FI65244C - PROCEDURE FOR FRAMSTATION OF AV 9- (3- (3,5-CIS-DIMETHYLPIPERAZINE) PROPYL) CARBAZOLE ANVAENDBAR SAOSOM ETT PSYKOTROPISKT MEDEL - Google Patents

Description

»- -1 r_, ADVERTISEMENT. r n. .

jAST * W (11) UTLÄCGNINGSSKRIFT 6 5 244 C (45) P - '·'! - .: '..y-t / 10 04 1904

Patent patent (51) κ * .ηι? /Ϊ́ι*.α.3 C 07 D 403/06 FINLAND —FINLAND (21) Pwnttihsksmm - P »tsnaw« eknln | 793 ^ 05 (22) Hakaml * ptlvi - AntBknlngtdag 31.10.79 (23) Initial line — GMtighatsdag 31.10.79 (41) Tulhit public— Blhrit offantllf Q2 Qq

Patent and Registration Office * Date of filing and other audit. _

Patent and Register Office Ant & kan utbgd och utijkrKten public end 30.12.83 (32) (33) (31) Pyr> «tty eluoikeus — Bejkrd prlorttet oi. 11.78

England-England (GB) U28U5 / 78 02.03.79 USA (US) 01691 ^ (71) The Wellcome Foundation Limited, 1Ö3-193 Euston Road, London NW1, England-England (GB) (72) Morton Harfenist, Chapel Hill, North Carolina, Charles Thomas Joyner, Raleigh, North Carolina, USA (7 ^) 0y Roister Ab (5 Ab) Method for preparing 9- / 3- (3,5-cis-dimethylpiperazine) propyl / carbazole useful as a psychotropic agent - For the preparation of 9- [3- (3,5-cis-dimethylpiperazine) -propyl] -carbazole as a psychotropic substance

The invention relates to a process for the preparation of a compound, a salt thereof and a solvate of such a salt having valuable anti-aggressive and antipsychotic properties.

AU Patent No. 201630 and FR Patent No. 1,167,510 describe carbazoles having anti-epileptic properties of formula (I): 65244

Yi γ (i) / \

A— \ _J— "I

wherein A is a divalent saturated aliphatic hydrocarbon radical having a straight or branched chain of 2 to 6 carbon atoms, is a hydrogen atom or a lower alkyl or aryl or araliphatic group, Y and represents a hydrogen or halogen atom or a lower alkyl, an alkoxy, aryl or aryloxy group, wherein the ring containing Y or Y 1 may contain other substituents in addition to Y and V 1, and one or more of the carbon atoms of the piperazine ring may have a substituent on the methyl group; in terms of.

It has now been found that a special compound 9- / 3,5-cis-dimethylpiperazine) propyl7carbazole (sometimes referred to as CXS-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole or 9- / 3- (cis-3.5 -dimethyl-1-piperazinyl) propyl-47-carbazole or cis-9- [N- (3,5-dimethyl-1-piperazinyl) -propyl] -carbazole) of the formula (CH_) I 1 3 (A) xa

H3C I CH3 H

3,65,244, hereinafter referred to as "carbazole", its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of its pharmaceutically acceptable salts surprisingly have valuable anti-aggressive and anti-psychotic properties which make them useful in the treatment of aggression and psychosis in humans. Contrary to expectations, these compounds do not have toxic side effects, e.g., dyslexia or sedative effects associated with antipsychotic drugs such as chlorpromazine, etc.

As used herein, the term "treatment" includes the prophylactic administration of "carbazole" to a patient (human) who has previously been shown to exhibit aggressive or psychotic symptoms, as well as the therapeutic administration of "carbazole" to a patient (human) having aggressive or psychotic symptoms. The pharmacological testing method used to demonstrate the anti-aggressive and anti-psychotic properties of "carbazole" is described by McKenzie, G.M. in Brain Research, 34, 323 (1971). In this test, "carbazole" resisted amorphine-induced aggression in the rat and, as further evidence of its anti-psychotic and anti-aggressive properties, it was found to suppress instinctive murderous behavior in rats (e.g., mouse killing) (see Leaf et al., Aggressive Behavior, ed. and EBSigg, pages 120-131, John Wiley and Sons, Inc., New York, 1969).

The potency of the anti-aggressive and anti-psychotic properties of "carbazoles" has been found to depend on the specific location of its methyl substituents. For example, it has been found to be more potent than either of the corresponding unmethylated compounds or analogous 4-methyl or 3,4,5-trimethyl compounds.

"Carbazole" is particularly valuable because its anti-psychotic and anti-aggressive effect is essentially free of unwanted side effects such as sedation, catalepsy and extrapyramidal dysfunction associated with commonly used anti-psychotic drugs such as phenothiazines. One indication that "carbazole" is not associated with extrapyramidal activity is that it is unable to resist apomorphine-induced compulsive behavior in the rat (see Andien, N.E., J. Psychiat. Res., 11, 1974). "Carbazoles" are also associated with ______ __ - τ ~~ 4 65244 significantly less sympathetic accelerator and anti-histamine activity than phenothiazines.

When the beneficial biological properties of "carbazole" are 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 this invention. For therapeutic purposes, the acid moiety of such salts is preferably pharmaceutically acceptable to the intended recipient. Examples of such pharmaceutically acceptable salts include (a) those formed with inorganic acids, for example sulphate and hydrogen halides such as hydrochloride, and (b) those formed with organic acids such as acetate, citrate, fumarate, lactate (e.g. DL-lactate), malate (e.g. L-malate), maleate, succinate and tartrate (e.g. L-tartrate) as well as alkane sulfonates such as roethanesulfonate and aryl sulfonates such as p-toluenesulfonate. The "carbazole" base can be converted to its salts and the salts converted to bases or salts of other acids by methods well known in the art. Thus, salts that are not pharmaceutically acceptable are useful in the preparation of salts that are. In addition, salts of the carbazole base may form certain solvates, such as hydrates and solvates of alcohols (e.g., methanol and ethanol), and all such solvates are intended to be encompassed within the scope of this invention.

"Carbazole" can be synthesized by any method known in the art for synthesizing compounds having an analogous structure.

1. A preferred synthesis comprises coupling an alkylene chain to a carbazole or piperazine ring. This can be done by reacting a compound of formula 5 65244 CHp ~ \ Ν '- ^ CH2 ^ 3 Z (II) ch3 or 0 1 y - (ch2) 3 - z (IIA) o in which Z is a leaving group to react with a carbazole. with 3,5-cis-dixethylpiperazine, respectively. Any atom or group can be used as the variable Z, which allows substitution with a suitable amino group; for example halogen (preferably chlorine), arylsulfonyloxy (preferably p-toluenesulfonyloxy) or alkylsulfonyloxy (preferably methanesulfonyloxy).

Although the compound (II) reacts directly with the carbazole, it is preferable to use a carbazole derivative; particularly suitable derivatives are those with alkali or alkaline earth metals, in particular lithium, sodium, potassium, zinc, cadmium and calcium, although carbazole magnesium halide, e.g. iodide, may also be used.

Alkali metal carbazoles are usually prepared by reacting the carbazole with a suitable alkali metal hydride or amide in an inert, preferably polar, approbated solvent such as liquid ammonia, dimethylformamide or dimethyl sulfoxide; other suitable solvents include hydrocarbons, e.g. alkanes, cycloalkanes and aromatic compounds. The same reaction medium can then be used to effect N-substitution, which is preferably accomplished by heating. It is desirable that the N-substitution take place in an inert atmosphere such as nitrogen.

Alternatively, the compound of formula (II) is 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 suitably the corresponding alkanol; for example in potassium tert-butoxide tert-butanol.

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

The intermediates of formula (II) are readily obtained from the corresponding alcohol by conventional methods. For example, the alcohol can be converted to the chloride by reaction with thionyl chloride. The alcohol itself can be prepared by reacting a substituted alcohol of formula Z- (Cl 2) 3 -OH, wherein Z is as defined in formula (II), with 3,5-cis-dimethylpiperazine.

The synthesis of intermediates of formula (IIA) may be carried out by N-substitution analogously to the reaction of compound (II) with carbazole to give "carbazole" of formula (A).

Alternatively, a "carbazole" can be prepared by reacting an aldehyde of formula (IIE) or (IIF) with carbazole or 3,5-cis-dimethylpiperazine, respectively, followed by selective reduction. The first reaction step can be carried out in an inert, preferably polar, approbated solvent such as dimethylformamide or dimethyl sulfoxide, while selective Delking can be performed in the same medium as a "one-pot" reaction using hydride, borohydride or borane, for example sodium borohydride or lithium aluminum hydride or lithium a functionally equivalent reagent.

7 ch ^ 6 5 24 4 / \ ^ J-CH2.CH2.CHO (HE) CH3

O

N-CH.CH_.CHO (IIF) δ

The aldehyde starting materials can be prepared from the corresponding acetal, for example the appropriate 3,3-diethoxypropyl compound, using a reagent such as pyridine p-tolyl sulfonate in acetone / water at reflux. The acetal, in turn, can be prepared by standard methods from 3,5-cis-dimethylpiperazine or carbazole, as desired; for example, in the specific case mentioned above, by reaction with chloropropionaldehyde diethyl acetal under the conditions described above for reactions comprising compounds of formulas (II), (IIA) and (HB).

Syntheses of "carbazole" also involve reduction of an analogous carbonyl compound of formula (VII):

O

W 1, ts 1, / -C 1 N - C - C -N N-H (VII) / = (i i i ^

(_J

65244 (a) wherein two hydrogens on one or more carbon atoms numbered 1 to 4 are replaced by oxo; most reagents capable of reducing the amide carbonyl group can be used, for example, hydrogenation at elevated temperature and pressure using nickel, platinum, palladium or copper chromite as the catalyst; concentrated hydroiodic acid with red phosphorus and lithium aluminum hydride, diborane and Vitride are particularly suitable, electrolytic reduction may also be used; or (b) when the two hydrogens on carbon atom No. 5 are replaced by an oxo group.

Most reagents capable of reducing a ketone group can be used, for example, by hydrogenation using nickel, platinum, palladium or copper chromite as a catalyst at elevated temperature and pressure; zinc and hydrochloric acid (Clemmensen); and hydrazine in the presence of a base (Wolff-Kischner).

Compounds of formula (VII) in which the oxo group is on either carbon number 3 or 4 may be prepared by a reaction similar to that described above comprising a compound of formula (IIA) but using a substituted piperazine of formula (VIII):

CH0 O

HN NH (VIII) X-7 CH3

A suitable way to prepare (VIII) is to react a compound of formula (IX) with a large excess of 1,2-diaminopropane of formula (X): CH 3 <4 V / CH 3

"X X

N) H2 O oc2h59 65244 wherein W is a leaving atom or group such as halogen, e.g. chlorine or bromine, or alkylthio. The reaction can be carried out simply by heating the reactants, although it is preferable to use an inert solvent such as acetonitrile or dioxane, and it is particularly preferable to use a lower alkanol such as ethanol as the solvent.

Alternatively, compounds of formula (VII) may be prepared by reacting piperazine or carbazole or a reactive derivative thereof as described above with an acrylic halide such as acrylic chloride or alkyl acrylate to give a compound of formula C / P.CO.CH 2 Cl 2 wherein C / P is 3 , 5-cis-dimethyl-lipiperazinyl or carbazolyl, respectively, followed by reaction with carbazole or 3,5-cis-dimethylpiperazine as desired.

The compound of formula (VII) in which the oxo group is on carbon number 5 can be prepared, for example, by reacting C-dichloroacetone with 3,5-cis-dimethylpiperazine in ethanol to give 4- (3 ”chloro-2-oxopropyl) -3,5- cis-dimethylpiperazine, which in turn is reacted with carbazole in dimethylformaride in the presence of a strong base such as sodium hydride.

"Carbazole", its pharmaceutically acceptable salts and solvates of these pharmaceutically acceptable salts are useful for controlling psychotic and aggressive conditions in humans. It can be used, for example, to prevent and / or treat metastatic disease, passion or old age, menopause or organic psychoses, as well as depressive psychoses.

"Carbazole" can also be used to prevent and treat aggressive behavior. Such behavior may be associated with other illnesses, such as psychotic illnesses and personality-related illnesses, as well as, in children, congestion and obesity.

"Carbazole", its pharmaceutically acceptable salts and solvates enhance the locomotor activity of d-amphetamine, a property most tricyclic antidepressants have. This enhancement of d-amphetamine is reminiscent of the fact that "car- _____ - r ~ _____ ίο 65244 bazole" may have antidepressant effects in humans.

An additional use for "carbazole", its pharmaceutically acceptable salts, and solvates of these salts is in the control of aggressive symptoms, which may be associated with mentally retarded and / or dysfunctional patients, or the control of aggression associated with epileptic or acute diseases. , alcoholism, drug addiction and other forms of aggression with known or unknown causes.

The "carbazole" compound, pharmaceutically acceptable salts thereof, and solvates of these pharmaceutically acceptable salts are administered to mammals, e.g., humans, preferably orally at a dose of from 1 mg to 30 mg / kg (calculated as base) of the body weight of the mammal being treated for aggression or due to psychosis and most preferably administered orally at 2-5 mg / kg at this dose. The "carbazole" compound, its pharmaceutically acceptable salts and solvates are preferably administered three times a day in the above-mentioned dose for these conditions. For intramuscular injection, the dose is usually half the oral dose. For example, in osteoarthritis, a suitable dose would be between 1 mg / kg and 15 mg / kg, and most preferably 2 mg / kg to 5 mg / kg, for example 60 rag-900 mg per unit dose. Suitably the unit dose is administered once or several times a day, for example as one or more tablets each containing 10 to 300, preferably 60 mg of "carbazole", its pharmaceutical salts or its solvates three times a day.

Although, for use in medicine, "carbazole" or a salt thereof may be administered as a crude chemical, it is preferably administered with an acceptable carrier as a pharmaceutical combination. The carrier must, of course, be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. A carrier may be a solid or liquid or a mixture of solid and liquid materials, and preferably is modified with carbazole or a salt thereof yksik-köannosyhdistelmäksi, for example, tablets, capsules or Importa-kelyskapseliksi for administration orally or via a suppository for rectal administration. Other pharmaceutically active agents may also be present in the combinations of this invention, and combinations 11,65244 may be formed by any of the well-known methods in pharmacy, which essentially comprise mixing the compounds. For example, tablets may be prepared by granulating, grinding, mixing, coating, rolling, drumming, compressing or molding.

A unit dose combinations for administration rectally or parenterally, preferably containing from 5-75 mg of "carbazole" -emästä, its pharmaceutically acceptable salt or solvate of salt thereof, calculated as the base.

For oral administration, the fine powders or granules of the compounds may contain excipients as well as dispersing and surfactants, and may be administered in dosage form in water or syrup, capsules or starch capsules in a dry state or as an aqueous or non-aqueous suspension, in which case a suspending agent may be present; as tablets, preferably made from the granules of the active ingredient with an excipient by compression with binders and lubricants; or in suspension in water or syrup or in oil or water / oil emulsion, which may also contain flavoring, preserving, suspending, thickening and emulsifying agents. Granules or tablets may be coated and tablets may be scored.

For parenteral administration (intramuscularly, intravenously, intraperitoneally, or subcutaneously by injection), "carbazole" may preferably be in the form of a pharmaceutically acceptable salt or hydrate in unit dose or multi-dose containers. substances and solvents which render the compounds isotonic with water; or in aqueous or non-aqueous suspensions, in which case suspending agents and thickeners may also be present; non-prepared injectable solutions and suspensions may be made from sterile powders, granules or tablets which may contain excipients, dispersants and surfactants, binders and lubricants.

"Carbazole", its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of such salts may also be in storage combinations of those known in the art and from which the active ingredient (drug) is released over a longer period of time while the combination is in place in the recipient's body. Such combinations 12 65244, for example in the form of long-acting injections, are advantageous in human medicine for the treatment of, for example, psychotic conditions, such as jaundice, in which the patient unacceptably often misses a particular medication in the form of tablets, etc.

In the veterinary field, "carbazole", its pharmaceutically acceptable salts, pharmaceutically acceptable solvates of such salts have particular use and value in the treatment of aggression in mammals shown to have aggressive symptoms, such as dogs, pigs, horses and cattle, and may be administered as described above. Particularly preferred combinations for veterinary use are the stock combinations described above for use in situations where it is desirable or practical to administer a "carbazole", salt or solvate only at extended intervals.

"Carbazole", pharmaceutically acceptable salts and pharmaceutically acceptable solvates have also been found to have antidepressant activity at the same doses as given above.

Table I shows the significant therapeutic advantage of "carbazole" when given as the dihydrochloride hemihydrate of Example 1 (Compound A) over the prior art carbazole derivative, 9- [3- (4-methylpiperazine) propyl / carbazole as the dihydrochloride (Compound B).

Table I

Comparison of the activity and toxicity of "carbazole" (compound A) with the activity and toxicity of 9- [3- (4-methylpiperazine) propyl] carbazole (compound B)

Compound Anti-aggressive LD50 (mg / kg) ED5Q (mg / kg) LD5Q / ED50

Rat, p.o. Rat, p.o._ A 957 48 20 B 830 75 11

Table II summarizes e.g. several other essential advantages of "carbazole" over Compound B. The minimum dose of "carbazole" (in mice) at which the loss of righting reflex occurs (ED min.) is about 3 times that of Compound B. At the same time, I: 13 65244 shows a decrease in muscle tension (rat) with compound B at a much lower dose than "carbazole".

Table II also compares the antispasmodic effect of the two compounds and a commercially available anticonvulsant, phenytoin (Dilantin). Phenytoin is at least 2.5 times as active as compound B and 5 times as active as "carbazole" (compound A). The level of anticonvulsant activity shown by Compound B is a limit value for the amount in question in this use. "Carbazole" having anticonvulsant activity less than half the activity of Compound B is considered to have insufficient potential value as an anticonvulsant to be considered for this use.

Table II

Comparison of some properties of Compound A, Compound B and phenytoin.

Kouristuksen-

Corrective Reflex Muscle Tension Action

Compound disappearance ED min. thinning ED min. density (MES) a (mg / kg) mouse, m.p. (mg / kg) rat, m.p. ED 2 (mg / kg) mouse, __i.p._ A 160 125 43 B 50 50 20 phenytoin> 100 - 8.5 a) maximal electroshock test (Woodbury and Davenport, Arch. Int. Pharmacodyn, Ther., 92, 97 - 107 (1952)

The prior art carbazole derivative, 9- [3- (4-methylpiperazine) -propyl] -carbazole, which was designated Compound B in Tables I and II above, is exemplified in the Australian and French patents cited above.

The following examples are provided to illustrate the invention. In these examples, all temperatures are in degrees Celsius and vacuum distillation was performed on a steam bath using a pressure of about 20 mm Hg unless otherwise indicated.

14 65244

Example 1 Preparation of 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride hemihydrate A. 3- (3/5-cis-dimethylpiperazine) propanol dihydrochloride 2,6-cis-dimethylpiperazine (114.2 g , 1.0 mol), 3-chloropropanol (94.5 g, 1.0 mol), sodium carbonate (105 g) and ethylene glycol monomethyl ether (400 ml) were stirred and refluxed for 4 hours. The reaction mixture was filtered while warm and the solvent was removed from the filtrate by vacuum distillation.

The resulting solid was dissolved in ethanol (500 mL) and this solution was saturated with dry hydrogen chloride. The white precipitate was collected, dried in vacuo and used in the next step of the hydrochloride salt without further purification, m.p. 240-241 ° C.

B. 3- (3,5-Cls-dimethylpiperazine) propyl chloride dihydrochloride

Thionyl chloride (300 g) was slowly added to 3- (3,5-cis-dioethylpiperazine) propanol dihydrochloride (200 g). The reaction was gently heated to reflux for one hour, after which excess thionyl chloride was removed by vacuum distillation. The resulting solid was washed with several portions of benzene and then with several portions of ether, m.p. 291-292 ° C.

C. 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride hemihydrate

To a slurry of sodium hydride (1.6 moles) prepared from 70 g of a 57% dispersion in mineral oil and 200 mL of dimethylformamide (DMF) was added a solution of carbazole (83.5 g, 0.5 moles). In DMF (150 mL). When no more hydrogen evolved, a slurry of 3- (3,5-cis-dimethylpiperazine) propyl chloride dihydrochloride (131 g, 0.5 mol) in DMF (200 mL) was added to the reaction mixture at a slow rate. The reaction was carried out under a nitrogen atmosphere using a feed system with an oil pulverizer. Some foaming occurred during the addition of the slurry and the addition rate was adjusted to keep this to a minimum. After the addition was complete, the reaction mixture was heated (90-120 ° C) for 16-18 hours, cooled, filtered and the solvent removed by vacuum distillation. The viscous residue was heated to 2 L.

15 65244 with 1 N hydrochloric acid, cooled and washed with ether (500 ml). The ether layer containing all the unreacted carbat-Sol was discarded. The aqueous layer was treated with activated (r) carbon and filtered through Celite®. The filtrate was basified on Alkacid ® paper using sodium hydroxide and then extracted with ether Four times. Both the ether and water layers were clear at the end of the extraction. The ether layer was dried over anhydrous magnesium sulfate or molecular sieves, and the hydrochloride salt of 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole was precipitated by passing dry hydrogen chloride into the solution. The precipitate was collected and recrystallized from ethyl acetate or ethanol / ether to give 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride hemihydrate (50 g), m.p. 288-290 ° C.

Example 2

The compound synthesized according to Example 1 was administered intraperitoneally to rats to determine its murderous activity and inhibition of apomorphine-induced aggression. Its ED values (.g) were found to be 15 mg / kg (anti-murderous) and 12.5 mg / kg (anti-aggressive).

Example 3

The compound of Example 1 was administered to male mice for oral and intravenous LD50 values and was found to be as follows:

Oral Intravenous 977 mg / kg to 31 mg / kg

Example 4 Preparation of 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride hemihydrate (150 g), anhydrous ethanol containing n 5% methanol (680 ml), water (275 ml) and 10 N sodium hydroxide (76 ml) were combined and heated to dissolve them. Water (500 ml) was slowly added to the hot solution and allowed to slowly cool to room temperature. The mixture was further cooled to 0 ° C for 1 hour and filtered. The product was washed thoroughly with water and dried to give 9- [3- (3,5-cis-dimethyl- [..] -? 16 65244 piperazine) propylcarbazole (110 g, 92% of theory), m.p.

107-109 ° C.

Calculated for C 21 H 27 N 3 C 78.46 H 8.47 N 13.07 S Found: C 78.43 H 8.46 N 13.05

Example 5 I- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole- monohydrochloride {Example 19- [3- (3,5-cis-dimethylpiperazine) propyl] -1 carbazole dihydrochloride hemihydrate (5 g) was dissolved in water (250 ml) and the solution was neutralized to pH 7 with 5N sodium hydroxide. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 9- [3- (3,5-cis-dimethylpiperazine) -propyl] carbazole monohydrochloride (3.7 g), m.p. 309-311 ° C (decomposes), which gave the following elemental analysis:

Calculated for C 21 H 28 N 3 Cl C 70.47 H 7.89 N 11.74 Cl 9.91 Found: C 70.53 H 7.93 N 11.69 Cl 9.83

Example 6 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole maleate

The 4- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole of Example 4 (10 g) was dissolved in warm acetone (71 mL). Maleic acid (3.7 g) was added slowly, causing precipitation. The resulting slurry was stirred while refluxing for 10 minutes. 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-dimethylpiperazine) propyl] carbazole maleate (10.5 g), m.p. 162-163 ° C (decomposes), which gave the following elemental analysis:

Calculated for CocHo <1N_0 -.lie: C 68.63 H 7.14 N 9.60 25 3Ί 34 Found: C 68.91 H 7.25 N 9.74

Example 7 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole-3/4-succinate

The 4- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole of Example 4 (10 g) was dissolved in warm SD 3A (ethanol containing about 5% methanol - 50 mL) and succinic acid (3.8 g) was added slowly. .

65244 17

The mixture was stirred and refluxed for 10 minutes and then cooled to 5 ° C. The product was collected by filtration and crystallized from SD3A / water (95/5 v / v) to give 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole-3/4-succinate (10.4 g), m.p. 175.5-176.5 ° C (stoichiometry confirmed by single magnetic resonance spectrum, nmr) which gave the following elemental analysis: Calculated for C24H315N3O3: C 70.30 H 7.74 N 10.24 Found: C 70.21 H 7.71 N 10.20

Example 8

Cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole acetate 1/4 hydrate

To the 4- [3- (3,5-cis-dimethylpiperazine) propyl] -carbazole of Example 4 (10 g) dissolved in hot toluene (70 ml) was added acetic acid (2.0 ml). The mixture was stirred and cooled to 2 ° C. The resulting product was collected by filtration, washed with cyclohexane (35 ml) and dried under reduced pressure to give cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole acetate 1/4 hydrate (10.4 g), m.p. 144-146 ° C, which gave the following elemental analysis:

Calculated C0_H_. Found: C 71.56 H 8.22 N 10.88 6 j F j «5/3 Found: C 71.57 H 8.08 N 10.84

Example 9

Cis-9- / 3- (3,5-dimetyylipiperatslnyyli) propyylj / carbazole-sulphate

To the cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole (10 g) of Example 4 dissolved in warm acetone (100 ml) was added slowly with stirring a solution of sulfuric acid (3.05 g) in water. (5 ml), which caused immediate precipitation. The slurry was stirred at reflux for 10 minutes and then cooled to 20 ° C. 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 pressure to give cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole sulphate monohydrate (12.9 g), m.p. 243-246 ° C (decomposes), which gave the following analysis:

Calculated for C 21 H 31 N 3 O 5 S: C 57.46 H 7.14 N 9.60 Found: C 57.75 H 7.10 N 9.47 18 6524 4

Example 10

Following the procedure of Example 6, 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole was reacted with an equimolar amount of the appropriate acid to give the following salts: 9- [3- (3,5-cis-dimethylpiperazine) prapyl / carbazole fumarate 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole citrate 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole L-malate 9- [3- (3,5-cis-dimethylpiperazine) propyl 4-carbazole L-tartrate 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole methanesulfonate 9- [5- (3,5-cis-dimethylpiperazine) propyl] carbazole DL-lactate, m.p. 194.5 - 197 ° C.

Example 11 9- [3- (3,5-cis-dimethylpiperazinyl) propyl] carbazole dihydrochloride hemihydrate A. 9- (3-chloropropyl) carbazole

Carbazole (134 g, 0.8 mol) in dimethylformamide (1.5 L) was added slowly to a slurry of sodium hydride (0.8 mol) prepared from 39 g of a 50% dispersion in mineral oil and 500 g of ml of dimethylformamide while keeping the temperature below 60 ° C. When no more hydrogen evolved, the reaction temperature was lowered to about 5 ° C in an ice bath and 1,3-dichloropropane (500 g, 4.4 moles) was added at a rate of greater than 10 mL / min. After all of the 1,3-dichloropropane was added, the reaction mixture was stirred slowly while allowing to warm to room temperature (about 1.5 hours).

The reaction mixture was filtered to remove the sodium chloride formed, then the solvent was separated by vacuum distillation (water pump). The thick syrupy residue was then placed under high vacuum. The first fraction removed at 70 ° C and 300 microns was the excess 1,3-dichloropropane, which was recovered for reuse. The second fraction distilled 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. 34-35 °.

Calculated for C 15 H 14 NCl: C 73.91, H, 5.79, N, 5.75 Found: C 73.85, H 5.81, N, 5.72 (B) 9- 3- (3- ( 3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride dihemihydrate-9- (3-chloropropyl) carbazole (12.2 g, 0.05 mol), 2,6-cis-dimethylpiperazine (5.7 g, 0.05 mol) , potassium carbonate (10 g) and dimethylformamide (50 ml) were heated at reflux for one hour, cooled and filtered. The residue was crystallized from ethanol / ether to give 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole dihydrochloride hemihydrate (18 g, 90%: n salt), mp 288-290 ° C.

Example 12 A slurry of 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole monohydrochloride; 3- (3,5-cis-dimethylpiperazine) propyl chloride dihydrochloride (Example 1, Step B) in toluene was cooled with ice and 10N in a mixture of sodium hydroxide and the mixture was adjusted to pH 13.5. The toluene phase was separated and four additional extractions were performed with toluene. After drying, the solvent of the toluene solution was removed to give crude 3- (3,5-cis-dimethylpiperazine) propyl chloride as an oil.

Equimolar amounts of sodium methoxide and carbazole were reacted in dimethylformamide, followed by vacuum separation to ensure removal of liberated methanol. This mixture was combined with the appropriate amount of crude oil from the previous step and the resulting mixture was heated at 100 ° for 15 hours.

Dilution of the thus obtained cooled mixture with water caused the crude 9- [3- (3,5-cis-dimethylpiperazine) propyl] carbazole to crystallize. This was filtered, heated with 1N hydrochloric acid and the resulting solution was extracted, after cooling, with ether. The ether layer was discarded and the remaining aqueous layer was 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-dimethylpiperazine) -propyl] carbazole monohydrochloride, m.p. 309-311 ° (decomposes).

Example 13 9β- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole monohydrochloride ___ A. 9- (3,3-diethoxypropyl) carbazole

To a solution of 50.1 g (0.3 mol) of carbazole and 300 ml of dimethylformamide (DMF) was slowly added 17.28 g (0.36 mol) of a 50% suspension of sodium hydride in 225 ml of dimethylformamide and the resulting mixture was stirred. at room temperature for 1 h To the mixture was added 2 g (0.04 mol) of sodium iodide followed by 60 ml (0.36 mol) of 3-chloropropanol diethyl acetal, which was added dropwise over 15 min. The mixture was heated at 70 ° C for 3 h, allowed to cool and poured into 1.8 L of water. The aqueous mixture was extracted with hexane (4 x 600 mL) and the residue was poured off. The extracts were combined and dried over sodium sulfate. Upon concentration, 54.1 g (61%) of 9- (3,3-diethoxypropyl) carbazole precipitated, which was filtered and vacuum dried, m.p. 57-58 ° C.

B. 3- (9-carbazolyl) propanol

A solution of 30 g (0.1 mol) of 9- (3,3-diethoxypropyl) carbazole and 5 g (0.02 mol) of pyridinium tosylate in 500 ml of acetone was refluxed for 4 h, the solution was allowed to cool and the volatile components were removed. under reduced pressure (15 mm Hg; <40 ° C). Fresh acetone (500 mL) was added and refluxed for 18 h. The evaporation-addition procedure was repeated. The mixture was refluxed for a further 4 h, the volatile components were removed and 500 ml of ether were added to the residue. The crystallized pyridinium tosylate was filtered off and the filtrate was evaporated to a viscous oil which crystallized on trituration with 150 ml of hexane. The off-white solid was filtered and dried under reduced pressure to give 17.4 g (77%) of 3- (9-carbazolylpropanol), m.p. 78.5-79.5 ° C.

t.

21 65244 C. 9- (3-cis-dimethyl-1-piperazinyl) propylcarbazole monohydrochloride 2.25 g (20 mmol) of 2,6-cis-dimethylpiperazine were dissolved in 75 ml of methanol. The pH of the solution was adjusted to 5.1 with methanolic hydrochloric acid. The resulting amine salt solution was stirred and 4.0 g (18 mmol) of solid 3- (9-carbazolyl) propanol and 1.15 g (18 mmol) of cyanoborohydride were added rapidly in succession. After 2 h, the resulting precipitate was filtered, washed with 10 ml of cold methanol and 25 ml of ether and dried under reduced pressure to give 2.5 g (39%) of 9- [3- (cis-3,5-dimethyl). -1-piperazinyl) propyl] carbazole monohydrochloride, m.p. 307-309 ° C.

Elemental analysis: C 21 H 28 N 3 Cl 2

Calculated C 70.47% H 7.89% N 11.74% Found C 70.21% H 7.92% N 11.70%

Example 14 9- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole A. 3- (9-carbazolyl) -1- (3,5-cis-dimethylpiperazino) -1-propanone___________

A suspension of 25 g (0.10 mol) of 3- (9-carbazolyl) propanoic acid in 250 ml of 1,2-dichloroethane and 10 ml (0.14 mol) of thionyl chloride was heated under reflux until no more gas evolved. The mixture was allowed to cool and the volatile components were removed under reduced pressure to leave a greenish yellow oil which solidified on standing. The solid was dissolved in 250 ml of 1,2-dichloroethane and the resulting solution was added to a solution of 2,6-cis-dimethylpiperazine in 250 ml of 1,2-dichloroethane, keeping the temperature below 30 ° C. The mixture was stirred at room temperature for 2 h and the mixture was poured into 500 ml of water. The layers were separated and the pH of the aqueous phase was adjusted to 10 with solid potassium carbonate. The mixture was partitioned between methylene chloride (300 mL) and the aqueous phase was extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting oil was dissolved in ether (500 mL) and filtered through a pad of 8 x 6 cm "forisil" and extracted twice with 100 mL of 10% acetic acid. The aqueous extracts were combined, washed with 100 mL of ether and neutralized with 28% ammonium hydroxide. The aqueous mixture was extracted with two 250 mL portions of ether. The ether extracts were combined, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was dried at 50 ° C for 18 h at 0.1 mm Hg to give 3- (9-carbazolyl) -1- (3,5-cis-dimethylpiperazino) -1-propanone as a yellow glass.

B. 9- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole

A solution of 27 g (80 mmol) of 3- (9-carbazolyl) -1- (3,5-cis-dimethylpiperazino) -1-propanone in 250 ml of toluene was treated with 30 ml (105 mmol). With a "Red-Al" solution (sodium bis- (2-methoxyethoxy) aluminum hydride in toluene, 3.5 M) was added over 45 min at room temperature. The mixture was stirred for 2 h and then 24 ml of water was added portionwise. The toluene layer was decanted, washed neutral with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to leave a white solid. This was triturated with 50 ml of hexane and filtered to give 17.2 g (66%) of 9- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole, m.p. 103-105 ° C.

Elemental analysis: C21H27N3

Calculated C 78.46% H 8.47% N 13.07% Found C 78.43% H 8.54% N 12.95%

Claims (1)

23 6 5 2 4 4 Process for the preparation of 9- [3- (3,5-cis-dimethylpiperazine) propyl / carbazole of formula (A) Cco, CH2> 3 (A) Λ HjC i CH3 H or its useful as a psychotropic substance for the preparation of a salt or a solvate of such a salt, characterized in that a) a compound of the formula CH- \ HN - (ch2) 3-Z (II) / CH3 or p N - (ch2> 3-Z (IIA) O _______ · T-- 24 65244 wherein Z is a leaving atom or group is reacted with carbazole or a reactive derivative thereof with 3,5-cis-dimethylpiperazine, respectively, or b) an aldehyde of the formula CH Ύ ~ λ ^ f-CH2.CH2 .CHO (IIE) ch3 or <K1-CHo.CH_.CH0 (IIF)? Is reacted with carbazole, respectively, with 3,5-cis-dimethylpiperazine, followed by selective reduction, or c) selective reduction of a compound of formula VII \ iu r2 / -o NC -C -C - N NH (VII) O '' 'w' "! wherein two hydrogen atoms on one or more 1-5 numbered carbon atoms a is replaced by an oxo group, and that the obtained compound is, if desired, converted into a carbazole base, a salt thereof, or a solvate of a salt thereof. 6 5 2 4 4 25 For the preparation of 9- / 3- (3,5-cis-dimethylpiperazine) propyl7carbazole> the same is used as the psychotropic orhydrous form (A) cxxj l | CH2> 3 (A ) l'X H3C I CH3 H eller et sait därav eller et soivat av ett sädant sait, kännetecknat därav, att a) en förening med formuleln CH., Υλ HN N- (CH) _ Z (II) \ _ / ch3 p N-- (CH2) 3 - Z (HA) \ J?