MXPA00002342A - Tetrahydro gamma-carbolines - Google Patents

Abstract

The present invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R1 is hydrogen, optionally substituted C1-6alkyl, aryl;R2 is each independently a halogen, hydroxy, C1-6alkyl, C1-6alkyloxy or nitro;n is 0, 1, 2 ou 3;Alk is C1-6alkanediyl;D is optionally substituted saturated or unsaturated nitrogen containing heterocycle;and aryl is optionally substituted phenyl;having a great therapeutic breadth. It further relates to their use as a medecine, their preparation as well as compositions containing them.

Description

TETRAHIDRO GAMMA-CARBOLINAS DESCRIPTIVE MEMORY The present invention relates to tetrahydro? -carbolines which have a broad therapeutic potential. It also refers to its preparation, compositions that contain them and their use as a medicine. The patent E.U.A. No. 4,636,563, published on January 13, 1987 and the patent E.U.A. No. 4,672,117, published June 9, 1987, describe 2- (heteroaryl-alkyl) -tetrahydro-carbolines having anti-psychotic activity. EP-A-0,705,823, published on April 10, 1996, describes 1, 2,3,4-tetrahydro-9 / - / - pyrid, 4-b] indolyl-alkyl-1,3-dihydro- 2 / - / - benzimidazolones as serotonergic modulators. The compounds of the present invention are novel and have an interesting broad spectrum receptor binding profile. In comparison with the structurally related compounds known, these surprisingly show a greater therapeutic amplitude. The present invention relates to compounds of the formula (l) The? / -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: R1 is hydrogen, Ci-β alkyl, aryl or C-? 6 alkyl substituted with aryl: R2 is each independently a halogen, hydroxy, C-? 6 alkyl, C-? 6 alkyloxy or nitro; n is 0, 1, 2, or 3; Alk is C-γ-6 alkanyl; D is 2 (3H) benzoxazolone-3-yl or a radical of the formula (a) (b) (c) (d) (e) (f) in which each X independently represents O, S or NR12; R 3 is hydrogen, C 6 alkyl, aryl or aryl alkyl Cr 6; J ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ R4 is hydrogen, C1-6alkyl, C alkyloxy, Cr6alkyl, amyl, mono- or di (C6-6alkyl,) amino or mono -o di (aryl-alkyl Cr6) amlno; R5, R6, R7, R10, R11 and R12 are each independently hydrogen or Cr6 alkyl; R8 and R9 are each independently hydrogen, C-? -6 alkyl, or aryl; or R4 and R5 taken together can form a bivalent radical -R4-R5- of the formula 'CH2-CH2-CH- (a-1); CH2-CH2-CH2-CH2- (a-2); CH = CH-CH2- (a-3); CH2-CH = CH- (a-4) or CH = CH-CH = CH- (a-5); wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) can each be independently replaced by halogen, C-? -6 alkyl, aryl-C? -alkyl, trifluoromethyl, amino , hydroxy, Ci-βalkyloxy, or C-β-10 alkylcarbonyloxy; or where it is possible, two gemomic hydrogen atoms can be replaced by Cr6 alkenylidene, or aryl-alkyllidene of C? -6, or -R4-R5- can also be -S-CH2-CH2- (a-6); -S-CH2-CH2-CH2- (a-7); - • * _. »G-sJfe» iCai ».

-S-CH = CH- (a-8); -NH = CH2-CH2- (a-9); -NH-CH2-CH2-CH2- (a-10); -NH-CH2 = CH- (a-11); -NH-CH = N- (a-12); S-CH = N- (a-13) or -CH = CH-0- (a-14); wherein one or wherever possible two or three hydrogen atoms in said radicals (a-6) to (a-14) can each be independently replaced by C 1 -β alkyl or aryl; and aryl is phenyl or phenyl substituted with a halogen or C-r alkyl 6. As used in the above definitions the term halogen is generic for fluoro, chloro, bromo and iodo. The term "C" alkyl-4 defines straight and branched saturated hydrocarbons, having from one to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2- methylproplex and the like. The term "C" alkyl-6 denotes that it includes C 1 -4 alkyl and higher homologs thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl, or the like. The term "Cpo alkyl" means that alkyl radicals of d-6 and higher homologs thereof having 7 to 10 carbon atoms are included such as, for example, heptyl, octyl, nonyl, decyl, and the like. The term "C 1-4 alkyndiyl" defines straight-chain or branched bivalent alkylene radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and similar; the term "C-rβ alkanediyl" means that C-α-4 alkanoyl and higher homologs thereof having 5 or 6 carbon atoms such as, for example, 1,5-pentandiyl, 1-6 are included. hexandiyl and the like; the term C alqu alkylidene defines bivalent straight or branched chain alkylidene radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethylidene, 1-propylidene, 1, butylidene, 1-pentylidene, 1-hexylidene and Similar. In addition, as used hereinafter, the term benzyl refers to phenylmethyl. Other names for the term? -carbolines are 5 - / - pyrido [4,3-b] indole, 3-azacarbazole and 3-azarbazole. The addition salts as mentioned herein means that they comprise the therapeutically active addition salts that the compounds of the formula (I) are capable of forming with the appropriate acids such as, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and similar acids; or organic acids such as, for example, acetic, propanic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p -amino-salicylic, pamico and similar acids.

The pharmaceutically acceptable addition salts as mentioned hereinbefore also mean that they comprise the non-toxic therapeutically active base, in particular, a metal addition or amine salt which the compounds of the formula (I) are capable of forming. Said salts can be conveniently obtained by treating the compounds of the formula (I) containing acidic hydrogen atoms with the appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali metal and alkaline earth metal salts, Examples are the salts of lithium, sodium, potassium, magnesium, calcium and the like, the salts with organic bases, for example the benzathine,? / - methyl-D-glucamine salts, the hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base. The term "addition salt" as used herein also comprises the solvates that the compounds of the formula (I) are capable of forming and said solvates are included within the scope of the present invention. Examples of such solvates are hydrates, alcoholates, and the like. The? / -oxide forms of the compounds of the formula (I) comprise those compounds of the formula (I) in which one or more nitrogen atoms are oxidized to the so-called? / -oxide. ,: 38k * £ * * A ^ j The term stereochemically isomeric forms as used herein defines all possible isomeric forms in which the compounds of formula (I) may be presented. Unless otherwise mentioned or otherwise indicated, the chemical designation of the compounds indicates the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Some of the compounds of the formula (I) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, are designed to be included within the scope of the present invention. Each time it is used hereinafter, the term compounds of the formula (I) is meant to include also the? / -oxide forms, the pharmaceutically acceptable addition salts and all the stereoisomeric forms. A special group of compounds includes those compounds of the formula (I) in which one or more of the following restrictions apply: 1) R 2 is halogen, hydroxy, C 1 -β alkyl or C 1 -r alkyloxy; 2) n is 0 or 1; 3) Alk is C 1-4 alkanediyl; Preferably, Alk is 1,2-ethanediyl; 4) D is a radical of the formula (a) in which R3 is C6 alkyl, aryl or aryl-C6-alkyl; R 4 is amino, mono- or di (Crß alkyl) amino, or mono- or di (arylC Cr) amino; or -R 4 -R 5 is a radical of the formula (a-2) or (a-5) in which one or two hydrogen atoms can each be independently replaced by halogen, C-alkyl, trifluoromethyl or alkyloxy; C1-6. or -R4-R5. is a radical of the formula (a-6), (a-7), (a-8), (a-11), (a-13) or (a-14) in which one or each time possible two hydrogen atoms can each be replaced independently by d-β alkyl; 5) D is a radical of the formula (b) and R6 and R7 are appropriately methyl; 6) D is a radical of the formula (c) and R8 is suitably hydrogen, methyl or phenyl; 7) D is a radical of the formula (d) in which R9 is aryl; and suitably, R9 is 4-fluoro-phenyl, and the piperidine ring is connected in positions 3 or 4 to the rest of the molecule; 15 8) D is a radical of the formula (e) in which X is S or NH or R 10 is hydrogen; or 9) D is a radical of the formula (f) in which X is S or NCH3. In the case where n is 1, the substituent R2 is appropriately placed in the 6-, 7- or 8-position of the? -carboline portion preferably in the 7- or 8- position and R2 is preferably chlorine , fluoro, methyl, hydroxy or methoxy. Appropriately, D is a radical of formula (a), (d), (e), or (f) An interesting group of compounds includes those compounds of the formula (I) in which R 1 is hydrogen or aryl; R2 is halogen or d-β alkyl; n is 0 or 1; Alk is C 1-4 alkanediyl; D is a radical of the formula (a) or (e), especially a radical of the formula (a) in which R3 is d-β alkyl and -R4-R5- is a radical of the formula (a) 2), (a-5), (a-6), (a-7) or (a-8) in which one or wherever possible two hydrogen atoms can each be independently replaced by C1-alkyl 6 or a radical of the formula (e) in which X is S and R10 is hydrogen. Another interesting group of compounds includes those compounds of the formula (I) in which R 1 is hydrogen or d-β alkyl. R 2 is halogen, d-β alkyl or d-β- n alkyloxy is 0 or 1; Alk is C1-4 alkdedeiyl; D is a radical of the formula (a) or (f), especially a radical of the formula (a) in which R4 is amino, mono- or di (Cr6 alkyl) amino or mono- or di (aryl-alkyl) of d-β) amino or -R 4 -R 5. is a radical of the formula (a-2), (a-5), 15 (a-6), (a-7) (a-8) or (a-11) in which one or wherever possible two hydrogen atoms can each be independently replaced by alkyl of d-6 or a radical of the formula (f) in which X is NR12. Even another interesting group of compounds includes those compounds of the formula (I) in which R2 is halogen, hydroxy, Cr @ 20 alkyl or Crß alkyloxy. n is 0 or 1; Alk is C 1-4 alkanediyl; D is a radical of the formula (a) (e) or (f), especially a radical of the formula (a) in which R3 is (Cr) alkyl R4 is amino or -R4-R5. a radical of the formula (a-2), (a-5), in which one or two hydrogen atoms can be replaced each ^^ cg (^^^^^^ g ^^^^^ K ^^^^ i * ^ g & ^. i ^^ a-i &feK ^ fc * ". independently by halogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkyloxy, or -R 4 -R 5. is a radical of the formula (a-6), (a-7), (a-8), (a-11), (a-13) or (a-14), in which one or wherever possible two hydrogen atoms can each be independently replaced by Crß alkyl, or a radical of the formula (e) in which X is S or NR12 and R10 is hydrogen or a radical of the formula (f) in which X is S or NR12. Even another interesting group of compounds includes those compounds of the formula (I) in which R 1 is hydrogen, d-β alkyl or aryl; R2 is halogen, C6-6alkyl or d-βalkyloxy; n is 0 or 1; Alk is alkylene of d-4; D is a radical of the formula (a), (d) or (e), especially a radical of the formula (a) in which R3 is d-6 alkyl or aryl-C6-alkyl or -R4 -R5- is a radical of the formula (a-5) in which one or two hydrogen atoms can each be independently replaced by a halogen, or -R4-R5- is a radical of the formula (a-6) or (a-8), or a radical of the formula (d) in which R9 is aryl, or a radical of the formula (e) in which X is S or NR12 and R10 is hydrogen. Particular compounds are those compounds of the formula (I) in which R1 is hydrogen; n is 0 or n is 1 whereby R 2 is a halogen, d-β alkyl or d-6 alkoxy; Alk is 1,2-ethanediyl and D is a radical of the formula (a) or (f), especially a radical of the formula (a) in which R3 is C1-6 alkyl, R4 is amino, R5 is alkyl of d-β or -R 4 -R 5 - is a radical of the formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-11) ) in which a hydrogen atom can be replaced by d-β alkyl or a radical of the formula (f) in which X is NR 12 and R 11 is C 1 alkyl, more particularly, in which R 1 is hydrogen; n is 0 or n is 1 whereby R2 is a chloro, methyl or methoxy; Alk is 1,2-ethanediyl and D is a radical of the formula (a) in which R3 is methyl, R4 is amino, R5 is methyl, or -R4-R5- is a radical of the formula (a-2) , (a-5), (a-6), (a-7), (a-8) or (a-11) in which a hydrogen atom can be replaced by methyl, or D is a radical of the formula (f) in which X is N-CH3 and R11 is methyl. Other particularly interesting compounds are those compounds of the formula (I) in which R 1 is hydrogen; n is 0 or n is 1 whereby R2 is a halogen or alkyl of d-6; Alk is 1,2-ethanediyl and D is a radical of the formula (a), especially a radical of the formula (a) in which R3 is d-β alkyl, R4 and R5 are taken together to form -R4- R5- of the formula (a-2), (a-5), (a-6), (a-7) or (a-8) in which a hydrogen atom may be replaced by C alkyl, more in particular, in which R1 is hydrogen; n is 0 or n is 1 whereby R2 is a chloro, fluoro or methyl; Alk is 1,2-ethanediyl and D is a radical of the formula (a) in which R3 is methyl, R4 and R5 are taken together to form -R4-R5- of the formula (a-2), (a- 5), (a-6), (a-7) or (a-8) in which a hydrogen atom can be replaced by a methyl. A preferred set of compounds includes those compounds of the formula (I) in which R1 is hydrogen, methyl, n-butyl, phenyl, benzyl or 4-fluorophenyl. The compounds of the formula (I) can be prepared in a general manner by the N-alkylation of a 1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indole derivative of the formula (II) with an alkylating reagent of the formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.

D ' "a'qUiteCi¿" (In particular, intermediate (III) in which W1 represents an appropriate reactive leaving group such as for example a halogen, for example chlorine, bromine or iodine;? A sulfonyloxy, e.g. , methanesulfonyloxy, toluenesulfonyloxy, can be reacted with an intermediate of the formula (II) in a reaction-inert solvent such as, for example, N, N-dimethylformamide or methyl isobutyl ketone, in the presence of an appropriate base such as, for example, carbonate of sodium or triethylamine, and optionally in the presence of a catalyst such as for example potassium iodide In this and in the following reactions, the reaction products can be isolated from the reaction medium and, if necessary, further purified from the reaction medium. according to the methods generally known in the art such as extraction, crystallization, trituration and chromatography The compounds of the formula (I) in which D is a radical of the formula (e), by formula (I-e) being represented, can be prepared by N-acylating an intermediate of formula (IV) with an acyl derivative of formula (V) wherein W2 is an appropriate reactive leaving group . "" ^ Éa such as for example, a halogen, in an inert solvent to the reaction such as for example chloroform, in the presence of an appropriate base such as for example, sodium carbonate or triethylamine.

The compounds of the formula (I) in which D is a radical of the formula (f), being represented by the formula (I), can be prepared by N-alkylation of an amine of the formula (VI) with an intermediate of formula (VII) wherein W3 is an appropriate reactive leaving group such as for example a halogen, in an inert to the reaction such as, for example, ethanol or toluene solvent in the presence of an appropriate base such as, for example, sodium bicarbonate or sodium carbonate.

(Vil) (and,) (r-f) Alternatively, the intermediates (VI) can be N-alkylated with the intermediates (VII) in the presence of copper. The compounds of the formula (I) can be converted into one another following the functional group transformation reactions known in the art.

The compounds of the formula (I) can also be converted to the corresponding N-oxide forms following the procedures known in the art for converting a trivalent nitrogen to its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metal, for example sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxyacids such as, for example, benzenecarboperoxoic acid or benzenecarboperoxoic acid substituted with halogen, for example 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyl hydroperoxides, for example, tert-butyl hydroperoxide. Suitable solvents are for example, water, lower alkanols, eg ethanol and the like, hydrocarbons, eg toluene, ketones, eg 2-butanone, halogenated hydrocarbons, eg dichloromethane, and mixtures of such solvents. A number of intermediates and starting materials are commercially available or these are known compounds that can be prepared in accordance with methods known in the art. For example, some of the intermediates of the formula (III) and their preparations are described in EP-A-0, 037,265, EP-A-0,070,053, EP-A-0, 196, 132 and in EP-A-0,378,255.

GLM ^^^^^^^^^^^^^^^^^ Me ^? S Intermediates of formula (II) wherein R1 is hydrogen, said intermediates by formula (II-a) being represented, they can be prepared in a general manner by reacting an intermediate of the formula (VIII) in which P is a protective group such as, for example,, an alkyloxycarbonyl group, with an intermediate of the formula (IX) in a solvent inert to the reaction, thereby forming an intermediate of the formula (X), and subsequently removing the protecting group using known techniques such as for example , mix the intermediate of the formula (X) with potassium hydroxide in 2-propanol. Alternatively, the intermediate of formula (X) can be further reacted with a reagent of formula (XI) in which R1 is the same as R1 but different from hydrogen and W4 is an appropriate leaving group such as for example , a halogen in a suitable solvent such as, for example, hexamethylphosphorus triamide and the like, in the presence of an appropriate base such as, for example, sodium hydride, thereby forming an intermediate of the formula (XII) which can be deprotected subsequently using known techniques which results in a compound of the formula (II) in which R1 is different from hydrogen, said compounds being represented by the formula (ll-b). (ll *) (XII) (i.) The intermediates of the formula (IV) can be prepared by N-alkylation of an intermediate of the formula (II) with an intermediate of the formula (XIII) in which P is a protective group such as, for example, an alkyloxycarbonyl group and W5 is an appropriate leaving group such as, for example, a p-toluenesulfonyloxy group and the like, in a reaction-inert solvent such as, for example, N, N-dimethylformamide and in the presence of an appropriate base such as, for example, carbonate of sodium. The intermediate formed in this way can be deprotected using known deprotection techniques.

The intermediates of the formula (VI) can be prepared by N-alkylation of an intermediate of the formula (II) with an intermediate of the formula (XIV) in which P is a protecting group such as, for example, an alkoxycarbonyl group and W6 is an appropriate leaving group such as for example a halogen in a reaction inert solvent such as, for example, methyl isobutyl ketone in the presence of an appropriate base such as, for example, sodium carbonate and optionally in the presence of a catalyst such as example, potassium iodide. The intermediate formed in this way can be deprotected using known deprotection techniques.

(VI) Intermediates of the formula (VI) in which Alk is 1,3-propandiyl and R11 is hydrogen, said intermediates being represented by the formula (VI-3) can be appropriately prepared by reacting an intermediate of the formula ( II) with acrylonitrile in a reaction-inert solvent such as, for example, 2-propanol and in the presence of an appropriate catalyst such as for example a quaternary ammonium compound, for example Aliquat 336, thereby forming a nitrile derivative of the formula (XV) which can be subsequently reduced to the corresponding amine derivative using reduction techniques known as such, by example, using hydrogen with Raney Nickel as a catalyst in methanol, optionally in the presence of ammonia.

The intermediates of the formula (VI) in which Alk is 1,4-butanediyl and R11 is hydrogen, said intermediate being represented by the formula (VI-4), can be appropriately prepared by reacting an intermediate of the formula (II) with an intermediate of the formula (XVI) in which W7 is an appropriate leaving group such as, for example, a halogen in a reaction-inert solvent such as for example methyl isobutyl ketone and in the presence of an appropriate base such as for example , sodium carbonate and optionally in the presence of a catalyst such as for example potassium iodide thereby forming a nitrile derivative of the formula (XVII) which can subsequently be reduced to the corresponding amine derivative using reduction techniques known as such, by example, using hydrogen with Raney Nickel as a catalyst in methanol, optionally in the presence of ammonia.

Some of the compounds of the formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. The pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by applying procedures known in the art. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatography techniques, for example countercurrent distribution, liquid chromatography and similar methods. The enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with appropriate resolving agents such as, for example, chiral acids to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by for example, selective crystallization or chromatographic techniques, for example liquid chromatography and the like method; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. The pure stereochemically isomeric forms of the compounds of the formula (I) can also be obtained from pure stereochemically isomeric forms of the appropriate intermediates and starting materials, with the condition that the reactions taking place occur in a stereo-specific manner . The pure and mixed stereochemically isomeric forms of the compounds of the formula (I) are designed to be encompassed within the scope of the present invention. The compounds of formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, or the N-oxide forms thereof, all show a particular affinity towards serotonin receptors, such as the 5-hydroxytryptamine receptors of the Type 5HT? and 5-HT2, and have an antagonistic, partially antagonistic or agonist effect thereon. In addition to their affinity for serotonergic receptors, the compounds herein also bind as ligands on a2 receptors or dopamine receptors, or selectively inhibit the reuptake of serotonin. This broad spectrum receptor binding profile of the compounds herein provides them with a greater therapeutic range. These are useful for controlling diseases that are characterized by disturbances of the serotonergic system, in particular with the involvement of the 5HT2 type receptors. These are therefore suitable for treating disorders of the central nervous system including psychotic disorders such as schizophrenia, tension and states of depression, neurosis, psychosis, bipolar disorders, aggressive behavior, anxiety and the like. In addition, serotonin is a potent bronchoconstrictor and vasoconstrictor and therefore the compounds of the present that act as antagonists on serotonin receptors may also be useful against hypertension and vascular disorders such as for example migraine and migraine-related disorders. Compounds that control the serotonergic system have been associated with a number of other properties such as suppressing appetite and promoting weight loss, which may prove effective in combating obesity; the improvement of withdrawal symptoms in addicted subjects who try to stop taking and smoking; and also in gastrointestinal disorders such as, for example, disturbances of the kinetics of the colon. In addition, the inhibitory activity of a particular group of compounds of the present on the reabsorption of serotonin contributes to the effectiveness to treat stress and depression states. An additional feature of the compounds of the present invention is that they have central a2 adrenoreceptor antagonist activity. It is known that central a2 adrenoreceptor antagonists increase the release of noradrenaline by blocking the presynaptic receptors 2 which exert an inhibitory control on the release of the neurotransmitter. By increasing norepinephrine concentrations, α2-antagonists can be used particularly for the treatment or prophylaxis of depression, and are also potentially useful in the treatment of Alzheimer's disease and dementia since it is known that α2-antagonists promote the release of acetylcholine (Téllez et al., 1997, J. Neurochem. 68: 778-785). A particular group of compounds of the present invention exhibit a marked affinity towards dopaminergic receptors, which in combination with an affinity towards serotonergic receptors is of therapeutic importance in the treatment of psychosis. The 5HT2 receptor binding profile of the compounds of the formula (I) is discussed in pharmacological example C.1. The binding profile for other receptors, such as a2 adrenergic receptors or dopaminergic receptors, can be demonstrated using analogous radioligand binding studies. In addition, the serotonergic properties of the compounds of the present can be made evident by the "apomorphine, tryptamine, norepinephrine (ATN) test in rats", described in Arch. Int. Pharmacodyn., 227, 238-253 (1977). Therefore the present invention relates to compounds of the formula (I) as defined hereinabove to be used as a medicament. In addition, the present invention relates to the use of the compounds of the present invention for the manufacture of a medicament for treating depression, anxiety and psychosis. In view of the utility of the compounds present in the treatment or prevention of the aforementioned disorders, the present invention provides a method of treatment for warm-blooded animals suffering from such disorders, in particular depression, anxiety and psychosis, said method is the systemic administration of a therapeutically effective amount of a compound of the formula (I), an N-oxide or a pharmaceutically acceptable addition salt thereof, which is effective to treat disorders associated with the serotonergic system. It is generally contemplated that a Therapeutically effective daily amount could be from about 0.01 mg / kg to about 4 mg / kg of body weight. The exact dosage to be used in the treatment of any of the aforementioned disorders must be determined subjectively by the physician j manager. The variables involved include the severity of the disorder and the patient's size, age and response pattern. For administration purposes, the compounds of the present invention can be formulated into various pharmaceutical compositions containing a pharmaceutically acceptable carrier and, as the active ingredient, a therapeutically effective amount of a compound of the formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of addition salt or in the form of free acid or base, as the active ingredient, is combined in a mixture.

Intimate with a pharmaceutically acceptable carrier, which can have a wide variety of forms depending on the form of preparation desired for administration. It is desired that these pharmaceutical compositions are in appropriate unit doses, preferably, for oral administration, percutaneously or by parenteral injection. For example in In the preparation of the compositions in oral dosage form, any of the common pharmaceutical media, such as for example water, glycols, oils, alcohols and the like can be used in the case of liquid oral preparations such as suspensions, syrups, elixirs and solutions; or you can use solid vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, tablets, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case they are obviously used ^^ ¡^? ^ M ^ ~ S & ^^^ g &l solid pharmaceutical vehicles. For parenteral compositions, the vehicle will usually be composed of sterile water, at least for the most part, although other ingredients, for example, solubility aids, may be included. For example, injectable solutions can be prepared in which the vehicle is composed of saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable solutions containing compounds of the formula (I) can be formulated in oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for percutaneous administration, the carrier optionally contains a penetration enhancing agent and / or an appropriate wetting agent, optionally combined with appropriate additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Such additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various forms, for example, as a transdermal patch, as a spot application or as an ointment. The addition salts of (I) due to their increased solubility in water with respect to the corresponding free base or acid forms, are obviously more appropriate for preparing the aqueous compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage forms to facilitate administration and uniformity of dosage. Unit dosage forms as used in the specification and claims herein refer to physically appropriate discrete units as unit doses, each containing a predetermined amount of active ingredient that is calculated to produce the desired therapeutic effect. , in association with the necessary pharmaceutical vehicle. Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, lozenges, powder bags, wafers, injectable solutions or suspensions, metered doses with tea or soup spoons and the like, and segregated multiples thereof. . The following examples were designed to illustrate the present invention.

EXAMPLE A1 Experimental part A. Preparation of the intermediates a) A mixture of ethyl 4-oxo-1-piperidinecarboxylate was stirred (0.23 mmoles) and 4- (benzyloxy) -phenylhydrazine (0.23 moles) in ethanol (400 ml) and refluxed for 5 hours. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed on the filter with H20 / 2-propanol (200 ml). The precipitate was dissolved in CHCl3 (300 ml), washed with water (2x5 ml), dried, filtered and the solvent was evaporated. The residue was crystallized with CH 3 CN (300 ml) and cooled to 0 ° C. The resulting precipitated material was filtered and dried, yielding 51.0 g (63%) of 1, 3,4,5-tetrahydro-8- (phenylmethoxy) -2H-pyrido [4,3-b] indole-2-carbonylate. ethyl (intermediate 1). b) A mixture of intermediate (I) (0.9 mol) in N, N-dimethylformamide (200 ml) was stirred at 10 ° C under a stream of N2. Sodium hydride (60%) was added; 0.1 mol) in portions. The mixture was stirred for 1 hour at room temperature, and then cooled to 5 ° C. Benzyl bromide (0.1 moles) was added dropwise. Stirring was continued for 2 hours. The mixture was cooled to 10 ° C and poured into cold water (500 ml). The mixture was extracted with CH2Cl2 (2x250 ml). The separated organic layer was washed with water (100 ml), dried, filtered and the solvent was evaporated. The solid residue was washed with CH 3 CN (50 ml), cooled and the resulting precipitated material was filtered and dried, . -spheres, yielding 30.0 g (76%) of 1, 3,4,5-tetrahydro-8- (phenyl-methoxy) -5- (phenyl-methyl) -2H-pyrido [4,3-b] indole-2 ethyl-carboxylate (intermediate 2). c) A mixture of intermediate (2) (0.067 mol) and KOH (0.67 mol) in 2-propanol (250 ml) was stirred and refluxed for 5 hours. The solvent was evaporated. Water (300 ml) was added and the organic solvent was removed by azeotropic distillation. The precipitated material was filtered and dissolved in CH2Cl2 (300 mL). The organic solution was dried, filtered and the solvent was evaporated. The residue was washed with CH 3 CN (50 ml), filtered and dried, yielding 22.7 g (92%) of 2,3,4,5-tetrahydro-8- (phenylmethoxy) -5- (phenylmethyl) -1. / - / - pyrido [4,3-b] indole (intermediate 3). d) A mixture of intermediate (3) (0.062 mol) in methanol (400 ml) and tetrahydrofuran (100 ml) was heated at 50 ° C until complete dissolution. This solution was hydrogenated at 50 ° C with palladium on carbon (10%, 5 g) as a catalyst. After uptake of H 2 (1 equivalent), the hydrogenation was stopped and acetic acid (50 ml) was added to dissolve the precipitate. The catalyst was filtered and the filtrate was acidified with HCl / 2-propanol (30 ml). The precipitated material was filtered, suspended in CH3CN (100 ml), filtered and dried, giving 14.5 g (74%) of 2,3,4,5-tetrahydro-5- (phenylmethyl) -1H-pyrido monohydrochloride [ 4.3-b] indole-8-ol (intermediate 8).

EXAMPLE A.2 a) A mixture of 2,3,4,5-tetrahydro-8-methyl-1 / - / - pyrido [4,3-b] indole, (0.079 moles), ethyl 3-chloropropanamide (0.097 moles) was stirred. , Na 2 CO 3 (15 g) and potassium iodide (0.1 g) in methyl isobutyl ketone (350 ml) and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated, yielding 20 g (80%) of [3- (1, 3,4,5-tetrahydro-8-methyl-2 / - / - pyrido [4.3-] b] indol-2-yl) propyl]] ethyl cabamate (intermediate 10). b) A mixture of intermediate (10) (0.063 mol) and KOH (35 g) in 2-propanol (30 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was stirred in water and this mixture was extracted with methyl isobutyl ketone. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / (CH 3 OH / NH 3) 85/15). The pure fractions were collected and the solvent was evaporated, yielding 7 g (46%) of 1, 3,4,5-tetrahydro-8-methyl-2 / - -pyrido [4,3-b] indole-2-propanamine (intermediary 1 1).

EXAMPLE A.3 a) A mixture of 2,3,4,5-tetrahydro-5-methyl-1 H-pyrido [4,3-b] indole (0.07 moles), acrylonitrile (0.14 moles) and Aliquat 336 (3 drops) was stirred. in 2-propanol (150 ml) and refluxed for 30 minutes. The reaction mixture was cooled in an ice bath and the resulting precipitated material was filtered, washed with diisopropyl ether (50 ml) and dried, yielding 14.5 g (87%) of 1, 3,4,5-tetrahydro- 5-methyl-2H-pyrido [4,3-b] indole-2-propane-nitrile (intermediary 15). b) A mixture of intermediate (15) (0.06 moles) was hydrogenated in NH3 / CH3OH (400 ml) at 20 ° C with Raney nickel (3 g) as catalyst. After consuming the hydrogen (2 equivalents), the catalyst was filtered and the filtrate was evaporated, yielding 14.6 g of 1, 3,4,5-tetrahydro-5-methyl-2 / - / - pyrido [4.3- b] indole-2-propanamine (intermediate 16).

EXAMPLE A.4 a) A mixture of 1, 2,3,4-tetrahydro-5H-pyrido [4,3-b] indole (0.2 moles) and 1- (phenyl-methyl) -4-piperidine (0.2 moles) in methanol (700 ml) was hydrogenated at 50 ° C with palladium on carbon (10%, 3 g) as a catalyst in the presence of thiophene (4%, 2 ml). After consumption of hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated, yielding 69 g of 2,3,4,5-tetrahydro-2- [1- (phenylmethyl) -4-piperidinyl] -1 / - / - pyrido [4,3-b] indole (intermediate 24). b) A mixture of intermediate (24) (0.20 moles) 20 in methanol (700 ml) at 50 ° C was hydrogenated with palladium on charcoal (10%, 3 g) as a catalyst. After consuming the hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated. The residue was crystallized with diisopropyl ether / CH3CN. The precipitated material was filtered and dried giving 44.1 g * ^^ á ^^ j ^^^ s ^^^ Z & + 1SFS & (86.4%) of 2,3,4,5-tetrahydro-5-methyl-2- (4-piperidinyl) -1 H -pyrido [4,3-b] indole (intermediate 25). The following intermediates were prepared according to one of the above examples.

TABLE 1 EXAMPLE B.1 B. Preparation of the compounds of the formula (I) a) A mixture of 6- (2-bromoethyl) -3 > monobromohydrate was stirred. 7-dimethyl-5 / - -thiazole [3,2-a] pyridimin-5-one (0.017 mol), intermediate (9) (0.015 moles) and sodium carbonate (0.075 moles) in methyl isobutyl ketone (250 ml) and refluxed for 18 hours. The mixture was filtered hot and the filtrate was evaporated. The residue was crystallized with N, N-dimethylformamide (20 ml). The precipitated material was filtered, washed on the filter with methanol (5 ml) and dried, yielding 0.8 g (14%) of 3,7-dimethyl-6- [2- (1, 3,4,5-tetrahydro -8-hydroxy-2H-pyrido [4,3-b] indol-2-yl) etl-5H-thiazole [3,2-a] pyrimidin-5-one (compound 59). b) 7- [2- (8-Fluoro-1, 3,4,5-tetrahydro-8-hydroxy-2H-pyrido [4,3-b] indol-2-yl) ethyl] -3.4 was prepared dihydro-8-methyl-2H, 6H-pyrimido [2,1-b] [1, 3] -thiazin-6-one (compound 2) in a manner similar to that of compound 59 but a catalytic amount of Sodium methoxide (30% solution) to the reaction mixture. c) ey.β.-Tetrahydro-methyl-S-2-γ-γ-d-tetrahydro-d-methyl-2H-pyrid [4,3-b] n-dol-2-yl was prepared. ethyl] -4H-pyrimido [1,2-a] pyrimidin-4-one (compound 81) in a similar manner to that of compound 59 but a catalytic amount of potassium iodide was added to the reaction mixture. d) (±) -4- (4-flurobenzoyl) -3 - [(1, 3,4,5-tetrahydro-5-methyl-2 / -pyrido [4,3-b] indole-2- was prepared il) methyl] pyridine (E) -2-butenedioate (1: 1) (compound 117) in a manner similar to that of compound 59 but N, N-dimethylformamide was used as the solvent inert to the reaction instead of methyl isobutyl ketone. e) 3- [2- (7-chloro-1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-yl) ethyl] -9-methoxy-2 was prepared -methyl-4H-pyrido [1,2-a] pyrimidin-4-one (compound 20) in a similar manner to that of compound 59 but triethylamine was used instead of sodium carbonate. f) 2,3-Dihydro-7-methyl-6- [2- (1, 3,4,5-tetrahydro-8-hydroxy-2 / - / - pyrido [4,3-b] indole-2 was prepared -yl) ethyl] -5H-thiazole [3,2-a] pyrimidin-5-one (compound 62) in a similar manner to that of compound 117 but triethylamine was used in place of sodium carbonate. g) A mixture of 6- (2-chloroethyl) -2,7-dimethyl-5H-1, 3,4-thiadiazole [3,2-a] pyrimidin-5-one (4.2 g), 1, 2 was refluxed. 3,4-tetrahydro-5H-pyrido [4,3-b] indole, (2.65 g), sodium bicarbonate (2 g), potassium iodide (0.1 g), in 1 -butanol (122 ml) for 20 hours . The reaction mixture was filtered hot and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / CH3OH 95/5). The solvent of the desired fraction was evaporated and the residue was crystallized from acetonitrile, giving 1.6 g (28.1%) of 6- [2- (1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] -indol-2-yl) ethyl] -2,7-dimethyl-5H-1, 3,4-thiadiazol [3,2-a] pyrimidin-5-one (compound 42). h) Prepared (±) -4- (4-flurobenzoyl) -3- [2- (1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-yl) ethyl] pyridine (E) -2-butenedioate (2: 3) (compound 120) in a manner similar to that of compound 59 but chloroform was used as the solvent inert to the reaction in place of methyl isobutyl ketone.

EXAMPLE B.2 A mixture of intermediate 26 (0.01 mol) and triethylamine (0.011 mol) in chloroform (150 ml) was stirred at room temperature. 4-Fluoro-benzoyl chloride (0.011 mol) was added. The reaction mixture was stirred for 60 minutes at room temperature. Water (50 ml) was added and the mixture was stirred for 10 minutes. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was solidified in CH3CN (40 mL), filtered and dried, yielding 2.7 g (66%) of (±) -1- (4-fluoro-benzoyl) -3 - [(8-fluoro-1, 3 , 4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-yl) methyl] piperidine (compound 119).

EXAMPLE B.3 a) A mixture of 2-chloro-benzothiazole (0.02 moles) was stirred, intermediate18 (0.018 moles) and sodium bicarbonate (0.040 moles) in ethanol (120 ml) and refluxed overnight. The mixture was cooled and filtered until it was clear. The material evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue was crystallized with CH3CN. The precipitate was filtered and dried to give 3.4 g (50%) of? / - 2-benzothiazolyl-1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-butanamine (compound 107).

. : J5 & lb., b) was prepared? / - 2-benzothiazolyl-8-fluoro-1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-butanamine (compound 108) . in a similar manner to that of compound 107 but the sodium carbonate was replaced by sodium bicarbonate and the ethanol was changed to toluene.

EXAMPLE B.4 A mixture of 2-chloro-1 H-benzimidazole (0.015 mol), intermediate 16 (0.015 mol) and copper (0.015 mol) was stirred in an oil bath at 180 ° C. The mixture was cooled and the product was dissolved in CHCl3 (50 ml). The solution was filtered over dicalite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / CH3OH / NH3) 95/5). The pure fractions were collected and the solvent evaporated. The residue was dissolved in CH3CN (50 ml) and converted to the hydrochloride salt (1: 2) with HCI / 2-propanol. The salt was filtered, washed on the filter with cold CH3CN (20 ml), then dried to give 1.1 g (17%) of? / - 1 H-benzimidazol-2-yl-1) 3,4,5-dihydrochloride. -tetrahydro-5-methyl-2H-pyrido [4,3-b] indol-2-propanamine hemihydrate (compound 105). Tables 2 to 8 list the compounds of the formula (I) which were prepared according to one of the above examples as indicated in the column "Ex. No.".

CUA RO 2 & m &g TABLE 3 TABLE 4 TABLE 5 ¿¿^ ^ ¿S ¿^ ^ ^ MO & U ^ TABLE 7 • > * .- and »- ^ - ^ ni EXAMPLE C.1 C. Pharmacological example The 5HT2 receptors were measured by radioligand binding studies either in homogenates from rat brain or in membrane fractions prepared from L929sA cells (mouse fibrokinase cells), stably transfected with human dHTztx receptor cDNA.

Sample preparation Binding to 5HT2 in rat frontal cortex 5HT2 receptors were measured in a membrane fraction of the rat frontal cortex. For this Wistar rats were sacrificed by decapitation, the brains were removed and the frontal cortex was dissected. The frontal cortex was homogenized in 50 mM Tris-HCL buffer pH 7. 7. The homogenized material was centrifuged at 23,000 g for 10 minutes.

The resulting pellet was washed twice by resuspension and recentrifugation and the pellet was finally suspended in 50 mM Tris-HCL buffer solution 7.7 at a dilution of 100 (volume / wet weight of tissue). 400 μl of homogenate was incubated with 1 nM [3H] cetanserin in a total incubation volume of 0.5 ml for 30 minutes at 37 ° C.

Incubation was stopped by rapid filtration using a manual filtration manifold. The filters were rinsed twice with ice-cold buffer and counted in a flash counter in liquid medium. The non-specific binding was determined in the presence of 1 μM methysergide.

Binding to 5HT2A in L929sA cells L929sA cells expressing 5HT2A receptors were cultured in Petri dishes in DMEM medium (Gibco cat.No.41965-039) enriched with 5% fetal bovine serum inactivated with heat and in the presence of penicillin and sulfate. streptomycin. 24 hours before collection, the cells were induced with m-interferon-b (1000 U / ml medium). The cells were collected by scraping and centrifugation at low speed (5 minutes at 1500 g). The cells were homogenized and centrifuged for 10 minutes at 23,000 g. The resulting pellet was diluted in 50 mM Tris-HCl pH 7.7 and stored at -70 ° C. On the day of the experiment, a vial was thawed and diluted in Tris-HCl buffer. The dHT ^ receptors were labeled with [125l] 4-amino-γ / - [1- [3- (4-fluorophenoxy) propyl] -4-methyl-4-piperidinyl] -2-methoxybenzamide dihydrate 0.1 mM. The membranes (0.2 ml) were incubated with the radioligand for 60 minutes at 37 ° C in a total volume of 0.25 ml. The reaction was stopped by rapid filtration and the filter disks were counted in an auto-gamma spectrophotometer.

Data analysis The counting of data from the tests in the presence of the test compounds was automatically expressed as a percent of the total binding measured in the absence of the test compound. Therefore, plC5o (-log IC5o) values were obtained (CI5o = concentration in M that inhibits 50% specific radioligand binding or neurotransmitter consumption) and are listed in Table 9 (a "-" means "no"). measured ").

TABLE 9 EXAMPLE C.2 In vitro binding affinity to a2 receptors The interaction of the compounds of the formula (I) with the a2 receptors was evaluated in an in vitro radioligand binding experiment. In general, a low concentration of a radioligand with a high binding affinity towards a particular receptor is incubated with a & amp; amp; amp; sample of an enriched tissue preparation with respect to a particular receptor or with a preparation of cells expressing cloned human receptors in a medium with buffer solution. During incubation, the radio ligand binds to the receptor. When the binding equilibrium is achieved, the radioactivity bound to the receptor is separated from the unbound radioactivity, and the receptor binding activity is counted. The interaction of the test compounds with the receptor is evaluated in competitive binding experiments. Various concentrations of the test compounds are added to the incubation mixture containing the receptor preparation and the radio ligand. The binding of the radio ligand will be inhibited by the test compounds in proportion to their binding affinity and their concentration. The radioligand used for the binding to the a2 receptor was 3H-clonidine and the tissue preparation used was rat cortex. The compounds with the numbers 1 to 1 1, 13, 14, 16, 17, 20, 23 to 41, 43, 52 to 57, 60, 63, 66 to 74, 81 to 89 and 96 to 98 produced an inhibition of more 50% at a test concentration of 10"6 M or less, and the other compounds produced an inhibition of less than 50% at a test concentration of 10" 6 M.

D. Composition Examples "Active ingredient" (I.A.) as used throughout these examples refers to a compound of the formula (1), an addition salt pharmaceutically acceptable or a stereochemically isomeric form thereof.

EXAMPLE D.1 Capsules g of I.A., 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate are stirred vigorously together. With the resulting mixture, 1000 suitable hard gelatin capsules each containing 20 mg of I .A are subsequently filled.

EXAMPLE D.2 Film-coated tablets Preparation of the core of the tablet A mixture of 100 g of LA, 570 g of lactose and 200 g of starch is mixed well and after that they are moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinyl pyrrolidone in approximately 200 ml of water. The wet powder mixture is screened, dried and sieved again. Then add 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil. The whole is mixed well and compacted into tablets, giving 1000 tablets, each containing 10 mg of the active ingredient.

Coating To a solution of 10 g of methylcellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the previous one and then 2.5 g of magnesium octadecanoate, 5 g of polyvinyl pyrrolidone and 30 ml of concentrated color suspension are added and the whole is homogenized. The tablet cores are coated with the mixture obtained in this way in a coating apparatus.

EXAMPLE D.3 Oral solution Dissolve 9 grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate in 4 liters of boiling purified water. In 3 liters of this solution, 10 grams of 2,3-dihydroxybutanediic acid are dissolved first and then 20 grams of the active ingredient. This last solution is combined with the remaining part of the previous solution and 12 liters of 1, 2,3-propanetriol and 3 liters of sorbitol at 70% are added thereto.

Dissolve 40 grams of sodium saccharin in 0.5 liters of water and add 2 ml of raspberry essence and 2 ml of gooseberry essence. This last solution is combined with the previous one, water is added in sufficient quantity up to a volume of 20 liters supplying an oral solution containing 5 mg of active ingredient for each teaspoon of tea (5 ml). With the resulting solution, appropriate containers are filled.

EXAMPLE D.4 Injectable solution Dissolve 1.8 grams of methyl 4-hydroxybenzoate and 0.2 grams of propyl 4-hydroxybenzoate in approximately 0.5 liters of boiling water for injection. After cooling to about 50 ° C, 4 grams of lactic acid, 0.05 grams of propylene glycol and 4 grams of the active ingredient are added while stirring. The solution is cooled to room temperature and is completed with water for injection in sufficient quantity for 1 liter, giving a solution containing 4 mg / ml of active ingredient. The solution is sterilized by filtration and poured into sterile containers.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula a? / -oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: R1 is hydrogen, Cr3 alkyl, aryl or CrCl alkyl substituted with aryl; R2 is each independently a halogen, hydroxy, Cr-, Cr- or nitro alkyloxy; n is 0, 1, 2, or 3; Alk is d-ß -alphandiyl; D is 2 (3H) benzoxazolone-3-yl or a radical of the formula (d) (e) (f) wherein each X independently represents O, S or NR12; R3 is hydrogen, Cr3 alkyl. aryl or aryl-alkyl of d-βi R 4 is hydrogen, Crß alkyl, Crß alkyloxy, Cr, amino alkyl, amino, mono- or di (d- 6 alkyl) amino or mono- or di (aryl-alkyl) Crß) amino; R5, R6, R7, R10, R11 and R12 are each independently hydrogen or alkyl of Crei R8 and R9 are each independently hydrogen, Cr3 alkyl, or aryl; or R4 and R5 taken together can form a bivalent radical -R4-R5- of the formula -CH2-CH2-CH2- (a-1); -CH2-CH2-CH2-CH2- (a-2); -CH = CH-CH2- (a-3); -CH2-CH = CH- (a-4) or -CH = CH-CH = CH- (a-5); wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) can each be independently replaced by halogen, Cr-alkyl, aryl-Cr-alkyl, trifluoromethyl, amino, hydroxy, alkyloxy Cr, or Crio alkylcarbonyloxy; or where possible, two gemomic hydrogen atoms can be replaced by Crß alkylidene, or Cr-aryl-alkylidene, or -R4-R5- can also be -S-CH2-CH2- (a-6); -S-CH2-CH2-CH2- (a-7); -S-CH = CH- (a-8); -NH = CH2-CH2- (a-9); -NH-CH2-CH2-CH2- (a-10); -NH-CH2 = CH- (a-11); - NH-CH = N- (a-12); S-CH = N- (a-13) or -CH = CH-0- (a-14); wherein one or wherever possible two or three hydrogen atoms in said radicals (a-6) to (a-14) can each be independently replaced by d-β or aryl alkyl; and aryl is phenyl or phenyl substituted with a halogen or Cr alkyl

2. - A compound according to claim 1, wherein n is 0 or 1 and R2 is placed in the 6-, 7- or 8-position of the? -carboline moiety.

3. A compound according to claim 1 or 2, wherein R2 is halogen, hydroxy, Cr- or Cr- alkyloxy; n is 0 or 1; Alk is C 1-4 alkanediyl; D is a radical of the formula (a) in which R3 is Cr3 alkyl, R4 is amino or -R4-R5. is a radical of formula (a-2) or (a-5) in which one or two hydrogen atoms can each be independently replaced by halogen, Cr-trifluoromethyl alkyl or d-β-alkyloxy or -R4-R5 . a radical of the formula (a-6), (a-7), (a-8), (a-11), (a-13) or (a-14), in which one or wherever possible two hydrogen atoms can each be independently replaced by alkyl of d-6 or a radical of the formula (e) in which X is S or NR12 and R10 is hydrogen or a radical of the formula (f) in which X is NR12.

4. A compound according to any of claims 1 or 2, wherein R1 is hydrogen; n is 0 or n is 1 whereby R 2 is a halogen, d 6 alkyl or d 6 alkoxy; Alk is 1,2-ethanediyl and D is a radical of the formula (a) in which R3 is d-6 alkyl, R4 is amino, R5 is d-6 alkyl or -R4-R5- is a radical of the formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-11) in which a hydrogen atom can be replaced by alkyl of C? -6 or a radical of the formula (f) in which X is NR12 and R11 is alkyl of d-6.

5. - A compound according to any of claims 1 or 2, wherein R1 is hydrogen; n is 0 or n is 1 whereby R2 is a halogen or C? -6 alkyl; Alk is 1,2-ethanediyl and D is a radical of the formula (a) in which R3 is alkyl of d-6, R4 and R5 are taken together to form -R4-R5- is a radical of the formula (a -2), (a-5), (a-6), (a-7) or (a-8) in which a hydrogen atom can be replaced by d-β alkyl.

6. A compound according to claim 1, wherein R1 is hydrogen, methyl, n-butyl, phenyl, benzyl or 4-fluorophenyl.

7. A compound according to any of claims 1 to 6 for use as a medicine.

8. A composition containing a pharmaceutically acceptable carrier and, as the active ingredient, a therapeutically effective amount of a compound according to any of claims 1 to 6.

9. A process for preparing a composition in accordance with the claim 8 by combining a compound as defined in any of claims 1 to 6, as the active ingredient, in intimate admixture with a pharmaceutically acceptable carrier.

10. A process for preparing a compound according to claim 1, characterized by, a) N-alkylation of a 1, 3,4,5-tetrahydro-2H-pyrido [4,3-b] indole derivative of the formula (II) with an alkylating reagent of the formula (III) in which W1 represents an appropriate reactive leaving group and D, Alk, n, R1 and R2 are as defined above in claim 1, in a solvent inert to the reaction and in the presence of an appropriate base and optionally in the presence of a catalyst; b) deprotecting an N-protected intermediate of the formula (IV) in which P is a protecting group and Alk, n, R1 and R2 are as defined above in claim 1, and subsequently N-acylating the resulting intermediate with an acyl derivative of the formula (V) in which W2 is an appropriate reactive leaving group and R10 is as defined in claim 1, in a solvent inert to the reaction and in the presence of an appropriate base, 20 thereby forming a compound of the formula (I-e); c) N-alkylating an amine of the formula (VI) in which Alk, n, R1, R2 and R11 are as defined in claim 1, with an intermediate of the formula (VII) in which W3 is a group appropriate reagent and X is as defined in claim 1, ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ faith * »^ lM ^^^^^^^^^ ^^^^ in a solvent inert to the reaction and in the presence of a base; or N-alkylating an intermediate of the formula (VI) with an intermediate of the formula (VII) in the presence of copper; (VII) (VI) (1-0) thus forming an intermediate of the formula (lf); d) and if it is desired to convert the compounds of the formula (I) one into the other following the transformations known in the art, and if desired also, by converting the compounds of the formula (I), into a non-toxic therapeutically active acid addition salt by treatment with an acid, or into a therapeutically active, non-toxic basic addition salt by treatment with a base, or conversely, converting the acidic addition salt form into the free base by treatment with alkali, or converting the basic salt form of addition into the free acid by acid treatment; and if desired, preparing stereochemically isomeric forms or N-oxides thereof.