CS225849B2 - The production of the 9-/3-/3,5-cis/dimenhylpiperazine/propyl/carbazole - Google Patents

Description

The invention describes a process for the production of substances having valuable anti-aggressive and antipsychotic properties. These substances can be used in the form of pharmaceutical compositions in human and veterinary medicine.

In Australian patent specification no.

201630 and the French patent

No. 1167510 discloses carbazoles of formula I

A —N N-R (I)

in which AND denotes a straight-chain or branched saturated aliphatic hydrocarbon radical having 2 to 6 carbon atoms, ^R 1 represents a hydrogen atom, a lower alkyl group, an aryl group or an aliphatic group, Y and Y | independently of one another hydrogen or halogen, lower alkyl, alkoxy, aryl or aryloxy, the ring bearing Y or Y may contain further substituents and one or group. several piperazine ring carbon atoms can be substituted with methyl

These carbazoles are said to have antiepilaptic properties.

It has been found that a particular compound which is 9-ΓЗ- (3,5-iis-iimetNIP. piperazines) 225849 propyl] carbazole / sometimes referred to as cis-9- [3- (3,5-dimethyl-1- piperazinyl) propyl] carbazole or as 9- [β-diis-1-dimethyl-1-piperazinylpropyl] carbazole, corresponding to formula A

and, for simplicity, called carbazole A, its pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of these pharmaceutically acceptable sold unexpectedly exhibit valuable anti-aggressive and anti-psychotic properties that can be used to treat aggression and psychosis in the human medcine. Surprisingly, these substances do not exhibit toxic side effects, such as dislexion or sedative efficacy, that antipsychotics such as chlorpromazine and the like have.

The term treatment used is understood to mean both the hypersensic administration of carbezode A to a patient (in a humorous medication), which has previously shown aggressive or psychotic symptoms, and the therapeutic application of carbazole A to patients (in a human meedoin) who develop acute aggressive or psychotic Symptoms · A pharmacological test used to detect the anti-aggressive and antipsychotic properties of carbazole A has been described by GM McKeenie in Brain Research, (4,323 (197D). In this test, carbazole A antagonists and apomorphine-induced aggressive symptoms in rats. that suppresses instinctive muricidal breeding rats (i.e., killing of mSI) (see Leaf et al., A ^rea sive Betevioiu, ed. S. Gaaratini and EB Sigg, pp. 120-131, John Wiley and Sons, Inc.). (New York, 1969).

It has been found that the degree of anti-aggressive and antipsychotic properties of carbazole A depends on the specific position of its methyl sub-titers. For example, carbazole A has been found to be more potent than the corresponding unmethylated derivative and than the analogous 4-mmtyl or (4,5-trimethyltyl derivative).

ZvdáSt. the valuable history of carbazole A is that as antipsychotic and anti-aggressive effects, it is essentially free of undesirable side effects, such as sedation, cataracts and extrapyramidade dysfunctions, which are commonly used antipsychotics, such as phenothiazines. The fact that carbazole A does not interfere with extrapyramidade function suggests that it does not antagonize apomorphine-induced stereotypic behavior in rats (see N.E. Aidien, J. Psychhat. Rees, 11, 97, 1974). Significantly lower anticillinic and antihlsamine effects are also associated with the activity of carbazole A than with phenothiazine.

Useful biological properties of carbazole A form the basic moiety This base may form salts (i.e., acid addition salts), which are generally within the scope of the invention. For therapeutic purposes, the acidic residue of these salts is preferably pharmaceutically acceptable to the recipient. Examples of the aforementioned pharmaceutically acceptable salts include

(a) salts with inorganic acids such as sulfuric acid and hydrohalic acids such as hydrochloric acid; and

b) salts with organic acids such as acetic acid, citric acid, fumaric acid, lactic acid (e.g. DL-lactic acid), malic acid (e.g. L-malic acid), mmleic acid, succinic acid and tartaric acid (e.g. with L-tartaric acid) as well as salts with alcoholsulfonic acids, such as methanesulfonic acid, and arylamino acids, such as p-toluenesuffonic acid.

Carbazole A in the free base form can be converted into salts and these salts can be converted into the free base or into salts with other acids in a manner known per se. Thus, salts that are not themselves pharmaceutically acceptable may be valuable for the preparation of pharmaceutically acceptable salts. In addition to salts, the basic carbazole A may form well-defined solvates such as hydrates and solvates derived from alcohols (e.g. methanol or ethanol), all of which are within the scope of the invention.

Carbazole A can be prepared by any of the methods known in the art for preparing compounds of analogous structure.

The present invention provides a process for the preparation of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole of formula A

salts thereof and solvates thereof, characterized in that the compound corresponding to formula II is selectively reduced

(II) wherein two hydrogen atoms on one of the carbon atoms designated 1, 2 and 3 are replaced by an oxo group, and the resulting product of formula A is isolated as the free base or as a pharmaceutically acceptable acid salt, preferably hydrochloric acid, or as pharmaceutically acceptable solvate of this pharmaceutically acceptable salt.

Most reagents capable of reducing the amide carbonyl group, such as hydrogenation at elevated temperature and pressure, using nickel, platinum, palladium, or copper (II) chromium catalyst, concentrated acid, can be used to reduce the starting compounds bearing the oxo group at the 1 or 3 position. hydrogen iodide with red phosphorus and especially lithium aluminum hydride and diborane. An electrolytic reduction can also be used for this purpose.

The starting compound bearing the oxo group on the carbon at the 2-position can be reduced using most keto-reducing agents. Examples are hydrogenation to. the use of nickel, platinum, palladium or copper (II) chromite as a catalyst at elevated temperature and pressure, treatment with zinc and hydrochloric acid (Clemmensen reduction) and hydrazine in the presence of a base (Wolff-Kižner reduction).

The starting material of formula II can be prepared by reacting piperazine or kerbazole, or a reactive derivative thereof, with an acrylic acid halide or ester, such as acryloyl chloride or alkyl acrylate, to give a compound of formula c / p-co-ch = ch ₂ where C / P means either a 3,5-cis-dimethylpiperazinyl or carbazolyl residue, followed by treatment with either carbazole or 3,5-cis dimethylpiperazine.

The starting material of formula (II) bearing an oxo group on carbon 2 can be prepared, for example, by reacting alpha, alpha * -dichloroacetone with 3,5-cis-dimethylmethylpiperazine in ethanol to give 4- (3-chloro-2-oxopropyl) -3,5 cis-dimethylpiperazine, which is then reacted with dimethylformamide carbazole in the presence of a strong base such as sodium hydride.

Carbazole A, its pharmaceutically acceptable salts and solvates of these pharmaceutically acceptable salts are useful for controlling the psychotic and aggressive conditions of a human. For example, they can be used for the prophylaxis and / or treatment of schizophrenia, mania or senility, involuntary or organic psychoses, and depressive psychoses.

Carbazole A can also be used for the prophylaxis and treatment of aggressive behavior. This behavior may be associated with other disorders, such as pechotic and personality disorders, as well as in children with cars, shifts and hyperkinetics.

Carbazole A, pharmaceutically acceptable salts and solvates thereof, dances the locomotor activity of d-amphetamine, similar to most tricyclic antidepressant agents. This potentiation of the effects of d-amphetamine suggests that carbazole A may have anti-depressant activity in humans.

Furthermore, carbazole A, its pharmaceutically acceptable salts and solvates thereof can be used to control aggressive symptoms that may be present in mentally delayed patients and / or patients and behavioral disorders, or to control aggression associated with epilepsy, acute or chronic organic brain syndromes, alcoholism and addiction to narcotics, and other forms of aggression and of known or unknown origin.

Carbazole A, its pharmaceutically acceptable salts, and solvates of these pharmaceutically acceptable salts are preferably administered orally to a mammal, e.g. a human, at a dosage of from 1 mg to 30 mg (calculated on a free basis) per kilogram body weight of the mammal being treated for aggression or psychosis. the most preferred oral dose being 2 to 5 mg / kg. For the treatment of the above-mentioned conditions, carbazole A, its pharmaceutically acceptable salts and solvates are preferably administered at the above-mentioned doses three times a day. Intramuscular injections generally use half the dose used for oral administration. For example, in the treatment of schizophrenia, a suitable dose is from 1 mg / kg to 15 mg / kg, preferably from 2 mg / kg to 5 mg / kg, for example in the form of a unit dose containing 60 to 900 mg of active ingredient. . The unit dose is conveniently administered once or several times a day, for example in the form of one or more tablets each containing 10 to 300, suitably 60 mg of carbazole A, a pharmaceutically acceptable salt or solvate thereof, preferably three times a day.

While carbazole A or a salt thereof can be used as such for therapeutic application, it is nevertheless preferred to administer it in the form of a pharmaceutical composition comprising scaled with a suitable carrier. This 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 to whom the composition will be administered.

The carrier may be a solid or a liquid, or a mixture of solids and liquids, and is preferably formulated with carbazole A or a salt thereof in unit dosage forms such as tablets, capsules or caches for oral administration or suppositories for rectal administration. The compositions of the invention, which may also contain other pharmaceutically active substances, may be prepared by any of the known pharmaceutical techniques based mainly on mixing the individual components. For example, tablets may be made by granulation, crushing, mixing, coating, grinding, compression or compression.

Suitably, unit dosage forms for rectal or parenteral administration comprise from 5 mg to 75 mg of carbazole A or a pharmaceutically acceptable salt or solvate thereof, calculated on the free base.

The fine powder or granular formulations of the present invention for oral administration may contain diluents, dispersants and surfactants and may be administered as beverages in water or syrup, in capsules or cachets in a dry state or in an aqueous or non-aqueous suspension. in which the suspending agent may also be present, in tablets which are preferably prepared from the granulate of the active substance together with the diluent, by compression together with binders and glidants, or in suspension in water, syrup or oil, or and water oils, which preparations may also contain flavoring agents, preservatives, flavoring agents, thickeners, and emulators. The granules or tablets may be coated, and the tablets may be provided with a breaking bar.

For parenteral administration (intravenous, intravenous, intraperitoneal, or subcutaneous injection), carbazole A, preferably in the form of a pharmaceutically acceptable salt or hydrate, may be present in single or multiple dose containers in aqueous or non-aqueous injection solutions. which may contain antioxidants, buffers, bacteriostatic additives and soluble substances for isotonic treatment - of preparations, or in aqueous or non-aqueous suspensions, which may also - contain suspending agents and thickeners. Occasionally, injectable solutions and suspensions may be prepared from sterile powders, granules or tablets which may contain diluents, dispersants and surfactants, binders and glidants.

Carbazole A, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of these salts may also be included in known depot preparations, from which, upon their introduction into the body of the recipient, the active ingredient (drug) is released gradually over a prolonged period of time. Such formulations, such as long-acting injections, are useful in human medicine for the treatment of, for example, psychotic conditions such as schizophrenia, where unacceptably frequent omissions of the regular use of the drug by the patient - when prescribed, for example, in the form of tablets - occur.

In the veterinary field, carbazole A, its pharmaceutically acceptable salts, and pharmaceutically acceptable solvates thereof are of particular importance in the treatment of aggressive behavior in mammals, such as dogs, pigs, horses and cattle. These can be used for this purpose. to administer the active compounds as described above. Especially preferred compositions for veterinary use are depot preparations as described above, which are used in situations where it is desirable or practical to apply carbazole A, its salt or solvate - only at longer intervals.

Carbazole A, its pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of these salts at the above dosages also exhibit anti-inflammatory activity.

DETAILED DESCRIPTION OF THE INVENTION The invention is illustrated by the following examples, which are not to be construed in any way. Vacuum distillations are carried out on a steam bath at 20 psi.

P A tunes

Preparation of 9- [3- (3,5-cis-dimethyl-1-piperazinyl) -propyl] carbazole

A. 3- (9-carbazolyl) -1- ^(3,5-CS-R iillmehln lplp <rraznno) -1-roopanou,

A suspension of 25 g. (0.10 mol) of 3- (9-carbazolyl) -popanoic acid in 250 ml of 1,2-dlchloroethane and 10 ml (0.14 mol) of thiounlchlorite is heated to reflux until gas evolution ceases. The mixture was allowed to cool and the volatiles were removed under reduced pressure.

The green-yellow oily residue solidified on standing. The solid material was dissolved in 250 ml of 1,2-dichloroethane, and the solution was added to a solution of 2,6-cis-methyl-diphosphate in 250 ml of 1,2-dichloroethane while maintaining the temperature below 30 ° C. The mixture was stirred at room temperature for 2 hours, then poured into 100 ml of water, the layers were separated and the pH of the aqueous layer was adjusted to 10 with solid sodium hydroxide. The mixture was shaken with 300 ml of methylchloride and an aqueous layer. is extracted again with methylene chloride. The organic extracts were combined, dried over anhydrous

- sodium and evaporated under reduced pressure. The oily residue is dissolved in 500 ml of ether, filtered through a pad of silica (8 x 6 cm) and extracted with 10 ml of 10% acetic acid in each case. The aqueous extracts are added, mixed with 100 ml of ether and not neutralized with 28% ammonium hydroxide.

The aqueous mixture was extracted twice with 250 ml of ether each time, the ether extracts were combined, dried over anhydrous sodium sulphate and evaporated under reduced pressure. After drying for 15 hours at 50 [deg.] C. at a pressure of 13 Pa, 3- (9-klbalbalyl-L-1- (3,5-cis-dimethylpiptrezino) -1-propanone) is obtained in the form of a yellow glassy mass.

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

To a solution of 27 g (80 moles) of 3- (9-carbazolyl) -1- (3,5-dimethylylP-Peaeaino) -1-propanone in 250 ml of toluene was added 3.5 ml of 3.5M at room temperature over 45 minutes at room temperature. N-tri-b8 (2-methysyreth10) -Sulphide in toluene. The reaction mixture is stirred for 2 hours and 24 ml of water are added in portions. The toluene layer is decanted, washed with water until neutral, and dried over anhydrous magnesium sulphate, the solvent is evaporated off under reduced pressure, the white solid is triturated with 50 ml of hexane and the mixture is filtered. There was obtained 17.2 g (66%) of 9- [3- (3,5-l8-dimethyl-1-piperidyltryl) -polyl] melting point 103-105 ° C.

H, 8.47; N, 13.07. Found:% C, 78.43;% H, 8.54;% N, 13.95.

Example 2.

Preparation - 9- [3- (3,5ciid-ditttyLlpPerlaztno) propil]

150 g of 9- (3- (3,5-di-cyclopiperazin) propyl) -benzyl-dihydrochloride hexahydrate, 680 ml of anhydrous ethanol containing about 5% oethunol, 275 ml of water and 76 ml of 10N sodium hydroxide, The solution was then cooled slowly to room temperature, cooled to 0 ° C for one hour, and then filtered, and the product was thoroughly washed with water to give the product. 110 g (92% of theory) of 9- [3- (3,5-dimethylethylpiperazin-1-yl) propionyl] -benzene, m.p. 107-109 ° C.

Found:% C, 78.43;% H, 8.46;% N, 13.05. Found: C, 78.46;% H, 8.47;% N, 13.07;

Example 3

9- [3- (3,5-di-tetraethylpiperidine) -polyglycine-1-monohydrohydrocylsulfide 9- (3- (3,5-di-8-diethylpiperazine) prspll) is cleaved in 250 ml. The solution was neutralized with 5 N sodium hydroxide to pH 7. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure.

3.7 g of 9- [3- (3,5-ciddioethylpiperazine) propylcarbazole-msnshydrochloride, m.p. 309 DEG-311 DEG C. (decomposition). The product follows! ιΙ ^ ι ^ ο ^ ι ^ Ι ^ Ι ^: ^:! analysis.

H, 7.89; N, 11.74; Cl, 9.91.

Found: C 70.53, H 7.93, N 11.69, Cl 9.83.

Example 4

9- [3- (3,5-C8-Dimethyl-piperazino) -propyl] -carbazole maleate 9- [3- (3,58-Cid-Diethyl-piperazino) -propyl] -carbazole is dissolved in 71 ml of warm acetone and 3.7 g of mmleic acid are slowly added. to form a precipitate. The resulting thick suspension was heated to reflux for 10 minutes with stirring, then cooled to room temperature and filtered. The precipitate was washed with acetone and then recrystallized from water. 10.5 g of 9- (3- (3,5-di-8-yl-piperazino) -propyl] -carbanoleate), m.p. 162 DEG-163 DEG C. (decomposition), are obtained, which is carried out as an elemental analysis.

For C25H31N3O4: calculated: 68.63% C, 7.14% H, 9.60% N; Found:% C, 68.91;% H, 7.25;% N, 9.74.

Example 5

9- [3- (3,5-cis-Dimethyl-piperanio) -propyl] -carbazole-3/48-succinate of 9- [3- (3,5-cis-dimethyl-piperanino) -propyl] -carbanol is dissolved in 50 ml of hot ethanol containing about 5% of methanol and 3.8 g of succinic acid are slowly added. The mixture was stirred at reflux for 10 minutes and then cooled to 5 ° C. The product was isolated by filtration and crystallized from ethanol with 5% methanol and water (95: 5 v / v) to give 9- (3- (3,5-cis-diethylpiperaniio) propyl] carbonyl-3- _> 48-succinate (10.4 g). m.p. 175.5-176.5 ° C (stoichiometry confirmed by NM), which has the following elemental analysis.

^{For C} 24 ^H 31.5 ^M 3 ^O 3 calculated: 70.30% C, 7.44% H, 10.24% N;

Found: C, 70.21; H, 7%; H, 10.20.

EXAMPLE 6 8-9- (3- (3,5-Dihydrocarbonyl) pro-propyl) ckabaaneacate-1/4-hydrate 9- (3- (3,5-dihydroethylpiperanino) propyl) carbazole was dissolved in 70 mL of hot toluene and added The mixture is cooled to 2 ° C with stirring, the resulting product is collected by filtration, washed with 35 mL of cyclohexane and dried under reduced pressure to give 10.4 g of 18-9- [38 (3, m.p. 144 DEG -146 DEG C., m.p. 144 DEG -146 DEG C., which has the following analysis.

^{For C} 23 ^H 31.5 ^N 3 ^O 2.25 calculated: found:

71.56% C _:

71.77% C

8.22% H,

8, 08% H.

N, 10.88;

10.84% N.

Example 7

Cis-9-? -O-Dimethyl-4-piperidinylspropylcarbazole sulphate

10 g cÍ8-9- [3- (3 ₉ 5-dirnetldJLpiperasino) priydl] kabaaoplu, bPoynuStěrým · in 100 ml of warm acetone was added pommlu OA bootok stirring 3.05 g of sulfuric acid in 5 ml of water to precipitate immediately . The Suspeooe was stirred and refluxed for 10 minutes and then cooled to 20 ° C. The product is collected by filtration, washed with 20 ml of acetone, stirred in 70 ml of water, filtered, washed with 40 ml of acetone and exploded under reduced pressure. There were obtained 12.9 g of C185-9-3- (3,5-diolylthiazolidinyl) cadbazoP-8Ulfate monohydrate having a melting point of 243-246 [deg.] C. (assuming), which was followed by electrolysis analysis.

For C ₂ ^1H 31 ^N 3 O5 ^S vyyočteno: 57.46% C, 7.14% H, 9.60% N; H, 7.10; N, 9.47.

^ Example 8

By analogy to the previous examples, 9- (3- (3,5-cis-3,5-dimethylyiyeraoino) pboyll) cabaazole is obtained by reacting 9- (3- (3,55-cis-dimethyl-5-yyderazin-1-yl) -carbonyl] -carazyl with equimolar masculinity of DL-lactic acid. DL · -5accate, mp 194.5-197 ° C.

The following are the results oknušek fadmakologické Eff <^ s ^ 8 _(i substances according Invention in.

Test 1

Inhibition of apomolfininel-induced muurcid activity and aggression following intrapeditpneal administration of hemiiyl allyl 9- (3- (3,5-3,5-dihydro-dlpiyedazino) ylpiperidine) -didyl-dridylpride has been reported.

EDθ values of 15 mg / kg (anti-mucicidal efficacy and 12.5 mg / kg (anti-aggressive efficacy)) were found for the test substance.

'Test 2

9- (3- (3,5-cis-diethylyl-indazin-1-yl) -carbazinyl-dihydrochloride) hemiihydrate was administered intravenously and intravenously to the male animals to determine toxicity.

oral administration: 977 mg / kg intravenous administration: 31 mg / kg

In the follow-up to Table I, the efficacy and toxicity of 9- (3- (3,55-α-diethylglycerazin-1-yl) -carbonyl] -cadazole-dihydrochloride (Compound A) and 9- (3- (4-methyl-4-methyl-methyl) -amide) are compared. BACKGROUND OF THE INVENTION [0003] From the data presented in Table 1, the advantageous advantage of Compound A according to the invention is compared to that of Compound B.

225849,

Table 1

Substance

LD ₅₀ (mg / kg) rat (per os) ^ed 50 (mg / kg) anti-aggressive activity rat (per os)

LD ₅ o / ^ED 50 therapeutic index

957

830

The following Table II shows, among other things, the significant advantages of carbazole A over substance B. The minimum dose of carbazole A (for mass) at which the loss of equilibrium reflex (ED min) is about three times greater than that of the substance B. Similarly, a decrease in muscle tone was observed in rats at a much lower dose than carbazole.

Table II also compares the anticonvulsant effects of the above two substances and the commercial anticonvulsant active phenytoin (Diiannin). Fernytoin is almost 2.5 times more potent than substance B and five times more potent than substance A. The degree of anticonvulsive activity of Compound B is at the limit for its intended ingestion, while the anticonvulsive activity of Compound A, which is less than half that of Compound B, the intended use of substance A.

Table II

Substance

Loss of equilibrium reflex ED min (mg / kg) mouse (intraperitoneal)

Muscle reduction. ton

Ed min (mg / kg) rat intraperitoneally)

Ainiconnvileive efficacy (M2S) ^and ED50 (mg / kg) carrion (intraperitoneal)

A 160 12543

B 50 5020 phenytoin> 100 -8.5

Legend:

Maximal Electroshock Test [Woodbtury and Davveppot, Arch. Int. Pharmacodyn. Ther., 22, 97-107 (1952)).

The prior art 9- [3- (4-methylpiperazine) -propyl] carbazole, reported as Tables B in Tables I and II, is described in Example 7 of the aforementioned Australian and French patents. '

Claims (1)

A process for the preparation of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole of formula A (A), its salts and solvates thereof, characterized in that the compound corresponding to formula II (II) is selectively reduced in which: the two hydrogen atoms on one of the carbon atoms designated 1,2 and 3 are replaced by an oxo group and the resulting product of formula A is isolated as the free base or as a pharmaceutically acceptable acid salt, preferably hydrochloric acid, or as a pharmaceutically acceptable solvate thereof.