5-HT_TwoHas a strong affinity for serotonergic receptors, Indicates a mixed ligand.   Other compounds are D_ThreeHas a strong affinity for dopaminergic receptors D_TwoType dopaminergic receptor, and 5-HT_1AAnd 5-HT_TwoType serotoni With a weak affinity for the agonistic receptor and thus a selective and specific ligand Is. IC₅₀(D_Two) / IC₅₀(D_Three) Is 1 to 60. What is an IC₅₀(5-HT_1A) / IC₅₀(D_Three) Is 1 to 30. It is.   The compounds of the present invention were further subjected to pharmacological tests in vivo.Inhibition test of D-amphetamine-induced hyperactivity in rats   30 minutes after the injection of D-amphetamine (2 mg / kg), 2 Immediately after housing the animal in an activity cage that allows the passage of vertical rays, Hyperactivity is recorded for 20 minutes. The break of the beam is automatically recorded.   Thirty minutes prior to injection of D-amphetamine, the compounds are administered at 0.3, 1, 3, and And 6 mg / kg, injected intraperitoneally and given an effective dose ED₅₀That is, hyperactivity The dose that reduces by 50% is measured.   ED of the most active compound₅₀The value is about 1 mg / kg.Provocation test of catalepsy in rats   Worms P. and Lloyd K. G. by Pharamcol. Ther. (1979), 5,445 Rat by the four-stopper method described in -450. Is tested for expression of catalepsy.   Each limb of the rat is placed on a stopper 2.5 cm high and 1.2 cm in diameter. The distance between the two contralateral stops is 8 cm and the distance between the two contralateral stops is The distance is 13 cm.   If the rat holds the limb on the stopper for at least 10 seconds, the rat Considered to be in a state of lepsy. Test compounds were 1, 3, 10, 30, and 1 hour, 2 hours, and 4 hours after intraperitoneal administration at a dose of 60 mg / kg At this point, the duration of catalepsy is measured for a maximum of 2 minutes. The compound has a low It has cataleptigenic activity or has this activity at the test dose. Completely absent.   The results of that test indicate that the compounds of the invention can be used to treat psychoses, especially schizophrenia (deficient and And acute or chronic extrapyramidal symptoms induced by neuroleptics. For treatment of various types of anxiety, panic attacks, fear, obsessive-compulsive disorder, for psychosis Alcohol abuse or withdrawal disorders in the treatment of various types of depression, including depression Can be used to treat sexual behavior disorders, eating disorders, and migraine I do.   Finally, the compounds of the present invention can be prepared by combining them with any suitable excipient. Can be in any form suitable for oral, parenteral, or oral administration Can be administered to be 1 to 1000 mg.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG), EA (AM, AZ, BY, KG, KZ , MD, RU, TJ, TM), AL, AM, AT, AU , AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, G B, GE, GH, HU, IL, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, N O, NZ, PL, PT, RO, RU, SD, SE, SG , SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU (72) Inventor Georges, Pascal             F-78730 Saint-Arnaud, France             Ann-Yvelines, Ryu de Cartle-             Van 19 (72) Inventors Merlee, Jean-Pierre             France, F-93330 Thor, Abnu             Jules-Gates 11

Claims (1)

[Claims] 1. The general formula (I) in pure geometric isomer form or in the form of a mixture of such isomers: Wherein R ₁ , R ₂ and R ₃ each independently represent a hydrogen or a halogen atom, or a hydroxyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group; R ₄ represents a hydrogen atom or a halogen atom, or a (C ₁ -C ₄ ) alkyl, 2-methoxyethoxy, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₆ ) cycloalkylmethoxy or phenylmethoxy group R ₃ and R ₄ together form a methylenedioxy group; Z represents an oxygen atom or two hydrogen atoms; and R is ethoxy when Z represents an oxygen atom. Phenyl which represents a group or is optionally substituted with one or more halogen atoms, or (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, or amino groups Represents a group. And a compound in the form of a base or an addition salt with an acid. 2. 2. The compound according to claim 1, wherein R ₄ represents an alkoxy group and R represents an optionally substituted phenyl group. 3. The method for producing a compound according to claim 1, wherein, according to the first aspect, ethyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate is reacted with sulfur ylide to obtain a compound represented by the formula ( III): Which is reacted with a Lewis acid to give an epoxide of the formula (IV): Which is subsequently converted by the action of a mixed alkali hydride of the formula (V): After the reduction to the alcohol of formula (I), the hydroxyl group of this alcohol is converted into a reactive group W 2 to give a compound of general formula (VI): Of the general formula (VII): Wherein R ₁ , R ₂ , R ₃ , and R ₄ are as defined in claim 1], and reacted with 1,2,3,4-tetrahydroisoquinoline of the general formula (Ia): (Corresponding to the general formula (I) where Z represents an oxygen atom and R represents an ethoxy group), followed by separation, if desired, of the two obtained isomers The compound of general formula (Ia) is then deprotected to produce a compound of general formula (I) wherein R represents a phenyl group which may be optionally substituted, ): Which has the general formula (IX): Wherein R is as defined in claim 1 and reacting with an acid chloride of the general formula (Ib): (Corresponding to the general formula (I) where Z represents an oxygen atom and R represents an optionally substituted phenyl group); The compound is reduced by the action of a mixed alkali hydride to form a compound of the general formula (Ic) wherein Z represents two hydrogen atoms: Or, in one embodiment, converting an amine of general formula (VIII) to a compound of general formula (X): Wherein R is as defined in claim 1 to produce the reduced compound of general formula (Ib) directly, or alternatively according to the second aspect Ethyl 8- (phenylmethyl) -8-azabicyclo [3.2.1] octane-3-carboxylate is prepared from dimethylaluminamide previously prepared from trimethylaluminum, and a compound of the general formula (VII) as defined above. With 1,2,3,4-tetrahydroisoquinoline of formula (XII): Which is reduced by the action of a mixed alkali hydride to give a compound of general formula (Id): (Corresponding to the general formula (I) where Z represents two hydrogen atoms and R represents an unsubstituted phenyl group), if desired, the compound is debenzylated To obtain an amine of general formula (VIII), which is treated as described with respect to the first embodiment of the method. 4. A pharmaceutical comprising the compound according to claim 1. 5. A pharmaceutical composition comprising a compound according to claim 1 in combination with an excipient.