CZ2000946A3 - Combination of inhibitor of 5-HT and antagonist or partial agonist h5-HT1B uptake - Google Patents

Abstract

This solution relates to the combination of the first component (a) being a 5-HTa-inhibitor of the second component (b) h5-HT1B selective antagonist or partial agonist of formula (I) wherein X is CH 2, oxygen, Y is CONH, NHCO, R 1 is hydrogen, C 1 -C 6 an alkyl group, a C 1 -C 6 cycloalkyl group, R 2 is an atom hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, atom halogen, R 3 is (1), (2), (3), (4) CF 3, R 4 and R 5 are ■ ** independently of one another a hydrogen atom or a C 1 -C 4 alkyl group in the form of the racemate, the R-enantiomer or the S-enantiomer and these the components (a) and (b) are in the form of free bases, solvates or their pharmaceutically acceptable salts, their preparation, pharmaceutical compositions containing these combinations, use and method of treating affective disorders such as depression anxiety and obsessive compulsive disorder with this combination as well such as kits comprising the combination.

Description

Combination of 5-HT uptake inhibitor and h5-HT _xB antagonist or partial agonist

Technical field

The present invention relates to a composition comprising a combination of a 5-HT uptake inhibitor (SSRI) and a selective antagonist or partial agonist of h5-HT _xB receptors, more particularly 1,2,3,4-tetrahydronaphthalene or 3,4-dihydro-2H- a 1-benzopyran derivative substituted with a piperidyl or piperazinyl group, wherein each of the components is in the form of the free base, solvates or pharmaceutically acceptable salt thereof. The invention also relates to a method of preparing a combination of the invention, a pharmaceutical composition comprising the combination, and the use of the combination either by simultaneous administration or separate administration to improve the treatment of affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD) etc.

BACKGROUND OF THE INVENTION

It is currently considered that a period of 2-4 weeks is required to achieve the full clinical effect of antidepressants, including selective serotonin 5-HT uptake inhibitors (SSRIs). On the other hand, side effects occur immediately. Therefore, the slow onset of antidepressant action leads to a period of vulnerability in a patient in which he experiences side effects and not therapeutic effects of drugs. It is often difficult for the attending physician to persuade the patient to continue treatment during this period. In addition, suicide-prone patients may increase this activity with gradual onset of onset of action, giving rise to the risk of suicide, and the frequent need for efficacy. frfrfr fr frfr frfr frfr. A rapid onset antidepressant would not only be beneficial in view of a faster reduction in symptoms, but would also be more acceptable to patients and physicians and would reduce the need for hospitalization and its duration. In the treatment of other affective disorders, such as anxiety and OCD (obsessive compulsive disorder), there is a need for an equally long period to achieve full clinical effect.

SUMMARY OF THE INVENTION

The present invention is directed in part to a combination of an SSRI and a 5HT _ib receptor antagonist.

Treatment with this combination preferably results in an increased synaptic concentration of 5-HT. SSRIs reduce 5-HT release in 5-HT neurons by negative feedback reactions partially mediated by terminal h5-HT _{iB receptors} . By inhibiting the terminal 1-5- _{ι: θ} terminal autoreceptors, selective receptor antagonists counteract the decrease in 5-HT release caused by 5-HT uptake inhibitors. This demonstrates that selective blocking of terminal h5-HT antagonist terminal autoreceptors can provide clinical options for improving the efficacy of 5-HT uptake inhibitors (SSRIs) and offer a new basis for the rapid onset of affective actions, such as antidepressant actions.

Combination

Combining the first component (a), which is a 5-HT uptake inhibitor, with the second component (b), which is a selective h5-HT _1B antagonist or partial agonist of Formula I

γ · .R, (i) in which

X is CH ₂ , an oxygen atom,

Y is CONH, NHCO, is hydrogen, C 1 -C 4. alkyl, C ₃ -C _g cycloalkyl,

R ₂ is hydrogen, C _i -C _e alkyl group, C _{= l} -C _s alkoxy, halogen,

R ₃ is

-C (O > -NO — N

IN-/

O-CF, -C (O) NR ₄ R 8

999

9. ·

R and R ₌ are independently hydrogen or C -C

S ^J 14 alkyl, as racemate, R-enantiomer or S-enantiomer, wherein components (a) and (b) are in the form of free bases, solvates, preferably hydrates, or pharmaceutically acceptable salts thereof, is thus achieved in a faster onset of action and consequently more effective treatment of patients.

In further preferred embodiments of the second component (b), those compounds of formula I are those wherein X is CH _2, and therefrom those compounds wherein Y is NHCO, and again those wherein R 1 is morpholino. Compounds in which R ₁ is a hydrogen atom, a methyl group or an ethyl group and in which R ₂ is a hydrogen atom, a methyl group, an ethyl group, a methoxy group or a bromine atom are preferred.

Preferred compounds of formula I are (R) -N- [8- (Piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8] - (4-Ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-Methylpiperazin-1-yl) -1] (R) -N- [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro] -2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide -2-naphthyl] -4-morpholinobenzamide, (R) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4 ·· 99

9 9 9 9 9 9 ·· «· · 9 4 4 4 4 f 9 9

999 99 4,994 · 4 9

994 * 4 4 9 9 «4 • 9

-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl (4) -N- [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morphol] -4-morpholinocarbonyl) benzamide (R) -N- [5-Bromo-8- (4-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) - N- [5-Bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5-Bromo-8] - (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) -N- [5-Methyl-8- (4-methylpiperazine-1- yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide,

N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- (4-Morpholinophenyl) -8- (4) (S) -N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; 3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- (Morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, ( S) -N- [5- (4-Methylpiperazin-1-yl) -3,4-dihydro-2H-1-phe [phe] phe [phe] fefe fe · »· fe · f · fe · fefe fe ·· ·

(S) -N- [5- (4-Methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-methyl-benzopyran-3-yl) (piperidin-1-yl) benzamide, (S) -N- [8-Methyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4 - (dimethylaminocarbonyl) benzamide,

N- [4- (4-Morpholinyl) phenyl] -8-methoxy-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran-3-carboxamide

Particularly preferred compounds are (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5] -methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and (R) -N- [5-methyl-8- (4- methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide.

Compounds of formula I in the form of the (R) -enantiomers, (S) -enantiomers or racemates may exist as the free base or a pharmaceutically acceptable salt or hydrate thereof.

In this context may be a C _x -C _g alkyl group is straight or branched. C _x -C _g alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert pentyl, neopentyl, n-hexyl or isohexyl. A preferred group is a C ₁ -C ₄ alkyl group and a particularly preferred group is a methyl group and an ethyl group.

«· ·« 9 9 • 4 9 • · 49 · 9 9 9 9

9 *

4 β »·

9 9 9 • 9

9 4 4

9 9 9

9 9 4

9 4 9

In this context, the C ₁ -C ₄ alkyl group may be straight or branched. The C ₁ -C ₄ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Methyl and ethyl are preferred.

In this context, may be C ₃ -C _s cycloalkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group.

In this context, the C 1 -C 2 alkoxy group may be straight or unbranched. C _x C _g alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, isopentyloxy, terč.pentyloxyskupina, neopentyloxy, n-hexyloxy or isohexyloxy. C ₁ -C ₄ alkoxy is preferred and methoxy is particularly preferred.

In this context, the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a bromine atom is preferred.

Suitable known 5-HT uptake inhibitors (SSRIs) which can be used are norzimeldin, fluoxetine, paroxetine, citalopram, clomipramine, sertraline, fluovoxamine, alaproclate, preferably citalopram or paroxetine, but component (a) in the combination of the invention is not limited on these SSRIs.

The combination of the present invention may exist in a single form.

This pharmaceutical composition comprising both the first active ingredient (a) and the second active ingredient (b) or in two pharmaceutical compositions such that one comprises the first active ingredient (a) ) and the second comprises a second active ingredient (b). The pharmaceutical composition may be in the form of tablets, capsules, powders, mixtures, solutions or other suitable pharmaceutical forms.

The combination of the invention may be prepared by including a 5-HT uptake inhibitor in the same formulation together with a selective h5-HT antagonist as defined above, for example by mixing in a conventional manner.

The invention also encompasses a method of improving the onset of therapeutic effect by coadministering a combination of a first component (a) that is an inhibitor of 5-HT uptake and a second component (b) that is a selective hS-HT 1 antagonist as defined above.

Another embodiment of the invention is a kit comprising a combination of a first component (a) that is an inhibitor of 5-HT uptake and a second component (b) that is a selective h5-HT antagonist as defined above. This kit may include instructions for use.

Pharmaceutical preparations

According to the invention, the compounds in this combination will be administered by the normal route, orally, rectally or by injection, in the form of pharmaceutical compositions comprising the active ingredient either in free base, solvate, e.g. hydrate, or pharmaceutically acceptable nontoxic acid addition salt e.g. hydrochloride, hydrobromide. , lactate, V * f

Acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semi-solid or liquid composition. Typically, the active ingredient is between 0.1 and 99% by weight of the composition, more particularly between 0.5 and 20% by weight of the compositions intended for injection, and between 0.2 and 50% by weight for compositions suitable for oral administration.

The pharmaceutical composition comprises the active ingredients, optionally in conjunction with adjuvants, diluents, excipients and other inert carriers. To form the combined pharmaceutical compositions of this invention in the form of dosage units for oral administration, the selected compounds may be mixed with a solid excipient such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, with cellulose. derivatives, with a binder such as gelatin or polyvinylpyrrolidone, with disintegrating agents such as sodium starch sugar, cross-linked polyvinylpyrrolidone, croscarmellose sodium, and lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and the mixture obtained it can then be compressed into tablets. If coated tablets are desired, the cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, acacia, gelatin, talc, silica and the like. Alternatively, the tablets may be coated with a polymer known to those skilled in the art, provided that the polymer is dissolved in a readily volatile organic solvent or in a mixture of organic solvents. Dyestuffs can be added to these coatings to easily distinguish tablets containing different active substances or different amounts of these active substances.

* to to · »« · to · to · f to to ··

In order to form soft gelatin capsules, the active compounds can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active ingredients using either the above-described tablet excipients, for example lactose, sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Liquid or semi-solid drug substances may also be filled into hard gelatin capsules.

Dosage units for rectal administration may be solutions or suspensions or formulations obtained in the form of suppositories containing the active ingredients in admixture with a neutral fat base or in the form of gelatin rectal capsules containing the active ingredients in admixture with vegetable oil or paraffin oil. Liquid preparations for oral administration may be in the form of syrups or suspensions, for example in the form of solutions containing from about 0.2 to about 20 weight percent of the active ingredients described herein, wherein the remainder is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid compositions may optionally contain coloring, flavoring, saccharin, and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.

Solutions for parenteral injection may be prepared in an aqueous solution of a pharmaceutically acceptable salt of the water-soluble active ingredient, preferably at a concentration of from about 0.5 to about 10 weight percent. These solutions may also contain stabilizing agents and / or buffering agents and may conveniently be provided in ampoules for various dosage units.

· Fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr · Fr · fr · fr · fr fr · fr

Suitable daily dosages of the active ingredients in the combination of the invention for human treatment are about 0.01 to 100 mg / kg body weight for oral administration and 0.001 to 100 mg / kg body weight for parenteral administration. The daily doses of potent h5-HT _1B antagonists may be clearly different from those of SSRIs, but these may also be the same for both active compounds.

Medical and pharmaceutical use

In another aspect of the invention, there is provided the use of a combination of a first component (a) that is a 5-HT uptake inhibitor with a second component (b) that is a selective h5-HT _1B antagonist or partial agonist, preferably antagonist, as defined herein, and uses in the treatment of 5-hydroxytryptamine-mediated disorders, such as affective disorders. Examples of affective disorders are central nervous system disorders such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorders, depressive phase of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with or without agaraphobia, social phobia, specific phobia, generalized anxiety disorder, post-traumatic stress disorder), personality disorders (impulse control disorders, trichotellomania). Other central nervous system disorders such as obesity, anorexia, bulimia, premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, lack of attention, hyperactivity disorders, migraine, memory disorders (memory impairment) may also be treated with the combination described herein. aging, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (e.g. hyperprolactinemia),

·

Stroke, dyskinesia, Parkinson's disease, thermoregulation disorders, pain, hypertension. Examples of other hydroxytryptamine-mediated disorders are urinary incontinence, vasospasm and tumor growth control (e.g., lung cancer), and these diseases can also be treated with the combination described herein.

Process for preparing intermediates

1. In the case where Y is NHCO and X is CH ₂ or O:

(i) benzylating the compound of formula II, either in the form of a racemate or in the form of an enantiomer

och ₃ (II) to obtain a compound of formula III may be carried out by reaction with a suitable benzylating agent, for example with a benzyl halide such as benzyl bromide or benzyl chloride, or with an activated alcohol, for example benzyl mesylate or benzyl tosylate. This reaction may be carried out using a salt or base of compound II in a suitable solvent, for example Ν, N-dimethylformamide, acetone or acetonitrile with a suitable base, for example sodium hydroxide, sodium bicarbonate, potassium carbonate or a trialkylamine such as

• Φ ΦΦ »» »· · ·

Φ Φ Φ ·

• triethylamine, at a temperature ranging from + 20 ° C to +150 ° C. The presence of a suitable catalyst, for example potassium iodide or sodium iodide, may accelerate the reaction. The nitrogen in compound II can also be protected by reductive alkylation with arylaldehyde in the presence of a reducing agent such as sodium cyanoborohydride, sodium borohydride, or catalytically with hydrogen and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, for example tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine / enamine by adjusting the pH to slightly acidic with an appropriate acid, such as acetic acid, to accelerate the reaction leading to compound III.

(ii) Demethylation of a compound of formula III

(III) to obtain a compound of formula IV can be accomplished by treating the compound with an acidic agent such as aqueous hydrobromic acid, hydroiodic acid, hydrobromic acid / acetic acid, boron tribromide, aluminum chloride, pyridine hydrochloride or a basic nucleophilic agent such as CH ₃ C _g H ₄ S or C ₂ H _with S "in a suitable solvent. A suitable solvent may be methylene chloride or chloroform → 99 99 * 9 and the reaction may occur between -78 ° C and +60 ° C.

(iii) Conversion of a compound of formula IV to a compound of formula V

(IV) (V) can be carried out by reaction with a compound of formula VI,

where (VI) ·

4 • 4 4

0 0 »0 0 0

0

408 «49 * ♦ 9 9 4 ·

0 0 9 9 9 • * 4 ♦ • 4 4 ♦ • 0 4 · «0 9

9 4 4

L represents a leaving group, for example a halogen atom such as a chlorine atom, a bromine atom or an iodine atom or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and

R _a and R _a are hydrogen atoms or lower alkyl groups, for example methyl.

This reaction may be carried out with a salt of a compound of formula IV obtained by reaction with a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, butyllithium or sodium hydride. This reaction may be carried out in a suitable solvent, for example in an aprotic solvent such as dioxane, N, N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether, and the reaction may be carried out; between +20 ° C and +150 ° C.

(iv) Rearrangement of the compound of Formula V no. a compound of formula VII

(V) (Vil)

I • I

this may be carried out in a suitable solvent, for example in an aprotic solvent such as N, N-dimethylformamide, dioxane, 1,1,3,3-tetramethylurea , tetrahydrofuran or hexamethylphosphoric triamide with a suitable base, for example potassium carbonate, potassium hydroxide, potassium tert-butoxide or sodium hydride at a temperature in the range of +20 ° C to 150 ° C. The presence of a co-solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone or hexamethylphosphoric triamide in an appropriate concentration in the solvent may increase the reaction rate.

(v) Hydrolysis of a compound of formula VII to a compound of formula VIII can be carried out under acidic conditions using acids such as sulfuric acid, hydrochloric acid or hydrobromic acid in a suitable solvent, for example, water, ethanol, methanol or mixtures thereof; the reaction may occur between +20 ° C and +100 ° C or under basic conditions using bases such as sodium hydroxide or potassium hydroxide in a suitable solvent, for example in water, ethanol, methanol or mixtures thereof, and the reaction may be performed between +20 ° C and + 100 ° C.

(vi) Conversion of a compound of formula VIII to a compound of formula IX

(VIII) (IX) may take place

a) reaction with a compound of formula X

HIM

HIM

NR, (X) in which 4 9 9 99 4 9 9 4 9 9 4 9 9 ·· ·

9 4 4

R _x is a C _x -C _s alkyl or C ₃ -C _g cycloalkyl. This reaction may be carried out in a suitable solvent, for example in an aprotic / anhydrous solvent such as tetrahydrofuran or N, N'-di / methylformamide, in the presence of a coupling agent such as N, Ν'-carbonyldiimidazole, and this reaction may occur between +20 ° C and +130 ° C. Following the reaction subsequently, the imide reduction is a suitable reducing agent, for example lithium aluminum hydride in a suitable solvent, for example diethyl ether or tetrahydrofuran at a temperature between +20 ° C and reflux temperature, or

b) reaction with a compound of formula XI

(XI) in which

L denotes a leaving group, for example a halogen atom, such as a chlorine or bromine atom, or an alkane or arenesulfonyloxy group, such as a p-toluenesulfonyl / oxy group, and

R _x is hydrogen, C _x -C _s alkyl or C ₃ -C _e cycloalkyl.

This · this

This reaction may be carried out in a suitable solvent such as ethanol, butanol, N, N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, for example potassium carbonate, sodium bicarbonate or potassium hydroxide, and the reaction may occur between +20 ° C and + 150 ° C.

Conversion of a compound of formula IX in which R _x is a hydrogen atom to an alkylated compound of formula IX in which R _x is a C -C alkyl group can be carried out using a suitable alkylating agent such as R-L, where L is a suitable leaving group, for example halogen like chlorine, bromine or iodine, or an arylsulfonyloxy alkanči such as p-toluenesulfonyloxy group, and R _x is a C _x -C _g alkyl group. This reaction may occur in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran, with a suitable base such as potassium carbonate, sodium bicarbonate, sodium hydroxide or a trialkylamine such as triethylamine. This reaction can be carried out at a temperature between +20 ° C and +120 ° C, or the conversion of a compound of formula IX in which R _x is hydrogen to an alkylated compound of formula IX in which R _x is C _x -C _g alkyl or C ₃ -C _g cycloalkyl group, a reductive alkylation with a compound R -CHO, in which R is hydrogen or C -C alkyl or C -C _{x g} cyclic ketone in the presence of a reducing agent such as sodium cyanoborohydride, sodium borohydride, or catalytically with hydrogen and a suitable catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent, for example tetrahydrofuran, dioxane, methanol or ethanol. A proton donor, such as p-toluenesulfonic acid, can be used to catalyze the formation of imine / enamine and adjust the pH to slightly acid with a suitable acid, ····

999 · such as acetic acid, may accelerate the reaction.

(vii) Halogenation of the compound of formula IX in which R _x is hydrogen, C, -C _g alkyl or C ₃ -C _g cycloalkyl

(IX) (XII) to obtain a compound of formula (XII) may be carried out by aromatic electrophilic substitution using a suitable halogenating agent such as bromine, chlorine, iodine, iodine chloride or thionyl chloride. The reaction may be carried out using a salt or base of a compound of formula IX in a suitable solvent, for example acetic acid, in a mixture of hydrogen chloride / ethanol or water, in the presence or absence of a suitable base, for example an alkali metal acetate such as sodium acetate; a reaction temperature between -20 ° C and room temperature.

* · 0000 r · Φ ► · 0 0 0 0 0 0

(XII) (XIII) (viii) conversion of a compound of formula XII to a compound of formula XIII in which R is hydrogen, C -C alkyl or C ₃ -C _g cycloalkyl group, and R ₂ is C _i -C _g an alkyl group may be carried out by metal-halogen exchange in a suitable anhydrous solvent such as tetrahydrofuran or diethyl ether, using a suitable alkyl lithium or metal such as butyllithium, lithium or magnesium chips followed by treatment with a suitable alkyl halide such as methyl iodide, ethyl bromide or propyl iodide and it can occur at a reaction temperature in the range of -78 ° C to room temperature followed by cleavage of the benzyl groups by hydrogenation with a suitable catalyst containing palladium, rhodium, platinum or nickel in a suitable solvent such as acetic acid or ethanol and at a reaction temperature between +20 ° C and + 120 ° C or by treatment with other electrophilic agents such as acetaldehyde no or methyl chloroformate, followed by appropriate treatment. The reaction can be carried out at a reaction temperature ranging from -78 ° C to room temperature.

When acetaldehyde is used as an electrophilic reagent, the above reaction is followed by reduction of benzyl alcohol and cleavage of benzyl groups by hydrogenation with a suitable catalyst containing palladium, rhodium, platinum or nickel in a suitable solvent such as acetic acid or ethanol and may occur between +20 ° C and + 120 [deg.] C.

When methyl chloroformate is used as the electrophilic reagent, after the reaction described above, the methyl ester in a solvent such as diethyl ether or tetrahydrofuran is reduced with an appropriate reducing agent such as lithium aluminum hydride, and this reaction can occur between +20 ° C and reflux temperature. followed by cleavage of the benzyl groups and reduction of the benzyl alcohol by hydrogenation with a suitable catalyst comprising palladium, rhodium, platinum or nickel in a suitable solvent, for example acetic acid or ethanol, and this reaction may occur between +20 ° C and +120 ° C.

When R _x is hydrogen, the piperazine nitrogen is protected from the lithiation step with a suitable protecting group, such as a benzyl group or other protecting group known to the person skilled in the art, which is then removed by methods known to the person skilled in the art, to obtain a compound of formula XIII.

(ix) Conversion of a compound of Formula XIII wherein R is hydrogen to a compound of Formula XIV.

(XIII) (XIV) wherein

R _q is a suitable protecting group, may be carried out by protecting the piperazine ring in a suitable solvent, for example methylene chloride or chloroform, with an appropriate preservative, for example di- (tert-butyl) di carbonate with a suitable base, for example triethylamine or potassium carbonate at a temperature between - 20 ° C and + 60 ° C.

(ix) (x) (x) conversion of a compound of formula IX in which R _x is hydrogen, C _x -C ₆ alkyl or C ₃ -C _g cycloalkyl, to a compound of formula XV in which R _x is is hydrogen, C -C alkyl or C ₃ -C _g cycloalkyl, may be performed by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platina or nickel in a suitable solvent such as acetic acid or ethanol and the reaction may occur between +20 ° C and +120 ° C.

(xi) Conversion of a compound of formula (IX) in which R _x is a hydrogen atom to a compound of formula (XVI). frfr • frfrfr <<

frfr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr fr

AND

Ri

An ^R c (IX) (xvi) in which it represents a suitable protecting group can be carried out

(a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between +20 ° C and +120 ° C; or

b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and palladium on carbon at a reaction temperature between +20 ° C and reflux temperature.

This reaction is followed by protection of the piperazine ring in a suitable solvent such as methylene chloride or chloroform with a suitable preservative such as di- (tert-butyl) dicarbonate, with a suitable base such as triethylamine or potassium carbonate and at a temperature between -20 ° C and + 60 ° C.

0 (xii) Halogenation of the compound of formula XV, wherein R _x is hydrogen, C _x -C alkyl or C ₃ -C _e cycloalkyl,

AND

I * 1 (xv) (XVII) to obtain a compound of formula XVII can be carried out by aromatic electrophilic substitution with a suitable halogenating agent such as bromine, chlorine, iodine, iodine chloride or thionyl chloride. This reaction may be carried out using a salt or base of compound XV in an appropriate solvent such as acetic acid, hydrogen chloride / ethanol or water in the presence or absence of a suitable base such as an alkali metal acetate such as sodium acetate at the reaction temperature. between -20 ° C and room temperature.

(xiii) Conversion of a compound of formula (XVII) in which R _x is a hydrogen atom to a compound of formula (XVIII).

• 9 · 9

(XVII) (XVIII) in which:

R _c is a suitable protecting group, may be carried out by protecting the piperazine ring in a suitable solvent, for example methylene chloride or chloroform, with a suitable preservative, for example di- (tert-butyl) dicarbonate with a suitable base, for example triethylamine or potassium carbonate, at a temperature between 20 ° C and + 60 ° C.

(xiv) Halogenation of the compound of formula XIX, wherein R ₂ is C _x C _g alkoxy group [where X is oxygen, describes the reaction of SO Thorberg et al., Acta Pharma. Suec. 24.

169-182 (1987), when X is CH ₂ , the compound is commercially available], either in the form of a racemate or an enantiomer.

9 9 9

9 9 9

9 9 9

(XIX) (XX) to obtain a compound of formula XX can be accomplished by aromatic electrophilic substitution with a suitable halogenating agent such as bromine, chlorine, iodine, iodine chloride or thionyl chloride. The reaction may be carried out using a salt or base of compound XIX in a suitable solvent, for example acetic acid, a mixture of hydrogen chloride / ethanol or water, in the presence or absence of a suitable base, for example an alkali metal acetate such as sodium acetate at a reaction temperature between -20 ° C and room temperature.

(XXI) to «4»

(xv) Benzylation of a compound of formula XX either in the form of a racemate or an enantiomer to give a compound of formula XXI by reaction with a suitable benzylating agent, for example benzyl halide such as benzyl bromide or benzyl chloride, or with activated an alcohol such as benzyl mesylate or tosylate. This reaction may be carried out using a salt or base of a compound of formula XX in a suitable solvent, for example in N, N-dimethylformamide, acetone or acetonitrile, with a suitable base such as triethylamine, sodium hydroxide, sodium bicarbonate or potassium carbonate at range +20 ° C to + 150 ° C. The presence of a suitable catalyst, for example an alkali metal halide such as potassium iodide or sodium iodide, may accelerate the reaction.

I * 1 (XXI) (XXII) (xvi) Conversion of a compound of formula XXI to a compound of formula XXII, in which R is hydrogen, C -C alkyl or C ₃ -C _g cycloalkyl group, and R ₂ is C - C _g alkoxy, may be carried out by reacting a compound of formula XXIII, wherein R is hydrogen, C -C alkyl or C ₃ -C _g cycloalkyl.

• ·>

• 44 • 4

R, (XXIII)

The reaction may be carried out in a suitable solvent, for example in an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide, with a suitable base such as sodium tert-butoxide or lithium bis (trimethylsilyl) amide. , in the presence of a suitable palladium catalyst such as PdZ ₂ , L ' ₂ Pd (O) or L' ₂ PdZ ₂ , wherein Z is a halogen atom such as chlorine or bromine, and L 'is a suitable ligand such as triphenylphosphine , tri-o-tolylphosphine, trifurylphosphine, triphenylarsine or dibenzylideneacetone, with or without the addition of ligand L '', such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine,

2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (either as a racemate or as an enantiomer) or triphenylarsin, and the reaction may take place at temperatures between +20 ° C and +150 ° C.

(xvii) Conversion of a compound of formula XXII to a compound of formula XXIV from a compound of formula XXIV to a compound of formula XXIV

I ^R 1 (XXIV) wherein

R _x is hydrogen, C _x -C _s alkyl or C ₃ -C _g cycloalkyl group, and

R ₂ is C ₁ -C ₆ alkoxy, may be carried out by hydrogenation with a catalyst comprising palladium, platinum, rhodium or nickel in a suitable solvent, for example acetic acid or ethanol, at a reaction temperature between +20 ° C and +120 ° C.

(xviii) Conversion of a compound of formula XXIV in which R _x is hydrogen to a compound of formula XXV,

99 »·« φ

«Φ Φ ΦΦΦ Φ Φ Φ Φ Φ« «« · · · · · ·

(XXIV) (XXV) in which

R _c is a suitable protecting group, may be carried out by protecting the piperazine ring in a suitable solvent, for example methylene chloride or chloroform with a suitable preservative, for example di-tert-butyl dicarbonate, with a suitable base, for example triethylamine or potassium carbonate, at a temperature between -20 ° C and + 60 ° C.

(XV) (XXVI) (xix) converting a compound of formula XV, wherein R _x is a C _x -C ₆ alkyl or C ₃ -C _g cycloalkyl, to a compound of formula XXVI, where Y is NHCO and R ₃ , as defined above for formula (I) above, may be carried out by acylation with the appropriate benzoic acid of formula (XXVII) which is activated to the acid chloride in a suitable solvent such as methylene chloride or chloroform with a suitable base such as trialkylamine such as triethylamine; using a benzoic acid of formula XXVII with an activating agent, for example N, Ν'-carbonyldiimidazole,

N, N ¹ -dicyclohexylcarbodiimide or diphenylphosphine chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as Ν, Ν-dimethylformamide or tetrahydrofuran, and this reaction can be carried out at a temperature between +20 ° C and +150 ° C . ²

2. If Y is a CONH group and X is a CH ₂ group or an oxygen atom 49 · 4 * 9 · 9 · 4 4 4 · 444 4 4 · 4 9 4 ··· 44 · 49 · (i) Nitration of a compound of formula XXVIII, wherein R ₂ is C _x C _g alkoxy, either as racemate or enantiomer, to obtain a compound of formula XXIX

(XXVIII) (XXIX) in which

R _d is ^{C _C} the alkyl group may be performed by aromatic electrophilic substitution using a suitable nitrating agent such as nitric acid or nitric acid and sulfuric acid, in a suitable solvent such as acetic acid, acetic anhydride or water at a reaction temperature between -20 ° C and room temperature.

(ii) Hydrolysis of the compound of formula (XXIX) can be carried out under acidic conditions using acids such as sulfuric acid, hydrochloric acid, hydrobromic acid in a suitable solvent such as water, ethanol, methanol, acetic acid or mixtures thereof, and this reaction it can take place at a temperature between 20 ° C and reflux temperature or under

Ο 49 • 444 4 4 4 4 4 4 · ·· · 4 444 4 ·· 4 • ··· 4 4 · · 4 · 4 4 · • 4 ·· 444 ··

4444 44 44 4 · 4 49 49 basic conditions using bases such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, ethanol, methanol or mixtures thereof, and this reaction may occur at a temperature between +20 ° C and temperature refluxing to give a compound of formula XXX.

(XXX) (XXXI) (iii) converting a compound of formula XXX in which R _{x is} C, -C _s alkoxy, to a compound of formula XXXI, where Y is CONH and R _is C _x -C _s alkoxy, may be accomplished by activating the acid group of compound XXX to form an acid halide such as an acid chloride with a suitable base such as a trialkylamine such as triethylamine, or using an activating agent such as N, N'-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or diphenylphosphine chloride with a suitable base, such as N-methylmorpholine, in a suitable solvent, for example methylene chloride, chloroform, toluene, N, N-dimethylformamide, dioxane or tetrahydrofuran, followed by addition of the corresponding aniline XXXII, wherein R ₃ is as defined in formula I above . The reaction can take place between 0 ° C and +120 ° C.

(iv) Conversion of a compound of formula XXXI to a compound of formula XXXIII in which Y is a CONH group and R ₃ is generally defined for a formula I can be carried out

(XXXIII) hydrogenation with a palladium, platinum or nickel catalyst in a suitable solvent such as ethanol, methanol or acetic acid at a reaction temperature between +20 ° C and +120 ° C, or reduction with sodium dithionite in a suitable solvent.

3. Conversion of a compound of formula XXXIV to a compound of formula XXXV

NC (XXXIV)

N

(XXXV) • to ··· · can be performed

a) hydrolyzing the nitrile of the compound of formula XXXIV in a suitable solvent such as aqueous methanol or aqueous ethanol in the presence of a suitable base such as sodium hydroxide or potassium hydroxide at a reaction temperature between room temperature and reflux temperature followed by

b) hydrolyzing the above amide and ketal under acidic conditions in a suitable solvent, such as aqueous methanol, aqueous ethanol or water, in the presence of a suitable acid such as hydrochloric acid or hydrobromic acid at a reaction temperature between room temperature and reflux temperature.

Methods of preparation of end products

Another object of the present invention is process A (i), A (ii), B or C for the preparation of a compound of formula I

A (i) acylation, in the case that R _x is a C _x -C _g alkyl or C ₃ -C _g cycloalkyl, Y is NHCO and X, R ₂ and R ₃ are defined in formula I above, compounds of formula A • 0 «

0 · (• ·· • 0 0 1 • 0 0 · · 00 «·· 0 ·· 0 • ·· 0 ·· 0

* 1

(A) (I) with an activated benzoic acid of formula XXVII or using a benzoic acid of formula XXVII with an activating agent.

Thus, the acylation of Method A (i) may be carried out with a suitable benzoic acid of formula XXVII, wherein R _{3 is as} defined above for formula I, activated as the acid chloride in a suitable solvent such as methylene chloride or chloroform with a suitable base such as trialkylamine , such as triethylamine, at a temperature between -20 ° C and a reflux temperature, or using benzoic acid of formula XXVII, wherein R _{3 is as} defined for formula I above, with an activating agent such as N, N'-carbonyldiimidazole, N, N n-dicyclohexylcarbodiimide or diphenylphosphine chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as Ν, Ν-dimethylformamide or tetrahydrofuran, and this reaction may be carried out at a temperature between +20 ° C and +150 ° C.

·

04 9 • 9 99

0 0 0 0 0 0

0 0 9

0 0 9

40

A (ii) acylation when R 6 is hydrogen, Y is NHCO, R _c is a protecting group, and X, R ₇ , and R ₃ are as defined in formula (I) above, compounds of formula (B)

Thus, the acylation of process A (ii) can be carried out with the appropriate benzoic acid of formula XXVII, wherein R _{3 is as} defined above for formula I, activated as the acid chloride in a suitable solvent such as methylene chloride or chloroform with a suitable base, e.g. such as triethylamine, at a temperature between -20 ° C and a reflux temperature, or using benzoic acid of formula XXVII, wherein R _{3 is as} defined above for formula I, with an activating agent such as N, Ν-carbonyldiimidazole, N, Ν. n-dicyclohexylcarbodiimide or diphenylphosphine chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N, N-dimethylformamide or tet99 * 9 99 9 9 9

9 9

999 9

9

9999 99

9 9 9 9

9 9 • 9,999 • 9 9

9 9

999 rahydrofuran, and this reaction may be carried out at a temperature between +20 ° C and +150 ° C followed by removal of the protecting group R _by hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature of between +20 ° C and +60 ° C.

B reacting, in the case where Y is CONH, X, R, R _and R ₂ are as defined in general formula I above,

I (C) (i) with a compound of formula XI wherein L is a leaving group. Thus, the reaction of Method B may be carried out with a compound of formula XI wherein R _{x is as} defined above for formula I and L is a leaving group such as a halogen atom such as a chlorine or bromine atom or an alkane- or arenesulfonyloxy group such as p. -toluenesulfonyloxy. The process can be carried out in a suitable solvent such as ethanol, butanol, N, N-dimethylformamide, N, N-dimethylformamide. Acetonitrile or a mixture of water and acetonitrile in the presence or absence of a suitable base, for example potassium carbonate, sodium bicarbonate, or acetonitrile; potassium hydroxide and the reaction may take place between +20 ° C and +150 ° C.

C reactions, when Y is NHCO, R ₂ is halogen and X, R _x and R ₃ are as defined in formula I above, compounds of formula D

(D) (I) with a suitable halogenating agent such as bromine, chlorine, iodine, iodine chloride or thionyl chloride.

Thus, the reaction of Method C can be carried out by aromatic electrophilic substitution using a suitable halogenating agent such as bromine, chlorine, iodine, iodine chloride or thionyl chloride. This reaction may be carried out using a salt or a base of a compound of formula D in a suitable solvent, for example acetic acid, in a mixture of hydrogen chloride. ···························· or in water, in the presence or absence of a suitable base, for example an alkali metal acetate such as sodium acetate, at a reaction temperature between -20 ° C and room temperature.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of intermediates and starting materials for antagonists

Preparation 1 (R) -2-N, N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene

To a solution of (R) -8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (24 g, 0.11 mol) in acetonitrile (600 mL) was added potassium carbonate (53 g, 0.39). mol), potassium iodide (catalytic amount) and benzyl bromide (34 mL, 0.28 mol). The reaction mixture was stirred at reflux for 35 h. After filtering off the precipitate and evaporating the acetonitrile in vacuo, the residue was partitioned between diethyl ether and water. The organic phase was separated, dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified on a silica gel column using hexane / ethyl acetate (3: 1) as eluent. This produces the title compound as a white solid, mp 105-107 ^o C to yield 36 g (91%).

+124 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 357 (100, M ^& lt ^{; +} & gt ^; ).

• ··· · · · k · ♦ · fe · · · · ·

Fefe fefefe fefefe fefefe

Preparation 2 (R) -7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (R) -2-N, N-Dibenzylamino-8-methoxy-1,2,3,4 -tetrahydronaphthalene (43 g, 0.12 mol) was dissolved in diethyl ether (800 mL) and an excess of a solution of hydrogen chloride in ether was added dropwise. The precipitate was collected by filtration and dried in vacuo to give a white solid. This crude product (42 g, 0.11 mol) was dissolved in anhydrous methylene chloride (1 L) and cooled to -60 ° C. To the solution was added dropwise boron tribromide (16 mL, 0.15 mol) dissolved in anhydrous methylene chloride (100 mL). The reaction mixture was allowed to reach -5 ° C and maintained at this temperature overnight. To the ice cold solution was added dropwise a 2M aqueous ammonium hydroxide solution, and the mixture was extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to give a crude residue. Silica gel chromatography (methylene chloride) afforded 34 g (93% yield) of the title compound as a viscous, clear oil.

[α] + 118 ° (c 1.5, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 343 (53, M ^& lt ^{; +} & gt ^; ).

Preparation 3 (R) -2- (7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (R) -2-N, N-Dibenzylamino-5,6 7,8-tetrahydro-1-naphthol (10 g, 29 mmol) was stirred in anhydrous dioxane (150 mL) with sodium hydride (80% suspension in oil, 0.96 g, 32 mmol) for 1 h. with 2-bromo-2-methylpropanamide (4.8 g, 29 mmol) described in IGC Courtts and M.R. Southcott, J. Chem. Soc. Perkin Trans. 1, 767-770 (1990) and the reaction mixture was heated at 100 ° C for 2.5 h. After cooling, the precipitated sodium bromide was filtered off, the filtrate was evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated to give the crude product which was purified on silica gel using methylene chloride as eluent. The title compound was obtained as white crystals, m.p. 125-126 ° C, yield 9.6 g (76%).

[ ^α ] ²¹ D + 98 ° (c 1.1, chloroform).

EIMS (70 eV) m / z (relative intensity) 428 (13, M ^& lt ^{; +} & gt ^; ).

Preparation 4 (R) -N- (7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide

To a solution of (R) -2- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (9.1 g, 21 mmol) in anhydrous 1.3 - dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (10 ml) and dry N, N-dimethylformamide (100 ml) are added sodium hydride (80% suspension in oil, 1.4 g, 47 mmol) and the reaction mixture was heated at 130 ° C for 8 h. The solution was poured into ice-water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate. ; ····. ...... ·· ... · .. ·· filtered and evaporated in vacuo. Chromatography on silica (eluent: chloroform / ethanol saturated with ammonia 100: 0.5) gave the title compound as white crystals melting at 134-135 ° C to yield 7.6 g (84%) [a] ²¹ ^ + 130 DEG (c 1.1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 428 (1, M *).

Preparation 5 (R) -2-N, N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (R) -N- (7-N, N-Dibenzylamino-5,6,7,8- Tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropionamide (7.4 g, 17 mmol) was dissolved in a mixture of ethanol (200 mL) and 20% aqueous hydrochloric acid (300 mL) and refluxed for 3 hours. The ethanol was evaporated in vacuo and the remaining solution was washed twice with diethyl ether and cooled in an ice bath. After alkalization with a 45% aqueous sodium hydroxide solution, the mixture was extracted with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform as eluent afforded 3.8 g (76% yield) of the title compound as a light brown oil.

[α] + 124 ° (c 0.9, chloroform).

EIMS (70 eV) m / z (relative intensity) 342 (92, M &lt; + &gt;).

»··· ·· to ·

Preparation 6 (R) -1- (7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-N-methylpiperazine-2,6-dione

1,1'-Carbonyldiimidazole (6.0 g, 37 mmol) was added to a stirred suspension of methyl imino diacetic acid (2.7 g, 18 mmol) in anhydrous tetrahydrofuran (250 mL). The reaction mixture was heated at reflux for 1.5 h. Then (R) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (5.7 g, 17 g) was added. mmol) and stirring at reflux was continued for 17 h. An additional amount of 1,1'-carbonylimidazole (2.9 g, 18 mmol) was added and reflux was continued for another 17 h. The solvent was evaporated in vacuo. The crude product was purified on silica gel eluting with chloroform / ethanol saturated with ammonia (100: 0.5). The yield of the title compound as an oil was 6.6 g (87%).

+90 DEG (c 0.52, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 453 (8, M *).

Preparation 7 (R) -2-N, N-Dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -1- (7-N, N-Dibenzylamino- 5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazine-2,6-dione (1.4 g, 3.1 mmol) is added to a suspension of lithium aluminum hydride (0.57 g, 15 mmol) ) in anhydrous diethyl ether (70 mL). The reaction mixture was heated under • ••• 9 9 9 9 9 99 t · G ¹ «reflux for 7 h. The reaction was quenched by adding water (0.60 mL), 15% aqueous sodium hydroxide solution (0.60 ml) and additional water (1.8 ml). The mixture was filtered, dried over sodium sulfate and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol saturated with ammonia (100: 2) as eluent gave 1.0 g (79% yield) of the title compound as a viscous oil.

[Α] ²³ D + 53 ° (c 0.5, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 425 (2, M *).

Preparation 8 (R) -5-Bromo-2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

To a solution of (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (2.8 g, 6.5 mmol) and sodium acetate ( 6.8 g, 83 mmol) in acetic acid (100 mL) was added in one portion of bromine (370 μΐ, 7.2 mmol) and the reaction mixture was stirred for 5 min. The solvent was evaporated in vacuo and the remaining solid was partitioned between water and methylene chloride and cooled in an ice bath. The aqueous phase was basified with 2M aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product, which was purified on a silica gel column using chloroform / ethanol saturated with ammonia (100: 2). A viscous oil is obtained in a yield of 2 g (61%).

(Relative

EIMS mass spectrometry (70 eV) m / z intensity) 503 and 505 (0.6, M +).

Preparation 9 (R) -2-N, N-Dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-Dibenzylamino-8-amino- 1,2,3,4-tetrahydronaphthalene (9.8 g, 39 mmol) and bis- (2-chloroethyl) amine hydrochloride (5.5 g, 32 mmol) were dissolved in n-butanol (80 mL). The reaction mixture was stirred at 100 ° C and after 65 h the mixture was filtered and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 6.0 g (51% yield) of the title compound as a viscous oil.

[a] ² ^ + 72 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 411 (2, M ^& lt ^{; +} & gt ^; ).

Preparation 10 (R) -2-Amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

To a solution of (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (5.5 g, 13 mmol) in methanol (400 mL) was added ammonium formate (20 g, 0.32 mol) and palladium (10%) on activated carbon (1.9 g). The mixture is refluxed for 1h and then the palladium is filtered off.

···· • · φ φφφ

The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and 2M ammonium hydroxide solution. The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product which was purified on a silica gel column using chloroform / ethanol / concentrated ammonium hydroxide (80: 20: 2.5) as eluent. The yield of the compound as an oil was 2.4 g (76%).

[α] ²¹ D + 9.9 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 231 (24, M *).

Preparation 11 (R) -2-Amino-5-bromo-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

The title compound was prepared from (R) -2-amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene according to the general preparation method 8. Purification on a silica gel column with methylene chloride / ethanol / concentrated hydroxide ammonium (80: 20: 2) affords 0.8 g (67% yield) of a viscous light brown oil.

[alpha] ^{2: l} D -6.2 ° (c 1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 309 and 311 (3.5, M *).

Preparation 12 tert -Butyl (R) -4- (7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate

To an ice-cold solution of (R) -2-amino-5-bromo-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (0.8 g, 2.6 mmol) and triethylamine (0). (53 mL, 3.9 mmol) in methylene chloride (50 mL) was added di-tert-butyl dicarbonate (0.56 g, 2.6 mmol) dissolved in methylene chloride (10 mL). After the addition, the reaction mixture was allowed to stir at room temperature for 1 h. Water (10 mL) was added and the mixture was cooled in an ice bath. The aqueous phase was basified with 2M aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product which was purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent. A viscous colorless oil is obtained in a yield of 0.41 g (38%).

[ο:] ^ ²¹ + 13 ° (c = l, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 409 and 411 (75, M *).

Preparation 13 (R) -N- [5-Bromo-8- (4-tert-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

4-Morpholinobenzoic acid (0.50 g, 2.4 mmol) as described in J. Degutis, L. Rasteikien and A. Degutien, Zh. Org. Khim., 14, 2060-2064 (1978), was dissolved in thionyl chloride (10 mL). After 2 min, the thionyl chloride was evaporated in vacuo and the residue was treated with toluene and the solvent was evaporated again in vacuo. The crude acid chloride (81 mg, 0.36 mmol) was dissolved in methylene chloride (10 mL) and added dropwise to a solution of tert-butyl- (R) -4- (7-amino-4-bromo-5,6, 7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylate (140 mg, 0.34 mmol) and triethylamine (71 μΐ, 0.51 mmol) in methylene chloride (10 mL). After the addition, the reaction mixture is stirred at ambient temperature for 15 min and then washed with dilute aqueous sodium bicarbonate solution and the phases are separated. The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo and the residue is purified on a silica gel column using chloroform / ethanol saturated with ammonia (100: 2) as eluent. The yield of a viscous colorless oil was 160 mg (79%).

[a] ² ^ -11 (c = l, chloroform).

TSPMS m / z (relative intensity) 599 and 601 (35, M ⁺ +1).

Preparation 14 (R) -2-Amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

To a solution of (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (4.0 g, 9.4 mmol) in methanol (250 mL). ammonium formate (14 g, 56 mmol) and palladium (10%) on charcoal (1.4 g) were added. The mixture was refluxed for 3 h and then the palladium was filtered off. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and 2M ammonium hydroxide solution. The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product which was purified on a silica gel column using a mixture chloroform / methanol / concentrated ammonium hydroxide (90: 9: 0.5) as eluent. The result was 1.9 g (83%) of an oily liquid.

[α] ^{2 D} at -2.7 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 245 (5, M ^& lt ^{; +} & gt ^; ).

Preparation 15 (R) -2-Amino-5-bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

The title compound was prepared from (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene according to the general preparation method 8. Purification on a silica gel column using chloroform / Ethanol / concentrated ammonium hydroxide (80: 20: 2) as eluent gave 630 mg (89% yield) of a viscous colorless oil.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 323 and 325 (20, M *).

Preparation 16 (R) -2-Amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (R) -2-Amino-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (5) (0 g, 23 mmol) was dissolved in acetic acid

9 ·· 999 · · 4 «(300 ml) under. nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) was added followed by bromine (3.5 g, 23 mmol) in one portion. The mixture was stirred for 5 min at room temperature. The solvent was removed in vacuo to give a solid residue which was partitioned between ethyl acetate and 2M sodium hydroxide solution. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated in vacuo to give a brown oily residue. The hydrochloride is precipitated from diethyl ether / methylene chloride by addition of a 3M solution of hydrochloric acid in diethyl ether. Yield: 7.7 g (94%). Recrystallization from methanol affords the title compound as needle crystals, m.p. 264-265 ° C.

[ ^α ] ^2x D + 54 ° (c 1, MeOH).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 257 (30, M *, ^sl Br), 255 (31, M ^- *, ⁷⁹ Br).

Preparation 17 (R) -8-Bromo-2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (R) -2-Amino-8-bromo-5-methoxy-1 2,3,4-tetrahydronaphthalene hydrochloride (4.5 g, 17.5 mmol), benzyl bromide (6.6 g, 38 mmol), potassium carbonate (9.7 g, 70 mmol) and potassium iodide (100 mg, a catalytic amount) was treated with acetonitrile (250 mL) under argon and refluxed for 18 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 2M ammonium hydroxide solution. The layers were separated and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo • · · · _K ......

·· ···· · · • ·· ♦

The residue was purified by flash chromatography on silica gel eluting with hexane / methylene chloride. 8: 2 as eluent. The title compound was obtained as an oil in a yield of 7.5 g (98%).

[α] D + 87 ° (c 1, MeOH).

EIMS (70eV) m / z (relative intensity) 437 (12, M ⁺ , ^ei Br), 435 (13, M ⁺ , ^7S Br).

Preparation 18 (R) -2-N, N-Dibenzylamino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

To a solution of (R) -8-bromo-2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (19 g, 44 mmol) in dry toluene (500 mL) under argon was added N-methylpiperazine (5.9 mL, 53 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.41 g, 0.44 mmol), (R) -BINAP (0.82 g, 1.3 mmol) and sodium tert-butoxide (0.40 mg, 4.2 mmol). The dark solution was stirred at room temperature for 23 h and then cooled, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol saturated with ammonia (100: 2) as eluent afforded 19 g (97% yield) of a viscous colorless oil.

[α] ²¹ D + 72 ° (c = 1, chloroform).

Mass spectrometry (70 eV) m / z (relative intensity) 455 (15, M *).

Preparation 19

(R) -2-Amino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene

The title compound was prepared from (R) -2-N, N-dibenzylamino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene according to General Preparation 10 in yield. 5.3 g (82%) of a viscous colorless oil.

[α] ²¹ D + 20 ° (c = 1.1, chloroform).

EIMS (70eV) m / z (relative intensity) 275 (53, M ^& lt ^{; +} & gt ^; ).

Preparation 20

5-Methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester

5-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (1.1 g, 5 mmol), described by D. W. Johnson and L. N. Mander, Aust. J. Chem., 8, 1277-1286 (1974), dissolved in acetic anhydride (20 mL), is treated with 70% nitric acid (0.4 mL) at 0 ° C for 1 h and the mixture is poured into ice water and diethyl ether. The organic phase was separated, evaporated in vacuo and the residue triturated with diisopropyl ether to give 0.27 g (20%) of the title compound as a crystalline solid, mp 100-104 ° C.

EIMS (70 eV) m / z (relative intensity) 265 (35, M &lt; + &gt;).

*::::::::: ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** i * * · ♦ «« • • • • •

Preparation 21

5-Methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid methyl ester (1.9 g, 7.1 mmol) in methanol (20 mL) and 2M sodium hydroxide solution (10 mL) The mixture was refluxed for 1.5 h and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and acidified. The organic phase was separated, dried and evaporated in vacuo to give 1.7 g (95% yield) of crystals of m.p. (recrystallized from diisopropyl ether / ethanol) 189-190 ° C.

EIMS (70 eV) m / z (relative intensity) 251 (30, M &lt; + &gt;).

Preparation 22

N- (4-Morpholinophenyl) -5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3 g, 5 mmol), toluene (20 mL) and thionyl chloride (1.8 mL, 25 mmol) was added. Heat at 80 ° C for 1 h. Solvents were evaporated in vacuo and the residue dissolved in methylene chloride (10 mL) was added to a solution of 4-morpholinoaniline (890 mg, 5 mmol) and triethylamine (1.0 g, 10 mmol). in methylene chloride (20 mL) at 0 ° C. The mixture was stirred at 20 ° C for 2 h, water was added and the precipitate was filtered off to give 1.9 g (90%) of the crystalline product of the title melting point 251-253 ° C.

• 44 * 44

4 4 4 * 4 ♦

Mass spectrometry (70 eV) m / z (relative intensity) 411 (100, M ^& lt ^{; +} & gt ^; ).

Preparation 23

N- (4-Morpholinophenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution of N- (4-morpholino-phenyl) -5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide (2.05 g, 5 mmol) and sodium dithionite (3.5 g, 20 mmol) ) in N, N-dimethylformamide (20 ml) and water (2 ml) was heated at 90 ° C for 7 h. After cooling, the reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was washed twice with water and evaporated in vacuo. The residue was triturated with diisopropyl ether / ethyl acetate to give 1.4 g (72% yield) of the title compound as crystals, mp 219-222 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 381 (70, M *).

Preparation 24

N- (4-Morpholinocarbonylphenyl) -5-methoxy-8-nitro-1,2,3,4-1-ethoxydronaphthalene-2-carboxamide

A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.0 g, 4 mmol), toluene (20 mL),

N, N-dimethylformamide (10 drops) and thionyl chloride (1.5 mL, 20 mmol) were heated at 60 ° C for 1 h. The solvents were evaporated in vacuo and the residue dissolved in methylene chloride (20 mL) was added to the solution. 4-aminobenzoyl-morpholine (820 mg, 4 mmol) described by JP Devlin, Chem. Soc. Perkin Trans X, 830-884 (1975), and triethylamine (800 mg, 8 mmol) in methylene chloride (30 mL) at 5 ° C. After stirring at 20 ° C for 2 h, water is added and the organic phase is separated, dried and the solvent removed in vacuo. The oily residue was crystallized from diisopropyl ether / ethyl acetate to give 1.2 g (73% yield) of the title compound as crystals, m.p. 186-189 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 439 (20, M *).

Preparation 25

N- (Morpholinocarbonylphenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution of N- (4-morpholinocarbonylphenyl) -5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.3 g, 2.8 mmol) and sodium dithionite (2.0 g, 11 mmol) in N, N-dimethylformamide (20 mL) and water (2.5 mL) was heated at 85 ° C for 3 h. After cooling, the reaction mixture was partitioned between water and ethyl acetate, the phases separated and the organic phase The mixture was washed twice with water and evaporated in vacuo. The organic phase was dried and evaporated. The residue was treated with diisopropyl ether to give 310 mg (30% yield) of the title compound as crystals.

EIMS (70 eV) m / z (relative intensity) 409 (100, M &lt; + &gt;).

Preparation 26 • (R) -2-N, N-Dibenzylamino-5- (1-hydroxyethyl) -8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -5 -Bromo-2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (1.4 g, 2.8 mmol) was dissolved in freshly distilled tetrahydrofuran ( 100 mL), washed with a stream of argon and cooled to -78 ° C. To the solution was added tert-butyllithium (2.6 mL, 1.4 M solution in pentane, 3.7 mmol) and the reddish solution was stirred at ambient temperature for 10 min. Acetaldehyde (320 μΐ, 5.7 mmol) was added and the reaction mixture was stirred at -78 ° C for 10 min, at 0 ° C for 2 h and at room temperature for 10 min. The reaction was quenched with water and the solvent was evaporated in vacuo. The residue was partitioned between diethyl ether (100 mL) and 2M ammonium hydroxide solution (20 mL) and the aqueous phase was extracted with diethyl ether (20 mL). The combined organic layers were washed with brine (20 mL) and dried over magnesium sulfate. The solvent was evaporated to give 2.0 g of crude product. Purification by silica gel column chromatography using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 910 mg (68% yield) of the title compound as a yellowish foam.

ESI m / z (relative intensity) 470 (100, M + 1).

Preparation 27 (R) -2-Amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-dibenzylamino-5- ( 1-hydroxyethyl) -1,2,3,460

• to to · to ·

it to this · this • · · *

-tetrahydronaphthalene (1.6 g, 3.4 mmol) was dissolved in acetic acid (80 mL) and stirred at 100 ° C for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in methanol (150 mL). . 10% Palladium on charcoal (600 mg) was added and the solution was purged with a stream of nitrogen. To the solution was added ammonium formate (1.7 g, 28 mmol) and the reaction mixture was stirred at 65 ° C for 2 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1.3 g of crude product. The residue was partitioned between methylene chloride (120 mL) and 2M ammonium hydroxide solution (30 mL). The organic phase was washed with brine (20 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 740 mg (79% yield) of the title compound as a white semicrystalline solid.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 273 (24, M ¹ ).

Preparation 28 (R) -N- [8- (4-Methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide

To an ice-cold solution of (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-naphthalene (110 mg, 0.44 mmol) and triethylamine (91 μΐ, 0, 66 mmol) in methylene chloride (20 mL) was added 4- (trifluoromethyl) benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 mL) dropwise. After the addition, the reaction mixture was stirred at ambient temperature for 15 min and then washed with dilute aqueous sodium bicarbonate solution. The phases were separated and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product, which was purified on a silica gel column using ammonia saturated chloroform / ethanol (100: 2) as eluent. The yield of the title compound as white solid crystals, m.p. 202-204 ° C, was 150 mg (81%).

[ ^α] D 20 -20 ° (c 1.0, chloroform).

EIMS mass spectrometry (70eV) m / z (relative intensity) 417 (10, M ¹ ).

Preparation 29 (R) -2-N, N-Dibenzylamino-5-hydroxymethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -5-Bromo-2-N N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (800 mg, 1.6 mmol) was dissolved in freshly distilled tetrahydrofuran (80 mL), washed with a stream of argon and cooled to -78 ° C. To the solution was added tert-butyllithium (1.5 mL, 1.4 M solution in pentane,

2.1 mmol) and the reaction mixture is stirred at ambient temperature for 10 min. Methyl chloroformate (250 μΐ, 3.2 mmol) was added and the reaction mixture was stirred at -78 ° C for 50 min and at 0 ° C for 1 h. The reaction was quenched with water and the solvent was evaporated in vacuo. The residue was partitioned between diethyl ether (90 mL) and 2M ammonium hydroxide solution (15 mL). The organic layer was washed with brine (10 mL) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 770 mg of crude product. Purification by silica gel column chromatography using chloroform / methanol / concentrated ammonium hydroxide (250: 5: 0.5) as the eluent afforded 610 mg of (R) -5-carboxymethyl-2-

-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (containing 13% of the corresponding analogue hydrogenated at the 5-position) as a yellowish oil.

EIMS (70 eV) m / z (relative intensity) 483 (1, M *).

The methyl ester (610 mg, 1.1 mmol) was dissolved in freshly distilled tetrahydrofuran (35 mL) and lithium aluminum hydride (120 mg, 3.1 mmol) was added. The reaction mixture was stirred at 45 ° C for 2 h followed by cooling to room temperature. The reaction is terminated by the addition of water (120 μΐ), 15% sodium hydroxide (120 μ.1) and water (240 μΐ) and the suspension is stirred at room temperature for 2.5 h. yielding 730 mg of crude product. Purification by silica gel column chromatography using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 360 mg (50% yield) of the title compound as a white foam.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 455 (1, M ⁺ ).

[α] ²³ D + 44 ° (c 0.12, chloroform).

Preparation 30 (R) -2-Amino-5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (R) -2-N, N-Dibenzylamino-5-hydroxymethyl -8- (4-methyl-9)

9

0 9 9 • 9 • 0 0 * 9 4 0 · 9 * · * • 00 * 4 9 099 94 0

09 · «909

900 09099 (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (360 mg, 0.78 mmol) was dissolved in methanol (35 mL), palladium (10%) on charcoal was added (170 mg) and the solution was purged with a stream of nitrogen. To the solution was added ammonium formate (390 mg, 6.2 mmol) and the reaction mixture was stirred at 65 ° C for 13 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 220 mg of a residue. The crude hydroxymethyl compound was dissolved in acetic acid (25 mL), 10% palladium on charcoal (60 mg) was added and the solution was purged with a stream of hydrogen. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 4 h. The catalyst was filtered off and additional 10% palladium on charcoal (160 mg) was added followed by hydrogenation at room temperature and atmospheric pressure for 24 h. the solvent was evaporated in vacuo. The residue was partitioned between diethyl ether (70 mL) and concentrated ammonium hydroxide solution, and the organic phase was washed with brine (5 mL). The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 120 mg (61% yield) of the title compound as a white semicrystalline solid.

EIMS m / z (relative intensity) 259 (20, M &lt; + &gt;).

[α] ²¹ D -1 ° (c 0.09, chloroform).

Preparation 31 (S) -3-N, N-Dibenzylamino-5-methoxy-3,4-dihydro-2 H -1-benzopyran hydrochloride (S) -3-Amino-5-methoxy-3,4-dihydro-2 H -1 -benzopyran · fefe (45 g, 0.25 mol) as described in WO 93/07135, potassium carbonate (120 g, 0.87 mol) and benzyl bromide (65 mL, 0.55 mol) were combined in acetonitrile (1000 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 45 h. The mixture was filtered and the solvent was evaporated in vacuo and the residue partitioned between diethyl ether and aqueous saturated sodium chloride solution. The layers were separated and the organic phase was dried over magnesium sulfate and filtered, followed by precipitation of the hydrochloride at room temperature. Yield: 99 g (99%). The analytical sample is converted to base.

[a] ²³ _'e> + 116 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 359 (28, M @ +).

Preparation 32 (S) -3-N, N-Dibenzylamino-5-hydroxy-3,4-dihydro-2 H -1-benzopyran (S) -3-N, N-Dibenzylamino-5-methoxy-3,4-dihydro -2H-1-benzopyran hydrochloride (67 g, 0.17 mol) was dissolved in methylene chloride (500 mL) under nitrogen and the solution was cooled to -75 ° C. Boron tribromide (32 mL, 0.34 mol) was added dropwise over 5 min. The temperature was then allowed to slowly reach +5 ° C and the reaction mixture was stirred overnight. The reaction was slowly quenched by the addition of 2M aqueous ammonium hydroxide solution with stirring. The layers were separated and the aqueous phase was extracted twice with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give a brownish oily residue which was purified by silica gel column chromatography. eluting with methylene chloride. The yield of the title compound was 50 g (86%).

[α] ²¹ D + 109 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 345 (5, M *).

Preparation 33 (S) -2- (3, N, N-Dibenzylamino-3,4-dihydro-2 H -1-benzopyran-5-yloxy) -2-methylpropanamide (S) -3-N, N-Dibenzylamino-5 -hydroxy-3,4-dihydro-2H-1-benzopyran (50 g, 0.14 mol) was dissolved in anhydrous

1,4-dioxane (450 mL) under nitrogen. Sodium hydride (60-65% dispersion in oil, 6.1 g,

0.15 mol). The mixture was stirred for 1 h at room temperature. To the dark green solution was added 2-bromo-2-methylpropanamide [24 g, 0.14 mol, I.G. Coutts, M.R. J. Southcott,

J. Chem. Soc. Perkin Trans. 1, 767-771 (1990)]. and the mixture was refluxed with stirring for 3 h. Additional sodium hydride (60-65% suspension in oil, 2.8 g, 70 mmol) and 2-bromo-2-methylpropanamide (4.6) were added portionwise. g, 28 mmol) and heating at 60 ° C was continued for 17 h. After cooling, a small amount of methanol (10 mL) was added and the solution was filtered and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a brownish residue which was recrystallized from ethyl acetate / hexane. The yield of the white solid according to the heading is «9 ·· 9« • 444 9 4

4 4 9 · ·· ♦ 94 4

4494 44 44

44

4 4 4 9

444 4 44 ·

4 <9 9

4 · 4 ·

4 4 4 · 4 4 g (71%) and has a melting point of 133-134 ° C.

[a] ² ^ + 99 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 430 (9, M ^& lt ^{; +} & gt ^; ).

Preparation 34 (S) -5-Amino-3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran

To a solution of (S) -2- (3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yloxy) -2-methylpropanamide (46 g, 0.11 mol) in anhydrous N, N-dimethylformamide (450 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (45 ml) are added portionwise to sodium hydride (60-65% suspension in oil). , 5 g,

0.21 mol) under nitrogen. The reaction mixture was heated to 110 ° C with stirring for 13 h. Then the mixture was allowed to cool and the solution was partitioned between ethyl acetate (400 mL) and 2M sodium hydroxide solution (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were dried over magnesium sulfate and evaporated in vacuo to give a brownish oil.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 430 (3, M *).

The obtained material (0.11 mol) was dissolved in ethanol (350 ml). 6M hydrochloric acid solution (250 ml) was added and the reaction mixture was refluxed for 16 h. After stirring, the mixture was allowed to cool to 35 ° C, the ethanol solvent was evaporated in vacuo and ethyl acetate was added to the aqueous residues. The mixture was cooled on ice and slowly stirred with stirring

67 • 9

9 99 9999

9 9 9 9 9 9

9

99999 9 999 99 9 9 9 99 9 9 adds concentrated ammonium hydroxide solution. The layers were separated and the aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo to give a brownish oil which was purified on a short silica gel column (eluting with hexane / ethyl acetate, 8: 2) to give 25 g (68% yield) of the title compound as light oily liquid. The product slowly crystallizes on standing in the refrigerator. An analytical sample was recrystallized from diethyl ether / petroleum ether, m.p. 101-103 ° C.

[α] ² D + 123 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 344 (17, M ^-4 ).

Preparation 35 (S) -1 (3-N, N-Dibenzylamino-3,4-dihydro-2 H -1-benzopyran-5-yl) -4-methylpiperazine-2,6-dione

To a dispersion of N-methyliminodiacetic acid (6.90 g, 46.9 mmol) in anhydrous tetrahydrofuran (575 mL) was added 1,1'-carbonyldiimidazole (15.2 g, 93.9 mmol) and the mixture was heated to reflux. for 2 h under a nitrogen atmosphere. A solution of (S) -5-amino-3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran (15.0 g, 42.7 mmol) in tetrahydrofuran (120 mL) was added with stirring The reaction mixture was refluxed for 28 h, then allowed to cool and the solvent was evaporated in vacuo. The residue was purified on a short silica gel column (eluent: methylene chloride and ethyl acetate) to give 14.1 g (71% yield) of the title compound as a yellow solid from a sintering temperature > 60 ° C.

+ 89 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) (relative intensity) 455 (8, M ⁺ ).

Preparation 36 (S) -3-N, N-Dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran

To a stirred solution of (S) -1- (3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yl) -4-methylpiperazine-2,6-dione (25.4 g, 55.8 mmol) in anhydrous diethyl ether (800 mL) was added portionwise lithium aluminum hydride (9.30 g, 246 mmol). The reaction mixture was refluxed for 6.5 h under nitrogen and stirred overnight at room temperature. The mixture was cooled in an ice bath and water (10 mL) was added followed by a 15% aqueous sodium hydroxide solution (10 mL) and an additional portion of water (30 mL). The precipitate was filtered off and washed with several portions of warm tetrahydrofuran. The organic layers were combined and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform / ethanol 95: 5 + 0.5% ammonium hydroxide) to give 13.6 g (yield 57%) of the title compound as a pale yellow oil.

[α] ²¹ D + 63 ° (c 1.0, methanol).

EIMS (70 eV) m / z (relative intensity) 427 (5, M &lt; + &gt;).

It to this it to it it to it it to it ··

Preparation 37 (S) -3-Amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran

To a solution of (S) -3-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (2.6 g, 6.2 mmol) in anhydrous of methanol (100 mL) was added palladium (10%) on charcoal (0.97 g) and ammonium formate (3.1 g, mmol) under a nitrogen atmosphere. Heat the reaction mixture to ° C with stirring overnight. The solution was filtered through Celite * ¹ and the solvent evaporated in vacuo. The residue was partitioned between 2M ammonium hydroxide solution (20 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo to give 1.4 g (89% yield) of the title compound as a pale yellow oil.

[α] ²¹ D -15 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 247 (74, M *).

Preparation 38

4- (4-Piperidon-1-yl) benzoic acid

2M sodium hydroxide solution (10 mL) of 3- (8-aza-1,4-dioxaspiro [4.5] dec-8-yl) benzonitrile [820 mg, 3.36 mmol, described in EC Taylor and JS Skotnicki, Synthesis , £, 606-608 (1981)] and ethanol (7.5 mL) are refluxed for 3 h. External heating is discontinued and the reaction

4444 • 44

4 4 4 4 444 44 4 444 44 4 444 44444

4444 44 44 444 44 44 the mixture was stirred at room temperature overnight. The ethanol solvent was evaporated in vacuo and the residue acidified to pH 4 with a 2M hydrochloric acid solution followed by extraction with ethyl acetate (50 mL). The layers were separated and the pH was adjusted to 6 with 2M sodium hydroxide solution followed by extraction with ethyl acetate (50 mL). The combined organic layers were evaporated in vacuo and the solid residue was dissolved in 6M hydrochloric acid solution (10 mL). Heat the reaction mixture at 75 ° C for 2.5 h and then at 55 ° C overnight. The temperature was raised to 75 ° C for 2 h and then allowed to cool. The pH was adjusted to 4 and the solution was extracted with ethyl acetate (50 mL). The layers were separated and further extraction was performed at pH 5. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was recrystallized from ethyl acetate to give 300 mg (41% yield) of the title compound as yellowish crystals having a sintering temperature> 215 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 219 (100, M *).

Preparation 39 (S) -3-N, N-Dibenzylamino-8-iodo-5- (4-methylpiperazin-1-yl-3,4-dihydro-2 H -1-benzopyrah (S) -3-N, N- Dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzo-1-pyran (6.9 g, 16 mmol) and sodium acetate (1.5 g, 18 mmol) Dissolve in acetic acid (430 mL), add iodine chloride (18 mL, 1M solution, 18 mmol) and stir the reaction mixture at room temperature protected from light for 24 h. 5 ml, 1M solution, 2.5 mmol) followed by stirring for this to this. · • ··· ·· · ··· ····················································

h. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride (800 mL) and 2M sodium hydroxide solution (120 mL). The aqueous phase was extracted with methylene chloride (100 mL) and the combined organic layers were washed with sodium chloride (2 x 100 mL) and dried over magnesium sulfate. Evaporation of the solvent gave 8.6 g of crude product. Purification by silica gel column chromatography using ethyl acetate / ethanol (saturated with ammonia) (25: 1) as eluent gave 4.1 g (43% yield) of the title compound (containing about 7% of the starting material) as a yellowish solid .

EIMS mass spectrometry (70eV) m / z (relative intensity) 553 (15, M ⁺ ).

This product was used in the next step without further purification attempts.

Preparation 40 (S) -8-Carboxymethyl-3-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran (S) -3-N, N Dibenzylamino-8-iodo-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (2.6 g, 4.8 mmol) was dissolved in Ν, Ν-dimethylformamide ( 100 ml) and washed with a carbon monoxide stream. Palladium acetate (110 mg, 0.48 mmol), 1,3-bis (diphenylphosphino) propane (200 mg, 0.48 mmol), methanol (25 mL), and triethylamine (3.3 mL, 24 mmol) were added to the solution. ). The mixture was allowed to react with carbon monoxide at 90 ° C and atmospheric pressure for 8 h. The solution was filtered and the solvent was evaporated. The residue evaporates together with xy00 0000 · 0 · 0 000

0

0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

The reaction mixture was partitioned between methylene chloride (300 mL) and 2M ammonium hydroxide solution (50 mL). The aqueous phase was extracted with methylene chloride (50 mL) and the combined organic layers were washed with brine (2 x 50 mL) and dried over magnesium sulfate. The solvent was evaporated to give 4.0 g of crude product. Purification by silica gel column chromatography using methylene chloride / ethanol (saturated with ammonia) (50: 1) as eluent gave 1.7 g (yield 68%) of the title compound (containing about 5% of the corresponding 8-H analog) as a yellowish solids.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 485 (8, M *).

This product is used in the next step without further purification efforts.

Preparation 41 (S) -3-N, N-Dibenzylamino-8-hydroxymethyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran (S) -8-Carboxymethyl-3 -N, N-dibenzylamino-5- (methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (490 mg, 1.0 mmol) was dissolved in dry tetrahydrofuran (40 mL) and added portion-wise. lithium aluminum hydride (76 mg, 2.0 mmol) was added. The reaction mixture was stirred at 45 ° C for 4 h and cooled to room temperature. The reaction is terminated by the addition of water (76 μΐ), 15% sodium hydroxide (76 μΐ) and water (225 μΐ) and the mixture is stirred for 18 h. The white precipitate is filtered off and the solution is dried over magnesium sulfate. Evaporate the solvent in vacuo to give 520 mg of crude fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fefe fe fefe · fefe · fe · fefe · fe fefe product. Purification by column chromatography on silica gel using chloroform / ethanol (saturated with ammonia) (15: 1) as eluent afforded 390 mg (85% yield) of the title compound containing about 8% of the corresponding analog with the methyl group at the 8-position as yellowish oil.

EIMS (70 eV) m / z (relative intensity) 457 (15, M ^& lt ^{; +} & gt ^; ).

Preparation 42 (S) -3-Amino-8-methyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran (S) -3-N, N-Dibenzylamino-8 -hydroxymethyl-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (420 mg, 0.90 mmol) was dissolved in methanol (60 mL) and ammonium formate (460) was added. mg, 7.3 mmol). The solution was purged with a stream of nitrogen and palladium on charcoal (120 mg, 10%) was added. The reaction mixture was stirred at 50 ° C for 16 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 260 mg of crude product. The residue was dissolved in acetic acid (50 mL) and palladium on charcoal (120 mg, 10%) was added. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 46 h. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (120 mL) and 2M sodium hydroxide solution (10 mL) and the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate and the solvent was evaporated in vacuo to give 200 mg of crude product. Purification by thin-layer prep silica gel chromatography eluting with chloroform / ethanol (saturated with ammonia) (10: 1) afforded 150 mg (64% yield) of the title compound as an oily liquid.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 261 (100, M *).

Preparation 43

8-Methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester

To a stirred solution of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester [5.5 g, 23 mmol, described by S.O. Thorberg et al., Acta Pharm. Suec.

24. 169-182 (1987)] in methylene chloride (50 mL) was added dropwise 65% nitric acid (2.0 mL) at 0 ° C. The solution was stirred at room temperature for 2 h and washed with water. The organic phase was dried and the solvent was evaporated in vacuo. The residue was treated with diisopropyl ether (30 mL) and ethyl acetate (5 mL) to give 1.5 g (5.3 mmol) of 6-nitroisomer crystals. The mother liquor was purified by column chromatography using diisopropyl ether as eluent to give 1.3 g (20% yield) of the title compound, mp 66-68 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 281 (100, M *).

Preparation 44

8-Methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid • 0

0000 0 0 «00

0000 00 «acid

A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in ethanol (150 mL) and 2M sodium hydroxide solution (15 mL) is refluxed for 30 min. The solvent was evaporated in vacuo and the residue was dissolved in water. Acidification to pH 2 and extraction with ethyl acetate followed by evaporation of the solvent in vacuo gave 4.9 g (94% yield) of the title compound, mp 181-183 ° C.

EIMS (70eV) m / z (relative intensity) 253 (55, M ^& lt ^{; +} & gt ^; ).

Preparation 45

N- [4- (4-Morpholinyl) phenyl] -8-methoxy-5-nitro-3,4-dihydro-2 H -1-benzopyran-3-carboxamide

To a solution of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.5 g, 10 mmol) in toluene (40 mL) and N, N-dimethylformamide (1 mL) Thionyl chloride (3.6 mL, 50 mmol) was added. The reaction mixture was refluxed for 2 h and the solvent was evaporated in vacuo. The remaining acid chloride was added to a solution of 4- (1-morpholino) aniline [1.78 g, 10 mmol, described by J. P. Devlin et al., J. Chem. Soc. Perkin Trans., 1, 830-841 (1975)] and triethylamine (2.0 g, 20 mmol) in methylene chloride (30 mL) and stirred at 0 ° C for 10 min and at room temperature for 1 h The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with 2M sodium hydroxide solution. Evaporation of the solvent in vacuo gave 1.5 g (36% yield) of the title compound as white crystals, mp 238-240 ° C.

EIMS (70 eV) m / z (relative intensity) 413 (5, M ^& lt ^{; +} & gt ^; ).

Preparation 46

N- [4- (4-Morpholinyl) phenyl] -5-amino-8-methoxy-3,4-dihydro-2 H -1-benzopyran-3-carboxamide

To a solution of N- [4- (4-morpholinyl) phenyl] -8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxamide (1.2 g,

A solution of sodium dithionite (2.1 g, 12 mmol) in water (5 mL) was added in Ν, Ν-dimethylformamide (10 mL). The mixture was stirred at 55 ° C for 3 h and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate as eluent to give 273 mg of the title compound (yield 55%).

EIMS (70 eV) m / z (relative intensity) 383 (100, M &lt; + &gt;).

Preparation of the disclosed 5-Β _{χΒ antagonists}

Example 1 (R) -N- [8- (Piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

To an ice-cold solution of (R) -N- [8- (4-tert-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinophenylcarboxamide (1.0 g, 2 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (3 mL). The reaction mixture is stirred at ambient temperature for 7 h. The solvent is evaporated in vacuo and the residue is dissolved in water. (20 mL), basified with 2M aqueous sodium hydroxide solution and extracted twice with methylene chloride. The phases were separated, the combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 580 mg (70% yield) of the title compound as white crystals, mp 202-203 ° C.

[α] ²¹ D -56 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 420 (5, M *).

Example 2 (R) -N- [8- (4-Ethylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

To a solution of (R) -N- [8- (Piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (90 mg, 0.21 mmol) in acetone (20 mL). Potassium carbonate (44 mg, 0.32 mmol) and iodoethane (26 μΐ, 0.32 mmol) were added and the reaction stirred for 48 h at ambient temperature. The reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was partitioned between methylene chloride and water, the phases were separated and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using ammonia saturated chloroform / ethanol (100: 3) as eluent gave 63 mg (66% yield) of the title compound as white crystals, mp 204-206 ° C.

[Α] ²¹ <-67 ° (c 1.0, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 448 (21, M *).

Example 3 (R) -N- [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

To a solution of 4-morpholinobenzoic acid [0.92 g, 4.5 mmol, described by J. Degutis, L. Rasteikiene, A. Degutiene, Zh. Org. Khim., 14, 2060-2064 (1978)] in anhydrous N, N-dimethylformamide (75 mL) was added 1,1'-carbonyldiimidazole (0.76 g, 4.8 mmol) and the reaction mixture was boiled at 75 ° C. When carbon dioxide evolution ceased (after 45 min), the reaction mixture was cooled to room temperature and (R) -2-amino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3 was added. 4-tetrahydronaphthalene (1.2 g, 4.2 mmol) dissolved in anhydrous N, N-dimethylformamide (20 mL). The reaction mixture was stirred at ambient temperature for 48 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (180: 5: 0.5) as eluent followed by recrystallization from ethyl acetate with a few drops of ethanol gave 1.0 g (yield 53%) of white crystals of melting point. Mp 237-238 ° C.

[α] ²¹ D -40 ° (c = 1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 464 (5, M +).

• it

999 · * 9 · 9 9 • · · · to to to to to to to 9

Example 4 (R) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

4-Morpholinobenzoic acid (64 mg, 0.31 mmol) was dissolved in dry N, N-dimethylformamide (1 mL) and 1,1'-carbonyldiimidazole (52 mg, 0.32 mmol) was added. The reaction mixture was stirred at 75 ° C for 1h and cooled to room temperature. Add a solution of (R) -2-amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (80 mg, 0.29 mmol) in dry Ν, Of Ν-dimethylformamide (3 mL) and the reaction mixture was stirred at room temperature for 14 h. The solvent was evaporated and the residue was dried in vacuo. The crude product was purified by preparative thin layer silica gel chromatography using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent to give 85 mg (yield 59%) of the title compound as a white solid mp 234 ° C (dec.).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 462 (27, M *).

[α] ²³ D -48 ° (c 0.09, chloroform).

Example 5 (R) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] - (4-morpholinocarbonyl) benzamide

4-Morpholinocarbonylbenzoic acid [180 mg, 0.77 mmol, described in J. Med. Chem., 37, 4538-4554 (1994)] and this to this. · ·· ·· ··· ··

1,1 ¹ -carbonyldiimidazole (130 mg, 0.80 mmol) was dissolved in dry Ν, Ν-dimethylformamide (3 ml) and the mixture was stirred at 75 ^P C for 2 h. After cooling to room temperature, a solution of (R) -2-amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3, -tetrahydronaphthalene (200 mg, 0.73 mmol) in dry N, Nd | The solvent was evaporated in vacuo and the residue was partitioned between t-ethylene chloride (60 mL) and 2M ammonium hydroxide solution (5 mL). The organic phase was washed with brine (10 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded 360 mg of crude product. Purification on a silica gel column using chloroform / methanol / / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 240 mg (65% yield) of the title compound as a white solid, mp 213-214 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 490 (27, M *).

[α] -28 ° (c 0.15, chloroform).

Example, 6 (R) -Nt [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide

The title compound was prepared from (R) -2-amino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene according to the general preparation method 16. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (96: 4: 0.3) as the eluent afforded 93 mg (52% yield) of white crystals after recrystallization from ethyl acetate / diethyl ether. * * 000 * 0 0 ·· ··· M.p. 209 DEG-210 DEG.

[α] ²¹ D -18 ° (c = 1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 492 (36, M @ +).

Example 7 (R) -N- [5-Bromo-8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

To an ice-cold solution of (R) -N- [5-bromo-8- (4-tert-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (150 mg) Trifluoracetic acid (0.7 mL) was added in methylene chloride (20 mL). The reaction mixture was stirred at ambient temperature for 20 h. The solvent was evaporated in vacuo and the residue was dissolved in water (20 mL), basified with 2M aqueous sodium hydroxide solution and extracted with methylene chloride. The phases are separated and the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (90: 10: 1) as eluent to give white crystals, mp 228-229 ° C, yield 94 mg (72%).

-6 ° (c = 1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 498 and 500 (1.5, M *).

Example 8 4444 (R) -N- [5-Bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

The title compound was prepared from (R) -2-amino-5-bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene according to the general preparation method 16. Purification on a silica gel column elution with chloroform / methanol / / concentrated ammonium hydroxide (95: 5: 1) gave 100 mg (62% yield) of white crystals, mp 245-246 ° C.

[a] ^{2: l} D -23 ° (c = l, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 512 and 514 (1, M *).

Example 9 (R) -N- [5-Bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide (R) -N- [ 8- (4-Methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide (80 mg, 0.19 mmol) and sodium acetate (200 mg) were dissolved in acetic acid ( 3 ml) and the mixture was stirred at room temperature. To the reaction mixture was added bromine (34 mg, 0.21 mmol) dropwise and the mixture was stirred for 2 h at ambient temperature. 2M Sodium hydroxide solution (100 ml) was added and the mixture was extracted with diethyl ether (2 x 50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using ammonia saturated methylene chloride / ethanol (94: 6) as the eluent afforded 80 mg (85% yield) of the title compound as a white solid. Fefe fefe fefe fe fefefefe M.p. 229 DEG-230 DEG C. m.p.

[α] ²³ D -5.5 ° (c = 1, chloroform).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 495 and 497 (3, M *).

Example 10 (R) -N- [5-Methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

4-Morpholinobenzoic acid (92 mg, 0.44 mmol) was dissolved in dry N, N-dimethylformamide (2 mL) and purged with a stream of nitrogen. To the solution was added 1,1'-carbonyldiimidazole (76 mg, 0.47 mmol) and the reaction mixture was stirred at 75 ° C for 1.5 h. The solution was cooled to room temperature and (R) -2 was added. -amino-5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.42 mmol) dissolved in dry N, N-dimethylformamide (2 mL). The solution was stirred at room temperature for 30 h. The solvent was evaporated in vacuo to give 290 mg of crude product. Purification by preparative thin layer silica gel chromatography eluting with chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) afforded 145 mg (yield 73%) of the title compound as a white solid, mp > 231 ° C (dec.).

EIMS (70eV) m / z (relative intensity) 448 (3, M *).

²¹

-60 ° (c 0.15, chloroform).

0 · * 090 ··

Example 11

N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution of N- (4-morpholinophenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.4 g, 3.5 mmol), bis (2-chloroethyl) -methylamine hydrochloride (960 mg, 5 mmol) and sodium bicarbonate (420 mg, 5 mmol) in n-butanol (30 mL) was heated at 90 ° C for 5 h. After cooling, a 2M solution of ammonium hydroxide (30 mL) was added. The mixture is heated at 50 ° C for 1 h. The phases are separated, evaporated in vacuo and purified by silica gel flash chromatography using chloroform / ethanol / concentrated ammonium hydroxide (90: 10: 0.3) as eluent. The title compound is obtained, m.p. 230-232 ° C, yield 320 mg (20%).

EIMS mass spectrometry (70 eV) m / z (relative intensity) 464 (75, M *).

Chromatographic preparation of N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide enantiomer

N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (5 mg) was dissolved in 4 ml of eluent containing acetonitrile and phosphate buffer. pH 3.0, μ = 0.1 (volume ratio 62.5: 37.5). This solution was purified on a Nucleosil 7 C _{= 1s} (25 x 250 mm) column with the mobile phase described above to remove later eluting impurities. The fractions of the main constituent are collected. . . · *. - ··········· ··· · »·.

• Evaporate under reduced pressure. • Evaporate under reduced pressure. at a temperature of 35 to 39 ° C. The residue was dissolved in 30 mL of 10 mM ammonium acetate solution, diethylamine and acetic acid (4000 + 2 + 2, pH 5.26) and chiral semipreparation of the N- (4-morpholinophenyl) -8- ( 4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide on a Chiral AGP semiprep column (10 x 150 mm) using a protective column of the same stationary phase. The flow rate is 2.0 ml / min and detection is performed at 260 nm. The fractions of the two enantiomers were collected separately and evaporated to a volume of about 5 ml at 35-39 ° C under reduced pressure. The pH of the concentrated fractions was adjusted to 10-11 with 5M sodium hydroxide solution followed by extraction with chloroform. The two phases are washed with water and dried over anhydrous magnesium sulfate. After filtering with glass wool, the organic filtrates were evaporated in vacuo to give both enantiomers as two faintly yellow solids.

Example 12

N- (Morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide

A solution of N- (morpholinocarbonylphenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (280 mg, 0.69 mmol), bis (2-chloroethyl) methylamine hydrochloride (190 mg, 1 , 0 mmol) and sodium bicarbonate (84 mg, 1.0 mmol) in n-butanol (20 mL) was boiled at 90 ° C for 5 h. After cooling, 2M ammonium hydroxide solution (10 mL) was added and the mixture The organic phase is evaporated in vacuo and the residue is purified by silica gel flash column chromatography using chloroform / ethanol / concentrated ammonium hydroxide (90: 10: 0.5) as eluent. to obtain 60 mg (18%) of the title compound.

^; * ·: ··%::; :

• 9

EIMS mass spectrometry (70 eV) m / z (relative intensity) 492 (50, M *).

Example 13 (S) -N- [5- (4-Methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-morpholinobenzamide

4-Morpholinobenzoic acid solution [380 mg, 1.83 mmol, described in J. Degutis, L. Rasteikiene, A. Degutiene,

Zh. Org. Khim., 14, 2060-2064 (1978)] and 1,1 ¹ -carbonyldiimidazole (310 mg, 1.92 mmol) in anhydrous

N, N-dimethylformamide (12 mL) was stirred at 75 ° C for 30 min. The mixture was allowed to cool and then a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (430 mg, 1.74 mmol) in Ν, Ν-dimethylformamide (8 mL). The reaction mixture was stirred at room temperature for

d. Add an additional 1,1 ^L- carbonyldiimidazole (57 mg,

The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform / ethanol, 93: 7 + 0.5% ammonium hydroxide) to give a solid. to give 513 mg (yield 68%) of the title compound as a white solid, mp 210-212 ° C.

[A;] ^{2: L} D -145 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 436 (65, M ^& lt ^{; +} & gt ^; ).

Example 14

• · · ·

0 0 0 0 0 0 0

(S) -N- [5- (4-Methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) -benzamide

A solution of 1,1'-carbonyldiimidazole (116 mg, 0.716 mmol) and 4- (4-piperidon-1-yl) benzoic acid (150 mg, 0.683 mmol) in anhydrous N, N-dimethylformamide (5 mL) was stirred at 75 ° C for 50 min. The mixture was allowed to cool and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (161 mg, 0.651 mmol) in N, N was added. dimethylformamide (4 mL). The reaction mixture was stirred at room temperature for 8 d. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform / ethanol, 90:10 + 0.5% concentrated ammonium hydroxide) to give 54 mg ( yield 19%) of the title compound as a white solid, m.p. 222-225 ° C (dec.).

[α] -136 ° (c 0.30, chloroform).

TSPMS (70eV) m / z 449 (M + 1).

Example 15 (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide

4- (dimethylaminocarbonyl) benzoic acid (AT Jurewicz, U.S. Patent 3,607,918, 1971) (38 mg, 0.20 mmol) and 1,1'-carbonyldiimidazole (34 mg, 0.21 mmol) are dissolved in dry N, N-dimethylformamide (4 mL) and stirred at 75 ° C for 1.5 h. The reaction mixture was cooled to room temperature and a solution of (S) -3-amino-8-methyl-5- (4-methylpiperazine) was added. -1-yl) -3,4-dihydro-2H-1-benzopyran (49 mg)

0.19 mmol) in dry Ν, Ν-dimethylformamide (5 mL). The reaction mixture was stirred at 50 ° C for 14 h and the solvent was evaporated in vacuo to give 120 mg of crude product. Purification by preparative thin layer chromatography using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 40 mg (48% yield) of the title compound as a white foam.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 436 (26, M *).

[α] ²³ - ^ -9 ° (c 0.20, chloroform).

Example 16

N- [4- (4-Morpholinyl) phenyl] -8-methoxy-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran-3-carboxamide

A solution of N- [4- (4-morpholinyl) phenyl] -5-amino-8-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxamide (270 mg, 0.7 mmol), bis (2 -chloroethyl) methylamine hydrochloride (288 mg,

1.5 mmol) and sodium bicarbonate (126 mg, 1.5 mmol) in n-butanol (10 mL) was stirred at 90 ° C for 2.5 h. A 2M solution of ammonium hydroxide (10 mL) was added at The mixture is cooled and the phases are separated. The organic phase was evaporated in vacuo and the residue was purified by silica gel column chromatography using ethyl acetate / triethylamine (100: 8) as eluent to give 170 mg (yield 50%) of the title compound as white crystals, m.p. 202-204. Deň: 32 ° C.

EIMS mass spectrometry (70 eV) m / z (relative intensity) 466 (100 M *).

• ·

Example 17 (R) -N- [8- (4-Methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide

To a solution of 4-morpholinobenzoic acid [0.89 g, 4.3 mmol, described in J. Degutis, L. Rasteikiene, A. Degutiene,

Zh. Org. Khim., 14, 2060-2064 (1978)] in anhydrous N, N-dimethylformamide (30 mL) was added 1,1-carbonyldiimidazole ^one (0.73 g, 4.3 mmol) and the reaction mixture was heated to 75 ° C. After carbon dioxide evolution ceased (after 30 min), the reaction mixture was cooled to room temperature and a solution of (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene was added. (1.0 g, 4.1 mmol) in anhydrous N, N-dimethylformamide (5 mL). The reaction mixture was stirred at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as eluent gave 1.5 g (85% yield) of the title compound as white crystals, m.p. 230-231 ° C. C.

[cd ^2X D -49 ° (c 1.0, chloroform).

EIMS (70 eV) m / z (relative intensity) 434 (10, M &lt; + &gt;).

Pharmacology

Test Methods (i) Functional Assay for h5-HT Receptors

A standard assay based on stimulation of [ ³ H] -5-HT release from guinea pig occipital cortex in an electric field can be used to evaluate antagonist properties for 5-ΗΤ _χΒ receptors.

Methods of execution and material

Buffer composition (mM)

Sodium bicarbonate (25), sodium dihydrogen phosphate monohydrate (1,2), sodium chloride (117), potassium chloride (6), magnesium sulfate heptahydrate (1,2), calcium chloride (1,3), ethylenediaminetetraacetic acid disodium salt (0) , 03). The buffer is saturated with an inert gas for at least 30 minutes before use. The pH of the buffer is 7.2 at room temperature, but rises to about 7.4 at 37 ° C.

Preparation of sections of occipital cortex

Guinea pigs (200-250 g) are decapitated and whole brains removed. Separate the occipital cortex and cut into 0.4 x 4 mm sections using an Mcllwain. The white tissue is carefully separated with tweezers before cutting. The sections are incubated in 5 ml of buffer in the presence of 5 mM pargyline chloride. After incubation with 0.1 mM [ ³ H] -5-HT solution for an additional 30 min, sections are transferred to a tube and washed three times with equal volume of buffer. Sections are transferred to superfusion chambers with a plastic pipette and washed for 40 min with buffer in the presence of citalopram uptake inhibitor (2.5 μΜ) at a flow rate of 0.5 ml / min.

Electrical stimulation of 5-HT release

The superfusion buffer was collected in 2 ml fractions. Sections are stimulated electrically by a 3 Hz pulse sequence, 2 ms duration and 30 mA current for 3 min at Fractions 4 and 13. Test drugs are added from fraction 8 until the end of the experiment.

Results

First stimulation by electric current (or potassium ions) resulted in a standard amount of [ ³ H] 5-HT (Sx) released. Between the first and second stimulations, the h5-HT antagonist is added to the medium, resulting in a dose-dependent increase in release (S2) during the second stimulation. The S2 / Sx ratio is the percentage of [ ³ H] 5-HT released on the second stimulation (S2) divided by the value for the first stimulation (S _x ) and is used to determine the effects of the drug on transmitter release. See Figure 1.

(ii) Effects of h5-HT _xB receptor antagonists / partial agonists in combination with SSRIs as measured by microdialysis in guinea pig brain

The effects of various ϊι5-ΗΤ _χΒ receptor antagonists in combination with a selective serotonin uptake inhibitor on extracellular levels of 5-HT in guinea pig frontal cortex are measured by microdialysis.

Male Dunkin Hartley guinea pigs (Charles River, Sweden) weighing 270-500 g are subjected to intramuscular anesthesia with a mixture of Rompun ³⁵¹ , veterinary formulation (20 mg / ml) and Ketalar ^R , veterinary formulation (50 mg / ml) in a 1: 3 by volume ratio. and placed in a stereotactic frame. A guiding cannula is carefully inserted into the frontal cortex using stereotactic coordinates for the bregma (the point on the skull surface at the junction of the coronal and sagittal seam used as a craniometric mark): AP +4.5 mm, L -2.0 mm and DV 0 mm from the surface brain. Animal fe fe · fe feefefe fe feefefe feefefe feefefefeefefefe

The fefe is allowed to recover for 2 to 3 days prior to the experiment. The day before the start of the dialysis sampling, microdialysis probes with 3 mm membranes are placed in the guiding cannula. These probes are washed with Ringer's solution at a flow rate of 2.0 μΐ / min and samples are taken every 20 min. Compound A (selective serotonin uptake inhibitor, SSRI) is administered at 0 min and compound B, C, D or E (h5-HT antagonist or saline) is administered 60 min later. All drugs are administered subcutaneously. The 5-HT content is analyzed by high performance liquid chromatography with electrochemical detection. For data analysis, the mean 5-HT values of three to four pre-drug samples are defined as 100% (baseline) and the following samples are expressed as a percentage of this value.

Results

Giant. 2 shows the effects of compound A in combination with compound B, C, D, or E on extracellular levels of 5-HT in guinea pig frontal cortex as measured by microdialysis. Data represent mean ± SD of n = 5-6. The arrows indicate drug administration.

Compound A: Citalopram

Compound B: (R) -N- [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl]] - 4-morpholinobenzamide

Compound C: Saline

Compound D: (R) -N- [8- (4-Methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide · ·· ♦ ··· ♦ 4 ·

Compound Ε: (R) -4- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide • *;; • •;;; .....

Dooo - do · dooo - dooo -

Claims (20)

PATENT CLAIMS Combination of a first component (a) which is an inhibitor of 5-HT uptake, with a second component (b), which is a selective antagonist or partial agonist of h5-HT _{xs of the} general formula I in which: X is CH _and O, Y is CONH, NHCO, R _x is hydrogen, C _x -C _s alkyl, C ₃ -C _g cycloalkyl, R ₂ is hydrogen, C _x -C _g alkyl group C _x -C _s alkoxy, halogen, R is 3 ^J • · · · · · _ · _ (-C) - (O) -NO o-cf ₃ -C (O) NR ₄ R ₅ R and R are independently hydrogen or C-alkyl, in the form of a racemate, R-enantiomer or S-enantiomer, and these components (a) and (b) are in the form of the free bases, solvates or pharmaceutically acceptable salts thereof. A combination according to claim 1, wherein the second component (b) is a compound of formula I wherein X is CH ₂ . 3. The combination of claim 2, wherein the second component (b) is a compound of formula I wherein Y is NHCO. Combination according to claim 3, characterized in that the second component (b) is a compound of formula I in which R ₃ is a morpholino group. A combination according to any one of claims 1 to 4, wherein the second component (b) is a compound of formula I wherein R ₁ is hydrogen, methyl or ethyl and R ₂ is hydrogen; Methyl, ethyl, methoxy or bromo. The combination of claim 1, wherein the second component (b) is a compound selected from the following set of compounds: (R) -N- [8- (Piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-Ethylpiperazine) (1) -1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5-Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-Morpholinobenzamide, (R) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-1-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) ) -N- [5-Ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonyl) benzamide, (R) -N- [5] -Methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonyl) benzamide, (R) -N- [5-Bromo-8- (4-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5-Bromo-8- (4-methylpiperazin-1-yl)] ) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide • 9> 9 9 9 9 9 9 9 999 9 9 99 9 9 9 (R) -N- [5-Bromo-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide, (R) - N- [5-Methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- (4-Morpholinophenyl) -8- (4) (S) -N- (4-Morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; 3,4-tetrahydronaphthalene-2-carboxamide, (R) -N- (Morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, ( S) -N- [5- (4-Methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -morpholinobenzamide, (S) -N- [5- (4-Methyl-piperazine) -1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) benzamide, (S) -N- [8-Methyl-5- ( 4-methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide, N- [4- (4-Morpholinyl) phenyl] -8-methoxy-5- (4-methylpiperazin-1-yl) -3,4-dihydro-2 H -1-benzopyran-3-carboxamide Combination according to claim 6, characterized in that the second component (b) is a compound selected from • 9 • 4 4 0 • 4 0 * 44099 • 0 0044 • 0 4 • 4 · 0 9 • 4 0 • 4 49 cases of (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [5- methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and (R) -N- [5-methyl-8- [4-methylpiperazine] -1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide. Combination according to any one of claims 1 to 7, characterized in that the 5-HT uptake inhibitor is fluoxetine, paroxetine, citalopram, clomipramine, sertraline or fluvoxamine. Use of a combination according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of affective disorders. Use of a combination according to claim 9 for the preparation of a medicament for the treatment of depression. A method of treating affective disorders, comprising administering to a patient suffering from them a combination as defined in any one of claims 1 to 8. 12. A method of treating depression, comprising administering to a patient suffering from depression a combination as defined in any one of claims 1 to 8. A pharmaceutical composition, characterized in that its active ingredients are a combination as defined in any one of claims 1 to 8, optionally in conjunction with adjuvants, diluents, excipients and / or inert carriers. Pharmaceutical composition according to claim 13, characterized in that the first component (a) is administered simultaneously with the second component (b). A pharmaceutical composition according to any one of claims 13 to 14 for use in the treatment of affective disorders. The pharmaceutical composition of claim 15 for use in the treatment of depression. A method of preparing a combination according to claim 1, wherein the 5-HT uptake inhibitor as defined in any one of claims 1 or 8 is included in the same pharmaceutical composition as a selective 5-Β _χΒ antagonist or partial agonist as defined in any one of claims 1 to 7. A method of preparing a combination according to claim 1, wherein the 5-HT uptake inhibitor as defined in any one of claims 1 or 8 is incorporated into one pharmaceutical composition and the selective antagonist or partial agonist as defined in any one of claims 1 to 7 is in another pharmaceutical composition. A kit comprising a combination of a first component (a) that is a 5-HT uptake inhibitor as defined in any one of claims 1 or 8 and a second component (b) that is a selective antagonist or partial agonist 5-ΗΤ _χΒ as defined in any one of claims 1 to 7, optionally together with instructions for use. 20. A method of improving the onset of therapeutic action, comprising administering at the same time a first component (a) which is an inhibitor of 5-HT uptake, such as