(s)- or (r)-enantiomers, methods for their production, intermediate product

 

(57) Abstract:

(S)- or (R)-Enantiomer of the compound with the chemical formula IA, where Lk - alkyl having 1 to 3 carbon atoms, and the salt connection with a physiologically acceptable acid possess pharmacological indicators similar to those of trazodone, but with reduced affinity to adrenergic receptors. The method of obtaining compounds of formula IA or its acid additive salts lies in the fact that the compound of formula III or its salt with an alkaline metal is subjected to reaction with piperazinone compound of the formula II, in which Lk has the abovementioned meaning and X is tsepliaeva group from the group consisting of chlorine, bromine and-O-SO2-Z, where Z is alkyl or aryl, with a compound II has an absolute (R)- or (S) - configuration in the presence of a suitable organic solvent or mixture of organic solvents at a temperature of from 40oC to the boiling temperature of the reaction mixture and, if desired, form the salt thus obtained enantiomer with a physiologically acceptable acid. Describes a number of new intermediate compounds. 5 S. and 11 C.p. f-crystals. 3 table.

This invention relates to pharmacologically asset is octavam, thereof.

In the application PCT/EP 93/00080 describes a class of new compounds of General formula

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where only one of R', R" and R"' is alkyl having from 1 to 3 carbon atoms, while the others are hydrogen.

As shown by pharmacological data reported in the above-mentioned application, the compounds with the chemical formula I possess pharmacological indicators similar to those of trazodone (1, R = R' = R"= R' = H), but also have some advantages, such as reduced affinity for adrenergic receptors.

As unexpectedly set in the present time, both (S)- and (R)-enantiomer of compounds with the chemical formula I, where R, R', R"' is hydrogen and R" is alkyl having from 1 to 3 carbon atoms, possess superior analgesic activity compared with their racemates.

This discovery is even more surprising, since both enantiomers have lower allpolitical activity and, consequently, fewer unwanted effects compared with the corresponding racemates.

Therefore, the first object of this invention is to obtain (S)- and (R)-enantiomers of compounds with the chemical formula IA

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where ALk is alkyl, Im2">

Examples of suitable acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, lactic acid, succinic acid, acetic acid, tartaric acid, malic acid, citric acid, benzoic acid, 2-naphthalenesulfonate acid, adipic acid and Emelyanova acid.

Although both (R)- and (S)-enantiomer is more active than the corresponding racemate, (S)-enantiomers active (R)-enantiomers. Therefore, the preferred (S)- enantiomers. With regard to the designation of ALk, methyl is preferred.

Thus, a preferred compound according to this invention is (S)- enantiomer with the chemical formula IA, where ALk is methyl.

Analgesic activity of the compounds according to this invention was tested in mice by finishingmove test with subcutaneous application method (Pharmacol. Exp. Ther. 125, pp.237 - 240, 1959). Each compound was administered to thirty animals. The results of the experiments are given in table. 1.

As the table shows. 1, to achieve the same analgesic activity requires a higher dose of racemic compounds. This means that the racemic compound has a lower analyse active, than (R)-enantiomer.

As the disorder adrenergic system is an indicator of undesirable effects was assessed as the ability of binding to alpha-1 adrenergic receptors, such as IC50(PL. 2), and allpolitics activity (table. 3) the same connection.

As for testing the binding of receptors, reference is made to "Molecylar Pharmacology", 20, 295-301 (1981).

In turn was estimated allpolitics activity on a stand-alone body (taken from rats) in accordance with the procedure described in "Clinical and Experimental Pharmacology & discrimination", 6, 275-279 (1979).

The results of the experiments are presented in table. 2 and 3.

In table. 2 affinity for alpha-1 adrenergic receptors is higher, the lower the value of the IC50while in the table. 3 allpolitics activity is higher, the higher the magnitude of the pA2. In addition, the data table. 2 and 3, therefore, be a complete surprise, as they show that as a violation of adrenergic receptor and allpolitics activity, and, therefore, undesirable actions of both (S)-and (R)- enantiomers less than the racemate, while allpolitics activity of (S)-enantiomer is less than himicheskoi formula IA, the less junk allpolitics activity.

Compounds according to this invention can be obtained by fractionated crystallization of their salts with optically active acid or by stereospecific synthesis.

In the first method were particularly useful salt of tartaric acid.

Hence, the second purpose of this invention is to provide a method of producing enantiomers with the chemical formula IA, wherein the salt form of racemic mixtures of compounds with the chemical formula IA (R, R or S, S) - tartaric acid, by fractionated crystallization separates the two thus obtained diastereoisomeric salt from a suitable solvent and, if desired, form the salt thus obtained enantiomer with a physiologically acceptable acid.

Examples of suitable solvents are lower alcohols and water.

Salts of enantiomers according to this invention with (R, R or S, S)-tartaric acid are also new and, therefore, represent the third objective of this invention.

Another object of this invention is to provide a method stereospecific synthesis of the enantiomers with chemical formichelli formula III

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or its salt of the alkali metal reacts with piperazinone compound of chemical formula II

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in which ALk has the above meaning;

X" is tsepliaeva group from the group consisting of chlorine, bromine and-O-SO2-Z, where Z is alkyl or aryl,

in this connection II, has an absolute (R)-or (S)-configuration, in the presence of a suitable organic solvent or mixture of organic solvents at a temperature of from 40oC to the boiling temperature of the reaction mixture and, if desired, form the salt thus obtained enantiomer with a physiologically acceptable acid.

The above reaction is essentially alkalization secondary amino group and can be conducted by conventional methods (J. March, Advanced Organie Chemistry, 3 rd ed, J. Wiley & Sons, NY, pages 364-365).

Is preferred that the compound of chemical formula III is reacted in the form of salts of alkaline metal such as sodium, described in US-A-3.381.009.

Typical values of Z are methyl, phenyl, tolyl and paraprotein.

The reaction is conducted by reacting the sodium salt of the compound of chemical formula III with the compound of the formula II in the presence of a suitable organization is of the reaction mixture. Examples of suitable organic diluents are aromatic hydrocarbons, aliphatic alcohols, amides, and mixtures thereof.

Examples of preferred aromatic hydrocarbons are benzene, toluene and xylene, and examples of aliphatic alcohols - butanol, tert-butanol, sec-butanol, Isobutanol, pentanol and tert-pentanol. A typical example of the preferred amide is dimethylamide.

In turn, stereoscopic synthesis of compounds with the chemical formula II can be carried out by reaction of the compound of formula VIII

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where ALk has the above value

X' is CH3-O-SO2-O - or halogen;

Y is alkyl having from 1 to 3 carbon atoms,

which is absolute (S)- or (R)-configuration,

with the compound of the formula VII

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to obtain the compounds of formula VI

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where Y and ALk have the above meaning,

which is absolute (R)-configuration, when the compound VIII is (S)-configuration, and Vice versa.

The reaction between the compound VIII and compound VII to obtain a compound VI is preferred to carry out in the presence of an acid acceptor and a suitable solvent.

Examples of suitable acceptors cycloprine toluene and xylene.

This is followed by a cyclization of compound VI to obtain a compound with the chemical formula V

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having the same absolute configuration as the compound (VI).

The cyclization of the compound (VI) to the compound (V) was not carried out according to the method described in PCT/EP 93/00080 in connection with the corresponding racemic compounds, as this methodology was full racemization. After a number of unsuccessful attempts that led to either racemization or removing the unchanged compound (VI), it has been unexpectedly discovered that the desired cyclization could be very easily carried out by dissolving compound (VI) in an aqueous solution of a strong acid and separation (after a short heating) of the desired compound (V) by alkalizing the resulting solution.

A typical example of the preferred strong acid is hydrochloric acid.

The compound (V) thus obtained, and then restore, in a manner similar to that described for reaction scheme 3 in the aforementioned patent application PCT/EP 93/00080.

The receiving process then continues in the manner similar to that described in the aforementioned patent is the following stages there is no inversion of configuration, and the thus obtained target compound with the chemical formula IA has the same absolute configuration as the compound (V). Possible racemization is very small, if at all.

For practical purposes the compounds according to this invention can be administered in the form in which they are available, but it is preferable to introduce them in the form of pharmaceutical compositions.

These compounds are an additional part of this invention and contain a therapeutic quantity of at least one enantiomer with the chemical formula lA or salts of its accession to the physiologically acceptable acid together with solid or liquid pharmaceutical carriers.

The pharmaceutical compositions according to this invention may be solid, for example in the form of tablets, pills with sugar coating, capsules, powders or forms with controlled selection or semi-liquid, for example in the form of pastes or ointments, or liquid, for example in the form of solutions, suspensions or emulsions.

In addition to conventional media, the compositions of this invention can contain other suitable pharmaceutical additives such as preservatives, stabilizers, emulsifiers, salts for regulating the osmotic pressure to the invention can also contain other compatible active ingredients, the simultaneous introduction of which is therapeutically useful.

For therapeutic purposes can widely change the input current dose enantiomer with the chemical formula lA, depending on various factors, such as the required specific therapy, pharmaceutical composition, method of administration and the effectiveness of particular used enantiomer according to this invention. However, the optimal current dose can be selected simple in the usual way.

In General, a daily intake of enantiomers with the chemical formula IA preferably ranges from 0.1 to 10.0 mg/kg

The pharmaceutical compositions according to this invention can be prepared by conventional means known to the chemist, pharmacist and including adulteration, granulating and compressing or, if necessary, mixing and dissolving the components, when it is getting the desired result.

The following examples are intended to illustrate this invention.

Example 1.

A mixture of 12.5 g (to 0.032 moles) of racemate (1, R = R'= R"' = H, R" = CH3) as the basis and 4.8 g (to 0.032 mol) of the naturally occurring (R, R )-tartaric acid Varinia.

The solid is separated by cooling, was collected by filtration and recrystallization of absolute ethyl alcohol until it reaches a constant melting point.

Getting salt (S) enantiomer of formula IA with (R, R )-tartaric acid.

The melting point of 151-152oC []2D0= +13,20,3 (1% in water).

The corresponding base was obtained by suspension of the salt in water and podlachian (under stirring) of powdered potassium carbonate.

The remainder of ekstragirovanija dichloromethane melted at 63-65oC (hexane), []2D0= +32,00,3 (1% in absolute ethanol).

Hydrochloride, melting point 122-124oC (from ethanol is hygroscopic).

Sulphate, melting point 204-250oC.

Maleate, melting point 142-143oC.

From the filtered solution, which was pre-separated (S) (R, R )-Sol, drew (R)-based and dissolved it in absolute ethyl alcohol.

Then to this solution was added an equimolar amount of (S, S) - tartaric acid. By cooling the separated (R) (S, S)-salt. This salt has the same melting point (151-152o(C) as ( C, []2D0= -32,00,3 (1% in ethyl alcohol).

Hydrochloride, melting point 122-124oC (hygroscopic).

Example 2.

a) (R)-1-(3-chlorophenyl)-3-methyl-piperazine-2-he (formula V, Alk = CH3)

Boiled and heated under reflux overnight, the solution of 18.4 g (to 0.108 mol) of N-(3-chlorophenyl)academia (compound of formula VII; J. Med. Chem., 9., 858-860 (1966)), 19,3 ml (0,119 mol) of ethyl ester of (S)-methysulfonylmethane acid (compound of formula VIII, Alk = CH3Y = C2H5X' = CH3-SO2-O-) and 22.8 ml (0,163 mol) of triethylamine in 200 ml of toluene.

The reaction mixture was washed with water and was extracted with 1N. solution of hydrochloric acid. The aqueous phase was parselocale powdered potassium carbonate and was extracted with methylene chloride.

Thus obtained base was purified flash chromatography (silica gel, hexane-ethyl acetate 1:1).

An oily residue (compound of formula (R) VI, Alk= CH3Y = C2H5), obtained after evaporation of the solvent, dissolved in 10 parts (by weight) 2 N. HCI, and then cooled and parselocale solid K2CO3. The oil which separated was extracted with dichloromethane and the residue after evaporation UB>), showing specific rotation []2D0= +50,0.

b) (R) -2-[3- [4-[3-Chlorophenyl)-1- (2-methyl)- piperazinil] propyl]-1,2,4-triazole[4,3-a]-pyridine-3(2H)-he (formula IA, Alk = CH3)

To a suspension of sociallyengaged (31.5 g) in ethyl ether (650 ml) was added a solution of 66 g (R) Y (Alk = CH3) in ethyl ether (350 ml) with vigorous stirring and dropwise, to prevent soft boiling solvent under reflux. Upon completion of the addition the mixture was boiled under reflux for another 2 h, then cooled and the excess hydride decomposed H2O and 2 N. NaOH. After stirring for 30 min at room temperature, filtered solution evaporated under reduced pressure to obtain 45 g of the base (R)-1-(3-chlorophenyl)-3-methylpiperazine showing specific rotation []D= +15 (1% in ethanol).

To a mixture of 1-bromo-Z-chloropropane (150 ml), K2CO3(55) and (H2O (4 ml), heated at 60oC for 48 h under vigorous stirring was added dropwise a solution of (R)-1-(3-chlorophenyl)-3-methylpiperazine (40 g) in toluene (50 ml). Then the mixture was filtered, the volatile portion was removed and the residue was purified by chromatography (SiO2, hexane-ethyl acetate 1:1). Thus there was obtained 25 g with the>, (43 g), sodium salts of the compounds of formula (III) (23,6 g), xylene (300 ml) and isobutyl alcohol (30 ml) was boiled under reflux for 8 hours then the reaction mixture was diluted with an equal volume of water and the residue obtained by removing the solvent was transferred into the corresponding hydrochloride, T. pl. 122-124oC.

Base (compound of formula IA ALk = CH3) showed a specific rotation +31,8 (1% in ethyl alcohol).

Example 3.

(S)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)piperazinil] -propyl] -1,2,4 - triazole[4,3-a]pyridine-3(2H)-he (chemical formula IA, ALk = CH3).

The target product was obtained according to the method similar to that described in example 2, except for the substitution (S)-ethyl ester methanesulfonyl-lactic acid with equimolar amounts of (R) -ethyl ester 2-bromopropionic acid.

The base, melting point 63-65oC []2D032,00,3 (1% in ethyl alcohol).

1. (S)- or (R)-Enantiomer of compounds of formula IA

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where Alk is alkyl with 1 to 3 carbon atoms,

and the acid additive salt.

2. Connection on p. 1, representing (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinil] -propyl] -1,2,4-triazole-[4,3-a] -pyridine-3(2H)-he and his sour is inyl] -propyl] -1,2,4-triazole-[4,3-a] -pyridine-3(2H)-he and his acid additive salt.

4. Connection on p. 1, representing the (S,S)-tartrate (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinil] -propyl] -1,2,4-triazole-[4,3-a]-pyridine-3(2H)-he.

5. Connection on p. 1, representing the (R,R)-tartrate (R)-2-[3-[4-(3-chlorophenyl)-1-(2-methyl)-piperazinil] -propyl] -1,2,4-triazole-[4,3-a]-pyridine-3(2H)-he.

6. The method of obtaining enantiomers of formula IA

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or its acid additive salts,

where Alk is alkyl with 1 to 3 carbon atoms,

characterized in that the racemic mixture of compounds of General formula IA are interacting with (R,R)- or (S,S)-tartaric acid in the medium of a suitable solvent, followed by fractionated crystallization separates the two thus obtained diastereoisomeric salt from the solvent, and if desired, the thus obtained enantiomer transferred to salt with a physiologically acceptable acid.

7. The method according to p. 6, characterized in that the solvent used is a lower alcohol.

8. The method of obtaining enantiomers of formula IA

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or its acid additive salts,

where Alk is alkyl with 1 to 3 carbon atoms,

characterized in that the compound of formula III

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or its salt with an alkaline metal is subjected to reaction with piperazinonyl soedinenii from the group containing chlorine, bromine, and-O - SO2- Z, where Z is alkyl or aryl,

in this connection II is absolute (R)- or (S)-configuration, in the presence of a suitable organic solvent or mixture of organic solvents at a temperature of from 40oC to the boiling temperature of the reaction mixture and, if desired, form the salt thus obtained enantiomer with a physiologically acceptable acid.

9. The method according to p. 8, wherein Z is methyl, phenyl, tolyl and paraprotein.

10. The method according to p. 8 or 9, characterized in that a suitable organic diluent is an aromatic hydrocarbon, an aliphatic alcohol, or amide.

11. The method according to one or more paragraphs.8 to 10, characterized in that the aromatic hydrocarbon is benzene, toluene or xylene.

12. The method according to one or more paragraphs.8 to 10, characterized in that the aliphatic alcohol is butanol, tert-butanol, sec-butanol, Isobutanol, pentanol and tert-pentanol.

13. The method according to one or more paragraphs.8 to 10, characterized in that Amida is dimethylamide.

14. The way cyclization of compounds of formula IV

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where Y and Alk, the same or different, are alkyl with 1 to 3 carbon atoms is cosy configuration, as the compounds VI, characterized in that the cyclization reaction is carried out in the presence of an aqueous solution of a strong acid and that the desired connection V after a short heat produced by alkalizing the resulting solution.

15. The method according to p. 14, wherein the strong acid is hydrochloric acid.

16. (S)- or (R)-Intermediate compound of formula V

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where Alk is alkyl with 1 to 3 carbon atoms.

 

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< / BR>
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