MXPA99001574A - Fused indolecarboxamides:dopamine receptor subtype specific ligands - Google Patents

Abstract

Disclosed are compounds of formula (I) or the pharmaceutically acceptable acid addition salts thereof wherein (a) represents an aromatic or alicyclic ring;R1 and R2 are the same or different and represent hydrogen, C1-C6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, -O2CR', -NHCOR', -COR', -SOmR', where R'is C1-C6 alkyl and wherein m is 0, 1 or 2;or R1 and R2 independently represent -CONR'R'', or -NR'R''where R'and R''independently represent hydrogen or C1-C6 alkyl;R3 is hydrogen, C1-C6 alkyl, or -COR'''whereR'''is C1-C6 alkyl;R4 is hydrogen or C1-C6 alkyl;and R represents an azacycloalkylalkyl group, which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease, movement disorders such as Parkinsonism and dystonia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

Description

- - • SIND FUSED CARBOXAMIDES; SPECIFIC LIGANDS OF THE DOPAHIDA RECEIVER SUBTYPE BACKGROUND OF THE INVENTION Field of the invention This invention relates to indolecarboxamide derivatives which selectively bind to the dopamine receptor subtypes of the brain. More specifically, it relates to fused indolecarboxamides such as the carbozolecarboxamides, tetrahydrocarbazolecarboxamides and cycloal "fused quilindolecarboxamides and to pharmaceutical compositions" comprising such components. They also relate to the use of such compounds in the treatment or prevention of various neuropsychological disorders such as schizophrenia and other disorders of the central nervous system.

Description of Related Art The therapeutic effect of conventional antipsychotics, seen as neuroleptics, is generally believed to be exerted through the blockade of dopamine receptors. In any case, neuroleptics are frequently - responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias that are attributed to the blockade of D2 receptors in the striated region of the brain. The D3 receptor subtype of dopamine has recently been identified (So oloff et al., Nature, 347, 146 (1990)). Its unique location in the limbic areas of the brain and its differential recognition of several antipsychotics suggest that the D3 receptor may play a greater role in the etiology of schizophrenia. Selective D3 antagonists may be an effective antipsychotic free of the side effects shown by conventional neuroleptics. The components of the present invention demonstrate a high affinity and selectivity in the binding of the D3 receptor subtype. These may be of potential use in the treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinson's disease and tardive dyskinesias may be treated directly or indirectly by modulation of the D3 receptors.

The U.S. patent No. 5,395,835 discloses that N-aminoalkyl-2-naptalamides have affinity to D-dopamine receptors. The components of the present invention differ significantly from this prior art in that they possess a substructure of dibenzofurancarboxamide.

- - The U.S. patent No. 3,932,456 discloses the compounds of the formula: wherein each R1 and R2 is hydrogen (lower) alkyl, cycloalkyl of 3 to 6 carbon atoms in the ring, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group, or Ra and R 2 taken together with the nitrogen atom to which they are attached is pyrrolidin, piperidino, N- (lower) alkylpiperazino, or monopoly; each A is alkylene of 2 to 8 carbon atoms and its separation is adjacent to Y and amino nitrogen by an alkylene chain of less than 2 carbon atoms; each Y is oxygen, or N-R wherein R is hydrogen, methyl or ethyl, and R3 is hydrogen or primary or secondary (lower) alkyl; or pharmaceutically acceptable acid addition salts thereof. These compounds have been expressed as useful pharmaceuticals for the prevention or inhibition of viral infections. International application WO94 / 14773 discloses the components have affinity for the receptor similar to 5-HT? and usefulness in the treatment of migraine. These components in this application have the following formula: where R? represents a halogen, a C1-4 alkyl, hydroxide, N02, -NR4R5, R4R5NCO (CH2) m-, R4R5NS02 (CH2) m-, R, C0NH (CH2) -, or R, SO, (CH2) -, R and R, each independently represents hydrogen or alkoyl C1_4 or N4R5 represents a heterocyclic ring of 5 to 7 members; R6 represents hydrogen or C14 alkyl, R7 represents C14 alkyl, m is zero, 1, or 2; n is zero or from 1 to 5; R2 and R3 each independently represents hydrogen, C16 alkyl or benzyl or -NR2R3 represents a pyrrolidino, piperidino or a hexahydroazepino ring; and A represents a bond, an alkylene chain Ca_s or a C 35 alkenyl chain in which the double bond is not adjacent to the nitrogen atom. Murray et al., Bioorg. Med. Chem. Let., 5: 219 (1995), describes 4-carboxamidobiphenyls and says they have affinity to the dopamine D3 receptor.SUMMARY OF THE INVENTION This invention provides novel components of Formula 1 which interact with the subtypes of the dopamine receptor. In this way, the invention provides components of the General Formula 1 useful in the treatment and / or prevention - of several neuropsychological disorders. The invention also provides pharmaceutical compositions comprising the compounds of Formula 1.

The invention furthermore relates to the use of such compounds and compositions in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinson's and dystonia. The components of this invention are also useful in the treatment of extrapyramidal side effects associated with the use of conventional neuroleptic agents. In addition, the components of the present invention are useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive-compulsive disorders.

Since D3 dopamine receptors are concentrated in the limbic system (Taubes, Science, 265: 1034 (1994)) which control cognition and emotion, compounds that interact with these receptors are also useful in the treatment of cognitive disorders. . Such disorders influence cognitive deficits which are a significant component of the negative symptoms of schizophrenia (social withdrawal and insensitivity). Other disorders include memory impairment or attention deficit disorders - they can also be treated with the components of this invention which interact specifically with the D3 dopamine receptor subtype.

In addition, the components of this invention are useful in the treatment of depression, impaired memory or Alzheimer's disease by the modulation of D3 receptors which selectively exist in the limbic area known to control cognitive functions and emotions. The corads of the present invention are also useful for the treatment of other disorders that respond to dopaminergic blockade such as substance abuse (Caine and Koob, Science, 260: 1814 (1993)) and obsessive-compulsive disorder (Goodman et al., Clin. Psychopharmacol; 7: 35 (1992)). The compounds of the invention interact with the dopamine receptor subtypes resulting in the pharmacological activity of these compounds.

Accordingly, a broad mode of the invention is directed to a compound of Formula 1: - or the pharmaceutically acceptable acid addition salts thereof; where: T: represents where R a and R b independently represent hydrogen, C 6 alkyl, hydroxide, C 1 -C 6 alkoxy or amino mono- or disubstituted with C 1 Cg alkyl and n is an integer from one to four; R? and R2 are the same or different and represent hydrogen. C -Cg alkyl, halogen, hydroxy, amino, cyano, nitro, trifluromethyl, trifluromethoxy, C1-Cβ alkoxy, -02CR ', -NHCOR', -COR ', or -SOmR', where R 'is C ^ Cj alkyl and where m is 0, what 2; or R? and R2 independently represents -CONR'R "O -NR'R" wherein R 'and R "independently represent hydrogen or C-C6 alkyl, R3 is hydrogen, C ^ C, alkyl, or -COR"' where R '" is CC alkyl, R4 is hydrogen or C1-C6 alkyl, and R represents an azacycloalkylalkyl group.

Thus, the invention relates to the use of - compounds of Formula 1 in the treatment and / or prevention of neuropsychological disorders including, but not limited to schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, abuse of substances, decreased memory, cognitive deficits. Motor disorders as Parkinson's and movement disorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION In addition to the compounds of the formula I described above; the invention encompasses compounds of formula IA: THE wherein ring A, R1 # R2, R3 and R4 are defined above by Formula I; and Rp represents an azacycloalkylalkyl group of the formula wherein Q represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 6 carbon atoms; Z is N or C; R5 and R6 are the same or different and represent hydrogen or C1-C6 alkyl; or Rs and R6 together with the 6-membered ring to which they are attached form a ring of 5 to 8 members; and W is phenyl, naphthyl, 1- (5, 6, 7, 8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, or benzothienyl, each of which is optionally substituted with up to three groups independently selected by halogen, C? -C alkyl, C1-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. Preferred components of Formula IA include those where R1-R4 are hydrogen or alkyl and Q is alkylene of 3-5 carbon atoms. Other preferred compounds of the formula IA are those where R? and R 2 are hydrogen, R 3 is hydrogen or alkyl, more preferably hydrogen or methyl R 4 is hydrogen, methyl, or ethyl, and Q is alkylene of 3-5 carbon atoms.

In addition to the compounds of Formula I in general described above, the invention includes compounds of the general Formula IB: IB wherein: Ring A and R1-R6 are defined above in Formula IA; and Q, Z and W are defined above.

The present invention encompasses compounds of Formula II: II where Ra, R ^ n, R, and R1-R4 are defined above by Formula IA. Preferred compounds of Formula II include those where RyR2 are hydrogen or alkenyl, Ra and ^ are hydrogen, and Q is alkaline of 3-5 carbon atoms. Other preferred compounds of Formula II are those where Ra and Rb are hydrogen, R? and R2 are hydrogen, R3 is hydrogen or alkyl, - more preferably hydrogen or methyl, R4 is hydrogen, methyl, or ethyl, Q is alkylene of 3-5 carbon atoms, more preferably butylene and W is quinoline, naphthyl, or phenyl optionally substituted with up to 2 substituents independently selected from halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy. In more preferred compounds of Formula II, Z is nitrogen, and W is quinolinyl, naphthyl, or phenyl optionally substituted with up to 2 groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the piperazine ring) , the groups are independently selected from halogen, C1-C alkyl and C -C alkoxy. Particularly preferred W groups of Formula II are those where W is naphthyl or phenyl optionally substituted with more than two groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the piperazine ring), the groups independently selected from chlorine, methyl and methoxy.

The present invention encompasses compounds of Formula III.

III where Ra, Rb, R and R? -R4 are defined above in the - - Formula IA. Preferred compounds of Formula III include those where R? -R4 are hydrogen or alkyl, Ra and Rb are hydrogen and Q is alkylene of 3-5 carbon atoms. Other preferred compounds of Formula III are those where Ra and R ^ are hydrogen, R? and R 2 is nitrogen, R 3 is hydrogen or alkyl, more preferably hydrogen or methyl, R 4 is hydrogen, methyl, or ethyl, Q is alkylene of 3-5 carbon atoms, more preferably butylene, and W is quinolinyl, naphthyl, or phenyl optionally substituted with up to two substituents independently selected from halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy. In more preferred compounds of Formula III, Z is nitrogen, and W is quinolinyl, naphthyl or phenyl optionally substituted with up to two groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the piperazine ring), independently selected groups created by halogen , CC alkyl and C1-C4 alkoxy. Particularly preferred W groups of Formula 111 are those in which W is naphthyl or phenyl optionally substituted with up to two groups in positions 2 and / or 3 (in relation to the point of attachment of the phenyl group to the piperazine ring), the selected groups independently created by chlorine, methyl and methoxy.

The invention also provides compounds of Formula IV - - IV wherein Ra, Rb, R, and R? -R4 are defined above by Formula IA. Preferred compounds of Formula IV include those where R1-R4 are hydrogen or alkyl, Ra and B ^ are hydrogen, and Q is alkylene of 3-5 carbon atoms. Other preferred compounds of Formula IV are those where Ra and R ^ are hydrogen, R? and R 2 is hydrogen, R 3 is hydrogen or alkyl, more preferably hydrogen or methyl, R 4 is hydrogen, methyl, or ethyl, Q is alkylene of 3-5 carbon atoms, more preferably butylene and W is quinolinyl, naphthyl, or phenyl optionally substituted up to 2 substituents independently selected by halogen, C 1 C alkyl, and C 1 -C 4 alkoxy. In more preferred compounds of Formula IV, Z is nitrogen, and W is quinolinyl, naphthyl, or phenyl optionally substituted with more than two groups at positions 2 and / or 3 (relative to the point of attachment of the phenyl group to the piperazine ring) , the groups are independently selected from halogen, C 1 -C 4 alkyl and C -C alkoxy. Particularly preferred W groups of Formula IV are those in which W is naphthyl or optionally substituted phenyl with up to two groups in positions 2 and / or 3 (in relation to the point of attachment of the phenyl group to the piperazine ring), Groups are independently selected from chlorine, methyl and methoxy. When a compound of the invention is obtained as a mixture of enantiomers, these enantiomers can be prepared when desired, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example using a quirol HPLC column. Representative compounds of the present invention which are encompassed by Formula 1, include, but are not limited to, the components shown below in Table 11 and the pharmaceutically acceptable salts. The non-toxic pharmaceutically acceptable salts include salts or acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, luenesulfonic, methanesulfonic, such as acetic, HOOC- (CH 2 TI-COOH where n is 0-4 and those similar to those skilled in the art rearrange an extensive variety of pharmaceutically acceptable non-toxic addition salts The present invention also encompasses prodrugs, eg, acylated prodrugs, of the compounds of Formula 1. Those skilled in the art will recognize various methodologies Synthetics which may be used to prepare pharmaceutically acceptable non-toxic addition salts and prodrugs of the compounds encompassed in Formula 1. The following numbered system is used to identify positions in the carbazole ring portion of the compounds of the invention : The following numbered system is used to identify positions in the tetrahydrocarbazole ring portion in the portion of the compounds of the invention: The following numbered system is used to identify positions in the tetrahydrocyclopent (b) ring portion of the compounds of the invention: The following numbered system is used to identify positions in the hexahydrocyclopent (b) ring in the portion of the compounds of the invention: By "alkyl" and "lower alkyl" there are indicated straight- or branched-chain alkyl groups having from 1 to 6 carbon atoms, e.g., C 1 -C 8 alkyl. By "lower alkoxy" and "alkoxy" are indicated straight or branched chain alkoxy groups having from 1 to 6 carbon atoms, e.g., alkoxy and 6. By halogen a fluorine, chlorine, bromine or iodine atom is indicated. Azacycloalkylalkyl denotes a portion of azacycloalkyl, e.g., piperazine or piperidine, linked via a nitrogen atom to an alkylene group, e.g., methylene, ethylene, or butylene.

Where the azacycloalkyl portion is piperazine and the alkylene group is butylene, the resulting group is a piperazinibulyl group. Such group has the formula: The azacycloalkyl group represented by R above includes groups represented by the formula T where Z and W are defined above. The formula T represents saturated heterocyclic ring systems such as, for example, piperidinyl and piperazinyl, - as well as a system of unsaturated heterocyclic rings such as, for example, 1, 2, 3, 6-tetrahydropyrinin. The preferred T groups are the following: where W is defined above. Preferred W groups of the invention are quinolinyl, naphthyl, or phenyl optionally substituted with more than two substituents independently selected from halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy. These optional phenyl substituents are preferably in the 2-position and / or 3-position of the phenyl group relative to the point of attachment of the phenyl group to the 6-membered nitrogen-containing ring. The azacycloalkyl group represented by R also encompasses groups of the formula: where Z and W are defined above and R5 and Rg together with the 6-membered ring are attached to the 5- to 8-membered rings. In such cases and where Z is hydrogen, the resulting group is a diazabicyclo group. examples included 3, 8-diazabicyclo [3.2.1] octane, 3, -diazabicyclo [3.3.1] nonane, -2,5-diazabicyclo [2.2.2] octane, 7, 9-diazabicyclo [4.2.2] decane , and 3, 9-diazabicyclo [3.3.l] nonane.

Representative examples of fused indolecarboxamides according to the invention are shown in Table 1 below. The number below each compound is its compound number. Each of these compounds can be prepared according to the scheme of general reactions set forth below. The compounds in Table I have the following general Formula A: where Rc and Rd independently represent hydrogen or a group of the formula I heard and R, R3 and R4 are defined in the table - - Table 1 Compound The invention also pertains to the use of the compound of General formula I in the treatment of neuropsychological disorders. The pharmaceutical utility of the compounds of this invention are indicated by the following tests on the affinity of the dopamine receptor subtype.

TEST FOR THE ACTIVITY OF THE LEGEND RECEIVER D2 AND D3 COS cell pellets containing recombinantly produced D2 or D3 receptors of green monkeys from Africa were used for the assays. The sample is homogenized in 100 volumes (p / 'vol) of 0.05 M neutral Tris HCl at 4 ° C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (weight / vol) in 0.05 M Tris HCl neutral containing 100 raM NaCl. Incubations are carried out at 48 ° C and contain 0.4 ml of tissue sample, 0.5 nM 3H-YM 09151-2 and the compound of interest in a total incubation of 1.0 ml. Non-specific ligands are defined as the ligands based on the presence of 1 mM spiperon; without further additions, the non-specific logging is less than 20% of the total ligand. The characteristics of the ligand of the representative compound of the invention of subtypes of receptors D2 and D3 are shown in Table 2 for the homogenate of the striatum of the -rata.

TABLE 2 Compound Number 1 D3 K. (nM) D2 K. (nM) 1 0.5 250 3 2 540 4 1 750 1 Compound numbers refer to compounds shown above in Table 1.

The compounds of the general Formula I can be administered orally, topically, parenterally, by inhalation or atomization or rectally in dosage units of formulations containing conventional non-toxic pharmaceutically acceptable carriers, auxiliaries and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically accepted carrier is provided herein. One or more compounds of general Formula I may be presented in association with one or more pharmaceutically acceptable carriers and / or diluents and / or auxiliaries and if desired other active ingredients. The pharmaceutical compositions containing compounds of the general Formula I can be in a form suitable for oral use, for example, tablets, cyclones, lozenges, oily or aqueous suspensions, soluble powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

The compositions planned for oral use can be prepared according to any method known for the pharmaceutical composition manufacturing technique and such composition can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. in order to provide elegance pharmaceutically and of pleasant preparation. The tablets contain the active ingredients in admixture with pharmaceutically acceptable non-toxic excipients where they are suitable for the manufacture of tablets. These substances can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulated and disintegrated agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be discovered or covered by known techniques to delay disintegration and absorption in the gastrointestinal-tract, that is why a sustaining action occurs over a long period, for example, a time-delay material such as glyceryl monostearate. or glyceryl distearate can be used. The formulation for oral use can also be presented by hard gelatin capsules wherein the active agent is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the ingredient active is mixed with water or a medium oil, for example, peanut oil, liquid paraffin, olive oil. The aqueous suspension contains the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspended by agents, for example, sodium carboxymethylcellulose, methylcellulose, hydropropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin or condensation products of an alkaline oxide with fatty acids, for example polyoxyethylene stearate, or condensate products of ethylene oxide with long chain of aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensate products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or - condensate products of ethene oxide with partial esters derived from fatty acids and hexyanolanhydrides, for example polyethylene sorbitan monoeleate. The aqueous suspension may also contain one or more preservatives, for example ethyl, 0 or n-p pyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. The oily suspension can be formulated by suspending the active ingredients in a vegetable oil, for example, dearachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those noted above, and flavoring agents can be added to give pleasant oral suspensions. These compositions can be preserved by the addition of an antioxidant such as an ascorbic acid. Soluble powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agents and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those mentioned above. Additional exipients, for example - flavoring agents, sweeteners and dyes may also be present. The pharmaceutical composition of the invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, for example, olive oil or arachis oil or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be naturally obtained gums, for example acacia gum or tragacanth gum, naturally obtained phosphatides, for example soybeans, lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate , and condensation products of the partial esters with ethylen oxide, for example polyoxyethylene sorbitan monolate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical composition can be in the form of a sterile injectable or oleaginous aqueous suspension. This suspension can be formulated according to the known technique using that suitable dispersing or wetting agent and suspending the agent which has already been mentioned previously. The sterile injectable preparation can also be an injectable solution or suspension in non-toxic parentally acceptable dilution or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used is water, similar solutions and isotonic sodium chloride solution. In addition, sterile, fixed acids are conventionally used as a solvent or medium suspending agent. For this purpose any fixed soft oil may be used including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid found use in the preparation of injections. The compounds of the general Formula I can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by drug mixtures with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at rectal temperature and can therefore dissolve in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the general Formula I can be administered parentally in a sterile medium. The drug, depending on the vehicle and concentration used, can be any suspension or solvent in the vehicle. Advantageously, auxiliaries such as local anesthetics, preservatives and neutralizing agents can be dissolved in the vehicle. The dose level of the order of about 0.1 mg to about 140 mg per kilogram of body weight per day is useful in the treatment of the indicated conditions (from 0.5 mg to 7g per patient per day). The amount of active ingredient that can be combined with the carrier materials to cause a single dose form can vary depending on the patient to be treated and the particular mode of administration. The dosage unit form may generally contain between about 1 mg to about 500 mg of an active ingredient.

This can be understood, however, as the specific dose level by any particular patient. Depend on a variety of factors including the activity of the specific component employed, age, weight, health status, sex, diet, time of administration, trajectory of administration, and percentage of excretion, drug combination and the severity of the particular disease suffering therapy. Preparation of N-aminoalkyldibenzofurancarboxamides The composition of the invention and its pharmaceutically acceptable acid addition salts can therefore be prepared according to the ratios shown below in the following schemes. The compounds of Formula I can be prepared by a process which consists of reacting a compound of the Formula V with a compound of Formula Vl as shown below.

Formula I Where R1, R2, R3, R4, R5, A, Q, Z and W are defined above in Formula I A compound of Formula V can be activated with a reagent such as 1, 1'-carbonyldiimidazole (CDl) similar to the solvent such as tetrahydrofuran or at room temperature. The resulting activated carboxylate intermediate can be subsequently reacted with a compound of Formula Vl to produce a compound of Formula I as the desired product.

A compound of the Formula Va (; CHyAl? NI i » Va - - wherein Ra, Rb, R1, R2 and n are defined above, can be prepared by a reacted compound of the Formula Val with a component of the Formula Va2 by the Fisher synthesis as shown below.

Ftschßr Synthesis * Formula Acetic Acid tín where Ra, Rb, R?, R2 and n are defined above. The reaction can be carried out according to well-written procedures in the literature. For example, see Robinson, "The Fischer Nature Synthesis", Wiley, New York, 1983. Preferably, the reaction is carried out in the presence of acetic acid under reflux for about four hours. In the case where n is 2, a compound of Formula Va3 can be prepared as described in the scheme below by dehydrogenation of a compound of Formula Va in a solvent reflux such as xylene or the like in the presence of a catalyst as, for example, palladium in carbon.

Preferably, the reaction is carried out with 10% palladium on carbon in xylene at reflux for about eight hours.

- - Va, n = 2 Va3 Similarly, a compound of Formula Vb Vb where Ra and 1 ** ^ are defined previously by the Formula 1, can be prepared by dehydrogenation of a compound of Formula Vbl as shown in the scheme below in solvent reflux such as, for example, xylene, in the presence of a catalyst such as the similar carbon palladium. Preferably, the reaction is carried out with 10% sodium palladium in xylene at reflux for about eight hours.

Vbl Vb Adelante, a compound of the Formula Vbl - - Vbl wherein Ra, and R ^ are defined above by Formula 1, can be prepared by the reaction of a compound of Formula Vb2 with a compound of Formula Vb3 by Fisher's synthesis as shown below: Formula Vb1 Vb2 Vb3 , Q wherein Ra and H ^ are defined above in Formula 1. The reaction can be carried out according to procedures well known in the literature. See, for example, Robinson, "The Fischer Nature Synthesis," Wiley, New York, 1983. Preferably, the above reaction is carried out in the presence of oily acid (HOAC) under reflux for about four hours.

A compound of Formula V - - v wherein R ^ R;, and A are defined above and R3 is hydrogen, can be prepared by methods analogous to those described above for Formula Va or those for Formula Vb. Where R3 is not hydrogen, a compound of Formula V can be prepared by reaction of a compound of Formula VCl Vcl wherein R1, R2 and A are defined above with a halide of the formula: R3-X, where R3 is defined above by Formula I and X is a halide. The reaction is usually carried out in the presence of a base such as, for example, K2C03 in a solvent such as acetone or the same at room temperature. Subsequently, the immediate result can be hydrolyzed with a base such as NaOH or the same in an aqueous solvent such as methanol at about 50 ° C to produce a compound of Formula V. Preferably, the reaction is carried out with K 2 CO 3 in acetone, and the - -hydrolysis is carried out with NaOH in aqueous methanol.

Where they are not commercially available, the compounds of Formula Val, Formula Va2, Formula Vb2 and Formula Vb3 can be prepared by procedures analogous to those described in the literature. The compounds of Formula VI can often be obtained from commercial sources.

Alternatively, such compounds are known compounds or are capable of being prepared by literary methods. Those of skill in the art can recognize that the beginning of materials can be varied and by employing additional steps to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, the protection of certain functional reagents may be necessary to achieve some of the above transformations. In general, the need to protect such groups can be apparently protected by them in the technique of organic synthesis, as well as the conditions necessary to adhere or remove such groups. The description of this application of all articles and references, including patents, are incorporated herein for reference. The invention is further illustrated by the following examples which can not be construed as -limrants of the invention in the scope or spirit of the specific procedures described therein. These examples illustrate the currently preferred methods for the preparation of the compounds of the invention.

Example 1 1. 1,2,3,4-Tetrahydrocarbazole-6-carboxylic acid A mixture of 4-hydrazinobenzoic acid (5.0 g, 32.9 mmol) and cyclohexanone (3.3 g, 33 mmol) in 30 mL of acetic acid is heated under reflux for 4 hours, then cooled, diluted with water and acidified with HCl. The resulting solid is collected by filtration, washed with water and dried to give 3.6 g of the title compound as a crystalline solid. 2. N- (1- {4- [4- (2,3-dichlorophenyl) piperazin-1-yl].} Butyl) -1,2,3,4-tetrahydrocarbazole-6-carboxamide hydrochloride - - (Compound 1). A mixture of l, 2,3,4-tetrahydrocarbazole-6-carboxylic acid (100 mg, 0.46 mmol) and 1,1 '-carbonyldiimidazole (78 mg, 0.48 mmol) in 5 mL of anhydrous tetrahydrofuran is stirred for 8 hours. A solution of 4- [4- (2, 3-dichlorophenyl) piperazin-1-lo] -1-aminobutane (140 mg, 0.46 mmol) in 1 mL of tetrahydrofuran was added and the result of the mixture is stirred for 30 minutes . The reaction of the mixture was divided between ethyl acetate and water. The organic layer was washed with aqueous Na 2 CO 3 solution, dried (Na 2 SO 4) and concentrated in vacuo to give the free base of the title compound, N- (1 -. {4- [4- (2, 3-dichlorophenyl) piperazine) 1-I].) Butyl) -1,2,4-tetrahydrocarbazole-6-carboxamide, (161 mg, 70%). The hydrochloride salt is prepared to treat the free base with a solution of hydrogen chloride in ethyl acetate (mp 236-238 ° C).

Example 2 The following compounds are prepared essentially according to the procedures outlined above in Example 1. (a) N- (1- {4- [4- (3-chloro-2-methylphenyl) piperazine-1-hydrochloride] -yl].} butyl) -1,2,3,4-tetrahydrocarbazole-6-carboxamide (mp 229-231 ° C) (b) N- (1- {4- [4- (2) hydrochloride , 3-Dimethylphenyl) piperazin- (1-yl) butyl) -1,2,3,4-tetrahydrocarbazole-6-carboxamide (p. 224-226 ° C) (c) N- (L-. {4- [4- (1-Naphthyl) piperazin-1-yl].] Butyl) -1,2,3,4-tetrahydrocarbazole hydrochloride -6-carboxamide (mp 207-210 ° C) (d) N- (1- {4- [4- (2,3-Dichlorophenyl) piperazin-1-yl] butyl) -1-butyl hydrochloride) -1 , 2,3, 4-tetrahydrocyclopen [b] -Indiene-7-carboxamide (Compound 6, mp 224-226 ° C) (e) N- (1-. {4- [4- (3-chloro- 2-methylphenyl) piperazin-1-lo].} Butyl) -1,2,3,4-tetrahydro-cyclopenfb] indole-7-carboxaraide (mp 231-233 ° C) (f) N- (N-alkyl) hydrochloride - { 4- [4- (2,3-Dichlorophenyl) piperazin-1-lo].} Butyl) -5,6,7,8,9, 10-hexahydro-cyclopen [b] indole-2 carboxamide (Compound 7, mp 212-214 ° C) Example 3 1 - Preparation of 9H-carbazole-3-carboxylic acid A suspension of 1,2, 3,4-tetrahydrocarbazole-6-carboxylic acid (1.0 g, 4.6 mmol) and 10% Pd / C (0.7 g) in 50 mL of xylene is heated under reflux for 8 hours. The hot reaction mixture is filtered through celite. The liquid is concentrated in vacuo to give the title compound (0.8 g, - - 80%) 2. N- (L-. {4- [4- (2, 3-dichlorophenyl) piperazin-1-yl].] Butyl) -9H-carbazole-3-carboxamide hydrochloride (Compound 2). A mixture of 9H-carbazole-3-carboxylic acid (50 mg, 0.23 mmol) and 1,1 '-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydrous tetrahydrofuran is stirred for 8 hours. A solution of 4- [4- (2, 3-dichlorophenyl) piperazin-1-yl] -1-aminobutane (70 mg, 0.23 mmol) in 1 mL of tetrahydrofuran was added and the result of the mixture is stirred for 30 minutes . The reaction of the mixture was divided between ethyl acetate and water. The organic layer was washed with aqueous Na 2 CO 3 solution, dried (Na 2 SO 4) and concentrated in vacuo to give the title compound (85 mg, 72%) The hydrochloride salt is prepared to treat the free base with a solution of hydrogen chloride in ethyl acetate ( mp 214-216 ° C).

Example 4 The following compounds are prepared essentially according to the procedures outlined above in Example 3. (a) N- (l-. {4- [4- (2,3-Dimethylphenyl) piperazin-1-yl hydrochloride ].) butyl) -9H-carbazole-3-carboxamide (mp 218-220 ° C) (b) N- (L-. {4- [4- (1-Naphthyl) piperazin-1-yl] Jbutyl) -9H-carbazole-3-carboxamide hydrochloride (mp 225-227 ° C) Example 5 1- 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid Q ?? tt'.OH A mixture of 3-ketocyclohexanecarboxylic acid (4.78 g, 33.9 mmol) and phenylhydrazin (3.66 g, 40 mmol) in 35 mL of acetic acid is heated under reflux for one hour, then cooled, diluted with water and acidified with HCl. The resulting solid is collected by filtration, washed with dried water to give 5.5 g of the title compound as a crystalline solid. 2. 9H-carbazole-2-carboxylic acid A suspension of 1,2,3,4-tetrahydrocarazol-2-carboxylic acid (0.6 g, 2.8 mmol) and 10% Pd / C (0.5 g) in 30 mL of xylene is heated under reflux for 8 hours. The hot reaction mixture is filtered through celite. The liquid is concentrated in vacuo to give the title compound (0.5 g, 85%). 3. N- (1- {4- [4- (2,3-dichloropenyl) piperazin-1-yl]} butyl) -9H-carbazole-2-carboxamide hydrochloride (Compound 4) A mixture of 9H-carbazole-2-carboxylic acid (50 mg, 0.23 mmol) and 1,1 '-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydrous tetrahydrofuran are stirred for 8 hours. A solution of 4- [4- (2, 3-dichlorophenyl) piperazin-1-yl] -1-aminobutane (70 mg, 0.23 mmol) in 1 mL of tetrahydrofuran is added and the result of the mixture is stirred for 30 minutes. The reaction of the mixture is divided between ethyl acetate and water. The organic layer is washed with aqueous Na 2 CO 3 solution, dried (Na 2 SO 4) and concentrated in vacuo to give the title compound (75 mg, 64%). The hydrochloride salt is prepared by treating the free base with a solution of hydrogen chloride in ethyl acetate (mp 240-241 ° C).

Example 6 The following compounds are prepared essentially according to the procedures outlined above in Example . (a) N- (1- {4- [4- (2, 3-Methylphenyl) piperazin-1-yl} butyl) -9H-carbazole-2-carboxamide hydrochloride (Compound 8, mp 250- 253 ° C). (b) N- (-1- (4- [4- (3-Chloro-2-methylphenyl) piperazin-1-yl] butyl) -9H-carbazole-2-carboxamide hydrochloride (Compound 10, mp. 246-248 ° C.) Example 7 1. 9-Acetylcarbazole-3-carboxylic acid A mixture of 9H-carbazole-3-carboxylic acid (300 mg, 1.42 mmol), K2CO3 (800 mg) and methyl iodide (1 mL) in 25 mL of acetone was heated under reflux overnight, then cooled and evaporated in vacuo. . A mixture of the resulting residue and NaOH (170 mg) in aqueous MeOH (90%, 25 mL) is stirred at 50 ° C for 30 minutes. The reaction mixture is concentrated and acidified with dilute HCl. The solids are collected by filtration and dried to give the title compound (280 mg, 87%). - - 2. N- (l- { 4- [4- (2, 3-dichlorophenyl) piperazin-l-yl].} Butyl) -9-methylcarbazole-3-carboxamide hydrochloride (Compound 3) A mixture of 9H-carbazole-2-carboxylic acid (50 mg, 0.23 mmol) and 1,1 '-carbonyldiimidazole (39 mg, 0.24 mmol) in 5 mL of anhydrous tetrahydrofuran are stirred for 8 hours. A solution of 4- [4- (2, 3-dichlorophenyl) piperazin-1-yl] -1-aminobutane (70 mg, 0.23 mmol) in 1 mL of tetrahydrofuran is added and the result of the mixture is stirred for 30 minutes . The reaction of the raezcla is divided between ethyl acetate and water. The organic layer is washed with aqueous Na 2 CO 3 solution, dried (Na 2 SO 4) and concentrated in vacuo to give the title compound (80 mg, 68%). The chloridrate salt is prepared to treat the free base with a solution of hydrogen chloride in ethyl acetate (mp 237-239 ° C).

Example 8 The following compounds are prepared essentially according to the procedures outlined above in Example 7. (a) N- (1- {4- [4- (3-Chloro-2-methylphenyl) - piperazin-1-hydrochloride] il].) butyl) -9-methylcarbazole-3-carboxamido (mp) 224-226 ° C) (b) N- (L-. {4- [4- (2,3-Dichlorophenyl) piperazin-1-yl].] Butyl) -9-methylcarbazole-2-carboxamide hydrochloride (Compound 5, mp 276-78 ° C) (c) N- (1- {4- [4- (3-Chloro-2-methylphenyl) piperazin-1-yl].} Butyl hydrochloride) - 9-methylcarbazole-2-carboxamide (Compound 9, mp 269-271 ° C) The invention and the mode and process of manufacture and use, is now described in complete similarity, clarity, conciseness and exactness as allowed by any person skilled in the art to which it belongs, for manufacture and use it This is to be understood as above, it describes preferred embodiments of the present invention and what modifications can be made without departing from the spirit or scope of the present invention, as pointed out successively in the claims To particularly and distinctly claim the subject matter of the invention, the following claims conclude this specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (26)

CLAIMS 1. A compound of the formula: or pharmaceutically acceptable addition salts thereof, characterized in that: T represents where Ra and ^ independently represent hydrogen, C ^Cg alkyl, hydroxy, alkoxy < 21-C6, or amino mono- or disubstituted with C1-C6 alkyl; and n is an integer from one to four; R1 and R2 are the same or different and represent hydrogen, C1-C6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy C? -C, -OCR ',
1. NHCOR ', -COR', -SOmR ', where R' is C? -C6 alkyl and wherein m is 0, 1 or 2; or R1 and R2 independently represent -CONR'R ", or -NR'R1 'where R' and R" independently represent hydrogen or C? -C? alkyl; R3 is hydrogen, C? -C8 alkyl, or -COR? " where R 1"is C 1 Cg alkyl, -R 4 is hydrogen or C 1 -C 8 alkyl, and R represents an azacycloalkylalkyl group.
2. 2. A compound of the formula: characterized because or represents where Ra and R ^ independently represent hydrogen, alkylCyC6, hydroxy, alkoxy-C8, or amino mono- or disubstituted with C ^ Cg alkyl, and n is an integer from one to four; R? and R 2 are the same or different and represent hydrogen, C 1 Cg alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, CC alkoxy, -OCR ', -NHCOR 1, -COR', -SOmR ', where R 1 is C1-C8 alkyl and wherein m is 0, 1 or 2; or R? and R2 independently represent -CONR'R ", or -NR'R" wherein R 'and R "independently represent hydrogen or C ^ Cg alkyl, -R3 is hydrogen, C ^ Cg alkyl, or -COR"' ' where R '' 'is Cl-C6 alkyl; R 4 is hydrogen or C 1 -C 6 alkyl; and R represents an azacycloalkylalkyl group of the formula where Q represents an alkali group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 6 carbon atoms; Z is N or C; R5 and R6 are the same or different and represent hydrogen or C ^ Cg alkyl; or Rs and Rg together with the 6-membered ring for which they are attached from 5 to the 8-membered ring; and W is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with above three independently selected groups by halogen, C-alkyl, CX-C4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
3. 3. A compound according to claim 2, characterized in that! is :
4. 4. A compound of the formula: characterized in that R a and R b independently represent hydrogen, C 1 -C 0 alkyl, hydroxy, C 1 -C 6 alkoxy, or mono- or de-substituted amino with C 6 -C 6 alkyl; and n is an integer from one to four; R? and R 2 are the same or different and represent hydrogen, C 1 -C 1 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 4 alkoxy, -OCR ', NHCOR', -COR ', -SOmR', where R 'is C ^ Cg alkyl and wherein m is 0, 1 or 2; or R and R2 independently represent -CONR'R ", or -NR'R" wherein R 'and R "independently represent hydrogen or C1-C8alkyl; R3 is hydrogen, C? -C? Alkyl, or -COR? '' Where R '' 'is C? Cg alkyl, - R4 is hydrogen or C? -C6 alkyl; and R represents an azacycloalkylalkyl group of the formula where Q represents an alkali group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; Z is N or C; R5 and R6 are the same or different and represent hydrogen or C1-C alkyl; or R5 and R6 together with the 6-membered ring for which they are attached from 5 to the 8-membered ring; and W is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with up to three groups independently selected by halogen, C-alkyl, C 1 -C 4 alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
5. 5. A compound according to claim 4, characterized in that:
6. 6. A compound of the formula: characterized in that Ra and Rb independently represent hydrogen, alkyl C ^ Cg, hydroxy, C ^ Cg alkoxy, or mono- or de-substituted amino with C ^ Cg alkyl, - and R? and R 2 are the same or different and represent hydrogen, C ^ -8 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, -02CR ', NHCOR ', -COR', -SOmR ', where R' is C? -C6 alkyl and where m is 0, 1 or 2; or R? and R2 independently represent -CONR'R1 ', or -NR'R "wherein R' and R" independently represent hydrogen or C ^ Cg alkyl, - R3 is hydrogen, C ^ Cg alkyl, or -COR "'where R '' 'is C1-C8 alkyl; R 4 is hydrogen or C 1 -C 8 alkyl; and R P represents an azacycloalkylalkyl group of the formula where Q represents an alkali group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; Z is N or C; R5 and R6 are the same or different and represent hydrogen or C ^ Cg alkyl; or Rg and Rg together with the ring of 6 members to which they are attached form a ring of 5 to 8 members; and W is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with up to three independently selected groups by halogen, C? -C8 alkyl, C? Cg alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluromethyl or trifluromethoxy
7. 7. A compound according to claim 6, characterized by:
8. 8. A compound of the formula: characterized in that Ra and R, 2 independently represent hydrogen, C 1 -C 6 alkyl hydroxy, C 1 -C 6 alkoxy, or amino mono- or de-substituted with C 1 -C 6 alkyl; and R? and R 2 are the same or different and represent hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy CC alkoxy, -OCR ', NHCOR', -COR ', -SOmR', where R 'is alkyl C? -C8 and wherein m is 0, 1 or 2; or R? and R2 independently represent -CONR'R ", or -NR'R" wherein R1 and R "independently represent hydrogen or C1-C3 alkyl; R 3 is hydrogen, C 1 Cg alkyl, or -COR * "wherein R '" is C 1 -C 8 alkyl; R 4 is hydrogen or C 1 -C 8 alkyl; and R represents an azacycloalkylalkyl group of the formula where Q represents an alkali group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; Z is N or C; R5 and R6 are the same or different and represent hydrogen or C1-C6 alkyl; or R5 and R6 together with the 6-membered ring for which they are attached from 5 to the 8-membered ring; and w is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, "quinolinyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with up to three groups independently selected by halogen, C -C alkyl, C 1 -C 4 alkoxy, thioalkoxy, hydroxy, amino, monoaxykylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
9. 9. A compound according to claim 8, characterized in that:
10. 10. A compound according to claim 1, which is N- (1- {4- [4- (2, 3-dichlorophenyl) piperazin-1-yl].} Butyl) hydrochloride -1,2, 3, 4 -tetrahydrocarbazole-6-carboxamido.
11. 11. A compound according to claim 1, which is N- (L-. {4- [4- (3-chloro-2-methylphenyl) piperazin-1-yl].] Butyl) hydrochloride -1, 2, 3 , 4-tetrahydrocarbazole-6-carboxamido.
12. 12. A compound according to claim 1, which is N- (1- {4- [4- (2,3-dimethylphenyl) piperazin-1-yl].} Butyl) hydrochloride -1, 2, 3, 4 -tetrahydrocarbazole-6-carboxamido.
13. 13. A compound according to claim 1, which is N- (L-. {4- [4- (1-Naphthyl) piperazin-1-yl].] Butyl) -1,2,3,4-tetrahydrocarbazole hydrochloride. -6-carboxamido.
14. 14. A compound according to claim 1, which is N- (1- {4- {4- (2,3-dichlorophenyl) piperazin-1-yl].} Butyl) hydrochloride -5,6,7,8 - tetrahydrocielopent [b] -7-carboxamido.
15. 15. A compound according to claim 1, which is N- (L-. {4- [4- (3-Chloro-2-methylphenyl) piperazin-1-yl].] Butyl hydrochloride) -5,6,7 , 8 -tetrahydro-cyclopent [b] -7-carboxamido.
16. 16. A compound according to claim 1, which is N- (L-. {4- [4- (2,3-Dichlorophenyl) piperazin-1-yl].] Butyl) hydrochloride -5,6,7,8 , 9, 10-hexahydro-cyclopen [b] indole-2-carboxamido.
17. 17. A compound according to claim 1, which is N- (1- {4- [4- (2,3-Dichlorophenyl) piperazin-1-yl].} Butyl) -9H-carbazole-3-carboxamide hydrochloride. .
18. 18. A compound according to claim 1 which is N- (1- {4- [4- (2, 3-Dimethylphenyl) piperazin-1-yl].} Butyl) -9H-carbazole-3-carboxamide hydrochloride .
19. 19. A compound according to claim 1, which is N- (l-. {4- [4- (1-Naphthyl) piperazin-1-yl].] Butyl) -9H-carbazole-3-carboxamide hydrochloride.
20. 20. A compound according to claim 1, which is N- (1- {4- [4- (2,3-Dichlorophenyl) piperazin-1-yl].} Butyl) -9-methylcarbazole-3-carboxamide hydrochloride. .
21. 21. A compound according to claim 1, which is N- (1- {4- [4- (3-Chloro-2-methylphenyl) piperazin-1-yl].} Butyl) -9-methylcarbazole-3 hydrochloride. -carboxamido.
22. 22. A compound according to claim 1, which is N- (L-. {4- [4- (2, 3-Dichlorophenyl) piperazin-1-yl].] Butyl) -9H-carbazole-2-carboxamide hydrochloride. .
23. 23. A compound according to claim 1, which is N- (1- {4- {4- (2, 3-methylphenyl) piperazin-1-yl].} Butyl) -9H-carbazole-2-carboxamide hydrochloride. .
24. 24. A compound according to claim 1, which is N- (L-. {4- [4- (3-Chloro-2-methylphenyl) piperazin-1-yl].] Butyl) -9H-carbazole-2 hydrochloride. -carboxamido.
25. 25. A compound according to claim 1, which is N- (L-. {4- [4- (2, 3-Dichlorophenyl) piperazin-1-yl].] Butyl) -9-methylcarbazole-2-carboxamide hydrochloride. .
26. 26. A compound according to claim 1, which is N- (1- {4- [4- (3-Chloro-2-methylphenyl) piperazin-yl].} Butyl) -9-methylcarbazole-2-hydrochloride. carboxamido, SUMMARY OF THE INVENTION Described are compounds of formula (I) or the pharmaceutically acceptable acid addition salts thereof, wherein (a) represents an aromatic or alicyclic ring; R? and R2, are the same or different and represent hydrogen alkyl of 1 to 6 carbon atoms, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, of 1 to 6 carbon atoms, -02CR ', -NHCOR ', -COR', -SOmR ', wherein R' is alkyl having 1 to 6 carbon atoms wherein m is 0, 1 or 2; or R? and R2 independently represent -CONR'R ', or -NR'R', wherein R 'and R1' independently represent hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydrogen, alkyl of 1 to 6 carbon atoms or -COR '"wherein R'" is alkyl of 1 to 6 carbon atoms; R 4 is hydrogen or alkyl of 1 to 6 carbon atoms; and R represents an azacycloalkylalkyl group, which compounds are useful in the treatment of effective disorders such as ezisophrenia, depression, Alzheimer's disease, movement disorders such as Parkinson's, and dystonia, and other conditions that respond to dopaminergic block, such as sufferings due to substance abuse and obsessive compulsive disorders. In addition, the compounds of this invention are useful in the treatment of extrapyramidal side effects associated with the use of conventional neuroleptic agents.