GB2040922A - Carbazoles - Google Patents

Abstract

9-[3-(3,5-cis- Dimethylpiperazino)propyl] carbazole, salts thereof and solvates of the salts are useful in treating aggression and psychoses in man and aggression in animals.

Description

SPECIFICATION Pharmaceutical heterocyclic compounds, preparation, use and intermediates therefor and their preparation The present invention relates to compounds having valuable antiaggression and antipsychotic properties, the preparation of such compounds, pharmaceutical compositions containing such compounds and the preparation of such compositions, the use of the compounds in human and veterinary medicine, and intermediates of value in theprepara- tion of the compounds by the methods described.

Australian Patent No. 201630 and French Patent No. 1167510 describe as having anti-epileptic properties carbazoles of formula (I):

wherein A represents a divalent saturated aliphatic hydrocarbon radical with a straight or branched chain containing 2 to 6 carbon atoms, R1 represents a hydrogen atom or a lower alkyl or an aryl or araliphatic group, Y andY1 are respectively a hydrogen or halogen atom or a lower alkyl, alkoxy, aryl or aryloxy group, the ring containing Y orY, may contain substituents additional to Y andY1 and one of more of the carbon atoms of the piperazine ring may carry a substituent in the form of a methyl group.

It has now been found that a particular compound 9 - [3 (3,5 - cis - dimethylpiperazino) propyls carbazole (sometimes named as cis - 9 - [3 - (3,5 dimethylpiperazinyl) propyl] carbazole or 9 - [3 - (cis 3,5 - dimethyl - 1 - piperazinyl) propyl] carbazole) of formula (A):

hereinafter referred to as the "Carbazole", its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of its pharmaceutically acceptable salts unexpectedly exhibit valuable antiaggressive and anti-psychotic properties rendering them useful for the treatment of aggression and psychoses in humans. The compounds herein unexpectedly do not exhibit the toxic side-effects, e.g.

dyslexia or sedative action associated with antipsycotics such as chlorpromazine and the like.

As used herein, the term "treatment" is meant to include the prophylactic administration of the "Carbazole" to a patient (human) who has already been identified as once having exhibited aggressive or psychotic symptoms as well as the therapeutic administration of the "Carbazole" to a patient (human) exhibiting aggressive or psychotic symptoms. The pharmacological test procedure used to demonstrate anti-aggressive and anti-psychotic properties of the "Carbazole" is described by McKenzie, G. M. in Brain Research, 34, 323 (1971). In this test, the "Carbazole" antagonised apomorphineinduced aggression in the rat and, as a further indication of its antipsychotic and anti-aggressive properties, it was found to suppress the instinctive muricidal (i.e. mouse killing) behaviour of rats (see Leaf et al., Aggressive Behaviour, edited by S. Garattini and E. B. Sigg, pages 120-131, John Wiley and Sons, Inc., New York, 1969).

The potency of the "Carbazole"s' antiaggressive and anti-psychotic properties has been found to depend on the particular positioning of its methyl substituents. For example, it has been found more potent than either the corresponding nonmethylated compound orthe analogous 4-methyl or 3,4,5- trimethyl compounds.

The "Carbazole" is particularly valuable since its anti-psychotic and anti-aggressive action is substan tiallyfree from undesirable side-effects such as sedation, catalepsy and extrapyramidal dysfunction associated with currently used anti-psychotics such as the phenothiazines. An indication that the "Carbazole" does not interfere with extrapyramidal function is its failure to antagonise apomorphine induced stereotyped behaviour in the rat (see Andien, N.E.,J.

Psychiat Res., 11,97, 1974. There is also significantly less anti-cholinergic and anti-histamine activity associated with the "Carbazole's" action than with the phenothiazones.

While the useful biological properties of the "Carbazole" reside in the base moiety, the latter is capable of forming salts (i.e. acid addition salts), and all such salts are included within the scope of the present invention. For therapeutic purposes the acid moiety of such salts is preferably pharmaceutically acceptable to the intended recipient. As examples of such pharmaceutically acceptable salts may be mentioned (a) those formed with inorganic acids, for example the sulphate and hydrogen halides such as the hydrochloride, and (b) those formed with organic acids such as the acetate, citrate, fumarate, lactate (for example the DL lactate), malate (for example the L-malate), maleate, succinate and tartrate (for example the L-tartrate) as well as alkanesulphonates such as the methane sulphonate and the arylsulphonates such as thep-toluenesulphonate. The "Carbazole" base may be converted to salts thereof, and the salts converted to the base of to salts of other acids, by means well known in the art. Thus, salts which are not pharmaceutically acceptable are of value in the preparation of salts which are. In addition the salts of the "Carbazole" base can form well-defined solvates such as hydrates and solvates of alcohols (for example methanol and ethanol) and all such solvates are also included within the scope of the present invention.

The "Carbazole" may be synthesised by any method known in the art for the synthesis of com pounds having an analogous structure.

1. A preferred synthesis involves linking the alkylene chain to either or both of the carbazole and piperazine rings. This may be done by reacting a compound of formula (II), (IIA), or (IIB) as appropriate, wherein each Z is a leaving atom or group;

3,5 - cis - dimethylpiperazine or both carbazole and 3,5 - cis - dimethylpiperazine, respectively. Any atom or group may be used for the variable Z which enables substitution to take place on the appropriate amino group; for example, halo (preferably chloro), arylsulphonyloxy (preferably p-toluenesulphonyloxy) or alkylsulphonyloxy (preferably methanesulphonyloxy).

Although compounds (II) and (IIB) will react directly with cabazole it is advantageous to use a carbazole derivative; particularly suitable derivatives are those with alkali or alkaline earth metals, especially lithium, sodium, potassium, zinc, cadmium and calcium, although carbazole magnesium halide, e.g., iodide, may also be used.

The alkali metal carbazoles are conveniently prepared by reacting carbazole with the appropriate alkali metal hydride or amide in an inert, preferably polar, aprotic solvent such as liquid ammonia, dimethylformamide or dimethylsulphoxide; other solvents which may be suitable include hydrocarbons, e.g., alkanes, cycloalkanes and aromatic compounds. The same reaction medium may then be used for effecting N-substitution which is preferably carried out with heating. It is advisable that the N-substitution take place in solution under an inert atmosphere such as nitrogen.

Alternatively, the compound of formula (II) may be reacted with carbazole in the presence of an alkali metal hydroxide or alkali metal alkoxide in a polar solvent such as dimethylformamide, dimethylacetamide, water or the corresponding alkanol as appropriate; for example potassium tertbutoxide in tert-butanol.

When 3,5 - cis - dimethylpiperazine is reacted with a compound of formula (IIA) this may be done in a polar aprotic solvent such as dimethylformamide, dimethylsulphoxide, or acetonitrile or a protic solvent such as water or an aliphatic alcohol.

The intermediates of formula (II) are readily obtained from the corresponding alcohol by conventional techniques. For example, the alcohol may be converted to the chloride by reaction with thionyl chloride. The alcohol may itself be made by reaction of a substituted alcohol of formula Z - (CH2)3 - OH, wherein Z has the same meaning as in formula (II), with 3,5 - cis - dimethylpiperazine.

Synthesis of intermediates of formula (IIA) may be by N-substitution analogous to the reaction of compound (II) with carbazole to produce the 'Carbazole' of formula (A).

A modification of the previously described synthesis comprises the use of intermediates of formulae (IIC) or (IID), thus effecting an addition, rather than a substitution, reaction. The reaction may be effected at high temperatures and pressures in the presence of an alkali, such as in an autoclave at a temperature up to 1200 for example about 115 with an alkali metal hydroxide such as sodium hydroxide. Desirably an equimolar amount of alkali is used.

Similarly intermediates of formula (II) and (IIA) may themselves be obtained by an addition reaction involving a Michael-type condensation of a piperazine or carbazole, respectively with acrylic acid or a derivative thereof such as acid halide, ester, amide or nitrile. The acid derivative can be hydrolysed to the acid which in turn can be reduced to the corresponding alcohol. The alcohol can then be converted to intermediates of formula (II) and (IIA) as previously described.

As a further possibility the 'Carbazole' may be prepared by reacting an aldehyde of formula (llE)or (IIF) with respectively carbazole or 3,5 - cis dimethylpiperazine and subsequent selective reduction. The initial reaction step may be performed in an inert, preferably polar aprotic solvent such as dimethylformamide or dimethylsulphoxide while the selective reduction may be effected in the same medium, as a 'one-pot' reaction, using a hydride, borohydride or borane, for example sodium borohydride or lithium aluminium hydride, or a functionaliy equivalent reagent.

The aldehyde starting materials may be prepared from a corresponding acetal, for example from the appropriate 3,3-diethoxypropyl compound using a reagent such as pyridinep-tolylsulphonate in acetone/water at reflux. The acetate in its turn may be prepared by standard techniques from 3,5 - cis dimethylpiperazine or carbazole, as appropriate; for example in the specific instance mentioned hereinabove by reaction with chloropropionaldehyde diethylacetal under the conditions hereinabove described for the reactions involving the compounds of formulae (II), (IIA) and (lIB).

2. The "Carbazole" may also be synthesized by reductive cyclisation of a compound of formula (III):

wherein Y' and V2 together form oxo, thioxo or imino, or V1 is hydroxy and V2 is hydrogen, and the groups Y3 and Y4 are defined in the same way as Y' and V2, with the proviso that both Y' and Y3 may not be hydroxy, except that when Y' to Y4 do not include a nitrogen atom the reduction takes place in the presence of ammonia or an ammonium salt such as ammonium chloride.

Many reducing agents are suitable for this pur pose depending on the particular case concerned.

For example, hydrogen in the presence of (Raney) nickel or palladium, or zinc in the presence of an ocid. Or, after an initial cyclisation of the compound of formula (III), lithium aluminium hydride, Vitride diborane and other aluminium and boron hydrides known to reduce amides may be used.

When, in formula (III), one of Y' and V2 and one of Y3 and V4 is hydroxythe compound is readily cyclised in the presence of ammonia to the "Carbazole" without the aid of a reducing agent. Reaction conditions may be selected from those known in the art as suitable for ammonolysis reactions, for example, heating under pressure in the presence of a catalyst such as copper chromite or alumina, optionally in the presence of an inert solvent.

The intermediates of formula (III) may be prepared by reaction of a compound of formula (V) with 3 - (9 carbazolyl) propylamine of formula (IV):

wherein Z, yl and V2 are as defined above in formulae (II) and (Ill) respectively; in a molar ratio of 2 to 1. The reaction is conveniently carried out in an inert polar solvent at an elevated temperature, and in the presence of an acid acceptor such as triethylamine to sequester hydrogen ions which are liberated in the reaction.

Intermediates of formula (III) suitable for conversion to the 'Carbazole' of formula (A) by ammonolysis may themselves be prepared by reacting the amine (IV) with 1,2-epoxypropane of formula (V):

The reaction will proceed if the reactants are simply heated together at about 100 C, but optionally a lower alkanol is used as a solvent in which case a lower temperature such as from 45" to 60"C may be used. By lower alkanol is meant an alkanol having 1 to 6 carbon atoms for example, methanol, ethanol, butanol or hexanol.

The compound of formula (IV) may be obtained by ammonolysis of the corresponding alcohol or halide, preferably using a large excess of ammonia under pressure often in the presence of a catalyst such as copper chromite or alumina, or reduction of the appropriate nitrile or amide. The desired alcohol, halide, nitrile or amide may be prepared by methods described above forthe preparation of compounds of formula (IIA).

3. A number of synthesis of the "Carbazole" involve, as the last step, the reduction of an analogous carbonyl compound of formula (VII):

(a) wherein the two hydrogens on one or more of the carbons numbered 1 to 4 are replaced by an oxo group (Most reagents capable of reducing an imide carbonyl group may be used for example hydrogenation at elevated temperature and pressure using nickel, platinum, palladium or copper chromite as a catalyst; concentrated hydroiodic acid with red phosphorous and particularly suitable are lithium aluminium hydride, diborane and Vitride. Electrolytic reduction may also be used.); or (b) wherein the two hydrogens on the carbon numbered 5 are replaced by an oxo group. [Most reagents capable of reducing a ketone group may be used, for example hydrogenation using nickel, platinum, palladium or copper chromite as a catalyst at elevated temperature and pressure; zinc and hydrochloric acid (Clemmensen); hydrazine in the presence of a base (Wolff-Kishner)].

The compounds of formula (VIII) wherein the oxo group is on either of carbons numbered 3 or 4 may be made by a reaction analogous to that described above involving a compound of formula (I IA), but using a substituted piperazine of formula (Vlil):

A convenient preparation of (VIII) is by reaction of a compound of formula (IX) with a large excess of 1,2 - diaminopropane of formula (X):

wherein W is a leaving atom or group such as halo e.g. chloro or bromo, or alkylthio. The reaction may be carried out by simply heating the reactants although it is preferable to use an inert solvent such as acetonitrile or dioxane, and it is particularly advantageous to use a lower alkanol such as ethanol as a solvent.

Alternatively, compounds of formula (VII) may be prepared by reacting a piperazine or carbazole, or a reactive derivative thereof such as are described hereinabove, with an acrylyl halide such as acrylyl chloride or alkyl acrylate to provide a compound of formula C/P.CO.CH:CH2 wherein C/P is 3,5 - cis dimethylpiperazinyl or carbazolyl, respectively, followed by reaction with carbazole or 3,5 - cis dimethylpiperazine as appropriate.

The compound offormula (VII) wherein the oxo group is on the carbon numbered 5 may be prepared, for example, by the reaction of a, a'- dichloroacetone with 3,5 - cis - dimethylpiperazine in ethanol to give 4 - (3 - chloro - 2 - oxopropyl) - 3,5 - cis - dimethylpiperazine which in turn is caused to react with carbazole in dimethylformamide in the presence of a strong base such as sodium hydride.

4. The 'Carbazole' may also be made by formation of the carbazole nucleus as the final step.

Thus as one possibility the corresponding phenothiazine analogue, i.e. 10 - [3 - (3,5 - cis dimethylpiperazino) propyl] phenothiazine, may be converted to the 'Carbazole' by heating with copper.

Alternatively, the diphenylamine of formula (Xl):

may be ring-closed by the reaction of a palladium (II) salt in a polar solvent. The preferred palladium (II) salts are the acetate and chloride which are generally used in equimolar amount with the diphenylamine.

Preferred solvents are acetic acid, acetonitrile, sulpholane and especiallytrifluoroacetic acid, and the reaction is advantageously effected at an elevated temperature up to the reflux temperature of the reaction medium. The reaction is conveniently carried out in the presence of catalytic amounts of a strong acid or boron trifluoride.

The diphenylamine of formula (Xl) may also be ring-closed by the action of ultraviolet light. Preferred solvents are tetrahydrofuran and ethanol. Irradiation is conveniently provided by a 450 watt HANOVIA (Registered Trade Mark) mercury vapour lamp.

A further synthesis of the 'Carbazole' is by selec tiveoxidation of the corresponding 1,2,3,4 - tetrahydro or 1,2,3,4,5,6,7,8 - octahydro compound, i.e.

1,2,3,4 - tetrahydro - 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole or 1,2,3,4,5,6,7,8 octahydro - 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole. Any conventional dehydrogenating agent may be used provided that it does not oxidize any of the nitrogens in the remainder of the molecule, for example Pb3O4, chromic oxide, alumina, a quinone such as tetrachloroquinone, or catalytically over hot platinum or palladium.

Synthesis of the intermediate phenothiazine, diphenylamine and octa- and tetrahydrocarbazole may be done using conventional techniques wellknown in the art.

5. Completion of the substituted piperazine ring may also be used to synthesize the "Carbazole".

The compound of formula (XII) may be reacted with a compound offormula (XIII):

wherein each X is a leaving atom or group such as halo, preferably iodo or bromo, hydroxy, sulphate or a sulphonate ester such as ap-toluenesulphonate.

The reaction may be carried out with heating in a polar solvent such as acetone or a lower alkanol by which is meant alkanols having 1 to 6 carbon atoms such as ethanol or butanol.

The "Carbazole", its pharmaceutically acceptable salts and solvates of these pharmaceutically accept able salts are useful in the control of psychotic and aggressive conditions in humans. For example, it is useful for the prophylaxis and/or treatment of schizophrenia, mania or senile, involutional or organic psychoses as well as depressive psychosis.

The "Carbazole" may be used in the prophylaxis and treatment of aggressive behaviour. Such behaviour may be associated with other disorders such as psychotic disorders and personality disorders as well as, in children, autism and hyperkinetics.

The "Carbazole," its pharmaceutically acceptable salts and solvates potentiates the locomotor activity of d-amphetamine, a property showed by most tricyclic antidepressant agents. This potentiation of d-amphetamine suggests that the "Carbazole" may have antidepressant activity in man.

A further use of the "Carbazole," its pharmaceutically acceptable salts and solvates of said salts is in the control of aggressive symptoms which may be associated with mentally retarded and/or behaviourally disturbed patients, or of aggression associated with epileptic disorders, acute or chronic organic brain syndromes, alcoholism, narcotic addiction and other forms of aggression of either known or unknown etiology.

The "Carbazole" compound, its pharmaceutically acceptable salts and solvates of these pharmaceutically acceptable salts are administered to mammals, e.g., humans, preferably orally at a dose of 1 mg to 30 mg/kg (calculated as base) of bodyweight of the mammal being treated for either aggression or psychosis and most preferably 2 to 5 mg/kg is pref erably administered orally at this dose. The "Car bazole" compound, its pharmaceutically acceptable salts and solvates are preferably given three times daily at the aforementioned dose for these conditions. For intramuscular injection the dose is gener ally one-half the oral dose. For example in schizop hrenia a suitable dose would be in the range of 1 mg/kg to 15 mg/kg and most preferably 2 mg/kg to 5 mg/kg, for example as a unit dose of from 60 mg to 900 mg. Conveniently the unit dose is administered one or more times daily, for example as one or more tablets each containing from 10 to 300, conveniently 60, mg, of the "Carbazole", its pharmaceutically salts or its solvates taken three times a day.

Although, for use in medicine, the "Carbazole" or a salt thereof may be administered as a raw chemical, it is preferably presented with an acceptable carriertherefor as a pharmaceutical composition. The carrier must of course be 'acceptable' in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient of the composition. The carrier may be a solid or a liquid or a mixture of solid and liquid substances, and is preferably formulated with the Carbazole or a salt thereof as a unit-dose composition, for example, a tablet, capsule or cachet for oral administration or a suppository for rectal administration. Other pharmaceutically active substances may also be present in composition of the present invention, and the compositions may be formulated by any of the well-known techniques of pharmacy consisting basically of admixture of the components. For example, tablets, may be made by granulating, grinding, stirring, coating, milling, tumbling, compressing or molding.

Unit dose compositions, for rectal or parenteral administration conveniently contain from 5 mg to 75 mg of the"Carbazole" base our a pharmaceutically acceptable salt or solvate thereof calculated as base.

For the oral administration, fine powders or granules of the compounds may contain diluents and dispersion and surface active agents, and may be presented in a draught in water or in syrup, in capsules or cachets in the dry state or in an aqueous or non-aqueous suspension, when a suspending agent may also be included; in tablets, preferably made from granules of the active ingredient with a diluent, by compression with binders and lubricants; or in a suspension in water or a syrup or an oil or in a water/oil emulsion, when flavoring, preserving, suspending, thickening and emulsifying agents may also be included. The granules or the tablets may be coated, and the tablets may be scored.

For parenteral administration (by intramuscular, intravenous, intraperitoneal or subcutaneous injection), the "Carbazole" preferably as a pharmaceutically acceptable salt or hydrate may be presented in unit dose or multi-dose containers in aqueous or non-aqueous injection solutions which may contain antioxidants, buffers, bacteriostats and salutes which render the compounds isotonic with the blood; or in aqueous or non-aqueous suspensions when suspending agents and thickening agents may also be included; extemporaneous injection solu tions and suspensions may be made from sterile powders, granules or tablets which may contain diluents, dispersing and surface active agents, bin ders and lubricants.

The "Carbazole", its pharmaceutically acceptable salts and pharmaceuticaily acceptable solvates of such salts may also be presented as depot compositions of the kind known in the art from which the active ingredient (medicament) is released, over a prolonged period, once the composition is in place within the body of the recipient. Such compositions in the form of for example long-acting injections are advantageous in human medicine in the manage ment of for example psychotic conditions such as schizophrenia where the frequency of the patients' failure to take prescribed medication when in the form of tablets etc. is unacceptably high.

In the field of veterinary medicine the "Carbazole", its pharmaceutically acceptable salts and phar maceutically acceptable solvates of such salts have particular application and value in the treatment of aggression in mammals, identified as exhibiting aggressive symptoms, such as dogs, swine, horses and cattle, and may be administered for this utility in the manner as hereinabove described. Particularly advantageous compositions for veterinary use are depot compositions, as hereinabove described, for use in situations where it may be desirable or practicable for the "Carbazole", salt or solvate to be administered only at prolonged intervals.

The "Carbazole", the pharmaceutically acceptable salts and the pharmaceutically acceptable solvates are also indicated as having antidepressant activity at the same dosages as given heretofore.

It will be understood from the foregoing description that what we will claim in accordance with this invention may comprise any novel feature described herein, principally but not exclusively as follows:- (a) 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, salts thereof and solvates of the salts.

(b) 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate.

(c) Methods as hereinbefore described for the preparation of a compound according to either of (a) and (b) above.

(d) A pharmaceutical composition comprising 9 - [3 (3,5 - cis - dimethylpiperazino) propyls carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof together with an acceptable carriertherefor.

(e) A method forthe preparation of a composition according to (d) above comprising admixture of the ingredients.

(f) A method of treating aggression in a mammal which has been identified as exhibiting aggressive symptoms which comprises administering to said mammal an effective nontoxic antiaggression amount of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof.

(g) A method according to (f) above wherein the mammal is man.

(h) A method of treating psychosis in a human which has been identified as exhibiting psychotic symptoms which comprises administering to said human an effective nontoxic antipsychotic amount of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof.

(i) 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, when used in a method according to (f), (g) or (h) above.

(j) A compound defined in (i) above as an antiaggressive agent.

(k) A compound defined in (i) above as an antipsychotic agent.

(I) Intermediates as hereinbefore identified, where novel, forthe preparation of a compound defined in (a) above.

The following Examples are given by way of illustration of the invention: they are not to be construed as a limitation thereof. In these Examples all temperature are in degrees Celsius and vacuum distillation was effected on a steam bath using a pressure of about 20 mm Hg, unless otherwise specified.

Example 1 Preparation of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl carbazole dihydrochloride hemihydrate.

A. 3 - (3,5 - cis - Dimethylpiperazino)propanol dihydrochloride 2,6 -cis - Dimethylpiperazine (114.2 g, 1.0 mole), 3-chloropropanol (94.5 g, 1.0 mole), sodium carbo nate (105 g) and ethylene glycol monomethyl ether (400 ml) were stirred under reflux for four hours. The reaction mixture was filtered warm, and the filtrate stripped of solvent by vacuum distillation.

The Calculated for C21 H23N3Cl: C, 70.47; H, 7.89; N,11.74; CI, 9.91 Found: C, 70.53; H, 7.93; N, 11.69; CI, 9.83 EXAMPLE 6 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl carbazole maleate The 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole (10 g) of Example 4 was dissolved in warm acetone (71 ml). Maleic acid (3.7 g) was slowly added, causing precipitate formation. The resulting slurry was stirred while heating at reflux for 10 min.

It was then cooled to room temperature and filtered.

The collected precipitate was washed with acetone and then recrystallized from water to give 9 - [3 - (3,5 -cis - dimethylpiperazino) propyl] carbazole maleate (10.5 g), m.p. 162-163" (dec.), which had the following elemental analysis: Calculated for C2sH3, N3O4: C, 68.63; H, 7.14; N, 9.60 Found: C, 68.91; H,7.25; N, 9.74 EXAMPLE 7 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl carbazole three-fourths succinate The 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole (10 g) of Example 4 was dissolved in warm SD3A (ethanol containing about 5% methanol - 50 ml) and succinic acid (3.8 g) was slowly added. The mixture was stirred and heated at refluxfor 10 min.

and then cooled to 5". The product was collected by filtration and crystallized from SD3A/water (95/5 v/v) to give 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazolethree-fourths succinate (10.40 g), m.p.

175.5-176.5 (stoichiometry confirmed by nmr), which had the following elemental analysis: Calculated for C24H31.5N3O3: C, 70.30; H, 7.74; N, 10.24 Found: C, 70.21; H, 7.71; N, 10.20 EXAMPLE8 Cis - 9 - [3 - (3,5- Dimethyl piperazinyl) propyl carbazole acetate one-quarter hydrate To the 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole (10 g) of Example 4 dissolved in hot toluene (70 ml) was added acetic acid (2.0 ml).

The mixture was stirred and cooled to 2". The resulting product was collected by filtration, washed with cyclohexane (35 ml) and dried under reduced pressure to give cis - 9 - [3 - (3,5 - dimethyl piperazinyl) propyl] carbazole acetate one-quarter hydrate (10.4 g), m.p. 144-146", which had the following elemental analysis: Calculated for C23H3,.sN302.25: C, 71.56; H, 8.22; N, 10.88 Found: C, 71.57; H, 8.08; N, 10.84 EXAMPLE 9 Cis - 9 - [3 - (3,5 - Dimethyl piperazinyl) propyl] carbazole sulfate monohydrate To the cis - 9 - [3 - (3,5 - dimethyl piperazinyl) propyls carbazole (10 g) of Example 4 dissolved in warm acetone (100 ml) was slowly added with stirring a solution of sulfuric acid (3.05 g) in water (5 ml), causing immediated precipitation. The slurry was stirred at reflux for 10 min. and then cooled to 209.

The product was collected by filtration and washed with acetone (20 ml). It was reslurried in water (70 ml), filtered, washed with acetone (40 ml) and dried under reduced pressured to give cis - 9 - [3 - (3,5 dimethyl piperazinyl) propyl] carbazole sulfate nonohydrate (12.9 g), m.p. 243-246" (dec.), which iad the following analysis: calculated for C2,H3,N3OsS: C, 57.46; H, 7.14; N, 9.60 =wound: C, 57.75; H, 7.10; N, 9.47 EXAMPLE 10 Following the procedure of Example 6, 9 - [3 - (3,5 cis - dimethylpiperazino) propyl] carbazole was allowed to react with an equimolar amount of the appropriate acid to give the following salts: 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] car bazole fumarate 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole citrate 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole L-malate 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole L-tartrate 9 -[3 - (3,5 -cis - dimethylpiperazino) propyl] carbazole methanesulfonate 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole DL-lactate, m.p. 194.5-197".

Pharmaceutical Compositions In the following examples of pharmaceutical compositions according to the present invention, unless otherwise indicated, the term "Active Ingredient" represents the "Carbazole" hereinbefore defined or a pharmaceutically acceptable salt solvate thereof.

The stated dose represents that appropriate for the base; if a salt is used the dose should of course be increased appropriately.

EXAMPLE 11-Tablet Amount per Ingredient tablet (mg) Active Ingredient (compound of Ex. 5) 60.0 Lactose 125.0 Corn Starch 50.0 Polyvinylpyrrolidone 3.0 Stearic acid 1.0 Magnesium stearate 1.0 EXAMPLE 12 -- Capsule Amount per Ingredient capsule (mug) Active Ingredient (compound of Ex. 6) 60.0 Lactose 174.0 Corn Starch 174.0 Stearic acid 2.0 EXAMPLE 13 -Ampoule Amount per Ingredient ampoule Active Ingredient (as a dihydrochloride salt of compound Ex.4) 60.0 mg Water for injection, q.s. 1.0 ml EXAMPLE 14 -- Suppository Amount per Ingredient suppository Active ingredient (compound of Ex. 1) 60.0 mg Theobroma oil (Cocoa Butter), q.s. 2.0 g EXAMPLE 75-- Tablet Amount per Ingredient tablet (mg) Active Ingredient (compound of Ex. 4) 30 Lactose 125.0 Corn Starch 50.0 Polyvinylpyrrolidone 3.0 Stearic acid 1.0 Magnesium stearate 1.0 Table I shows the significant therapeutic advantage of the "Carbazole" given as the dihydrochloride hemihydrate of Ex. 1 (compound A) over a prior art carbazole derivative, 9 - [3 (4 - methylpiperazino) propyl] carbazole given as the dihydrochloride (compound B).

TABLE I Comparison of activity and toxicity of the "Car bazole" (cpd. A) with that of 9 - [3 - (4 - methyl piperazino) propyl] carbazole (cpd. B).

Cp d. Antiaggressive LDs0(mglkg) ED50 (mglkg) Therapeutic Ratio Rat, p.o. Rat, p.o. LD,dED,, A 957 48 20 B 830 75 11 Table II summarizes inter alia several other substantial advantages of the "Carbazole" over compound B. The minimum dose (in the mouse) of the "Carbazole" at which loss of righting reflex occurs (ED. Min.) is about three times that of compound B.

Similarly, muscle tone decrease (in the rat) is observed with compound B at a much lower dose than with the "Carbazole".

Table II also compares the anticonvulsant activity of the two compounds and the commercial anticonvulsant phenytoin (Dilantine). Phenytoin is almost 2.5 times as active as cpd. B and 5 times as active as the "Carbazole" (cpd. A). The level of anticonvulsant activity shown by cpd. B is marginal for consideration in this end use. The "Carbazole", with less than half the anticonvulsant activity of cpd. B, would be considered to have insufficient potential value as an anticonvulsant to warrant further consideration for this use.

TABLEII A comparison of some properties of cpd. A, cpd. B and phenytoin.

Loss ofRighting Muscle Tone Anticonvulsant Reflex ED min. Decrease ED Activity IIMESJa (mg/kg) Mouse min. (mglkg) ED50 (mglkg) Cpd. i.p. Rat, i.p. Mouse, i.p.

A 160 125 43 B 50 50 20 Phenytoin > 100 - 8.5 (a) Maximal ElectroshockTest (Woodbury and Davenport,Arch. Int Pharmacodyn. Ther., 92, 97-107 (1952).

The prior art carbazole derivative, 9 - [3 - (4 methylpiperazino) propyl] carbazole, identified as compound B in the foregoing Tables I and II, appears as Example 7 in the above-referenced Australian and French patent publications.

Example 16 temperature dihydrochloride hemihydrate (A) 9- (3- Chloropropyl) carbazole Carbazole (134 g, 0.8 mole) in dimethylformamide (1.5 litres) was slowly added to a slurry of sodium hydride (0.8 mole) made from 39 g of 50% dispersion in mineral oil and 500 ml of dimethylformamide while maintaining the temperature below 60 . When hydrogen was longer evolved the reaction temperature was lowered to around 5 with an ice bath and 1,3-dichloropropane (500 9,4.4 mole) was added art a rate that did not exceed 10 ml per min. After all the 1,3-dichloropropane had been added the reaction mixture was slowly stirred while allowing it to come to room temperature (about 1.5 hours).

The reaction mixture was filtered to remove the sodium chloride that had formed, then stripped of solvent by vacuum (water pump) distillation. The thick syrup-like residue was then subjected to high vacuum distillation. The first fraction removed at 70 and 300 microns was the excess 1,3 - dichloropropane which was recovered for reuse. The second fraction distillating at 120 and 100 microns was unreacted carbazole and some product, 38 g. The third fraction (b.p. 145" at 60 microns) was 9 - (3 chloropropyl) carbazole, 107 g, 55% yield, m.p.

34-359.

Calculated for C,3H,4NCI: C 73.91, H 5.79, N 5.75 Found: C 73.85, H 5.81, N 5.72 (B) temperature dihydrochloridehemihydrate 9 - (3 - Chloropropyl) carbazole (12.2 g, 0.05 mole), 2,6 - cis - dimethylpiperazine (5.7 g, 0.05 mole), potassium carbonate (10 g) and dimethylformamide (50 ml) were heated at reflux for an hour, cooled and filtered. The filtrate was stripped of solvent by vacuum (water pump) distillation and the residue was treated with 250 ml of 1 N hydrochloric acid and the resulting solution was shaken with ether. The ether phase was discarded and the hydrochloric acid phase was treated with Elites, filtered and vacuum distilled to dryness. The residue was recrystallized from an ethanol/ether mixture to give 9 - [3 - (3,5 - cis - dimethylpiperazino)propyl]carbazoie dihydroch chloride hemihydrate (18 g, 90% yield) m.p. 288-290"C.

Example 17 9- [3- (3,5 - cis - Dimethylpiperazino) propyl] carbazole monohydrochloride A slurry in toluene of 3 - (3,5 - cis - dimethylpiperazino) propyl chloride dihydrochloride (Example 1, step b) was quenched in a mixture of ice and 1 ON sodium hydroxide and the mixture adjusted to pH 13.5. The toluene phase was separated and four additional toluene extractions performed. After drying, the toluene solution solvent was removed to yield crude 3 - 3,5 - cis - dimethylpiperazino) propyl chloride as an oil.

Equimolar amounts of sodium methoxide and carbazole were reacted together in dimethylformamide followed by vacuum stripping to ensure removal of liberated methanol. This mixture was combined with an appropriate amount of the crude oil from the previous step and the resulting mixture heated at 100" for 15 hrs. Dilution with water of the cooled mixture thus obtained effected crystallisation of crude 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole. The latter was filtered, warmed with 1 N hydrochloric acid and the resulting solution, after cooling, extracted with ether. The ether layer was discarded and the remaining aqueous layer neutralized to pH 7 with 5N sodium hydroxide. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 9 - [3 - (3,5 - cis dimethylpiperazino) propyl] carbazole monohydrochloride, m.p.309-311 (dec.).

Claims (59)

1. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a salt thereof or a solvate of such a salt.

2. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole.

3. A pharmaceutically acceptable salt of 9 - [3 (3,5 - cis - dimethylpiperazino) propyl] carbazole.

4. A pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of 9 - [3 - (3,5 - cis dimethylpiperazino) propyl] carbazole.

5. A hydrate of a pharmaceutically acceptable salt of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole.

6. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate.

7. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole monohydrochloride.

8. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole maleate.

9. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole three-fourths succinate.

10. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole acetate one-quarter hydrate.

11. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] ca rbazole sulphate monohydrate.

12. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazoleDL-lactate.

13. A salt of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole selected from the citrate, fumarate, L - malate, methanesulphonate andL-tartrate.

14. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, when used in the treatment of aggression in a mammal identified as exhibiting aggressive symptoms.

15. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, when used in the treatment of psychosis in a human identified as exhibiting psychotic symptoms.

16. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyls carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof as an antiaggressive agent.

17. 9-[3 - (3,5-cis - Dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof of a pharmaceutically acceptable solvate of a phar maceuticallyacceptable salt thereof as an antipsychotic agent.

18. A pharmaceutical composition comprising 9 [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof together with an acceptable carrier therefor.

19. A pharmaceutical composition comprising 9 [3 - (3,5 -cis - dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate together with an acceptable carriertherefor.

20. A composition according to either of claims 18 and 19, suitable for oral administration.

21. A composition according to either of claims 18 and 19, suitable for parenteral administration.

22. A composition according to either of claims 18 and 19, suitable for rectal administration.

23. A composition according to either of claims 18 and 19 comprising the carbazole, salt or salt solvate in solution in an aqueous medium.

24. A composition according to any of claims 18 to 23 in unit dosage form.

25. A composition according to claim 24 in the form of a tablet suitable for oral administration.

26. A composition according to claim 24 in the form of a capsule suitable for oral administration.

27. A composition according to claim 24 in the form of a sterile injection solution suitable for parenteral administration.

28. A unit dosage composition according to claim 20 containing from 10 to 300 mg. (calculated as the base) of the carbazole, salt or salt solvate.

29. A unit dosage composition according to either of claims 21 and 22 containing from 5 to 75 mg (calculated as the base) of the Carbazole, salt or salt solvate.

30. Amethodforthe preparation of a composition according to any of claims 18 to 29 comprising admixture of the ingredients.

31. A method for the preparation of 9 - [3- (3,5 cis - dimethylpiperazino) propyls carbazole, a salt thereof or a solvate of such a salt comprising: (a) reacting a compound of formula (II), (IIA) or (IIB),

Z-(CH2)3-Z (IIB) wherein in each case Z is a leaving atom or group, with respectively carbazole or a reactive derivative thereof, 3,5 - cis - dimethylpiperazine, or both carbazole or a reactive derivative thereof and 3,5 - cis dimethylpiperazine; or (b) reacting a compound of formula (IIC) or (IID)

with respectively carbazole or 3,5 - cis - dimethylpiperazine; or (c) reacting an aldehyde of formula (liE) or (IIF)

with respectively carbazole or 3,5 - cis - dimethylpiperazine with subsequent selective reduction; or (d) cyclizing a compound of formula (Ill)

wherein Y1 is hydroxy andY2 is hydrogen, orY' and y2 together form a group selected frombxo, thioxo and imino, and wherein Y3 and Y4 are respectively defined as for Y' and2; the reaction being conducted (when Y1/Y2 and Y3/Y4 are both otherthan imino) in the presence of ammonia or an ammonium salt and (except when Y' and Y3 are both hydroxy) either in the presence of a reducing agent or with subsequent selective reduction; or (e) selectively reducing a compound of formula (all)

wherein the two hydrogens on one or more of the carbons numbered 1 to 5 are replaced by an oxo group; or (f) heating 10-[3-(3,5-cis- dimethylpiperazino) propyl] phenothiazine with copper; or (g) cyclizing the diphenylamine of formula (XI)

or (h) selectively oxidising either 1, 2,3,4 - tet- rahydro - 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole or 1, 2, 3, 4, 5, 6, 7, 8 - octahydro - 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole; or (i) reacting the compound of formula (XII) with a compound of formula (XIII)

wherein each X is a leaving atom or group; followed as appropriate by conversion of the product to the carbazole base, a salt thereof or a salt solvate thereof.

32. A method according to claim 31(a), character ised in that a compound of formula (II) is reacted with carbazole or a reactive derivative thereof.

33. A method according to claim 31(a), characterised in that a compound of formula (IIA) is reacted with 3,5 - cis - dimethylpiperazine.

34. A method according to any of claims 31(a), 32 and 33, characterised in that Z is selected from halo, arylsulphonyloxy and alkylsulphonyloxy.

35. A method according to any of claims 31(a), 32 and 33, characterised in that Z is chloro.

36. A method according to any of claims 31(a), 34 and 35, characterised in that a compound of formula (II) is reacted with sodium carbazole.

37. A method according to claim 31(a), characterised in that 3 - (3,5 - cis - dimethylpiperazino) propyl chloride is reacted with sodium carbazole.

38. A method according to claim 31(a), characterised in that 9 - (3 - chloropropyl) carbazole is reacted with 3,5 -cis - dimethylpiperazine.

39. A method according to claim 31(e), characterised in that the compound of formula (VII) has the two hydrogens on one or more of the carbons numbered 1 to 4 replaced by an oxo group.

40. A method according to claim 31(e), characterised in thatthe compound offormula (VII) has the two hydrogens on the carbon numbered 2 replaced by an oxo group.

41. A method according to claim 31(e), characterised in that the compound of formula (VII) has the two halogens on the carbon numbered 5 replaced by an oxo group.

42. A method according to claim 3l(i),character- ised in that each X is selected from halo, hydroxy, sulphate and a sulphonate ester.

43. A method according to claim 31(i), characterised in that each X is iodo or bromo.

44. A method according to any of claims 31 to 43, characterised in that the product carbazole is isolated as a pharmaceutically acceptable salt thereof or as a pharmaceutically acceptable solvent of such a pharmaceutically acceptable salt.

45. A method according to any of claims 31 to 4S, characterised in that the product carbazole is isolated as a salt thereof with hydrochloric acid or as a pharmaceutically acceptable solvate of such a salt.

46. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a salt thereof our a solvate of such a salt, whenever prepared by a method according to any of claims 31 to 45.

47. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate whenever prepared by a method according to any of claims 31 to 45.

48. 9 - [3 - (3,5 - cis - Dimethylpiperazino) propyl] carbazole, a salt thereof or a solvate of such a salt, substantially as hereinbefore described.

49. A pharmaceutical composition substantially as hereinbefore described with particular reference to Examples 11 to 15.

50. A method for the preparation of 9 - [3 - (3,5 cis - dimethylpiperazino) propyl] carbazole, a salt thereof or a solvate of such a salt, substantially as hereinbefore described with particular reference to Examples, 1,4 to 10,16 and 17.

51. A method oftreating aggression in a mammal which has been identified as exhibiting aggressive symptoms which comprises administering to said mammal an effective nontoxic antiagression amount 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof.

52. A method according to claim 51 wherein the mammal is man.

53. A method of treating psychosis in a human which has been identified as exhibiting psychotic symptoms which comprises administering to said human an effective nontoxic antipsychotic amount 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof.

54. A method according to any of claims 51 to 53 which comprises administering an effective nontoxic amount of 9 - [3 - (3,5 - cis - dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate.

55. A method according to any of claims 51 to 54, substantially as hereinbefore described with particular reference to the accompanying Examples.

56. A compound selected from a cis - dimethylpiperazine of formula (Il)

and a carbazole of formula (IIA)

wherein, in each case, Z is selected from halo, arylsulphonyloxy and alkylsulphonyloxy.

57. A compound of formula (II) or (IIA) according to claim 56 wherein Z is selected from chloro,p toluenesulphonyloxy and methanesulphonyloxy.

58. 3 - (3,5 - cis - Dimethylpiperazino) propyl chloride.

59. 9 - (3 - Chloropropyl) carbazole.