HK1024232B - Therapeutically active levorotatory and dextrorotatory 1-((4-chlorophenyl)phenylmethyl)piperazines - Google Patents

Description

The enantiomers levogyre and dextrogyre, which are optically substantially pure, of 1-[[[4-chlorofenyle]phenylmethyl]-4-[[[4-methylphenyle]sulfonyl]piperazine of formula a process for the preparation of these compounds and their use for the preparation of the substantially optically pure levogyre and dextrogyre enantiomers of 1-[[(4-chlorophenyl) phenylmethyl]piperazine are described in patent EP0617028.

These therapeutically active compounds can be used in the treatment of asthma, allergies, inflammation, anxiety and as sedatives or tranquilizers. A property that is frequently observed in these compounds is their important peripheral and/or central antihistamine activity which is the origin of their use as medicines.

It is well known that the biological properties of many compounds, such as drugs, hormones, herbicides, insecticides or sweeteners are influenced by stereochemical factors. The importance of the relationships between optical activity and biological properties was emphasized as early as 1926 (A.R. CUSHNY, Biological Relations of Optically Isomeric Substances, Williams and Williams Co., Baltimore, 1926). Since then, many examples have continued to flow in to support the now generally accepted principle that a racemic compound and its leber and dextromogynous enantiomogyne should be considered as distinct pharmacological entities.The use of the levogyre or dextrogyre form of a pharmacologically active compound may result in profound changes in the properties of the compound, such as its transport, distribution in the body or elimination. These properties are decisive for the concentration of the drug in the body or its exposure time at the site of action. Furthermore, the pharmacological activity of the two isomers may be significantly different.In addition, metabolism and toxicity may be very different from one isomer to another, to the point that one of the optically active isomers may be more toxic than the other. One of the most striking examples in this area is thalidomide, where both enantiomers have similar hypnotic effects, but only the anti-senomer S has teratogenic effects.

Finally, it should be added that optical isomers are of prime importance for the study of chemical interactions with physiological mechanisms (e.g. selectivity of binding to a receptor).

This is why many pharmaceutical laboratories spend a lot of time and effort isolating or synthesizing the enantiomers of a pharmacologically active compound and studying its therapeutic properties.

British patent 2.225.321 describes a process for preparing enantiomers of 2-[2-[4-[4-chlorophenyl) phenylethyl]-1-piperazinyl]ethoxyl-acetic acid dichlorohydrate known as a non-sedative antihistamine drug under the generic name cetirizine. This process is based on the use of 1-[4-chlorophenyl) phenylethyl]piperazin leaf or dextrogyre as a product. In this patent, the enantiomers of 1-[4-chlorophenyl) phenylethyl]pyrethyl tartargin are obtained by chemical resolution of the racemic acid according to the known methods, in particular, by forming an isomer with a suitably selected isomeric acid.

The major disadvantages of this process are that, on the one hand, the efficiency of the 1-[4-chlorophenyl) phenylemethyl]piperazine racemic resolution step is extremely low (only 12.7%) and, on the other hand, the optical purity of the dextrogyre and levogyre enantiomers thus obtained is insufficient and does not allow the final product to be prepared with an optical purity of more than 95%.

It would therefore be highly desirable to have new ways of preparing 1-[[4-chlorophenyl) phenylmethyl]piperazine enantiomers with improved optical purity and with better yields, so as to provide excellent raw materials for producing optically active isomers of useful medicinal products which are also of very high optical purity.

But to achieve this objective, it is necessary to find precursors which already have the correct stereochemical configuration and which, on the one hand, can themselves be prepared easily and economically, and with satisfactory optical purity, and, on the other hand, can be transformed easily and with high yields into the substantially optically pure enantiomers of 1-[[4-chlorophenyl) phenylemethyl]piperazine.

1-[4-Chlorophenyl) phenylethyl]-4-[4-Chlorophenyl) sulphonyl]piperazine including the levogyre and dextrogyre forms, the levogyre and dextrogyre enantiomers, of 1-[4-Chlorophenyl) phenylethyl]-4-[4-Chlorophenyl) sulphonyl]piperazine with the formula The Commission has already taken a number of steps to ensure that the

The enantiomers of the compound of formula I are advantageously present in a substantially optically pure form.

Err1:Expecting ',' delimiter: line 1 column 79 (char 78) $\text{Pureté optique (en \%) =}\frac{\text{[(+)] - [(-)]}}{\text{[(+)] + [(-)]}}\text{x 100}$ Where is it? [+()] = concentration of the dextrogyre enantiomer, and[(-)] = concentration of the levogyre enantiomer.

Patent EP 0617 028 describes a process for the preparation of levogyre and dextrogyre enantiomers of 1-[[[4-chlorophenyl) phenylethyl]-4-[[[4-chlorophenyl) sulphonyl] piperazine formula I which is characterised by the reaction of an enantiomer of (4-chlorophenyl) phenylethylamine formula with a N,N-diethyl-4-methylbenzenesulfonamide formula where X is a chlorine, bromine or iodine atom or the (4-methylphenyl) sulphonyl-oxy or methylsulphonyl-oxy group, in the presence of 2,2 to 4,4 organic or mineral base equivalents per (4-chlorophenyl) phenylmethylamine enantiomer equivalent and at the boiling point of the reaction mixture.

The bases suitable for the preparation of formula I compounds are either organic bases such as ethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine, preferably ethyldiisopropylamine, or inorganic bases such as sodium carbonate.

The levogyre and dextrogyre enantiomers of (4-chlorophenyl) phenylmethylamine formula II used as starting products are known compounds which can be prepared by chemical resolution of racemic (4-chlorophenyl) phenylmethylamine by tartaric acid using known methods and have an optical purity of at least 98%.

The starting compounds of formula III are also known products; they are easily obtained from bis (((2-hydroxyethyl) amine by methods known in themselves.

Patent EP 0617028 describes the use of the levogyre and dextrogyre enantiomers of 1-[[[4-chlorophenyl) phenylethyl]-4-[[[4-chlorophenyl) sulfonyl] piperazine formula I for the preparation of the substantially optically pure enantiomers of 1-[[[4-chlorophenyl) phenylethyl] piperazine formula - What?

The levogyre and dextrogyre enantiomers of the compound of formula IV are prepared by a process characterised by hydrolysis by hydrobromic acid in an acetic acid medium in the presence of a phenolic compound, preferably 4-hydroxybenzoic acid, an enantiomer of 1-[(4-chlorophenyl) phenylethyl]-4- ((([4-methylphenylethyl) sulfonyl]piperazine of formula I.

This hydrolysis is usually carried out at a temperature of 18 to 100°C, preferably around 25°C.

The advantages obtained by the implementation of 1-[[[4-chlorophenyl) phenylethyl]-4-[[[4-methylphenyl) sulfonyl] piperazine formula I, in the form of its invention-conform levogyre and dextrogyre enantiomers, are manifold.

These advantages are not only apparent at the access pathway leading to the enantiomers of the compound formula I, but also at the transformation step of these enantiomers to prepare the substantially optically pure enantiomers of 1-[[(4-chlorophenyl) phenylmethyl]piperazine formula IV.

First, the applicant found that the enantiomers of the compound of formula I, tosylated on the amine function, were practically the only ones which could be synthesised in a completely satisfactory manner. If, in the preparation of those compounds, an attempt is made to replace the N,N-diethyl-4-methylbenzene sulfonamide of formula III by a corresponding compound in which the 4-methylphenylsulfonyl group is replaced by hydrogen or by another group protecting the amine function, such as a carbonyl group or an allele, such as the triphenylmethyl radical, a significant emission of racemamine from formula I is observed during the formation of the enzyme of the compound of formula I, and the appearance of numerous products, or the departure of the racemamine from formula II.

In addition, starting compounds of formula III in which the 4-methylphenylsulphonyl group has been replaced by hydrogen are known to be extremely toxic due to the presence of free amine (nitrogen mustards).

However, by using N,N-diethyl-4-methylbenzenesulfonamide formula III as the starting product, these major drawbacks are avoided, since the preparation of the enantiomers of 1-[[[4-chlorophenyl) phenylethyl]-4-[[[4-methylphenylethyl) sulfonyl] piperazine formula I, conforming to the invention, is carried out by a non-racemising process, with a high efficiency of up to 89%, and is obtained with an optical purity of more than 98%, which in many cases is close to 100%, from relatively toxic and dangerous to handle sulfonated raw materials.

On the other hand, the use of enantiomers of the compound of formula I is particularly advantageous for the preparation of enantiomers of 1-[[(4-chlorophenyl) phenylemethyl]piperazine of formula IV. On the one hand, the enantiomers of 1-[(4-chlorophenyl) phenylmethyl]piperazine formula IV are obtained with a high efficiency, well above 80%. This efficiency is significantly higher than that of the process described in UK patent 2.225.321.On the other hand, the hydrolysis reaction leading to the formation of the enantiomers of the formula IV compound is non-receptive, so they are obtained with an optical purity well above 98%, even close to 100%.

The enantiomers of 1-[[4-chlorophenyl]phenylmethyl) -4-[4-methylphenyle) sulfonyl]piperazine formula I therefore provide a highly favourable route for the preparation of the enantiomers of 1-[4-chlorophenyl]phenylmethyl]piperazine formula IV.

The invention relates to the use of the substantially optically pure levogyre and dextrogyre enantiomers of 1-[[4-chlorophenyl) phenylmethyl]piperazine formula IV for the preparation of 1-[4-chlorophenyl) phenylmethyl]piperazine therapeutically active levogyre or dextrogyre form, substantially optically pure, formula where R is the methyl radical, (3-methylphenyl) methyl, (4-tert-butylphenyl) methyl, 2-(2-hydroxyethy) ethyl, 2-(2-(2-hydroxyethy) ethyl, 2-(carbamoylmethy) ethyl, 2-(methy-carbonylmethy) ethyl and 2-(carboxymethy) ethyl.

These compounds, already known in racemic form, have interesting pharmacological properties and can be used to treat asthma, allergies, inflammation or as sedatives, tranquilizers or anxiolytics.

The invention relates, among the compounds of formula V, to the levogyre and dextrogyre enantiomers of 1-[(4-chlorophenyl-)phenylmethyl) -4-methylpiperazine, 1-[(4-chlorophenyl) phenylmethyl]-4-[(3-methylphenyl) methyl]piperazine, 1-[(4-tert-butylphenyl) methyl]-4-((4-chlorophenyl) phenyl) methylpiperazine, 2-[[[2-[4-chlorophenyl)-1-phenyl]pyramethyl]pyramethyl]pyramethyl, 2-[2-[(4-chlorophenyl) methylpyramethylpyramethylpyramethyl]-4-[(4-chlorophenyl) methylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethyl, 2-[2-[[2-[4-[4-chlorophenyl]pyramethyl] methylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyramethylpyrameth

The preparation of these substantially optically pure enantiomers is carried out by methods known in themselves and consists of heating an enantiomer of the compound formula IV with a halogenide of formula RX in which R has the meaning given above and X represents a halogen atom. The enantiomers of formula V are novel compounds except for compounds where R is the 2-carboxymethoxy (ethyl) radical and possess interesting antihistamine properties; in particular, they exhibit a very sharp difference in behavior with respect to inhibition of the histamine H1 receptor, one of the enantiomers being a noncompetitive inhibitor and the other a competitive inhibitor.

The pharmacological tests described below demonstrate these properties.

The following examples illustrate the invention without limiting it: In these examples, the melting points were determined by differential scanning calorimetry (DSC) with a temperature gradient of 20°C/min. The optical purity as defined above was determined by high performance liquid phase chromatography on a chiral stationary phase (Chiralpak AD column, 250 x 4.6 mm; electrolyte: mixture 50:50:0.1 (v/v/v) hexane-ethanol-diethylamine; 104 bars; temperature 25°C; flow rate 1 ml/min).

Example 1. Preparation of the levogyre and dextrogyre enantiomers of (4-chlorophenyl) phenylmethylamine of formula II. The substance is a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

This compound is prepared by the solution of racemic (4-chlorophenyl) phenylmethylamine with (+) -tartaric acid according to the method described by R. CLEMO et al. (J. Chem. Soc., 1939), p.

The substance is a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

This compound is prepared by the solution of racemic (4-chlorophenyl) phenylmethylamine with (-) tartaric acid according to the method described by R. CLEMO et al. (loc. cit.).

Recovery of the enantiomer of unused (4-chlorophenyl) phenylethylamine.

To recover and recycle the unused enantiomer of (4-chlorophenyl) phenylmethylamine, the compound is subjected to a racemisation reaction and the resulting racemic (4-chlorophenyl) phenylmethylamine is then used in a further step of resolution by means of a tartaric acid isomer as described in 1 or 2 above.

4.35 g (0.02 mole) of (+) -(4-chlorophenyl) phenylmethylamine dextrogyre, 244 mg (0.002 mole) of 2-hydroxybenzaldehyde and 1.1 g (0.02 mole) of sodium methyllate are placed in a suspension in 21.8 ml of methanol. The mixture is heated at low temperature for 5 and a half hours and then allowed to return to room temperature and 6.7 ml of concentrated chloric acid is added by drip. The methanol is evaporated, the residue is taken up with 50 ml of water and 25 ml of concentrated hydrochloric acid is added. After a further vacuum, the white precipitate formed is filtered and washed under water and dried at 40 °C. Onenic glycol-methylamine (3,7 g/mL) (4%): 73% efficiency. [α] $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be used:

Example 2 Preparation of N,N-diethyl-4-methylbenzenesulfonamides of formula III. The following is a list of the active substances which may be used in the preparation of the active substance:

This compound is prepared from N,N-bis ((2-hydroxyethyl) -4-methylbenzenesulfonamide according to the method described by D.H. PEACOCK and U.C. DUTTA (J. Chem. Soc., (1934), p.1303-1305). P.F.: 75.9°C. Yield is 79.7%.

The chemical composition of the product is determined by the following equation:

A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride is cooled at 5°C in 17.1 ml of dichloromethane. Then, by dripping and stirring, a solution of 13 g (0.05 mole) of N,N-bis ((2-hydroxyethyl) -4-methylbenzene sulfonamide and 10.1 g (0.1 mole) of triethylamine in 52 ml of dichloromethane is added. It is mixed back to room temperature and stirred for 3 hours. The extraction mixture is allowed to react three times with 40 ml of water. The organic phase is filtered over sodium sulfate, filtered and concentrated in a rotary evaporator.

The following is the list of active substances which are to be used in the preparation of the active substance:

This compound is prepared according to the method described by K.A. AL-RASHOOD et al. (Arzneim.-Forsch./Drug Res. 40(II) (1990), pp. 1242-1245). The temperature is 45.8°C. The efficiency is 69.0%.

The following is added to the list of active substances:

The solid residue is then removed by a mixture of 10 ml of water and 25 ml of dichloromethane and the two phases are separated. The solid phase is removed with 25 ml of dichloromethane and the organic phases are re-solved. This organic phase is washed with 10 ml of sodium thiosulfate, leaving the white phase with 10 ml of sodium thiosulfate, and the organic phase is removed with 10 ml of sodium thiosulfate. The temperature is 93.8°C. The efficiency is 98%.

The following is the list of active substances which are to be used in the preparation of the additive:

The reaction mixture is heated in the acetone for 16 days. The temperature is 69.2°C. The efficiency is 98.7%.

Example 3. Preparation of the enantiomers of 1-[[[4-chlorophenyl) phenylmethyl]-4-[[[4-methylphenyl) sulfonyl]piperazine of formula I. A1. (-)-1-[(4-chlorophenyl) phenylethyl]-4-[(4-methylphenylethyl) sulfonyl]piperazine levogyr.

In a 25 ml balloon, 3.4 g (0.0156 mole) of (-) - ((4-chlorophenyl) phenylmethylamine levogyre (prepared in example 1.1) and 5.1 g (0.0172 mole) of N,N-bis ((2-chloroethyl) -4-methylbenzenesulfonamide (prepared in example 2.3) are mixed in 6 ml (4.4 g or 0.0343 mole) of ethyldiisopropylamine. The mixture is heated at reflux (127 °C) for 4 hours. After vacuum heating, it is cooled to 86 °C and 13,8 ml of methanol is added at once. The mixture is then cooled in an ice bath and kept in the agent for 1 hour. The temperature is 171.1°C. The efficiency is 87.2%. [α] $\frac{\text{25}}{\text{D}}$ : -40.68° (c=1, toluene) Optical purity: 100% . - What?

calculé	C 65,37	H 5,71	N 6,35	Cl 8,04	S 7,27
trouvé	65,95	5,80	6,60	8,12	7,33

A2 to A5 Influence of the nature of the base.

The (-)-1[(4-chlorophenyl) phenylemethyl]-4-[(4-methylphenylemethyl) sulfonyl]piperazine levogyre is also prepared from N,N-bis ((2-chloroethyl)-4-methylbenzenesulfonamide using the method described in A1 above, but ethyldiisopropylamine is replaced by various other bases.

Table I shows the following: in the first column, the number of the sample, in the second column, the base used, in the third column, the basic quantity used expressed in equivalents per (-) - ((4-chlorophenyl) phenylmethylamine equivalent, in the fourth column, the time (in hours) during which the reaction mixture has been maintained at reflux, in the fifth column, the yield on (-)-1-[(4-chlorophenyl) phenylethyl]-4-[(4-methylphenylethyl) sulphanyl]piperazine levogyr; and in the sixth column, the optical purity of the product obtained, expressed as a percentage. TABLEAU I

Exemple 3	Base	Quantité de base (éq.)	Durée (heures)	Rendement (%)	Pureté Optique (%)
A1	éthyldiisopropylamine	2,3	4	87,2	≈ 100
A2	2,4,6-triméthylpyridine	3,0	1,5	64,2	≈ 100
A3	N-éthylmorpholine	2,2	4	61,2	98,4
A4	triéthylamine	3,0	48	59,7	≈ 100
A5		3,0	28	56,7	≈ 100

TABLEAU I

(*) solvant auxiliaire pour la réaction.

The analysis of this table shows that the nature of the base has very little influence on the optical purity of the resulting product, but that ethyldiisopropylamine is significantly more advantageous in terms of reaction efficiency.

A6 to A9 Influence of the nature of N,N-diethyl-4-methylbenzenesulfonamide of formula III.

The (-)-1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine levogyre is also prepared using the method described in A1 above, but the N,N-bis ((2-chloroethyl)-4-methylbenzene sulfonamide of formula III (X= Cl) used as starting product is replaced by the brominated (X= Br), iodated (X= I), tosylated (X= (4-methylphenyl) sulfonyl) and mesylated (X= methyl sulfonyl) derivatives prepared in Examples 2.5, 2.14 and 2.2. respectively.

Table II shows the following: in the first column, the number of the sample, in the second column, the nature of substituent X in the starting compound of formula III, in the third column, the amount of the compound of formula III used expressed in terms of equivalent per (-) - ((4-chlorophenyl) phenylmethylamine equivalent, in the fourth column, the time, expressed in hours, during which the reaction mixture is maintained at reflux, in the fifth column, the yield on (-)-1-[(4-chlorophenyl) phenylethyl]-4-[(4-methylphenylethyl) sulfonyl]piperazine levogyr and in the sixth column, the optical purity of the product expressed as a percentage. - What? TABLEAU II

Exemple 3	Composé de formule III Substituant X	Quantité de III (éq.)	Durée (heures)	Rendement (%)	Pureté optique (%)
A1	Cl	1,1	4	87,2	≈ 100
A6	Br	1	1	88,9	≈ 100
A7	méthylsulfonyloxy	1	2	84,6	≈ 100
A8	I	1	1	84,1	99,4
A9	(4-méthylphényl)sulfonyloxy	1	1	83,8	≈ 100

The nature of the compound of formula III has very little influence on the optical purity of the product obtained, and it is also clear that it has very little influence on the efficiency of the reaction, although the best efficiency is obtained with the brominated derivative.

B. (+)-1-[(4-Chlorophenyl) phenylethyl]-4-[(4-Chlorophenyl) sulphonyl]piperazine dextrogyre.

In a 500 ml three-neck balloon, 57 g (0.2618 mole) of (+) -4-chlorophenyl) phenylmethylamine dextrogyre (prepared in example 1.2) and 86.4 g (0.2917 mole) of N,N-bis ((2-chloroethyl) -4-methylbenzenesulfonamide (prepared in example 2.3) are introduced into 200 ml (1.15 mole) of ethyldiisopropylamine. The mixture is heated at reflux for 3 hours and then poured into 400 ml of pre-methyl methanol and the cooled mixture is stirred in an ice bath for 1 hour. [α] $\frac{\text{25}}{\text{D}}$ : +43.2° (c=0.5, toluene) Optical purity: 98.35% . - What?

calculé	C 65,38	H 5,71	N 6,35	Cl 8,04	S 7,27
trouvé	64,98	5,70	6,40	7,96	7,35

Example 4 Preparation of the levogyre and dextrogyre enantiomers of 1-[[4-chlorophenyl) phenylmethyl]piperazine formula IV. The use of the active substance in the manufacture of the active substance is authorised.

In 1 litre of a 30% bromine solution in acetic acid, 370 g (0.839 mole) of (-)-1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine levogyre (prepared in example 3.A1) and 405 g of 4-hydroxybenzoic acid are introduced, the suspension is agitated for 17 hours at 25°C. 2 litres of water are added and then cooled in an ice bath. A precipitate is formed which is filtered and washed with 750 ml of water. 2 litres of toluene and 0.9 litres of a 50% sodium chloride solution are added to the filter. The phase is washed with 100 ml of sodium chloride saturated solution 100 times and with 1 litre of organic water again.The organic phase is dried on sodium sulfate, the solvent is filtered and evaporated under reduced pressure. The residue is recrystallized at boiling in 600 ml of hexane. The filter is heated to remove a slightly insoluble and the filtrate is allowed to crystallize, first at room temperature, then by cooling in an ice bath for 24 hours. The crystals are filtered, washed with hexane and vacuum dried at 40°C. 204.15 g of (-)-1-[4-chlorophenyl) phenylephtyl]pyraphenylephtyrate is obtained. The temperature is 90.5°C. The efficiency is 84.8%. $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be used: Optical purity ≥ 99,8% - What?

calculé	C 71,19	H 6,68	N 9,77	Cl 12,36
trouvé	71,19	6,84	9,55	11,48

The substance is to be classified in the additive category 'Fluorocarbons'.

The (+)-1-[(4-chlorophenyl) methyl) piperazine dextrogyre is prepared in the manner described in 1 above, but the leftover enantiomer of the 1-[(4-chlorophenyl) methyl]-4-[(4-methylphenyl) sulphonyl] piperazine is replaced by the leftover enantiomer (prepared in example 3.B). The maximum temperature is 91.5 °C. [α] $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be used: Optical purity: 100% . - What?

calculé	C 71,19	H 6,68	N 9,77	Cl 12,36
trouvé	70,90	6,74	9,72	12,23

Example 5. Use of enantiomers of 1-[[4-chlorophenyl) phenylmethyl]piperazine for the preparation of therapeutically active compounds of formula V. 1. levohyric dichlorohydrate of 1-[[4-chlorophenyl) phenylethyl]-4-[[3-methylphenylethyl]methyl]piperazine.

A solution containing 10 g (0.0348 mole) of (+)-1-[(4-chlorophenyl) phenylmethyl]piperoglycerin dextrogyre (prepared in example 4.2) is heated at 50 °C. It is cooled, solid residues are removed by filtration and rinsed with 200 ml of toluene. The organic phases are collected and the solvent is evaporated until a red solution is obtained. Onophenyl-1-methyl-3-benzene is eventually dissolved in 100 ml of isopropyl-1-methyl and onophenyl-4-methyl-methyl. Onophenyl-1-methyl is a solution of isopropyl-methyl and onophenyl-methyl isophenol. The maximum temperature is 252.3°C. [α] $\frac{\text{25}}{\text{365}}$ : -27.96° (c=1, methanol) Optical purity: ≈ 100 percent . - What?

calculé	C 64,73	H 6,30	N 6,04
trouvé	64,45	6,42	5,93	15,18

2. dextrogyl dichlorohydrate of 1-[4-chlorophenyl) phenylethyl]-4-[3-methylphenylethyl] piperazine.

In the preparation of 1-[4-chlorophenyl) methyl]piperazine dextrogyre dichlorhydrate from 1-[[4-chlorophenyl) methyl]piperazine, the starting (+)-1-[4-chlorophenyl) methyl]piperazine dextrogyre is replaced by the levogyre enantiomer (prepared in example 4.1) using the same quantities of reagents in the method described in 1 above. 13 g of dextrogyre dichlorhydrate from 1-[4-chlorophenyl) methyl]piperazine is obtained. The temperature is 252.9°C. The efficiency is 80.4%. [α] $\frac{\text{25}}{\text{365}}$ : +27.5° (c=1, methanol) Optical purity: ≈ 100 percent . - What?

calculé	C 64,73	H 6,30	N 6,04
trouvé	64,47	6,32	5,88	15,18

The active substance is a hydrochloride of 1-[4-tert-butylphenylethyl]methyl]-4-[4-chlorophenylphenylethyl]piperazine.

A solution containing 10 g (0.0348 mole) of (+)-1-[(4-chlorophenyl) phenylmethyl]piperazine dextrogyre (prepared in example 4.2) is heated to 50 °C in 100 ml of n-butanol. 7.6 ml (0.0418 mole) of 1-chloromethyl-4-tert-butylbenzene, 8.9 g (0.0836 mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium iodide are added to the solution. The mixture is then heated to the reflux temperature for 1 hour. Then the mixture is cooled, the solids are removed by filtration and rinsed with 200 ml of toluene. The organic phases are combined and the solvents are cooled to a solution of 1-chlorophenyl-4-tert-butylbenzene. The temperature is 257.7°C. The efficiency is 83.3%. [α] $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 percent . - What?

calculé	C 66,47	H 6,97	N 5,54
trouvé	66,35	7,39	5,45	13,85

The following is the list of active substances which are to be used in the preparation of piperazine:

This compound was prepared using the method described in point 3 above to prepare the levogyre enantiomer, but starting from 4 g of (-)-1-[[4-chlorophenyl) phenylmethyl]levothyroxide piperazine (prepared in example 4.1) 4.75 g of dextrogyre dichlorohydrate is obtained from 1-[4-tert-butylphenyl) methyl]-4-[4-chlorophenyl]phenylmethyl]levothyroxide piperazine. The temperature is 273.9°C. The efficiency is 67.4%. [α] $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 percent . - What?

calculé	C 66,47	H 6,97	N 5,54
trouvé	66,37	7,16	5,27	13,85

The chemical composition of the product is determined by the following equation:

A solution containing 10 g (0.0348 mole) of (+)-1-[(4-chlorophenylphenylmethyl]piperazine dextrogyre (prepared in example 4.2) is heated to 50 °C. A further 2 ml of 2-chlorophenylphenyl) levinol is added to the reflux filter and left to cool for another 4 hours. The residue is refluxed, filtered and washed with 200 ml of chlorophenyl ethanol. The two residues are washed in a mixture of phenol and toluene. The resulting mixture is a mixture of isopropyl and methanol (12-methyl-1-methyl) levinol. The temperature is 229.8°C. The efficiency is 67.8%. [α] $\frac{\text{25}}{\text{365}}$ -6.07° (c=1, water) Optical purity: ≈ 100 percent . - What?

calculé	C 56,32	H 6,53	N 6,26
trouvé	56,32	6,79	6,08	15,63

6. Dextrogyl dichlorohydrate of 2-[2-[4-[4-[4-chlorophenyl) phenylethyl]-1-piperazinyl]ethoxy]ethanol.

Using the same quantities of reagents as described in point 5 above, the dextrogyre enantiomer is prepared in the same way from (-)-1-[[4-chlorophenyl) phenyl]methyl]piperazine levogyre (prepared in example 4.1) to obtain 11.7 g dextrogyre dichlorohydrate of 2-[2-[4-[4-chlorophenyl) phenyl]-2-piperazine]ethoxy]ethanol. The maximum temperature is 231.3°C. [α] $\frac{\text{25}}{\text{365}}$ : +5.16° (c=1, water) Optical purity: ≈ 100 percent . - What?

calculé	C 56,32	H 6,52	N 6,25
trouvé	55,75	6,54	6,10	15,81

The chemical composition of the product is determined by the following equation:

A solution containing 10 g (0.0348 mole) of (+)-1-[(4-chlorophenyl) phenylmethyl]piperase dextrogyre (prepared in example 4.2) is heated to 40 °C in 100 ml of n-butanol. 6.1 ml (0.0419 mole) of 2-[2-(2-chlorethoxy) ethoxy]ethanol, 8.9 g (0.0836 mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium iodide are added. The mixture is heated at room temperature for 6 hours.The remainder is again taken up in 100 ml of toluene, washed with 100 ml of water and evaporated in the organic phase. The oil obtained after evaporation is dissolved in 100 ml of isopropyl alcohol. A solution containing 12 ml of hydrochloric acid concentrated in 38 ml of isopropyl alcohol is added. The solvent is evaporated. The solid residue is taken up again in 150 ml of isopropyl alcohol, 100 ml of hexane is added and the solution is heated by reflux. The oil is cooled in an ice bath. The precipitate is filtered and washed with 50 ml of 1:1 (v/v) isopropyl alcohol-hexane mixture.The resulting solid product is vacuum dried at 50°C. 12,2 g of levogyric dichlorohydrate of 2-[2-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol is obtained. The maximum temperature is 198 °C. The yield is 71.13%. $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 percent . - What?

calculé	C 56,16	H 6,76	N 5,69
trouvé	56,34	7,00	5,67	21,76

8. Dextrogyl dichlorohydrate of 2-[2-[2-[4-[4-[4-chlorophenyl) phenylemethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol.

By the same process as described in paragraph 7 above, the dextrogyre enantiomer is prepared from (-)-1-[(4-chlorophenyl) phenylmethyl]piperazine levogyre (prepared in example 4.1). The temperature is 196.1°C. The efficiency is 73.8%. [α] $\frac{\text{25}}{\text{365}}$ : +8.94° (c=1, methanol) Optical purity: ≈ 100 percent . - What?

calculé	C 56,16	H 6,76	N 5,69
trouvé	56,48	6,96	5,65	22,1

The active substance is a substance that is capable of causing serious adverse effects on the health of humans and the environment.

77 g (0.2685 mole) of (-)-1-[(4-chlorophenyl) phenylmethyl]piperazine levogyre (prepared in example 4.1), 40.5 g (0.2932 mole) of 2-(2-chlorethoxy) acetamide, 62.8 g (0.591 mole) of sodium carbonate and 2 g (0.0120 mole) of potassium iodide are introduced into 700 ml of toluene. The mixture is heated to reflux temperature for 24 hours. 10 g of Norzine is added and heated with water on Diliteca filter. The filtrate is then washed with 500 ml of water heater and 500 ml of saturated solution of sodium chlorophyll. The temperature is 94.3°C. The efficiency is 79.6%. [α] $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 per cent - What?

calculé	C 65,02	H 6,76	N 10,83	Cl 9,14
trouvé	65,39	6,70	10,99	9,23

The active substance is a substance that is capable of causing serious adverse effects on the health of humans and the environment.

15 g (0.523 mole) of (+)-1-[(4-chlorophenyl) phenylmethyl]piperazine dextrogyre (prepared in example 4.2), 8.3 g (0.0601 mole) of 2-(2-chlorethoxy) acetamide, 12.8 g (0.1203 mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium iodide are introduced into a mixture of 100 ml of p-xylene and 150 ml of toluene. The mixture is heated to reflux temperature for 17 hours. A little Norite is added and hot filtered on Dicalite. The residue is rinsed on the filter with a little toluene and the filtrate and solvent are collected. The residues are washed and re-administered in 100 ml of toluene.The organic phase is washed successively with 100 ml of water and twice with 100 ml of a saturated aqueous solution of sodium chloride. The organic phase is separated and the solvent is evaporated. At this stage, the resulting crude residue can be purified in a manner similar to that described in point 9 above, to obtain the (+)-2-[2-[4-[[4-chlorophenyl) phenylmethyl]-1-piperazineyl]ethoxy]acetamide dextrogyre in the form of the free base. However, if desired, the resulting crude residue can also be transformed into the corresponding dichlorate in the following manner: the resulting crude residue is taken in 100 ml of acetone, cooled in an ice bath and added to 15 ml of hydrochloric acid.Then add another 200 ml of acetone and stir the cooled mixture in an ice bath for 1 hour. Filter the precipitate and dry in a vacuum at 50°C. Get 19 g of levogyric dichlorohydrate of 2-[2-[4-[4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]acetamide The temperature is 237.4°C. The efficiency is 78.8%. $\frac{\text{25}}{\text{365}}$ - 19.64° (c=1, methanol). Optical purity: ≈ 100 percent . - What?

calculé	C 54,73	H 6,12	N 9,12
trouvé	53,70	6,20	8,91	23,08	15,61

The chemical composition of the product is determined by the following equation:

46 g (0.16 mole) of (-)-1-[(4-chlorophenyl) phenylmethyl]piperazine levogyre (prepared in example 4.1), 36.6 g (0.24 mole) of (2-chlorethoxy) methyl acetate, 37.3 g (0.35 mole) of anhydrous sodium carbonate and 1.05 g (0.0064 mole) of potassium iodide are placed in a suspension in 46 ml of toluene. The agitation suspension is heated to reflux temperature for 18 hours. Then, the suspension is cooled to room temperature and filtered. The solids are washed with 100 ml of toluene and the filter and wash solution are brought together. The toluene is evaporated in the rotary evaporator at 50 °C and reduced to a pressure.76 g of brown oil is obtained and added to 80 ml of dichloromethane. The solution is purified by chromatography (silica column (15 to 40 μm) 1 kg; eluting: pure dichloromethane gradually added methanol up to a maximum of 2% methanol (v/v). This compound can be transformed into the corresponding dimaleate by dissolving 15 g (0.037 mole) of 2-[2-[4-[4-[4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]methyl acetate prepared above in 45 ml of methanol at the reflux temperature and adding 9 ml at a time.1 g (0.078 mole) of maleic acid. We keep the mixture at the reflux temperature until the maleic acid is completely dissolved, then we let the solution return to room temperature, still stirring. We filter the crystals that have formed and put them in suspension in 15 ml of methanol. We stir the suspension for an hour and a half at room temperature, again for an hour and a half, at 0°C. Then we filter the crystals, wash them with 15 ml of methanol at 0°C and dry them to a constant weight.5 g of levogyric dimalate of 2-[2-[4-[4-[4-chlorophenyl) phenylemethyl]-1-piperazinyl]ethoxy]methyl acetate. The temperature is 143.5 °C. The efficiency is 56%. $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 percent - What?

calculé	C 56,79	H 5,56	N 4,41
trouvé	56,81	5,68	4,12

The following is the list of active substances which are to be classified in the additive:

14.3 g (0.05 mole) of (+)-1-[(4-chlorophenyl) phenylmethyl]piperazine dextrogyre (prepared in example 4.2), 8.4 g (0.055 mole) of (2-chlorethoxy) methyl acetate, 11.7 g (0.11 mole) of anhydrous sodium carbonate and 0.332 g (0.002 mole) of potassium iodide are placed in a suspension in 14.3 ml of toluene. The suspension is heated by stirring at reflux temperature for 17 hours. 1.52 g (0.01 mole) of (2-chlorethoxy) methyl acetate is added and the suspension is heated by stirring at reflux temperature for 3 hours, cooled to ambient temperature and washed in a filter. The solution is washed with a solid solution of toluene and dichlorophenol (Chlorochloroethane) and then washed to a maximum of 55.1 μl (12.8 μl) of dichlorophenol (Chlorochlorochloroethane) and obtained by adding the chlorophenol to a solution of toluene and dichlorophenol (Chlorochloroethane) to a maximum of 50 μl (22.8 μl) (10.1 μl) (10.1 μl) (10.1 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl) (10.8 μl)

This compound can be transformed into the corresponding dimaleate as follows: 8 g (0.0198 mole) of 2-[2-[4-[4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]methyl acetate prepared above is dissolved in 16 ml of methanol at reflux temperature and 4.85 g (0.0417 mole) maleic acid is added at a time. The mixture is maintained at reflux temperature until the maleic acid is completely dissolved, then the solution is allowed to return to room temperature, still stirring. The crystals that have formed are filtered and placed in a suspension of 16 methanol. The temperature is 243.2°C. The efficiency is 32%. [α] $\frac{\text{25}}{\text{365}}$ The following is the list of substances which are to be used: Optical purity: ≈ 100 percent - What?

calculé	C 56,79	H 5,56	N 4,41
trouvé	56,71	5,58	4,17

The following is the list of active substances which are to be used in the preparation of the active substance:

A 25.2 g (0.065 mole) suspension of (+)-2-[2-[4-[4-chlorophenyl) phenylmethyl]-1-pipérazinyl]ethoxy]acetamide dextrogyre (prepared in item 10 above) is added to 70 ml of water, 26 ml of concentrated hydrochloric acid is added by drip. The temperature of the mixture rises spontaneously to 38 °C. The mixture is then heated to 50 °C for 17 hours. Then the reaction mixture is cooled in an ice bath and the pH is brought to between 4 and 5 by adding a solution of sodium hydroxide 4 N. The solution is extracted successively by 100 ml, twice by 50 ml of dichloromethane.The remaining oil is dissolved in 243 ml of acetone, treated with 3.5 g of Norit and filtered on Cellite. The solution is rinsed with 35 ml of acetone. The solution is heated to reflux temperature and drip-dried with 198 ml (0.13 mole) of concentrated hydrochloric acid. The mixture is cooled in an ice bath and allowed to stand for 1 hour. The precipitate formed is filtered, rinsed with 100 ml of acetone and dried at 50 °C. 24,1 g of levodigyl dichloride of 2-[2-[4-[4-[4-[4-chlorophenylmethyl]methyl-1-pipipipipyroxy]acetic acid is obtained.- What? The temperature is 229.3°C. The efficiency is 80.3%. $\frac{\text{25}}{\text{365}}$ -12.79° (c=1, water). Optical purity: ≈ 100 percent . - What?

calculé	C 54,61	H 5,90	N 6,07
trouvé	54,67	5,91	6,03	15,34	23,28

14. Dextrogyric dichlorohydrate of 2-[2-[4-[4-[4-chlorophenyl) phenylemethyl]-1-piperazinyl]ethoxy]acetic acid.

The dextrogyre dichlorohydrate of 2-[2-[4-[4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy) acetic acid is prepared by the method described in paragraph 13 above, using 25,2 g (0,065 mole) of (-)-2-[2-[4-[4-chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]levogyre acetamide (prepared in paragraph 9 above) to obtain 25,6 g of the desired product. The temperature is 227.9°C. The efficiency is 85.3%. [α] $\frac{\text{25}}{\text{365}}$ The temperature of the water is +12.87° (c=1, water). Optical purity: 99.87 percent . - What?

calculé	C 54,61	H 5,90	N 6,07
trouvé	54,71	5,92	6,04	15,34	23,19

15. Dextrogyl dichlorohydrate of 2-[2-[4-[4-[4-chlorophenyl) phenylemethyl]-1-piperazinyl]ethoxy]acetic acid.

At room temperature, 13.75 g (0.00216 mole) of 2-[2-[4-[4-chlorophenyl) phenylethyl)-1-piperazinyl]ethoxy]methyl acetate levogyr dimalate (prepared in 11 above) is introduced by stirring into 54 ml of an aqueous solution of 2N sodium hydroxide. The reaction mixture is extracted successively with 100 ml and 75 ml of diethyl ether and the organic phases are reassembled. This organic phase is dried on anhydrous sodium sulphate, the filtration residue is filtered and washed with 50 ml of diethyl ether. The organic phases are re-evaporated and the diethyl ether is re-administered. The resulting oil is added to 1,48 g (8,4 ml) of diethyl ether and the resulting ethanol is added.The solution is heated to the reflux temperature for one hour and then allowed to return to room temperature. The filtrate is filtered and evaporated. The residue is taken up into 50 ml of water and concentrated in the rotary evaporator to remove the residual ethanol. 10 ml of water is added to the partially concentrated solution and the pH of the solution is brought to a value between 4 and 5 by adding a 10% aqueous solution of hydrochloric acid. The solution is extracted by 50 ml of dichromethane, the pH of the solution is brought back to a value between 4 and 5 by adding a 10% aqueous solution of hydrochloric acid and the pH of the solution is extracted once again by 50 ml of dichromethane.The organic phases are collected and dried on anhydrous magnesium sulfate. The dichloromethane is filtered and evaporated. The resulting viscous oil (9.8 g) is dissolved in 68.6 ml of acetone, the solution is treated with 1 g of activated carbon and filtered hot on diatomaceous earth. The resulting clear yellow solution is topped with 3.6 ml (0.043 mole) of concentrated hydrochloric acid. The suspension is allowed to return to room temperature, stirred, and then stirred for one hour at 0 °C. The precipitate formed is filtered again, washed with 50 ml of acetone and dried at 40 °C.This results in 6.8 g of dextrogyre dichlorohydrate from 2-[2-[4-[4-[(chlorophenyl) phenylmethyl]-1-piperazinyl]ethoxy]acetic acid. The temperature is 227.8°C. The efficiency is 70.8%. $\frac{\text{25}}{\text{365}}$ The water temperature is + 13.7° (c=1, water). Optical purity: ≈ 100 percent . - What?

calculé	C 54,61	H 5,90	N 6,07
trouvé	54,18	6,02	5,68

The following compounds have been subjected to pharmacological trials, the results of which are reproduced below: (-) 1-[4-chlorophenyl) phenylmethyl]piperazine (compound A, prepared in example 4.1);(+)-1-[4-chlorophenyl) phenyl]piperazine (compound B, prepared in example 4.2);dichlorohydrate of 1-[4-chlorophenyl) dexinyl-methyl (example 4.2);dichlorohydrate of 1-[4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl) dexinyl-methyl (example 5.4-chlorophenyl) dexinyl-methyl) dexinyl-methyl (example 5.4-chlorophenyl) dexyl-methyl-methyl) dexinyl-methyl (example 5.4-chlorophenyl) dexyl-methyl-methyl-methyl-methyl-methyl) dexyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl

1. Affinity to the histamine H1 receptor.

The affinity of the compounds for the histamine H1 receptor in the rat cortex was determined by the method described by M.M. BILLAH et al., J. Pharmacol. Exp. Ther., 252 (3), (1990), 1090-1096.

These classic experiments involve the competition between the binding of the compound to be studied to the histamine H1 receptor and a radioligand, in the particular case of the histamine H1 receptor, [3H]mepyramine, which is known to be a selective antagonist of this receptor.

The [3H]mepyramine binding displacement curves are determined at different concentrations of the test compounds, ranging from 10-10 to 10-4 mole/l, and at 4.5 10-9 mole/l of [3H]mepyramine (24.8 Ci/mmole, provided by New England Nuclear, Belgium).

The cortex of male Sprague-Dawley rats is homogenised in 2 ml per cortex of a 20 mM (pH 7.4) Tris-HCl buffer containing 250 mM sucrose.

Centrifuge the homogenous products at 30,000 g for 30 minutes at 4°C. The centrifugation balls are resuspended in the same cool buffer and stored in liquid nitrogen.

For determining H1 receptor binding, samples containing 0.5 mg of cortical membrane protein are incubated in 0.5 ml of Tris-HCl 50 mM (pH 7.4) buffer containing 2 mM magnesium chloride at 25°C for 60 minutes in the presence of [3H]mepyramine and the test compound. The bound [3H]mepyramine is separated from the free radio-ligand by rapid filtration on a Whatman GF/C filter previously impregnated for at least 2 hours with a 0.1% polytetrafluoroethylene solution, to reduce the possibility of specific binding of the non-radio-ligand with other proteins. The filtration residue is then washed four times with 2 ml of Tris-HCl 50 mM (7,pH 7.The non-specific fixation was estimated in the presence of a 10 μM aqueous solution of cetirizine and represents 30% of the total fixation. The IC50 values of the compounds studied (mole/l concentrations required to inhibit 50% of the fixation of the radioligand on the H1 receptor) are determined by analysis of competitive fixation curves (A. DE LEAN et al., Mol. Pharmacol., 21 (1982), 5-16) and the values of the inhibition constants (Ki) were calculated by means of the equation of CHENG and PROFFUSY (see Figure 1).The following is a list of the most important scientific and technical studies in the field of biotechnology:

Table III below gives the pKi values (Ki collagarithm) calculated from Ki (mean value ± deviation from mean (n=2)). - What? TABLEAU III

Composé
C	6,2 ± 0,1
D	7,2 ± 0,2
E	5,9 ± 0,2
F	6,2 ± 0,0
G	7,6 ± 0,1
H	8,7 ± 0,0
I	7,1 ± 0,0
J	8,6 ± 0,0
K	8,6 ± 0,1
L	6,8 ± 0,1
M	7,1 ± 0,1
N	8,5 ± 0,1
O	7,4 ± 0,0
P	8,2 ± 0,0

The table shows that compounds of formula V have good antihistamine activity. These results also show that there is a difference in pKi between enantiomers of the same compound corresponding to a relative affinity difference (hence Ki) of a factor of about 2 to 64 for the H1 receptor in the rat cortex. Such a difference indicates that the enantiomer with the highest affinity for this receptor type (e.g. compound J relative to its enantiomer I) can be used specifically as an anxiolytic or tranquilizer in the treatment of conditions that are associated with central nervous system excitation.

2. Peripheral antihistamine properties.

The peripheral antihistamine properties of the compounds are demonstrated by measuring the inhibition of histamine-induced contraction of the isolated trachea of the guinea pig by the method described by M.H. AMIRI and G. GABELLA (Anat. Embryol., 178 (1988), 389-397).

The trachea is taken from Dunkin-Hartley guinea pigs of both sexes (weight: 250-500 g), and cut into four fragments of 3 cartilage segments each. These fragments are immersed in a Krebs-Heinseleit solution at 37°C containing 10-7 mole/l atropine and 10-5 mole/l indomethacin and are strained with a weight of 1 g. The solution is aerated by passing one hour of oxygen containing 5% carbon dioxide. Each change in voltage is recorded with an isometric force indicator K30 (Hugo Sachs Elektronik) coupled with an amplifier and a Sanborn 7700 (Hewlett Packard) recorder.

Each preparation is pre-contracted by addition to the medium of 10-4 moles/l of histamine; the observed contraction is taken as a reference (100%). After washing and stabilisation, a cumulative curve of histamine effects is plotted as a control according to its concentration (10-6, 10-5 and 10-4 moles/l).

On the same preparation, four additional cumulative curves of histamine effects are recorded according to its concentration, for four increasing concentrations of the test compounds.

The test compounds are incorporated into the preparation 5 minutes before histamine. Between each measurement, the preparations are washed at least four times with an interval of 5 minutes between each wash. Each compound is tested on at least 6 trachea fragments. When drawing the final curve, additional histamine concentrations of 3.2 10-4 and 10-3 mole/l are added to the medium to determine whether the antagonism is competitive in nature or not.

When noncompetitive inhibition is observed, pD2, i.e. the collagarithm of the concentration of the test compound that causes 50% inhibition of the maximum contraction recorded, is calculated (J.M. VAN ROSSUM, Arch. Int. Pharmacodyn., 143 (1963), 299-330).

Table IV below gives the calculated pA2 or pD2 (mean ± standard deviation) for the test compounds. - What? TABLEAU IV

Composé
A	5,7 ± 0,4	-
B	5.0 ± 0,1	-
G	6,5 ± 0,3	-
H	-	6,7 ± 0,1
I	6,5 ± 0,4	-
J	-	6,0 ± 0,3
K	-	6,3 ± 0,2
L	6,4 ± 0,2	-
O	6,6 ± 0,3	-
P	-	6,3 ± 0,2

This test highlights a surprising feature of the pair of levogyre and dextrogyre enantiomers tested. Except for the pair of enantiomers A and B, it is found that for all other pairs, one enantiomer is a competitive inhibitor, while the other is a non-competitive inhibitor hence the interest in preparing optically pure derivatives of 1-[4-chlorophenyl (P) phenylethyl) piperazine.

Competitive inhibitors are of interest because they generally have a lower affinity for the histamine H1 receptor in the rat cortex, suggesting that the antiallergic properties of these compounds are not or only slightly associated with adverse effects on the central nervous system, such as sedation or drowsiness.

Non-competitive inhibitors have the advantage of being able to inhibit the effects of histamine even when histamine is present at high local concentrations and are therefore better suited for topical treatment of skin or mucosal disorders.

Inhibition of histamine-induced skin reaction in dogs.

Dogs are considered to be the animal species with a relatively similar histamine sensitivity to humans, so the antihistamine activity of a compound observed in dogs is considered to be predictive of that which would be obtained in humans.

In this test, 9 Beagle dogs of an average weight of 12.6 kg and about 2 years old with their abdomen shaved locally were injected. In the area of the shaved area, 50 μl of 0.9% aqueous sodium chloride solution containing 10 μg/ml histamine was injected intradermally. At the same time, 0.1 ml/kg of Evans blue dye solution (60 mg/ml in 0.9% aqueous sodium chloride solution) was injected intravenously. An allergic reaction developed at the site of the intradermal injection and a papule appeared on the surface exactly 30 minutes after the two injections. This surface was taken as a reference (100%) surface.

The test compound is then administered orally at a dose of 0.15 mg/kg (0.32 10-6 moles/kg).

After 0.5, 1.5, 3, 6, 9, 12, 24 and 32 hours from the administration of the test compound, new papules are induced at different locations in the abdomen by histamine injection, and the surface area of the induced papule is measured each time 30 minutes after the histamine injection.

The antihistamine activity of a compound on allergic skin reaction is determined by measuring the decrease in the surface area of the induced papules after administration of the compound compared to the reference papule area and is expressed as a percentage.

Table V below gives the antihistamine activity obtained for compound P. The first column indicates the time, expressed in hours, since the test compound was administered. the second column, the area, expressed in mm2, of histamine-induced papules (mean observed in the 9 dogs ± standard deviation); the third column, the decrease (in percentage) in the area of the papules observed over time, relative to the reference area, and The fourth column is the statistical significance of the effect over time as assessed by the Wilcoxon test. - What? TABLEAU V

Temps (heures)		Diminution de la surface (%)	Valeur statistique.
0	76 ± 8	100
0,5	65 t 10	85	p≤0,01
1,5	44 ± 12	58	p≤0,001
3	33 ± 10	43	p≤0,001
6	41 ± 13	54	p≤0,001
9	41 ± 10	54	p≤0,001
12	41 ± 10	54	p≤0,001
24	45 ± 5	59	p≤0,001
32	51 ± 5	67	p≤0,01

The decrease in papule area observed 30 minutes after administration of P is 15%, and the maximum inhibition is observed after 3 hours and reaches 57%. After 32 hours, statistically significant inhibition of 33% is still observed.

4. Toxicity

The lethal dose (inducing death in 2 out of 3 mice in an intraperiotoneal injection of the compounds) is significantly higher than the dose that inhibits histamine-induced skin reaction in dogs. TABLEAU VI

Composé	Dose létale (mole/kg)
C
D
E
F
G
H
I
J
K
L
O
P

5. Posology and administration.

The compounds of formula V have in particular antiallergic, antihistamine, tranquilizing and anxiolytic activities. Pharmaceutical formulations containing these compounds may be administered orally, parenterally or rectally, or in the form of a nasal spray or aerosol, or as creams or ointments.

For oral administration, solid or liquid forms such as tablets, capsules, dredges, granules, solutions, syrups etc. are used.

For parenteral administration, for example, aqueous or oily solutions, suspensions or emulsions will be used.

Suppositories are used for rectal administration.

The above pharmaceutical forms are prepared by methods commonly used by pharmacists and may contain traditional adjuvants in pharmaceutically non-toxic doses, such as dispersants, stabilizers, preservatives, sweeteners, dyes, etc.

The percentage of active substance may vary widely between pharmaceutical forms depending on the method of administration and in particular the frequency of administration.

Claims (15)

1. Use of the laevorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula for the preparation of 1-[(4-chlorophenyl)phenylmethyl]piperazines of formula in therapeutically active laevorotatory or dextrorotatory form, in which R represents the methyl, (3-methylphenyl)methyl, (4-tert-butylphenyl)methyl, 2-(2-hydroxyethoxy)ethyl, 2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl, 2-(methoxycarbonylmethoxy)ethyl or 2-(carboxymethoxy)ethyl radical, by reaction hot with a halide of formula RX in which R has the significance given above and X represents a halogen atom.
2. Substantially optically pure dextrorotatory or laevorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula in which R represents the methyl, (3-methylphenyl)methyl, (4-tert-butylphenyl)methyl, 2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl or 2-(methoxycarbonylmethoxy)ethyl radical, as well as the pharmaceutically acceptable salts of these enantiomers.
3. Dextrorotatory or laevorotatory enantiomers according to claim 2, characterized in that they possess an optical purity of at least 98 %.
4. Laevorotatory enantiomer according to claim 2 or 3, characterized in that it consists of the laevorotatory enantiomer of 1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine or one of its pharmaceutically acceptable salts.
5. Laevorotatory enantiomer according to claim 2 or 3, characterized in that it consists of the laevorotatory enantiomer of 1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine or one of its pharmaceutically acceptable salts.
6. Laevorotatory enantiomer according to claim 2 or 3, characterized in that it consists of the laevorotatory enantiomer of 2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol or one of its pharmaceutically acceptable salts.
7. Laevorotatory enantiomer according to claim 2 or 3, characterized in that it consists of the laevorotatory enantiomer of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide or one of its pharmaceutically acceptable salts.
8. Laevorotatory enantiomer according to claim 2 or 3, characterized in that it consists of the laevorotatory enantiomer of methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate or one of its pharmaceutically acceptable salts.
9. Use of one or more laevorotatory or dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of formula in which R represents the methyl, (3-methylphenyl)methyl, (4-tert-butylphenyl)methyl, 2-(2-hydroxyethoxy)ethyl, 2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl or 2-(methoxycarbonylmethoxy)ethyl radical, or their pharmaceutically acceptable salts, for the preparation of a sedative, tranquilising or anxiolytic medication.
10. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the (3-methylphenyl)methyl radical, or one of its pharmaceutically acceptable salts.
11. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the (4-tert-butylphenyl)methyl radical, or one of its pharmaceutically acceptable salts.
12. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the 2-(2-hydroxyethoxy)ethyl radical, or one of its pharmaceutically acceptable salts.
13. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the 2-[2-(2-hydroxyethoxy)ethoxy]ethyl radical, or one of its pharmaceutically acceptable salts.
14. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the 2-(carbamoylmethoxy)ethyl radical, or one of its pharmaceutically acceptable salts.
15. Use according to claim 9, characterized in that the substantially optically pure laevorotatory or dextrorotatory enantiomer is the laevorotatory enantiomer of formula (V) in which R represents the 2-(methoxycarbonylmethoxy)ethyl radical, or one of its pharmaceutically acceptable salts.