HU199451B - Process for producing 2-square brackets open /piperidin-4-yl/-methyl square brackets closed-1,2,3,4-tetrahydroisoquinoline derivatives and pharmaceutical compositions comprising same - Google Patents

Abstract

Ni(piperidinylmethyl) -tetrahydroisoquinoline derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts are new: R = (a) H; (b) 1-6C alkyl, allyl, 3-6C cycloalkylmethyl, benzyl (opt. substd. by 1-3 of halo, CF3, NO2, NH2, NMe2, CN, CONH2, or 1-3C alkyl, alkoxy or alkylthio), 2-phenylethyl, 3-phenylpropyl, 3-phenylpropen-2-yl, phenylcarbonylmethyl, naphthylmethyl, pyridylmethyl, furanylmethyl, or thienylmethyl; (c) 2-6C alkanoyl, 3-6C cycloalkylcarbonyl, CF3CO, phenylcarbonyl (opt. substd. by halo, CF3, NO2 or 1-3C alkyl, alkoxy or alkylthio), 1-oxo-3-phenylpropen-2-yl, naphthylcarbonyl, pyridinylcarbonyl, furancarbonyl, thienylcarbonyl or 2- or 5-indolylcarbonyl.

Description

The present invention relates to novel 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline derivatives for use in medicine.

Analogous compounds are disclosed in U.S. Patent Nos. 7,607 M, 1,580,180 and 2,035,063. French patent specification.

The compounds of the present invention may be represented by the following general formula (I) as shown in Scheme 1 in which

R is

i) hydrogen;

ii) C 1 -C ₆ straight or branched alkyl; allyl; (C ₃ -C ₆ ) cycloalkylmethyl; optionally having 1 or 2 halogen atoms, trifluoromethyl, nitro, amino, dimethylamino, cyano, amino, carbonyl, straight or branched (C 1 -C ₃ ) alkyl, straight or branched Phenylmethyl substituted with (C 1 -C ₃ ) alkoxy, linear or branched (C 1 -C ₃ ) alkylthio; 2-phenylethyl group; 3-phenyl-propyl; 3-phenyl-propen-2-yl; phenyl-carbonyl-methyl; naphthylmethyl groups; pyridinyl-methyl; furanyl-methyl; or thienylmethyl;

iii) straight or branched (C ₂ -C ₆ ) alkanoyl; (C ₃ -C ₆ ) cycloalkylcarbonyl; a trifluoroacetyl group; optionally having 1 or 2 halogen atoms, trifluoromethyl, nitro, straight or branched (C 1 -C ₃ ) alkyl, straight or branched (C 1 -C ₃ ) alkoxy, or straight or branched (C -C ₃ ) phenylcarbonyl substituted with alkylthio; l-oxo-3-phenyl-propen-2-yl; naphthyl-carbonyl; pyridinyl-carbonyl; furanyl-carbonyl; a thienyl group; (indol-2-yl) carbonyl; or (indol-5-yl) carbonyl.

The compounds of the invention may be prepared in the form of free bases or pharmaceutically acceptable acid addition salts.

In the following description, the substituents R mentioned in (ii) above are referred to as "reduced groups" and those defined in (iii) above are referred to as "acyl" groups. According to the present invention, compounds of formula I are prepared according to Scheme 1.

The 1,2,3,4-tetrahydroisoquinoline (II) is reacted with the imidazolide (II) (prepared in situ from isonicotinic acid and N, N-carbonyldiimidazole) to give the amide (IV).

Thereafter, the amide of formula (IV) is catalytically hydrogenated to give the amide of formula (VI) (U.S. Pat. No. 4,243,666); the latter is reduced with lithium aluminum hydride, or with a borohydride, or with a boron complex such as diborane or borane-methylsulfide complex, to produce a compound of formula IX, i.e., a compound of formula I wherein R is hydrogen ; or the amide of formula (VI) is alkylated with a halide of formula RX (R "is a reduced group and X is a leaving group such as bromine) to produce a compound of formula (I) wherein R" is a reduced group and finally The amide of formula (VII) is reduced as described for the amide of formula (VI).

The intermediate amide of formula VII may also be prepared by first alkylating the amide of formula IV and then catalytically hydrogenating the resulting amide of formula V. In another process of the invention, the amide of formula (VII) is prepared by reacting 1,2,3,4-tetrahydroisoquinoline of formula (II) with an isonipecotate of formula (VIII) (wherein R "is a reduced group) in the presence of aluminum.

Of course, the amide of formula VII, wherein R is benzyl, can also be converted to the unsubstituted amide of formula VI by hydrogenolysis in the presence of palladium.

Similarly, a compound of formula (I) wherein R is benzyl can be converted to an unsubstituted amine of formula (IX).

In contrast, the alkylation of the amine of formula (IX) with the halide of formula RX (R "represents a reduced group and X represents a leaving group) can be converted to an amine of formula (I) where R" represents a reduced group. Compounds of formula (I) wherein R 'represents an acyl group may be prepared by reacting a compound of formula (IX) with a derivative of formula R'COY - wherein R'CO is an acyl group of formula R and Y is a halogen atom. such as chloro or imidazol-1-yl, or (C, -C ₆₎ alkoxy, q is ₂ or R'CON acyloxy groups of the formula - is reacted.

When Y is halogen, the compound of formula IX is reacted with an acid halide of formula R'COY in the presence of an organic base such as triethylamine in a solvent such as dichloromethane or ethyl acetate.

When Y is imidazol-1-yl, the compound of formula (IX) is reacted with an imidazolide of the formula R'COY (prepared in situ from N, N'-carbonyldiimidazole and the corresponding acid of the formula R'COOH), in a solvent such as tetrahydrofuran.

When Y represents an alkoxy group, the compound of formula IX is reacted with a trialkylaluminum such as trimethylaluminum and the resulting complex is reacted with an ester of the formula R'COY at a temperature of 50-110 ° C in an inert aromatic solvent such as toluene.

When Y is acyloxy, the compound of formula IX is represented by the formula (R'CO) ₂

-2HU 199451Β anhydride; the solvent is the anhydride itself, or an inert solvent is used at 0-60 ° C to obtain the amide of formula (X).

This latter compound can be prepared in a single operation. Accordingly, it is of formula (II)

1,2,3,4-tetrahydroisoquinoline is reacted with a tosylate of formula XI (Tos is tosyl and R'CO-R is an acyl group) in the absence of a solvent or in the presence of an inert solvent such as dimethylformamide or xylene, At a temperature of 20-150 ° C, and optionally in the presence of an organic base such as a tertiary amine or a mineral base such as an alkali hydrogen carbonate.

The tosylate of formula (XI) can be prepared according to Scheme 2. Accordingly, the 4-piperidine carboxylate of formula (XII) (where Alk represents a lower alkyl group) is reduced, for example, with lithium aluminum hydride to give 4-piperidine methanol; the latter is reacted with an acid chloride of the formula R'COCI (where R'CO is an "acyl group of the formula R") in an inert solvent such as a chlorinated solvent at a temperature of 20-80 ° C. Thus, an ester amide of formula XIV is obtained which is saponified with, for example, sodium or potassium hydroxide in a lower alcohol solvent, preferably ethanol; the resulting alcohol (XV) is finally converted to the tosylate in tosyl chloride in an alkaline medium such as pyridine.

The amides of formula (X) may then be reduced, if desired, to the amides of formula (I) wherein R 'is a reduced group; the reduction can be carried out with a simple hydride or boron complex such as diborane or borane methyl sulfide complex, lithium aluminum hydride, aluminum hydride and the like in an ether solvent such as diethyl ether, tetrahydrofuran or dioxane, temperature.

Of course, according to the substituents present in the R group, certain compounds of formula I can be converted to other compounds of formula I by well known methods by appropriate reaction of the above substituents. For example, a compound of formula (I) wherein R is a benzyl group having an aminocarbonyl group is a compound of formula (I). wherein R is a benzoyl bearing a cyano group, the latter compound being reacted with hydrogen chloride gas in the presence of formic acid.

The compound of formula (I) wherein R is a benzyl group bearing an amino group may be prepared from a compound of formula (I) wherein R represents a benzyl group containing a nitro group, the latter being reduced by diborane or diborane methyl sulfide in an ether solvent such as tetrahydrofuran. .

The compound of formula (I) wherein R is a benzyl group having a dimethylamino group can be prepared from a compound of formula (I) wherein the benzyl group has an amino group R by reducing alkylation, i.e. reacting with formaldehyde in the presence of an acid such as sulfuric acid ether, such as tetrahydrofuran, and the resulting compound is reduced with sodium borohydride.

The following Examples illustrate in detail the preparation of some compounds of the invention. Microanalysis and infrared and magnetic resonance spectra confirm the structure of the obtained products.

The numbers in parentheses in the example titles correspond to the numbers in the tables.

Example 1 (Compound # 5)

2 - [{1 - ((3-Chlorophenyl) methyl] plperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline diphenate

a) 2 - [(Pyridinyl-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline

Under argon atmosphere, 50 g (406 mmol) of isonicotinic acid. Dissolve in 1000 ml of tetrahydrofuran, add 25 g of Ν, Ν'carbonyldiimidazole with stirring, and after stirring for 1 hour, add another 25 g of Ν, Ν'-carbonyldiimidazole, and again after 15 hours of stirring, add 15 g Ν, Ν 'Carbonyldiimidazole is added to the solution. Stirring was continued for 1 hour and to the translucent mixture was added slowly 1,2,3,4-tetrahydroisoquinoline (51.39 g, 385.8 mmol) dissolved in a few ml of tetrahydrofuran. The mixture was stirred overnight at ambient temperature. The solvent was evaporated and the residue (oil) was dissolved in dichloromethane (about 700 ml), washed twice with saturated sodium bicarbonate solution, twice with water and dried over magnesium sulfate. 87.48 g of an orange oil are obtained, which slowly solidifies in the cold.

b) 2 - [(Piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline g (127.3 mmol) 2 - [(pyridin-4-yl) carbonyl] -1,2 3,4-Tetrahydroisoquinoline hydrochloride is catalytically hydrogenated in 600 ml of methanol in the presence of 1.2 g of platinum oxide under a hydrogen pressure of about 0.38 MPa for 17 hours. The catalyst is then filtered off, the methanol is evaporated off, the residue is dissolved in ether and the insoluble material is filtered off. The resulting hydrochloride (33.7 g) was added to a water / dichloromethane mixture to liberate the free base and potassium carbonate was added in portions until pH> 10. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated. The residue was recrystallized from ether, washed with pentane and dried. 17.2 g of base are obtained. Melting point: 200-205 ° C (dec.).

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c) 2 - [{1 - [(3-Chlorophenyl) methyl] piperidin-4-yl} carbonyl] -1,2,3,4-tetrahydroisoquinoline

For 100 ml of anhydrous acetone, 5.2 g (21.3 mmol) of 2 - [(piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline, 4.94 g (25.5 mmol) of 1- bromo-3-chloromethylbenzene and

Potassium carbonate (4.71 g, 34 mmol) was added. After stirring overnight at ambient temperature, the acetone was evaporated, dichloromethane and water were added to the residue, the organic layer was separated, washed, dried and the solvent was evaporated. The product (10.5 g) was purified by column chromatography over silica gel using dichloromethane then dichloromethane / methanol (97: 3) as eluent. The purified product is dissolved in pentane and the solvent is evaporated. 6.13 g of pure base are obtained. 114-115 ° C.

d) 2 - [{1 - [(3-chlorophenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difluorate

4.5 g (12.2 mmol) of 2 - [{1 - [(3-chlorophenyl) methyl] piperidin-4-yl} carbonyl] -1,2,3,4-tetrahydroisoquinoline are dissolved in 70 ml of tetrahydrofuran, 3.66 mL (36.6 mmol) of 10η borane methyl sulfide complex was added and the mixture was heated at 50 ° C for 2 hours and stirred at ambient temperature for 2 days. The mixture was hydrolysed with methanol (20 ml) and concentrated hydrochloric acid (10 ml), decomposed, refluxed for 3 hours and allowed to stand overnight. The solvent was evaporated, ether and water were added to the residue, the aqueous phase was separated, aqueous sodium bicarbonate solution was added to pH> 10 and extracted with dichloromethane. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent was evaporated. The resulting 4.5 g of a clear oil is purified by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2). 3.8 g of an oil are obtained, which is dissolved in ethyl acetate and this solution is added dropwise to a small volume of methanolic boric acid. The precipitated salt was filtered off, washed with ethyl acetate and diethyl ether and dried. 3.9 g of difumarate are obtained. 188-190 ° C (dec.).

Example 2 (Compound # 3)

2 - [(l- (phenylmethyl) piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline dihydrochloride

a) 2 - [(1- (Phenylmethyl) piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline

Under argon atmosphere, trimethylaluminum (251 mL, 594 mmol) (25% in hexane) was added to 400 mL of toluene. The solution was cooled in an ice bath and 81.5 g (612 mmol) of 1,2,3,4-tetrahydroisoquinoline in toluene (200 mL) was added. Warm to about 50 ° C and add ethyl 1- (phenylmethyl) piperidin-4-ylcarboxylate (95 g, 384 mmol) in toluene (400 mL). The mixture was refluxed for 2 hours, removing about 250 mL of solvent using a Dean-Stark apparatus. The mixture was cooled in an ice bath, hydrolysed by slow addition of 250 ml of water, the insoluble material was filtered off and washed with ethyl acetate. The filtrate was washed three times with water, the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue was recrystallized from cyclohexane.

116.6 g of product are obtained. Melting point 98-100 ° C.

b) 2 - [(1- (Phenylmethyl) piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline dihydrochloride - First variant.

To 150 ml of tetrahydrofuran was added 8 g (24 mmol) of 2 - [(1-phenylmethyl-piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydro-isoquinoline under argon atmosphere and 5 g (133 mmol) of the solution was added. sodium borohydride was added, the mixture was cooled to -10 ° C, boron trifluoride / ether complex (19 mL, 153 mmol) was added and the mixture was stirred at -10 ° C for 1 h. The mixture was hydrolyzed with 66 ml of IN hydrochloric acid at 0 ° C, decomposed with excess reducing agent, neutralized with concentrated ammonia solution and extracted with dichloromethane. The organic layer was separated, washed twice with water, dried and the solvent was evaporated. The residue was dissolved in ethanol (200 mL), flushed with hydrogen chloride gas, and refluxed for 6 hours. The solvent is evaporated, diethyl ether and water are added to the residue, concentrated ammonia solution is added, the organic phase is separated off, washed with water, dried and the solvent is evaporated. 6.9 g of an oily product are obtained, which is dissolved in isopropanol, flushed with a hydrogen chloride gas stream and the salt recrystallized from ethanol. 67.8 g of dihydrochloride are obtained. Melting point: 260-165 ° C.

- Second version of the procedure.

To a suspension of lithium aluminum hydride (10.2 g, 268 mmol) in diethyl ether (31 liters) was refluxed under argon in small portions 60 g (179 mmol) of 2 - [(1-phenylmethylpiperidin-4-yl) - carbonyl] -1,2,3,4-tetrahydroisoquinoline is added. After stirring for 2 hours, the mixture was cooled in an ice bath and hydrolysed with 24.12 ml of IN sodium hydroxide to remove excess reducing agent. The insoluble material is filtered off, the filtrate is evaporated and the residue is dissolved in diethyl ether and hydrogen chloride gas is added. 66.7 g of dihydrochloride are obtained. Melting point: 259-264 ° C.

Example 3 (Compound # 1)

2 - [(Piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline dihydrochloride

a). First Process Procedure 5.8 g (23.7 mmol) of 2 - [(piperidin-4-yl) carbonyl) in 0.9 g (23.7 mmol) of lithium aluminum hydride in 150 ml of diethyl ether are added under argon atmosphere. ] -1,2,3,4-Tetrahydroisoquinoline is added. The mixture was refluxed for 7 hours. Cool, hydrolyze with water (2 mL), filter the insoluble material, separate the organic layer, dry, evaporate the solvent, dissolve the residue in isopropyl 4-methanol and methanol and pass through a stream of hydrogen chloride gas. 3.7 g of dihydrochloride are obtained. Melting point: 252-255 ° C.

(b) Second procedure

11.2 g (28.4 mmol) of 2 - [(1-phenylmethyl-piperidin-4-yl) -methyl] -1,2,3,4-tetrahydro-isoquinoline dihydrochloride, 1.5 g of 10% Pd / A mixture of C and 200 ml of ethanol is catalytically hydrogenated at a pressure of about 0.41 MPa at 40 ° C. The catalyst is filtered off, washed with ethanol, the filtrate is evaporated and the residue is recrystallized from ethanol. 6.9 g of dihydrochloride are obtained. Melting point: 252-255 ° C.

Example 4 (Compound # 2)

2 - ((1-Methylpiperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline difumarate. A) 1-Methyl-4 - [(1,2,3,4-tetrahydroisoquinoline) -2-yl) carbonyl] pyridinium iodide in ml or 4.26 g (30.2 mmol) iodomethane and 6 g (25.2 mmol) 2 - [(pyridin-4-yl) carbonyl] - 1,2,3,4-Tetrahydroisoquinoline is added to 200 ml of ethyl acetate and the mixture is stirred for 24 hours at ambient temperature. The resulting yellow precipitate was filtered off and washed with ether. 8.3 g of product are obtained, which product is used directly in the next step.

b) 2 - [(1-Methyl-piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydro-isoquinoline

To 250 ml of methanol was added 4 g (10.5 mmol) of 1-methyl-4 - [(1,2,3,4-tetrahydroisoquinolin-2-yl) -pyridinium iodide and 0.4 g of platinum oxide and It is hydrogenated for 12 hours at about 0.41 MPa. The catalyst is filtered off, the solvent is evaporated and the residue is neutralized. The resulting oil crystallizes and is used directly in this form in the next step.

c) 2 - [(1-Methyl-piperidin-4-yl) -methyl] -1,2,3,

4-tetrahydroisoquinoline difumarate

Under argon atmosphere, 3 g (11.6 mmol) of 2 - ((1-methylpiperidin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline are dissolved in 100 ml of tetrahydrofuran, and 0.9 g of lithium are added. aluminum hydride, and the mixture was refluxed for 4 hours, stirred at ambient temperature for 12 hours, then hydrolysed with sodium hydroxide, the excess reducing agent removed, the organic phase separated and evaporated to give a yellow oil. difumarate, m.p. 157-158 ° C.

Example 5 (Compound 14)

2 - ((1- (Phenylcarbonyl) piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline hydrochloride

a) 2 - [(Piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline

2-[(1-Phenylmethyl-piperidin-4-yl) carbonyl] -1,2,3,4-tetrahydro-isoquinoline (115 g, 0.34 mmol) was dissolved in 1 L of acetic acid and 4 g of 10% Pd / C was added. and the mixture was hydrogenated at 75 ° C at 0.35 MPa.

After hydrogen consumption ceased, the mixture was allowed to warm to ambient temperature, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in water, cooled in an ice bath, sodium hydroxide was added to pH 10 and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, the solvent was evaporated and the residue was crystallized from anhydrous ether. The crystals were filtered off, washed with pentane and dried in vacuo. 73.5 g of product are obtained. Melting point: 201-205 ° C (slow decomposition).

b) 2 - [(Piperidin-4-yl) -yl] -1,2,3,4-tetrahydroisoquinoline dihydrochloride

To a suspension of lithium aluminum hydride (0.9 g, 23.7 mmol) in diethyl ether (150 mL) under argon atmosphere was added 2 - [(piperidin-4-yl) carbonyl] -1- (5.8 g, 23.7 mmol). 2,3,4-Tetrahydroisoquinoline was added. The mixture was refluxed for 7 hours. After cooling, hydrolysis with 2 ml of water decomposes the excess reducing agent, insoluble material is filtered off, the organic phase is separated off, dried, the solvent is evaporated, and isopropanol / methanol is added to the residue and a stream of hydrogen chloride is passed through.

3.7 g of the dihydrochloride salt are obtained. Melting point: 252-255 ° C.

c) 2 - ((1- (Phenylcarbonyl) piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline hydrochloride

Benzoic acid (2.68 g, 0.022 mmol) was dissolved in tetrahydrofuran (75 mL) and N, N'-carbonyldiimidazole (3.9 g, 0.024 mol) was added slowly under argon. The reactor was immersed in a lukewarm water bath and stirred for 1 hour. 4.6 g (0.02 mol) of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline in 75 ml of tetrahydrofuran are then added and the mixture is stirred at ambient temperature for 6 hours and Stir at reflux for 9 hours.

The mixture was poured into ice water, extracted with dichloromethane, the organic phase was separated and washed with ammonia then water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 6.2 g of an oily product are obtained, which is purified by chromatography on a silica gel column with dichloromethane / methanol 98: 2. The base was dissolved in a little isopropanol, passed through a stream of hydrogen chloride, the hydrochloride precipitated, filtered and recrystallized three times from ethanol. Finally, 3.0 g of the hydrochloride salt was isolated. Melting point: 228-235 ° C (dec.).

Example 6 (Compound # 16)

2 - [{1 - [(3-Chloro-phenyl) -carbonyl] -piperidin-4-yl] -methyl] -1,2,3,4-tetrathydro-isoquinoline hydrochloride

4.6 g (0.02 mol) of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline, 2 g or 2.8 ml (0.02 mol) of triethyl is weighed into a flask.

-5HU 199451 Β

amine and 100 ml of ethyl acetate. 3.5 g or 2.6 ml (0.02 mol) of 3-chlorobenzoyl chloride dissolved in 50 ml of ethyl acetate are added dropwise while maintaining the temperature at about 20 ° C. The mixture is stirred for 2 hours, the precipitate is filtered off, washed with ethyl acetate, the filtrate is washed with water, dried and the solvent is evaporated. 6.8 g of an oily residue are obtained. Dissolve in ethyl acetate, add ethereal hydrochloric acid, stir for 20 minutes, drain the hydrochloride, wash with ether and recrystallize from 50:50 isopropanol / ethyl acetate. Finally, 6.5 g of white crystals were isolated. 162-163 ° C.

Example 7 (Compound 19)

2 - [{1 - [(3-Methylphenyl) carbonyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

Dissolve 4.6 g (0.02 mol) of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline in 50 ml of dichloromethane, add 2.23 g or

Triethylamine (3.1 mL, 0.22 mol) was added dropwise followed by 3-methylbenzoyl chloride dissolved in dichloromethane (10 mL). The temperature of the mixture rises to 38 ° C. After stirring at ambient temperature overnight, the reaction mixture was poured into water, extracted with dichloromethane, the organic phase was washed four times with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The brown oily residue (7.8 g) was purified by column chromatography over silica gel using dichloromethane / methanol 90:10 as eluent. 6.9 g of the purified product are thus obtained. 3.45 g of this is dissolved in 50 ml of ethanol and 1.05 g of fumaric acid in 100 ml of ethanol are added. After stirring for 30 minutes, the solvent was evaporated under reduced pressure, the residue was dissolved in acetone (250 ml), allowed to crystallize in the cold, the crystals were filtered off and dried at 90 ° C under reduced pressure. Finally, 2.7 g of fumarate was isolated. Melting point: 149-151 ° C.

Example 8 (Compound 27)

2 - [{1 - [(3-Trifluoromethylphenyl) carbonyl] piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

3-Trifluoromethylbenzoyl chloride (4.7 g, 22.6 mmol) was dissolved in dichloromethane (20 mL), cooled in an ice bath, and triethylamine (3.8 mL, 0.027 mol) in dichloromethane (20 mL) was added dropwise. A mixture of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline (0.036 mol) was added to the above solution. After stirring for 20 hours at ambient temperature, the mixture is filtered, the filtrate is washed with water, dried and concentrated under reduced pressure. The residual oil was chromatographed on a silica gel column. The resulting oil (7 g) was dissolved in methanol (20 ml), fumaric acid (2.02 g) in methanol (20 ml) was evaporated, the residue was crystallized from ether and the solid was recrystallized from isopropanol. Finally, 7.4 g of fumarate was isolated. 162-164 ° C. 6

Example 9 (Compound 41)

2 - [(1- (Phenylcarbonyl) methylpiperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

2.46 g (15 mmol) of 2- (piperidin-4-ylmethyl) -1,2,3,4-tetrahydroisoquinoline are dissolved in 20 ml of anhydrous dichloromethane and 4.05 g (44 mmol) of anhydrous triethylamine are added. 3 g (15 mmol) of 2-bromo-1-phenyl-1-ethanone dissolved in 80 ml of dichloromethane are added dropwise. The suspension was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue is washed with water, the oil is extracted with dichloromethane, the organic phase is separated off, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent. The resulting red oil was dissolved in diethyl ether. The resulting insoluble material was removed by filtration and the filtrate was concentrated in 50 mL of methanol to give the title base. To obtain difumarate, 2.1 g of fumaric acid are dissolved in 50 ml of methanol and 3.34 g of the above base dissolved in 30 ml of ethyl acetate are added. The crystallized title salt was washed with ethyl acetate then diethyl ether and dried in vacuo. M.p. 203-205 ° C.

Example 10 (Compound 45)

2 - [{1 - [(4-Fluorophenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

Under argon atmosphere, 3.6 g (10 mmol) of 2 - ((1 - ((4-fluorophenyl) carbonyl] piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline in 40 ml of tetrahydrofuran solution of the borane / tetrahydrofuran complex in tetrahydrofuran (40 mL, 40 mmol) was added dropwise, and the mixture was stirred for 15 minutes, refluxed for 4 hours and allowed to stand at ambient temperature. The reaction mixture was quenched by the addition of hydrochloric acid and refluxed for 6 hours, the solvent was evaporated under reduced pressure, water was added to the residue, and the pH was adjusted to 10 with concentrated ammonia.

Extract the mixture with ethyl acetate, wash the organic phase to neutral with saturated sodium chloride solution and dry over sodium sulfate. The solvent was evaporated under reduced pressure to give 4.2 g of an orange oil which partially crystallized. Dissolve in 100 ml of ethanol, filter the solution and add 1.85 g (16 mmol) of fumaric acid in 100 ml of ethanol to the filtrate.

The resulting yellow solution partially crystallized. After evaporation under reduced pressure, the residue was recrystallized from ethanol (150 ml), washed with ice-cold ether and dried in vacuo. 3.4 g of difumarate were isolated. Melting point: 183-185 ° C.

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II. Example 49 (Compound 49)

2 - [[1 - [(3,4-Dimethoxyphenyl) methyl] piperidin-4-yl (methyl) -1,2,3,4-tetrahydroisoquinoline difumarate

a) 1 - [(3,4-dimethoxyphenyl) methyl] -4 - [(1,2,3,

4-Tetrahydroisoquinolin-2-yl) carbonyl] pyridonium chloride

4.76 g (20 mmol) of 2 - [(pyridin-4-yl) carbonyl] -1,2,3,4-tetrahydroisoquinoline, 4.5 g (24 mmol) of 3,4-dimethoxybenzyl chloride and 200 ml the ethyl acetate mixture was refluxed for 20 hours. The resulting mixture was allowed to cool, and the precipitate was collected by filtration and washed with ether. The resulting salt (6.6 g) was used directly in the next step.

b) 2 - [{1 - [(3,4-Dimethoxyphenyl) methyl] piperidin-4-yl] carbonyl] -1,2,3,4-tetrahydroisoquinoline

6.5 g of 1 - [(3,4-dimethoxyphenyl) methyl] -4- [1,2,3,4-tetrahydroisoquinolin-2-yl) carbonyl] pyridinium chloride were charged into a flask. of ethanol and 0.7 g of platinum oxide. The mixture was hydrogenated under a hydrogen pressure of about 0.35 MPa until hydrogen uptake ceased. The catalyst was filtered off, washed with ethanol, the filtrate was concentrated, neutralized with ammonia and extracted with dichloromethane. The organic layer was washed with water, dried and the solvent was evaporated. The resulting oil is used as such in the following step.

c) 2 - [{1- [3,4-Dimethoxyphenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline

A suspension of lithium aluminum hydride (0.6 g, 15.8 mmol) and tetrahydrofuran (50 mL) was stirred for 10 minutes, then slowly dissolved in 3- [1- [(3,4-dimethoxy) 3 g (7.6 mmol) in THF (100 mL). -phenyl) -methyl] -piperidin-4-yl) -. -carbonyl] -1,2,3,4-tetrahydroisoquinoline dissolved in 100 ml of tetrahydrofuran.

The mixture is refluxed for 5 hours, allowed to cool, sodium hydroxide solution is added, the mixture is stirred for 20 minutes, the mineral precipitate is filtered off, washed with ether, the filtrate is washed with water, dried and evaporated. The resulting difumarate salt (2.2 g) was prepared by treating the difumarate salt with two equivalents of fumaric acid and recrystallizing the difumarate from ethanol. Melting point: 175-176 ° C.

Example 12 (Compound 51)

2 - [{1 - [(3-Cyanophenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

6.79 g (31 mmol) of 2 - [(piperidin-4-yl) -1,2,3,

A mixture of 4-tetrahydroisoquinoline, 7.29 g (37 mmol) of 3-bromomethylbenzonitrile, 10.7 g (77 mmol) of potassium carbonate and 70 mL of acetone is stirred for 15 hours. After filtration, the filtrate is concentrated, water and dichloromethane are added, the organic phase is separated off, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol 97: 3 and dichloromethane / methanol 96: 4. 6.2 g of a yellow oil are obtained.

A solution of the above oil (g) (8.6 mmol) in ethyl acetate was added to a solution of fumaric acid (1.99 g, 17.2 mmol) in a little ethanol. Finally, 4.1 g of difumarate are obtained. Melting point: 179-181 ° C.

Example 13 (Compound 52)

2 - [{1 - [(3-Aminocarbonylphenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

2.3 g (66 mmol) of 2 - [{1 - [(3-cyanophenyl) methyl] piperidin-4-yl] methyl [-1,2,3,4-tetrahydroisoquinoline (free base) and A stream of hydrogen chloride gas was introduced into a mixture of 30 ml of formic acid, followed by disappearance of the starting material by thin layer chromatography.

After completion of the reaction, water, ammonia and dichloromethane were added, the organic phase was separated, washed with water, dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil (3.18 g) was purified by column chromatography over silica eluting with dichloromethane: methanol (95: 5, 94: 6, 93: 7, 92: 8, 91: 9 and 90:10).

1.5 g (4.1 mmol) of pure base were isolated and dissolved in ethyl acetate and added dropwise to a solution of 0.85 g (8.2 mmol) of fumaric acid in a little methanol. The resulting mixture was evaporated and washed with ether then ethyl acetate. Finally, 1.5 g of difumarate was isolated. Melting point: 182-184 ° C.

Example 14 (Compound 53)

2 - [{1 - [(3-Nitrophenyl) -methyl-11-piperidin-4-yl] -methyl] -1,2,3,4-tetrahydro-isoquinoline difumarate ^а ) 2- [{1- [ (3-Nitrophenyl) methyl] piperidin-4-ylcarbonyl] -1,2,3,4-tetrahydroisoquinoline g (28.6 mmol) 2 - [(piperidin-4-yl) carbonyl] A mixture of -1,2,3,4-tetrahydroisoquinoline, 6.8 g (31.5 mmol) of alpha-bromo-3-nitrotoluene and 6 g (43 mmol) of potassium carbonate was stirred in 140 ml of acetone for 15 hours. The solvent was evaporated, water and dichloromethane were added to the residue and the organic phase was separated, neutralized, dried and evaporated. The resulting yellow oil (13 g) was purified by column chromatography over silica gel using dichloromethane: methanol (98: 2). Recrystallization from ether gave 9.6 g of product which was used directly in the next step.

б) 2- [1- [3-Nitrophenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

6.6 g (17.4 mmol) of 2 - [{1 - [(3-nitrophenyl) methyl] piperidin-4-yl] carbonyl] -1,2,3,4-tetrahydroisoquinoline, 144 g A mixture of diborane (52 mmol) and tetrahydrofuran (90 mL) was heated at reflux for 5 hours. The mixture is allowed to stand and is hydrolysed by addition of 20 ml of methanol and 5 ml of concentrated hydrochloric acid to decompose the excess reducing agent.

-7HU 199,451 Β to ¹³ for 3 hours under reflux, evaporated, the residue dissolved in water, treated with activated charcoal, stirred at ambient temperature for 1 hour, filtered and the filtrate was neutralized. The organic layer was separated, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol (97: 3).

Recrystallization from pentane gives 5.27 g of purified base. To obtain difumarate, 2.5 g of base (6.84 mmol) was treated with 1.59 g (13.7 mmol) of fumaric acid in methanol. Melting point: 216-217 ° C.

Example 15 (Compound 54)

2- [1 - [(3-Aminophenyl) methyl] piperidin-4-ylmethyl] -1,2,3,4-tetrahydroisoquinoline difumarate

2.7 g (7.4 mol) of 2 - [{1 - [(3-nitrophenyl) methyl] piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline are dissolved in 135 ml of acetic acid and It is catalytically hydrogenated at 0.35 MPa in the presence of Pd / C until the absorption of hydrogen gas has ceased. The catalyst was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol 90:10). Recrystallized from pentane

1.9 g of purified base are obtained.

Dissolve 0.242 g (2.08 mmol) of fumaric acid and 0.349 g (1.04 mmol) of the above base in a small amount of ethanol, combine the two solutions, evaporate the solvent and recrystallize the residue from isopropanol. Finally 0.460 g of difumarate was isolated. Melting point: 163-166 ° C.

Example 16 (Compound 55)

2 - [{1 - [(3-Dimethylaminophenyl) methyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline difumarate

Formaldehyde (0.805 g, 26.8 mmol) was dissolved in tetrahydrofuran (30 mL) and concentrated sulfuric acid (1.1 g, 11.2 mmol) was added followed by 1.5 g (4.47 mmol) of 2 - [{1 - [(3-aminophenyl) ) -methyl] -piperidin-4-yl} -methyl] -1,2,3,4-tetrahydroisoquinoline. After stirring for 30 minutes at ambient temperature, the mixture was cooled in an ice bath and sodium borohydride (1.184 g, 31.3 mmol) was added portionwise, keeping the pH below 4.

After stirring at ambient temperature for 3 hours, the mixture was evaporated, carbonated water and dichloromethane were added to the residue, the organic layer was separated, filtered, dried, and the solvent was evaporated under reduced pressure and the residue was purified on a silica gel column. 0.400 g of purified base is obtained.

The fumaric acid difumarate was prepared from 0.364 g (1 mmol) of the base with 0.221 g (1.9 mmol) of the fumaric acid according to the procedure described in the previous example. 0.250 g of difumarate is finally obtained. Melting point: 180-182 ° C.

Example 17 (Compound 61)

2 - [{1- (Pyridin-2-yl) carbonyl] piperidin-4-yl] methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

Under argon atmosphere, 10.05 mL (24 mmol) of trimethylaluminum (25% solution in hexane) was added to 20 mL of toluene. The mixture was cooled in an ice bath and 2- (piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline (4.6 g, 20 mmol) in toluene (25 mL) was added.

The mixture is heated to about 50 ° C and 3.02 g (20 mmol) of ethyl 2-pyridine carboxylate in 15 ml of toluene are dissolved in 15 ml of toluene. About 10 ml of solvent was removed using a Dean-Stark apparatus and the mixture was refluxed for 3 hours.

After cooling in an ice bath, hydrolysis with 10 ml of water, the excess reducing agent is decomposed, filtered, the solid residue is washed with ethyl acetate, the filtrate is washed three times with water, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure.

6.7 g (20 mmol) of the free base are obtained. Dissolve in a little ethanol, add

2.3 g (20 mmol) of fumaric acid dissolved in 300 ml of ethanol. The ethanol was evaporated and the residue was recrystallized from ethanol. Finally, 5 g of fumarate was isolated. 115-118 ° C.

Example 18 (Compound 68)

2 - [{1 - [(Indol-2-yl) carbonyl] piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline finnarate

Under argon atmosphere, N, N'-carbodiimidazole (4.05 g, 25 mmol) was added in small portions to 2-indole carboxylic acid (3.7 g, 23 mmol) in tetrahydrofuran (37 mL).

The mixture was stirred at ambient temperature for 3 hours and then the solvent was evaporated. The residue is taken up in 46 ml of dichloromethane and a solution of 4.6 g (20 mmol) of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline in 40 ml of dichloromethane is added. added. The mixture was stirred for 12 hours and then poured into water. Extract with dichloromethane, wash the organic phase four times with water, dry over magnesium sulfate, filter, evaporate the solvent under reduced pressure and recrystallize the residue from tetrahydrofuran.

The resulting free base (5 g, 13.3 mmol) was added to a mixture of dichloromethane and methanol and 1.55 g (13.3 mmol) of fumaric acid in 20 mL of ethanol was added. After refluxing, ethanol was added until complete dissolution, the solvents were evaporated under reduced pressure and the residue was recrystallized from ethanol. Finally, 5.5 g of fumarate was isolated. M.p. 203-206 ° C.

-8HU 199451 Β

Example 19 (Compound 65)

2 - ({1 - [(3-Thienyl) carbonyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

a) 3-Thiophenecarboxylic acid chloride to ml of thionyl chloride 5.12 g (44 mmol)

3-Thiophenecarboxylic acid was added, the mixture was heated at reflux for 2 hours, then evaporated, the residue dissolved in toluene and the latter evaporated. The resulting 5 g residue was used directly in the next step.

b) 2 - [{1 - [(3-Thienyl) carbonyl] piperidin-4-ylmethyl] -1,2,3,4-tetrahydroisoquinoline

4.6 g (20 mmol) of 2 - [(piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline and 3.06 ml (22 mmol) of triethylamine are dissolved in 46 ml of dichloromethane and To the solution was added 2.5 g (17 mmol) of 3-thiophenecarboxylic acid chloride in 20 ml of dichloromethane at ambient temperature, and the mixture was stirred for 48 hours. If the reaction is not complete, 2.5 g (17 mmol) of acid chloride and 3 ml (22 mmol) of triethylamine in 20 ml of dichloromethane are added again.

The mixture was stirred for an additional hour, poured into water, extracted with dichloromethane, the organic phase was washed twice with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent _: dichloromethane _: methane: methanol = 98: 2). The resulting base (3 g, 8.8 mmol) was dissolved in a mixture of dichloromethane and ethanol and 1 g (8.8 mmol) of fumaric acid in 100 mL of ethanol was added. The solvents were evaporated and the residue was recrystallized from ethanol. Finally 3.3 g · of fumarate were isolated. 174-177 ° C.

Example 20 (Compound 74)

2 - [{1- (trifluoroacetyl) piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline hydrochloride

2.3 g (10 mmol) of 2- (piperidin-4-yl) methyl] -1,2,3,4-tetrahydroisoquinoline, 1.4 ml (10 mmol) of triethylamine and 100 ml of To the cooled mixture was added dropwise a solution of trifluoroacetic anhydride (2.3 g, 11 mmol) in tetrahydrofuran (50 mL). The mixture was allowed to warm to 20 ° C and stirring was continued for 20 hours.

The mixture was filtered, the filtrate washed with 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure.

1.7 g of an oily residue are obtained which crystallize. The hydrochloride salt was prepared by addition of 0.1 N hydrochloric acid in isopropanol and recrystallized from ethanol. 195-196 ° C.

Example 21 (Compound 19)

2 - [{1 - [(3-Methylphenyl) carbonyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroloquinoline fumarate

a) 4-Piperidine-methanol

28.5 g (0.75 mol) of lithium aluminum hydride and 1.2 liters of tetrahydrofuran were charged into a 4 L three-necked flask equipped with a mechanical stirring system and a condenser. To the resulting suspension was added ethyl ethyl 4-piperidin-4-carboxylate (117.9 g, 0.75 mol) in tetrahydrofuran (1.2 L) and the mixture was stirred at 20 ° C for 6 h. After cooling to 0 ° C, 22 ml of water, 22 ml of 1N sodium hydroxide solution and 46 ml of water are successively hydrolyzed. The mixture was stirred for 30 minutes at 20 ° C and filtered, and the precipitate was washed with tetrahydrofuran and then with ether. The solvents were evaporated under reduced pressure to give 84.4 g of an oil which was used directly in the next step.

b) [1- (3-Methyl-benzoyl) -pyridin-4-yl] -methyl-3-methyl-benzoate

Under argon atmosphere, 42.25 g (0.367 mmol) was weighed into a 3-liter three-necked flask.

4-Piperidine methanol and 430 ml 1,2-dichloroethane and 82 g (0.81 mol) triethylamine were added followed by 125.2 g (0.81 mol) 3-methylbenzoyl chloride. The mixture was refluxed for 4.5 hours, then 8.2 g (0.08 mol) of triethylamine and 12.5 g (0.08 mol) were added again.

3-methylbenzoyl chloride and the mixture was heated for a further 3 hours.

Filter the salts - the triethylammonium chlorides formed by the reaction of triethylamine and liberated hydrochloric acid, which are insoluble in the chlorinated solvent, to minimize product loss? for the sake of -

Wash with 1,2-dichloroethane, evaporate the filtrate under reduced pressure, dissolve the residue in ethyl acetate, wash the solution with saturated aqueous sodium chloride, evaporate the solvent under reduced pressure, and leave the residue with isopropanol / ethyl acetate 1: 1. recrystallize from a mixture. 80 g of a white solid are obtained. Melting point: 80-83 ° C.

c) 1- (3-Methyl-benzoyl) -4-piperidin-methanol g (0.23 mol) 1- (3-methyl-benzoyl) -piperidin-4-yl] -methyl-3-methyl-benzoate 400 mL To a solution of ethanol in ethanol was added potassium hydroxide (12.76 g, 0.23 mol) dissolved in a mixture of ethanol (75 ml) and water (75 ml). After stirring at 20 ° C for 3 hours, the solvent was evaporated under reduced pressure and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 53 g of alcohol which was used directly in the next step.

d) [1- (3-Methyl-benzoyl) -piperidin-4-yl] -methyl-4-methyl-benzenesulfonate g (0.22 mol) 1- (3-methyl-benzoyl) -4-piperidin-methanol 100 To a solution of pyridine (mL) was added 4-methylbenzenesulfonyl chloride (53.3 g, 0.28 mol) dissolved in pyridine (60 mL). The mixture was stirred at 20 ° C for 4 hours and then poured onto ice. After extraction with dichloromethane, the organic phase is washed with 10 vi aqueous hydrochloric acid and dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give 70 g of a white solid. Melting point: 68-70 ° C.

-9HU 199451 Β

e) 2 - [{1 - [(3-Methylphenyl) carbonyl] piperidin-4-yl] methyl] -1,2,3,4-tetrahydroisoquinoline fumarate

2.66 g (0.02 mole) of 1,2,3,4-tetrahydroisoquinoline and 7.75 g (0.02 mole) of [1- (3-methylbenzoyl) piperidin-4-yl] methyl The mixture of 4-methylbenzenesulfonate was heated at 150 ° C for 4 hours. The mixture was allowed to cool, dissolved in dichloromethane and concentrated ammonia was added. The organic layer was separated, washed three times with water, dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane / methanol (98: 2) as eluent. The resulting clear base (2 g, 5.7 mmol) was dissolved in ethanol, 0.66 g (5.7 mmol) of fumaric acid in 100 mL of ethanol was added, the ethanol was evaporated and the residue was recrystallized from acetone. Finally, 2 g of fumarate were isolated. Melting point: 149-151 ° C.

Example 22 (Compound 8)

2 - [{1- (3-Methylphenyl) methyl] piperidin-4-yl} methyl J-1,2,3,4-tetrahydroisoquinoline dlfumarate

1.36 g of 2 - [{1 - [(3-methylphenyl) carbonyl] piperidin-4-yl} methyl] -1,2,3,4-tetrahydroisoquinoline are dissolved in 30 ml of anhydrous ether and added in one portion. 0.29 g of lithium aluminum hydride and the mixture are stirred at ambient temperature for 3 hours. After cooling in an ice bath, hydrolysis with 2.4 ml of IN sodium hydroxide solution, the excess reducing agent is decomposed, filtered and the filtrate is evaporated. 1.2 g (3.5 mmol) of base are obtained, which is dissolved in a small amount of ethanol, 0.82 g (3.5 mmol) of fumaric acid is dissolved in 100 ml of ethanol, the precipitate is filtered off and dried. 1.2 g of difumarate are finally obtained. Melting point: 185-186 ° C.

The following table summarizes the chemical structures and physical properties of some of the compounds of the invention.

(1)

Woman. R Salt Melting point / 1 H diHCl 252-255. 2 ch ₃ - difumarate 157-158 3 CgH ^ CHg- diHCl 259-264 4 2-Cl-C ₆ H ₄ -CH ₂ - difumarate 209-211 5 3-Cl-CgH ₄ -CH ₂ 11 188-190 6 4-Cl-CgH ₄ -CH ₂ - π 205-207 7 2-05-0 4-012- ^ 11 182-183 8 3-ch ₃ -c ₆ h ₄ -o ₂ - you 185-186 9 4-CH ₃ -O ₆ H ₄ -CH ₂ - 11 190.5 to 193 10 2-CH ₃ OC ₆ H ₄ -CH ₂ 11 177-180 11 3-CH ₃ O-C ₆ H ₄ -CH ₂ - 11 173-174 12 4-0Η ₃ 0-0 ₆ Η ₄ -ΟΪ2- 11 204 to 206.5 13 CgH ^ -Chg-CHg- 11 '212-213 14 o ₆ h ₅ -co- HCI 228-235 15 2-Cl-O ₆ H ₄ -CO- fumarate 95-98 16 3-Cl-CgH ₄ -CO HCI 162-163 17 4-Cl-CgH ₄ -CO- fumarate 168-170 18 2-CH ₃ -CgH ₄ -CO- fumarate ^{/: L /} 115-120 19 3-CH ₃ -CgH ₄ -CO- 11 149-151

-10HU 199451 Β

Table / Continued /

Woman. R Salt melting point 20 4-OH ₃ -C ₆ H ₄ -CO- bore him t 134-136 21 2-OOH ₃ -CgH ₄ -CO- II 110-111 22 3-OOH ₃ -C ₆ H ₄ -CO- II 127-128 23 4-OCH ₃ -OgH ₄ -OO- II 132-133 24 2-F-CgH ₄ -00- 1 » 131-133 25 3-F + CgH ₄ -CO- II 166-167 26 4-F-CgH ₄ -CO- It 172-174 27 3-CF ₃ -CgH ₄ -CO- II 162-164 28 4-CF ₃ -CgH ₄ -CO- II 194-195 29 4-NO ₂ -CgH ₄ -C 0- HCI 209-210 30 4-FC _g H ₄ -CO- fumarate 172-174 31 4-SCH ₃ -CgH ₄ -C0- <1 164-166 32 3,5-Cl ₂ -CgH ₃ -CO- II 165-166 33 2,3- / O _3/2 -OgH ₃ -CO- II 185-186 34 3,5- / O _3/2 -CgH ₃ -CO- fumarate 83-86 35 3,5- / CH _3/2 -CgH ₃ -C0- II 90-95 36 3,5- / CF _3/2 -OgH ₃ -CO- fumarate 105-108 37 CioKf - ^ - co- ^x 11 103-107 38 CioV ^ ⁰⁰ · * II 163-165 39 ^ -0¾ ^-0 ¾ ^- difumarate 186-187 40 CH ₂ aCH-CH ₂ - II > 250 41 CgH ₅ -CO-CH ₂ - II 203-205 42 OgH ₅ -OH ₂ -CH ₂ -CH ₂ - difumarate 153-154 43 2-F-CgH ₄ -CH ₂ - 11 189-191 44 3-F-CgH ₄ -CH ₂ - II 184-186 45 4-PC ₆ H ₄ -CH 2 - II 183-185 46 3,5-F ₂ -C ₆ ^H 3 -CH ₂ - II 188-190 47 3,5-Cl ₂ -CgH ₃ -CH ₂ - you 198-199 48 3,5- / CH _3/2 -CgH -CH2- ₃ II 203-205 49 3,4- / CH ₃ O / ₂ -O g H ₃ -CH ₂ - II 175-176 50 3,5- / CH ₃ O / ₂ -CgH ₃ -CH ₂ - tr 199-201 51 3-NC-CgH ₄ -CH _p - 11 179-181

-11HU 199451 Β

Table / Continued /

Woman. R Salt melting point 52 3 h ₂ nco-c ₆ h ₄ -ch ₂ - II 182-184 53 3 o ₂ nc ₆ h ₄ -ch ₂ - II 216-217 54 3- ^H 2 ^N - ° 6 ^H 4- ^CH 2- tt 163-166. 55 3 / CH _3/2 NC ₆ H ₄ -CH 2 1 » 180-182 56 4-CH.jS-C ₆ H ₄ -CH ₂ - II 196-198 57 3 - ^ - 0 ^ 4 - (^ 2- II 193-195 58 3,5- / CF _3/2 -G ₆ H ₃ -CH ₂ - II 222-224 59 3-C ₂ H ₅ O-C ₈ H ₄ -CH ₂ - II 190-192 60 CgH ^ -CHxCH-CHg- / trans / diHCl 197-198 61 / group a fumarate 115-118 62 / b / « II 180-182 63 / a / pyridine -4- 179-180

yl-carbo-

64 / c nil groups. fumarate 169-172 65 / D / II II 174-177 66 / E / you tt 151-152 67 / F / II II 171-174 68 / 8 / 11 tt 203-206 69 / H / II fumarate 110-125 70 CH ₃ -CO- II 139-141 71 ηϋ ₃ Ηγ-00- II 168-170 72 cC ₆ II i i-CO-  (c ik 1 ob ex i 1 - 202-204

carbonyl)

73 CgH ₅ -CH ₂ -CO- tt 132-136 74 cf ₃ -co- HCI 195-196 75 C ₆ H ₅ -CH = CH-CO- / trans / HCI 214-215 76 c ₁₀ h ₇ - «- ch ₂ - * difumarate 208-212 77 'θ10 ^ 7 ^- / ^ ^-GH 2 ^- 11 190-192 78 Group 1 / tt 192-193 79 / □ / tt 191-193 80 3,5-Ρ ₂ -σ ₆ ^Η 3-οο- fumarate 177-179 81 3-0 ₂ H ₅ O-CgH ₄ -CO- II 74-77

-12HU 199451 Β

Notes;

HCl: hydrochloride diHCl; dihydrochloride

1 / fumarate 2 / fumarate hemihydrate 3 / fumarate monohydrate containing one equivalent of isopropanol and C ₁₀ H ₇ 4 and és ^ θΗγ-γβ mean o (- and, γ-naphthyl).

The pharmacological tests performed on the compounds of the present invention confirm the therapeutic efficacy of the compounds.

These were the subject of a study in the rat hippocampus,

5-HT, for detecting _the type of affinity for serotoninergic receptors.

The compounds abolish an isotope-labeled specific ligand, [ ³ H] -8-hydroxy-2-n-dipropylaminotetralin (hereinafter ³ H-8-OH-OOPAT, described by Gozlan et al., Nat. 305, 140-142 (1983)) to 5-HT, receptor binding.

Male Sprague-Dawley rats weighing 160-200 g were used for the experiments. After the head is excised, the brain is removed and the hippocampus is excised. Tissue was homogenized in Ultra-Turrax Polytron for 30 seconds at half the maximum speed with 10 volumes of 50 mM Tris buffer (100 mg fresh tissue per ml) adjusted to pH 7.4 with hydrochloric acid. The homogenized tissue was washed three times at 4 ° C, centrifuged at 48,000 g for 10 minutes each time, and the pellet was resuspended in fresh cold buffer. Finally, the final pellet was resuspended in enough buffer to provide 100 mg of starting tissue in 1 ml of 50 mM buffer. The suspension is then incubated at 37 ° C for 10 minutes.

To determine binding to ³ H-8-OH-DPAT (1 nM), 100 μΐ of membrane suspension * was incubated for 15 minutes at 37 ° C in 10 ml of final volume containing 10 μΜ of pargillin and 3 μΜ of paroxetine.

After incubation, membranes were harvested on Whatman GF / B filters. The filters were washed three times with 5 ml of ice-cold buffer. The filters were placed in a scintillation fluid and their radioactivity determined in a liquid scintillation apparatus. Specific binding of ³ H-8-OH-DPAT is defined as the amount of radioactivity remaining on the filters which can be inhibited by co-incubation with 10 μΜ of 5-hydroxytryptamine. At a concentration of 1 nM ³ H-8-OH-DPAT, the specific binding is 90% of the total radioactivity detected on the filter.

Each concentration of the test compound was determined by the percent binding of ³ H-8-OH-DPAT for inhibition and binding by 50% inhibitory concentration, i.e., the value _N5 1C.

The compounds of the present invention have an IC ₅₀ value in the range of 0.001 to 0.3 μΜ.

The central activity of the compounds of the present invention is assessed in Deporteere H. by Sleep 1976, 358-361, based on the effect of reserpine-induced "PGO-peaks" (ponto-geniculococcal peaks) in cats. (Karger, Basel 1977).

Cumulative doses of test compounds are administered to artificially ventilated curated cats (0.001-3 mg / kg, curve) at 30 minute intervals, with 0.75 mg / kg reserpine i.p. after 4 hours. injection. Electroencephalographic and phase activities (PGO-R peaks) were determined using cortical and deep electrodes (lateral geniculum). For each dose of compound tested, the percentage reduction in the number of PGO peaks was determined, followed by the effective dose to reduce AD ₅₀ , i.e., the number of these peaks by 50%. The compounds of the invention have an ED _{S0 of} between 0.001 and 3 mg per kg iv. broadcast.

The results of the experiment show that the compounds of the formula I have potent in vitro and selective affinity for 2HT, a type of serotonergic receptor. In the carrier. agonist, partially agonist, or antagonist activity at the level of these receptors.

Thus, ^the compounds of ^the invention are

5-HTa, can be used to treat diseases that directly or indirectly affect serotoninergic receptors of the type, namely depressed states, anxiety states, sleep disorders, food intake control, and vascular or cardiovascular diseases such as migraine and hypertension.

For such purpose, together with appropriate excipients for oral or parenteral administration may comprise any suitable form ⁶⁰ may be prepared and used in a dose of 1 mg to 1000 mg daily.

Claims (10)

A process for the preparation of the compounds of formula I and their acid addition salts -13HU 199451 Β R is hydrogen or benzyl or phenyl substituted with methyl, benzyl, or 1 chlorine, methyl or methoxy, characterized in that: a) for the preparation of compounds containing R in the form of hydrogen 1,2,3,4-Tetrahydroisoquinoline is reacted with the imidazolide (III) prepared in situ from isonicotinic acid and N, N'-carbonyldiimidazole to hydrogenate the amide (VI) from the amide (IV) thus obtained. prepared by reduction with lithium aluminum hydride or borohydride such as diborane or complex borohydride such as borane / methyl sulfide complex; obsession b) for the preparation of compounds containing substituents other than hydrogen at the point R, b) an amide of formula VI with a compound of the formula RX - wherein R is a group other than hydrogen, and X is a leaving group such as a bromine atom; or b ₂ ) reacting a compound of formula IV with a compound of formula RX wherein R and X are as defined above, and reacting the resulting compound of formula V wherein R and X is catalytically hydrogenated according to the above process; or b ₃ ) the 1,2,3,4-tetrahydroisoquinoline of formula II is reacted with an isonipecotate of formula VIII in which R is as described above in the presence of trimethylaluminum and reducing the resulting amide of formula (VII) wherein R is as defined above in process (a) to the amide of formula (VI) and forming an acid addition salt as desired and optionally. (Priority: August 7, 1987) 2. A process for the preparation of compounds of the formula I and their acid addition salts thereof R is phenylcarbonyl or naphthylcarbonyl group containing phenylcarbonyl, 1 or 2 halogen atoms, trifluoromethyl, nitro, C 1 or C 2 alkyl, C 1 or 2 alkoxy or C 1 or 2 alkylthio group - characterized in that the amine of formula IX is a compound of the formula RX - wherein R is a moiety X is a leaving group such as a halogen atom or an imidazol-1-yl group, and if desired and optionally an acid addition salt is formed. (Priority: December 30, 1987) 3. A process for the preparation of compounds of the formula I and their acid addition salts thereof R is a linear or branched (C ₂ -C ₆ ) alkyl group, an allyl group; cinnamyl; optionally 1-2 times with halogen, trifluoromethyl, nitro, amino, dimethylamino, cyano, aminocarbonyl, straight or branched (C 1 -C ₃ ) alkyl, straight or branched; phenylmethyl substituted with branched (C 1 -C ₃ ) alkoxy, linear or branched (C 1 -C ₃ ) alkylthio; 2-phenyl-ethyl; 3-phenyl-propyl; phenylcarbonylmethyl - a) reacting a compound of formula IV with a compound of formula RX: wherein: R is as defined herein and X is a leaving group such as a halogen atom, a leaving tosyloxy group in a ketone or amide solvent in the presence of a liberating acid-binding base, and the resulting compound of formula V is subjected to catalytic hydrogenation and reducing the resulting compound of Formula VII with lithium aluminum hydride, diDorane or borane / tetrahydrofuran or diborane / methylsulfide complex in an ethereal solvent such as diethyl ether or tetrahydrofuran at 20-60 ° C, or b) acylating the compound of formula IX with a compound of formula R'COX R'CO is an acyl homologue of R as defined above and X is a leaving group such as halogen, for example chlorine or imidazol-1-yl or C 1-6 -alkoxy or acyloxy of formula R'COO-, wherein R'CO- is as defined above, and the resulting compound of formula X, wherein R 'is as defined above, with lithium aluminum hydride, diborane or borane / tetrahydrofuran or borane / methylsulfide complex in an ethereal solvent such as diethyl ether or tetrahydrofuran at 20-60 ° C. and then optionally hydrolyzing a compound of formula I wherein R is cyanophenylmethyl to produce compounds of formula I wherein R is aminocarbonylphenylmethyl, or - for the preparation of compounds of formula I wherein R is aminophenylmethyl, a compound of formula I or a compound of formula (I) wherein R is dimethylaminophenylmethyl, a compound of formula (I) wherein R is a nitrophenylmethyl group; where R is aminobenzyl, is alkylated to form an acid addition salt if desired and optionally. (Priority: 19.04.1988) 4. A process for the preparation of compounds of the formula I and their acid addition salts thereof R is a straight or branched (C ₂ -C ₇ ) alkanoyl group; (C ₃ -C ₇ cycloalkylcarbonyl; trifluoroacetyl; 1-oxo-3-phenylpropen-2-yl; pyridine n-2-, 3- or 4-ylcarbonyl; furan-2 or 3-ylcarbonyl; thien-2- or 3-ylcarbonyl; (indol-2-yl) carbonyl; or (indol-5-yl) carbonyl, characterized in that the compound of formula (IX) with a derivative of formula RX R is as defined herein and X is a leaving group such as halogen, for example chlorine, imidazol-1-yl, lower alkoxy, or acyloxy of formula RO - R is as defined in the disclosure, forming an acid addition salt if desired and possible. (Priority: 19.04.1988) 5. A process for the preparation of compounds of the formula I and their acid addition salts, wherein R is i) hydrogen; ii) straight or branched (C 1 -C ₆ ) alkyl; allyl; (C ₃ -C ₆ ) cycloalkylmethyl; optionally with 1 or 2 halogens, trifluoromethyl, nitro, amino, dimethylamino, cyanoaminocarbonyl, straight or branched (C 1 -C ₃ ) alkyl, straight or branched ( C 1 -C ₃ ) phenylmethyl substituted on the phenyl by alkoxy, linear or branched (C 1 -C ₃ ) alkylthio; 2-phenylethyl group; 3-phenyl-propyl; 3-phenyl-propen-2-yl; phenyl-carbonyl-methyl; naphthylmethyl groups; pyridinyl-methyl; furanyl-methyl; or thienylmethyl; or iii) straight or branched (C ₂ -C ₇ ) alkanoyl; (C ₃ -C ₆ ) cycloalkylcarbonyl; a trifluoroacetyl group; optionally having 1 or 2 halogen atoms, trifluoromethyl, nitro, straight or branched (C 1 -C ₃ ) alkyl, straight or branched (C 1 -C ₃ ) alkoxy, or straight or branched (C - _C3) alkylthio group, a substituted phenyl group; l-oxo-3-phenyl-propen-2-yl; naphthyl-carbonyl; pyridinyl-carbonyl; furanyl-carbonyl; a thienyl group; (Indol-2-yl) carbonyl; or (indol-5-yl) carbonyl; characterized in that a) In order to prepare compounds containing a hydrogen atom in R, 1,2,3,4-tetrahyd28 roisoquinoline is reacted with the imidazolide of formula III, prepared in situ from isonicotinic acid and N, N'-carbonyldiimidazole, to give (IV). an amide of formula (VI) by catalytic hydrogenation to form an amide of formula (VI) which is reduced with lithium aluminum hydride, a borohydride such as diborane, or a borohydride complex such as a borane / methyl sulfide complex; (b) for the preparation of compounds containing the groups indicated in (ii) in R, an amide of formula (VI) with a compound of the formula RX - wherein R is a group as defined in (ii) above, and X is a leaving group, for example a bromine atom, and finally the resulting amide of formula VII is reduced as described in process a) to the amide of formula VI; and then, if desired, preparing a compound of formula (IX) obtained in process (a) with a derivative of formula RY to prepare compounds containing the groups indicated in (iii) in R; R is as defined in (iii) above and Y is a leaving group such as a halogen such as chlorine or a (C 1 -C ₆ ) alkoxy group or an acyloxy group of formula RO - wherein R is the former - and optionally R is For the preparation of compounds containing the groups given in (ii), the resulting compound is reduced with a borohydride such as diborane or a borohydride complex such as borane / methyl sulfide complex, lithium aluminum hydride or aluminum hydride in an ether solvent such as diethyl ether. tetrahydrofuran or dioxane, 20— I00 ° C, or For the preparation of compounds containing the groups indicated in (ii) in R, the amine of formula IX obtained in process a) with a compound of the formula RX R is as defined in (ii) and X represents a leaving group - alkylating or c) for the preparation of compounds containing the groups indicated in (ii) and (iii) of R, 1,2,3,4-tetrahydroisoquinoline of formula (II) with a tosylate of formula (XI) - wherein Tos represents a tosyl group and R'CO- is as defined for (iii) - in the absence of a solvent or in the presence of an inert solvent such as dimethylformamide or xylene at 20-150 ° C, optionally with an organic base such as a tertiary amine or a mineral base such as alkali hydrogen in the presence of carbonate; and the resulting compound, which ς -15HU 199451 R R is one of the groups listed in (iii), optionally reduced with an ether solution of a borohydride such as diborane or a borohydride complex such as borane methyl sulfide complex, lithium aluminum hydride or aluminum hydride. in diethyl ether, tetrahydrofuran or dioxane at 20-100 ° C to give a compound wherein R is one of the groups listed in (ii) or dj R is a compound of formula (1.2) for the preparation of compounds containing (II), 3,4-Tetrahydroisoquinoline is reacted with an isonipecotate of formula VIII wherein R is a group defined in ii) in the presence of trimethylaluminum and the resulting amide of formula VII is lithium aluminum hydride or a borohydride such as diborane , or by reduction with a borohydride complex such as borane methyl sulfide in an ether solvent such as in ether, tetrahydrofuran or dioxane at 20-100 ° C, or d ₂ ) to produce compounds having the hydrogen atom of formula II 1,2,3,4-Tetrahydroisoquinoline is reacted with an isonipecotate of formula VIII wherein R is benzyl and the resulting amide of formula VII where R is benzyl is reduced according to method d) and the resulting compound of general formula I is obtained. wherein R is as defined above, is debenzylated and an acid addition salt is formed as desired and optionally. (Priority: 08.08.1988) 6. A process for the preparation of a pharmaceutical composition for use in the central nervous system, comprising combining one or more compounds of formula (I) or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein R according to claim 1 with adjuvants customary in pharmaceutical technology. into a pharmaceutical composition. (Priority: August 7, 1987) 7. Procedure affecting the central nervous system. 5) for the preparation of a pharmaceutical composition, characterized in that one or more compounds of the formula I according to claim 2 or a pharmaceutically acceptable acid addition salt thereof - wherein R a 10. A compound according to claim 2, which is mixed with auxiliaries conventional in pharmaceutical technology to form a pharmaceutical composition. (Priority: December 30, 1987) 8. Procedure affecting the central nervous system 15) for the preparation of a pharmaceutical composition, characterized in that one or more compounds of the formula I according to claim 3 or a pharmaceutically acceptable acid addition salt thereof - wherein R a 20. A compound according to claim 3 which is mixed with auxiliaries conventional in pharmaceutical technology to form a pharmaceutical composition. (Priority: 19.04.1988) 9. Method affecting the central nervous system 25) for the preparation of a pharmaceutical composition, characterized in that one or more compounds of the formula I according to claim 4 or a pharmaceutically acceptable acid addition salt thereof - wherein R is 4; Claim 3Q - formulated into a pharmaceutical composition in admixture with excipients conventional in pharmaceutical technology. (Priority: 19.04.1988) 10. A method of acting on the central nervous system 35 for the preparation of a pharmaceutical composition, characterized in that one or more compounds of the formula I according to claim 5 or a pharmaceutically acceptable acid addition salt thereof - wherein R is A compound according to claim 40, which is mixed with a conventional excipient in pharmaceutical technology to form a pharmaceutical composition.