Alkyl derivatives of trazodone, the retrieval method, intermediate compounds and pharmaceutical composition

 

(57) Abstract:

Alkyl derivatives of trazodone the General formula I

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where only one of R, R', R" and R"' represents a C1-C3-alkyl, and the others are hydrogen, and their salts with physiologically acceptable inorganic or inorganic acids produced by interaction of the compounds of formula III

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or its salt with an alkaline metal piperazinone compound of formula II

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where R, R', R", R"' take the values specified for formula I and X is chlorine or bromine at the boiling temperature of the reaction mixture. The compounds of formula I in comparison with trazodone have reduced affinity for the adrenergic receptors and surpass trazodone when speech goes about LD50. 7 C. and 3 h.p. f-crystals.

The present invention relates to new alkyl derivative of trazodone with pharmacological activity, pharmaceutical compositions containing them, methods for their production and intermediate compounds suitable to receive them.

Trazodone formula (T) is a drug known for about twenty years and is widely used as an antidepressant

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On the other hand, some authors also reported some who should more fully understand its mechanism of action is almost certainly it is associated with the interference of trazadone system energicheskoi transmission in the Central nervous system.

The study of the chemical binding shows that trazodone manifests a certain degree of interference with the following receptors (see table.1).

Action on adrenergic receptors (alpha 1 and alpha 2) apparently causes some sporadic side effects of trazodone, such as hypotension and priapism, as far as we know, it is not related to psychopharmacological activity.

Now unexpectedly found that the compounds of formula (I)

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where only one of R, R', R" and R"' is alkyl and the other is H, and their salts with physiologically acceptable organic or inorganic acids, have low affinity for the adrenergic receptors (see table. 2).

In addition, the compounds of formula (I) are superior to trazodone, when it comes to LD50(see tab.3).

Therefore, the first aim of the present invention is the provision of compounds of the formula (I) where only one of R, R', R" and R"' is alkyl and the other is H, and their salts with physiologically acceptable organic or inorganic salts.

Examples of suitable physiological acceptable inorganic and organic acids are hydrochloric, Hydrobromic, what I Emelyanova acid.

Preferably, the compounds of formula (I) are obtained according to the following reaction scheme

The reaction scheme 1.

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where R, R', R" and R"' have the meanings described above, and

X - conventional leaving group selected from the class comprising chlorine, bromine, -O-SO2AlK, -O-SO2Ar.

Stage, shown in reaction scheme 1, essentially comprises the alkylation of aliphatic secondary amino group and can be performed according to conventional methods (J. March, Advanced Organic Chemistry, 3rd Ed., J. Wiley & Sons, N. V., pp. 364-365).

The compound of formula (III) is introduced into the reaction in salt form with an alkali metal, such as, for example, sodium salt is described in U.S. patent 3381009.

In leaving the groups-O-SO2AlK-O-SOAr, Alk and Ar mean the alkyl and aryl (J. March, Advanced Organic Chemistry, 3rd Ed., J. Wiley & Sons, N. V., page 312). Preferably, Alk is methyl and ar is phenyl, tolyl and p-bromophenyl.

The reaction preferably is performed by the interaction of the sodium salts of the compounds of formula (III) with the compound of the formula (II) with the presence of a suitable organic solvent or mixture of organic solvents at a temperature of from 40oC and the boiling temperature of the reaction mixture. Examples of suitable organic solvents are aromaticheskogo are: benzene, toluene and xylene. Examples of preferred aliphatic alcohols are butyl, tert-butyl, sec-butyl, isobutyl, pentalogy and tert-pentalogy alcohol. An example of the preferred amide is dimethylformamide.

The intermediate compound of formula (II) is new.

Therefore, an additional object of this invention is to obtain the compounds of formula (II), where R, R', R", R"' and X have the meanings given above.

Intermediate compounds of formula (II) can be obtained according to the following reaction scheme

The reaction scheme 2.

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where X, R, R', R" and R"' have the meanings specified above.

Stage, is shown in reaction scheme 2, is preferably adding piperazinovogo compounds of formula (IV) to the aqueous mixture of a bifunctional alkylating agent of the formula X-CH2-CHR-CHR'-X with a suitable derivative of an alkali metal.

Pieperazinove compound of formula (IV) is preferably dissolved in a suitable organic solvent, such as, for example, an aromatic hydrocarbon or a ketone. Examples of suitable aromatic solvents are benzene, toluene and xylene. Examples of suitable ketones - acetone and methylisobutyl sodium hydroxide and potassium.

Pieperazinove compound of formula (IV), where R" = R"' = H is a known compound (G. B. Pollard et al., J. O. C. 24, 764 (1959)), while the compounds of formula (IV), where R"' is H and R" is C1-C3-alkyl - new and can be obtained according to the following reaction scheme.

The reaction scheme 3.

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Ring closure in 2-R-(3-chlorophenyl)-3,6-diazapentane acid of formula (VI), leading to the formation of the corresponding piperazinone formula (V) preferably is performed by processing the lower ester hexanoic acid of formula (VI) an appropriate condensing agent in the presence of a diluent.

An example of a suitable condensing agent is sodium hydride, thionyl chloride and hydrogen chloride.

The solvent is selected depending on the condensing agent according to criteria well known from previous works. For example, if the condensing agent - NaH, suitable solvents are aromatic hydrocarbons, such as benzene, toluene and xylene, while the lower halogenated hydrocarbons such as chloroform and methylene chloride are preferred when using thionyl chloride as the condensing agent.

Subsequent vosstanovitelnye is performed using a conventional reducing agent, such as alumalite lithium.

Both piperazinone the compounds of formula (V) and 2-substituted (3-chlorophenyl)-3,6-deazaguanosine acid of formula (VI), where R" is C1-C3-alkyl, are also new compounds.

They therefore are also the aim of the present invention.

The compounds of formula (I) may have asymmetric carbon atom. Therefore, the next aim of the present invention is to obtain as separate optical active isomers of formula (I), and mixtures thereof.

The compounds of formula (I) of the present invention will be applicable in all those therapeutic areas where an effective trazodone, for example, in depression, but without the undesirable side effects of trazodone, such as hypotension and priapism. In particular the compounds of formula (I) of the invention are promising in the treatment state of fear.

In the practical use in therapy, the compounds of formula (I) and their physiologically acceptable salts with acids can be introduced and as themselves, but more preferably put into the form of pharmaceutical compositions.

The above compositions are another aim of the present invention and contain Ter is mimimi acids together with solid or liquid pharmaceutical excipients for systemic or local application.

The pharmaceutical compositions of the present invention can be solids, such as tablets, coated in sugar, plates, capsules, powders and slowly released form, or semi-solid, for example, suppositories, creams and ointments, or liquid, such as solutions, suspensions and emulsions.

Besides the usual excipients compounds may contain a pharmaceutical acceptable additives, such as protecting agents, stabilizers, emulsifiers, salts for regulating the osmotic pressure, buffers, perfumes and dyes.

When you need special therapy, the compositions of this invention may include other compatible active ingredients, which when accompanied the introduction provides a useful therapeutic effect.

For practical use in therapy, an effective amount of the compounds of formula (I), required for insertion, varies widely depending on such factors as specific therapeutic requirements of the pharmaceutical composition, the route of administration, the body weight and the effectiveness of a particular compound of the invention, However, the optimal value of the effective amount can be readily determined using conventional techniques.

Basically, the project may be increased to 1200 mg.

The pharmaceutical compositions of the invention can be obtained by using conventional techniques of pharmaceutical chemistry, including blending, granulation, pressing, if necessary or diverse combination of mixing and dissolving the ingredients as appropriate to obtain the desired product.

To better illustrate the invention the following examples are cited.

Example 1.

1-(3-Chlorophenyl)-3-methyl-piperazine-2-he

(formula (V), R" = CH3)

A solution of 76 g of N-(3-chlorophenyl)-ethyldiamine (J. Med. Chem.9, hh. 858-60 (1966)), 60 ml of ethyl ether 2-bromopropionic acid and 63 ml of triethylamine in 400 ml of toluene is boiled for 15 hours, cooled, washed with water, dried by azeotropic distillation and gradually add 9 g of sodium hydride (suspension in oil, 60%).Adding sodium hydride see spontaneous heating a mixture. The reaction mixture was stirred for 1.5 hours at 60oC (extreme heat), cool, bring water. The organic layer is separated, dried and evaporated in vacuum. The remainder (48 g) is distilled and obtain 35 g of 1-(3-Chlorophenyl)-3 methyl-piperazine-2-it (boiling point 160oC at 0.5 mm Hq. Hydrochloride connection is so pl. 170,5-171oC.

02 g of N-(3-chlorophenyl)-ethyldiamine, 117 g bitovogo alcohol 2-pamakani acid and 84 ml of triethylamine in 500 ml of toluene is boiled for 6 hours, cooled, washed with water, the solvent evaporated in vacuum. The oily residue (175 g) are suspended in 650 ml of 2 M NaOH, the mixture is heated under vigorous stirring at 70oC to dissolve oil (approximately 2 hours). The resulting solution is acidified and the solid precipitate filtered off and get (3 - chlorophenyl-2-ethyl-3,6-diazapentane acid (formula VI), R ' = ethyl), so pl. 207-208oC. Elemental analysis was in accordance with the formula C12H17ClN2O2.

To the solution obtained above acid 1.8 chloroform are added dropwise thionyl chloride, boiled for 3 hours, the solvent evaporated and the residue suspended in a solution of 70 ml of triethylamine in 1.8 g of toluene, is heated under stirring for 2 hours at 70oC, cooled, filtered to remove triethylamine hydrochloride and evaporated in vacuum. The residue is distilled and collected fraction between 195 and 200oC at 0.3 mm Hq. The hydrochloride of the above compound has so pl. 149-152oC.

Example 3.

1-(3-Chlorophenyl)-3-ethyl-piperazine

(formula (IV), R" = CH2H5)

To a suspension of 31.5 g of lithium aluminum hydride in 6 Astor 66 g piperazinone compound from example 2 in 350 ml of ethyl ether. After adding the resulting mixture is boiled for 2 hours, then the excess hydride is decomposed with water and the organic basis of produce through conventional methods. The hydrochloride of the above compound, paracrystalline from isopropyl alcohol, has so pl. 179-181oC

Example 4.

1-(3-Chlorophenyl)-3-methyl-piperazine

(formula (IV), R" = CH3)

1-(3-Chlorophenyl)-3-methyl-piperazine receive the same method, which is shown in example 3, but from piperazinovogo connection example 1.

The hydrochloride of the above compound has so pl. 178-178.5oC (from ethyl acetate).

Example 5.

1-(3-Chlorophenyl)-4-(3-chloro-2-methylpropyl)-piperazine

(formula (II), R = CH3, R' = R" = R' = H).

To a mixture of 150 ml of 1-bromo-3-chloro-2-methylpropane, 55 g of potassium carbonate and 4 ml of water at 60oC with vigorous stirring was added dropwise a solution of 40 g of 3-chlorophenyl-piperazine in 50 ml of toluene. After the addition the mixture is stirred for 48 hours, filtered off the solid precipitate, the filtrate evaporated, the residue chromatographic on a column of silica gel with elution by the mixture hexane-ethyl acetate= 1-1. Get 25 g of the product, and used for the next stage. The hydrochloride of the above compound has so pl. 178-1 is re 3, suitable compounds of the formula (IV) react with suitable dihalogenoalkane with the formation of the corresponding compounds of the formula (II):

-1-(3-chlorophenyl)-4-(3-chloro-1-methylpropyl " piperazine

(R' = CH3R = R" = R' = H)

The dihydrochloride of the compound has so pl. 160-162oC (Razlog.);

-1-(3-chlorophenyl)-4-(3-chlorpropyl)-3-methyl-piperazine

(R" = CH3R = R' = R"' = H)

The dihydrochloride of the compound has so pl. 174-176oC (Razlog.).

Example 7.

2-[3-[4-(3-chlorophenyl)-1-piperazine] -2-methylpropyl]-1,2,4-triazole[4,3 - a] pyridine-3-(2H)-he

(formula (I), R = CH3, R' = R" = R' = H).

A mixture of 43 g of the product from example 5, and 23.6 g of sodium salt of 1,2,4 - triazole[4,3-a]-pyridine-3-(2H)-it (Italian patent application N 27806/65), 300 ml of xylene and 30 ml of isobutyl alcohol is heated and boiled for 8 hours, diluted with an equal volume of water.

The residue obtained after removal of the solvent from the organic phase into the corresponding hydrochloride with a solution of 2M hydrochloric acid. After recrystallization from water obtain 35 g of the product with so pl. 196 - 198oC.

Elemental analysis and data spectrometric analysis correspond to the structure of these compounds.

Example 8.

According to the method of sinil] -3-methylpropyl]-1,2,4-triazole[4,3 - a] -pyridine-3-(2H)-he (R' = CH3R = R" = R' = H) (1,2,4 - triazole[4,3-a] -pyridine-3-(2H)-she and the compounds of formula (II), where R = R '= R"' = H, R' = CH3)

The dihydrochloride hydrate, so pl. 184-194oC;

-2-[3-[4-(3-chlorophenyl)-1-(2-ethyl)-piperazinil] -propyl] -1,2,4 - triazole[4,3-a] -pyridine-3(2H)-he (R" = ethyl, R = R' = R"' = H) (1,2,4-triazole[4,3-a] -pyridine-3-(2H)-she and the compounds of formula (II), where R = ethyl, R = R' = R"' = H)

Hydrochloride, T. pl. 180-182oC;

-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinil] -propyl] -1,2,4 - triazole[4,3-a]-pyridine-3-(2H)-he (R" = CH3), R = R' = R"' = H) (1,2, 4-triazole[4,3-a]-pyridine-3-(2H)-she and the compounds of formula (II), where R" = CH3R = R' = R"' = H, X = Cl

Hydrochloride, T. pl. 189-190oC;

-2-[3-[4-(3-chlorophenyl)-1-(3-methyl)-piperazinil] -propyl] -1,2,4 - triazole[4,3-a] -pyridine-3-(2H)-he (R" = CH3R = R' = R" = H) (1,2,4-triazole[4,3-a] -pyridine-3-(2H)-she and the compounds of formula (II) where R' = CH3), R = R' = R" = H) X = Cl

Hydrochloride, T. pl. 178-180oC;

1. Alkyl derivatives of trazodone the General formula I

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where only one of R, R', R"and R"'represents C1-C3alkyl, and the others are hydrogen, and their salts with physiologically acceptable organic or inorganic acids.

2. The compound of General formula II

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where that is, The

X represents a leaving group selected from the group comprising chlorine, bromine.

3. The compound of General formula IV

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in which R"'represents hydrogen, and R"represents C1-C3alkyl.

4. The compound of General formula V

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in which R"represents C1-C3alkyl.

5. The compound of General formula VI

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in which R"represents C1-C3alkyl.

6. Pharmaceutical composition having activity similar to trazodone with reduced side effects, including an active agent and a carrier, wherein the active agent it contains a connection on p. 1 in an effective amount.

7. The method of obtaining alkyl derivative of trazodone the General formula I on p. 1 and their salts with physiologically acceptable organic or inorganic acids, wherein 1, 2, 4-triazole[4,3-a]-pyridine-3-(2H)-he of the formula III

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or its salt with an alkaline metal is subjected vzaimodeistvie with piperazinone compound of formula II

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in which R, R', R", R"'and X have the meanings given in paragraph 2, in the presence of an organic diluent at Tempe is a mixture of aromatic hydrocarbon and a lower aliphatic alcohol.

9. The method according to p. 8, characterized in that the aromatic hydrocarbon is xylene.

10. The method according to p. 8, wherein the lower aliphatic alcohol is isobutyl alcohol.

 

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