HU224070B1 - Process for producing 1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine enantiomers, novels thereof and pharmaceutical compositions containing them - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to the preparation of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine of the formula (I) to the left and to the right rotational enantiomers, to the novel agents thereof, and to pharmaceutical compositions containing them, wherein R is methyl, (3-methyl) -phenyl) 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. Compounds of general formula (I) have antihistamines and can be used to treat asthma, allergies, inflammation, and fear.

Description

FIELD OF THE INVENTION The present invention relates to the preparation of the left-turning and right-turning enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] piperazine, to novel agents thereof, and to pharmaceutical compositions containing them as active ingredients.

Said drug agents can be used to treat asthma, allergies, inflammation and anxiety, and as a sedative or tranquilizer. The utility of the compounds as drugs is generally based on their potent peripheral and / or central antihistamine potency.

It is known that the biological effectiveness of many compounds, such as drugs, hormones, herbicides, insecticides or sweeteners, is influenced by stereochemical factors. The importance of the relationship between optical activity and biological properties has been known since 1926 [A. R. Cushny, Biological Relations of Optically Isomeric Substances, Williams and Williams Co., Baltimore (1926)]. Since then, many examples support the generally accepted principle that racemic compounds and their left-turning and right-turning enantiomers may have substantially different pharmacological properties. Optical activity, which is a sign of the asymmetric structure of an organic compound, is an important factor in the pharmacological efficacy of the compound and the biological response it produces. Accordingly, significant differences can be observed in the use of a left-rotating or right-rotating enantiomer in the transport, distribution or excretion of the active compound. These properties determine the concentration and duration of action of the active substance in the body. The pharmacological efficacy of the two isomers may also differ. For example, one enantiomer may be more potent than the other or, in the extreme, only one enantiomer will exhibit pharmacological efficacy while the other will be completely inactive and will serve only as a diluent. It is also possible that the pharmacological activity of the two isomers is different, i.e. that the two compounds have different therapeutic properties. There is also a difference in the metabolism and toxicity of the two isomers, i.e. one of the optically active isomers may be more toxic than the other. The most typical example in this field is thalidomide, where the two enantiomers exert similar hypnotic activity but only the S-enantiomer has a teratogenic effect.

Finally, it is noted that optical isomers can be used as samples, primarily to study chemical interactions of physiological mechanisms (e.g., receptor binding selectivity).

Therefore, researchers are devoting considerable time and effort to isolating and synthesizing the enantiomers of pharmacologically active substances and examining their therapeutic properties.

The preparation of the enantiomers of the non-sedative antihistamine 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride, commonly known as cetirizine, is disclosed in GB 2 225 321. . The starting material used is 1 - [(4-chlorophenyl) phenylmethyl] piperazine, which is either left-turning or right-turning. According to the document, the enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] piperazine are prepared by conventional chemical resolution of the racemic form, for example by salt formation with an appropriately selected tartaric acid optical isomer.

The main disadvantage of the process is that the resolution of the racemic 1 - [(4-chlorophenyl) phenylmethyl] piperazine is very low (only 12.7%) and the optical purity of the resulting right and left rotating enantiomers is not satisfactory , i.e., a final product with an optical purity greater than 95% cannot be obtained.

It was therefore necessary to develop a new process which enables the enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] -piperazine to be prepared in high optical purity and in higher yields, which can be used as starting materials for high optical purity optically. for the manufacture of active pharmaceutical ingredients.

In order to solve this problem, it was necessary to develop precursors having the appropriate stereochemical configuration, which can be prepared both relatively simply and economically with appropriate optical purity, and easily and in high yields essentially optically pure 1 - [(4-chlorophenyl) phenylmethyl] piperazine enantiomers They can be converted.

New compounds have been found, the left-turning and right-turning forms of 1 - [(4-chlorophenyl) -phenylmethyl] -piperazine, which fully meet the above requirement.

Accordingly, the present invention relates to a process for the preparation of the left-rotating and the right-rotating enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] -piperazine derivatives of the formula (I):

R is 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) -. an ethyl group by reacting a left-rotating or right-rotating enantiomer of a 1 - [(4-chlorophenyl) phenylmethyl] piperazine (II) with a halide of formula RX

R is as defined above, and

X is halogen.

According to the invention, the enantiomers of the compound of formula (II) preferably exist in substantially optically pure form.

In the context of the present invention, the term "substantially optically pure" means at least 98% optical purity, and this optical purity is the percentage of the optically active isomer present in the main mass relative to the optically active isomer present in the lower mass. determined by high performance liquid chromatography (HPLC).

This optical purity is calculated using the following formula [J. March: Advanced Organic Chemistry, John Wiley and Sons Inc., New York, USA, 3rd Edition, page 107 (1985)]:

Optical Purity (%) = ^ * 100 [(+)] - [(-)]

HU 224,070 Β1

In the formula:

[(+)] is the concentration of the right-rotating enantiomer, [(-)] is the concentration of the left-rotating enantiomer.

The compounds of formula I, which are already known in racemic form, possess valuable pharmacological properties and can be used in the treatment of asthma, allergy and inflammation, and as sedatives, tranquilizers or anxiolytics.

Preferred examples of the compounds of formula I include

1 - [(4-chlorophenyl) phenylmethyl] -4-methylpiperazine,

1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine,

1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] piperazine,

2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -ethanol,

2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy} -ethoxy] -ethanol,

2- [2- [4 - [(4-Chloro-phenyl) -phenylmethyl] -1-piperazinethoxy} -acetamide, Methyl 2- [2- [4 - [(4-chloro-phenyl) ) -phenylmethyl] -1-piperazinyljetoxy acetate,

The left-turning and right-turning enantiomers of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinethoxy] acetic acid, and their pharmacologically acceptable salts.

The enantiomers of formula (I) are novel compounds, with the exception of those containing a 2- (carboxymethoxy) ethyl group in the R group, and have valuable antihistamine properties. The compounds exhibit different behaviors with respect to inhibition of the histamine H receptor, with one of the enantiomers acting as a competitive inhibitor and the other as a non-competitive inhibitor. This property is clearly demonstrated by pharmacological tests.

The present invention relates to the left-turning and right-turning enantiomers of the novel 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivatives of formula I and their pharmacologically acceptable salts wherein R is methyl, (3- methylphenylmethyl, (4-tert-butylphenyl) methyl, 2- [2- (2-hydroxyethoxy) ethoxy] ethyl, 2- (carbamoylmethoxy) ethyl or 2- (methoxycarbonylmethoxy) ethyl.

The invention also relates to pharmaceutical compositions comprising the compounds of formula (I).

The left-turning and right-turning enantiomers of the compound of formula (II) used as starting material are prepared by reacting a 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) The sulfonyl] piperazine enantiomer is hydrolyzed with hydrogen bromide in acetic acid in the presence of a phenolic compound, preferably 4-hydroxybenzoic acid.

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

The left and right-turning enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] -piperazine of formula (III) may be prepared by reacting a compound of formula (IV): The (4-chlorophenyl) phenylmethylamine enantiomer is reacted with an N, N-diethyl-4-methylbenzenesulfonamide derivative of formula (V) wherein X is chloro, bromo or iodo; 4-methylphenylsulfonyloxy or methylsulfonyloxy, in the presence of 2.2 to 4.4 equivalents of an organic or inorganic base, relative to one equivalent of (4-chlorophenyl) phenylmethylamine at the boiling point of the reaction mixture.

Organic bases such as ethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine, preferably ethyldiisopropylamine, and inorganic bases may be used as bases in the preparation of compounds of formula (III). such as sodium carbonate.

The left-turning and right-turning enantiomers of (4-chlorophenyl) phenylmethylamine (IV) used as starting materials are known compounds that can be prepared by the known methods of racemic (4-chlorophenyl) phenylmethylamine. for example, by chemical resolution with tartaric acid. These compounds can be prepared with an optical purity of at least 98%.

Further compounds of formula (V) used as starting materials are known and can be readily prepared from bis (2-hydroxyethyl) amine by known methods.

There are many advantages to using the left or right-turning enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] -piperazine of formula (III).

The advantages are not limited to the preparation of the enantiomers of the compounds of formula (I), but also to the preparation of the substantially optically pure 1 - [(4-chlorophenyl) phenylmethyl] piperazine enantiomers of formula (II) as starting materials.

First, it has been found that the enantiomers of formula (III) containing only the 4-methylphenylsulfonyl group on the amine group can be satisfactorily prepared. When preparing the above compounds, the N, N-diethyl-4-methylbenzenesulfonamide of formula (V) is replaced by a compound wherein the 4-methylphenylsulfonyl group is hydrogen or another protecting group of the amino group, such as carbonyl, alkyl or triphenyl. methyl substituent, the starting material of formula (IV) and / or the compound of formula (III) are substantially racemized or undesirable by-products are formed in the preparation of the enantiomers of formula (III).

In addition, the starting compounds of formula (V), which contain a hydrogen atom instead of the 4-methylphenylsulfonyl group, are highly toxic (nitrogen mustard) due to the presence of the free amino group.

However, all these disadvantages can be overcome by using N, N-diethyl-4-methylbenzenesulfonamide (V) as starting material. Accordingly, the enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] -piperazine of formula (III) are prepared by a process that does not cause racemization, and having an optical yield of at least 98%, preferably about 100%, in a suitable yield, preferably 89%,

HU 224 070 Β1 yielding enantiomers. This is a sulfonated starting material of relatively low toxicity and less hazardous in use. The latter is significant in the industrial application of the process of the invention.

In addition, the use of the enantiomers of the compound of formula (III) to produce the enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] -piperazine of the formula (II) is preferred. During this

- the enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine of formula (II) are obtained in a yield of at least 80%, which is significantly higher than the yield obtained by the process described in GB 2 225 321;

- hydrolysis to the enantiomers of the compound of formula (II) does not cause racemization and the enantiomers are obtained with an optical purity of at least 95%, preferably about 100%.

Thus, the 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine enantiomers of formula (III) provide a particularly advantageous preparative process for the preparation of compounds of formula (II). - Enantiomers of [(4-chlorophenyl) phenylmethyl] piperazine.

The left-turning and right-rotating enantiomers of 1 - [(4-chlorophenyl) phenylmethyl] -piperazine of formula (II) thus obtained and substantially optically pure are preferably used as precursors of substantially optically pure and therapeutically active compound of formula (I). - for the production of the torsionally and torso-enantiomers of [(4-chlorophenyl) phenylmethyl] -piperazine derivatives.

The invention is further illustrated by the following examples, which are not to be construed as limiting the scope thereof. The melting point in the examples is determined by differential scanning calorimetry (D.S.C.) at a temperature gradient of 20 ° C / min. Optical purity by HPLC chromatography on a chiral stationary phase (CHIRALPAK AD column, 250 * 4.6 mm) with hexane / ethanol / diethylamine 50: 50: 0.1 (v / v) at 104 bar and 25 ° C at a flow rate of 1 ml / min. .

EXAMPLE 1 Preparation of the Rotating and Rotating Enantiomers of (4-Chlorophenyl) phenylmethylamine (IV)

Claims 1. A (-) - (4-chlorophenyl) phenylmethylamine, a spin-up

The compound was prepared by resolution of racemic (4-chlorophenyl) phenylmethylamine with (+) - tartaric acid according to R. Clemo et al., J. Chem. Soc. 1958-1960 (1939).

2. Reversible (+) - (4-chlorophenyl) phenylmethylamine

To prepare the compound, racemic (4-chlorophenyl) phenylmethylamine is resolved with (-) - tartaric acid according to R. Clemo et al.

3. Exploration of the unwanted (4-chlorophenyl) phenylmethylamine amine isomer

By digesting and recycling the unwanted (4-chlorophenyl) phenylmethylamine enantiomer, the compound can be racemized and the resulting racemic (4-chlorophenyl) phenylmethylamine re-resolved with the corresponding tartaric acid isomer. or 2.

4.35 g (0.02 mol) of right-turning (+) - (4-chlorophenyl) phenylmethylamine, 244 mg (0.002 mol) of 2-hydroxybenzaldehyde and 1.1 g (0.02 mol) of sodium methoxide was suspended in 21.8 ml of methanol. The mixture was refluxed for 5 and a half hours, allowed to cool to room temperature, and concentrated hydrochloric acid (6.7 mL) was added dropwise. The methanol was removed, the residue was taken up in 50 mL of water and another 25 mL of concentrated hydrochloric acid was added. After 1 hour, the resulting white precipitate was filtered off, washed with water and dried in vacuo at 40 ° C. 3.7 g of racemic (4-chlorophenyl) phenylmethylamine are obtained.

Yield: 73%.

[?] D ⁵ = 0 ° (c = 1, methanol).

Example 2 Preparation of N, N-diethyl-4-methylbenzenesulfonamide derivatives of formula (V)

1. 4-Methyl-N, N-bis [2 - [(4-methylphenyl) sulfonyloxy] ethyl] -benzenesulfonamide [In the formula V, X is (4-methylphenyl) sulfonyloxy].

The title compound was prepared from N, N-bis (2-hydroxyethyl) -4-methylbenzenesulfonamide according to D. H. Peacock and U. C. Dutta, J. Chem. Soc. 1303-1305 (1934).

Melting point: 75.9 ° C.

Yield: 79.7%.

2. 4-Methyl-N, N-bis [2- (methylsulfonyloxy) ethyl] benzenesulfonamide [In formula V, X is methylsulfonyloxy.]

A solution of methanesulfonyl chloride (11.4 g, 0.1 mol) in dichloromethane (17.1 mL) was cooled to 5 ° C. 13 g (0.05 mol) of N, N-bis (2-hydroxyethyl) -4-methylbenzenesulfonamide and 10.1 g (0.1 mol) of triethylamine in 52 ml of dichloromethane were stirred under stirring. solution was added dropwise with stirring. The resulting mixture was allowed to warm to room temperature and stirred for an additional 3 hours. It is then extracted three times with 40 ml of water each time. The organic phase was dried over sodium sulfate, filtered and concentrated in a rotary evaporator. The resulting oil was crystallized from ethanol. 17.8 g of 4-methyl-N, N-bis [2- (methylsulfonyloxy) ethyl] benzenesulfonamide are obtained.

Mp 64.6 ° C.

Yield: 85.7%.

3. N, N-Bis (2-Chloroethyl) -4-methylbenzenesulfonamide [In formula (V), X is chlorine.]

The title compound was prepared by K. A. Al-Rashood et al., Arzneim.- Forsch./Drug Sl. 40 (II), 1242-1245 (1990).

Melting point: 45.8 ° C.

Yield: 69.0%.

4. N, N-bis (2-iodoethyl) -4-methylbenzenesulfonamide [In formula (V), X is iodine.]

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5.7 g (0.01 mol) of 4-methyl-N, N-bis [2 - [(4-methylphenyl) sulfonyloxy] ethyl] -benzenesulfonamide (see point 1 above) are dissolved in a solution of 57 g of the title compound. ml of acetone and mixed with 4.5 g (0.03 mol) of sodium iodide. The resulting reaction mixture was refluxed for 22 hours, then allowed to cool and the acetone was removed. The solid residue was taken up in a mixture of water (10 ml) and dichloromethane (25 ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (25 mL) and the organic layers were combined. The combined organic phases were washed successively with 10 ml of 10% w / w aqueous sodium thiosulphate solution and 10 ml of water. The organic phase is dried over sodium sulfate, filtered and evaporated. The resulting white solid was dried under vacuum at 25 ° C. 4.7 g of N, N-bis (2-iodoethyl) -4-methylbenzenesulfonamide are obtained. M.p. 93.8 ° C.

Yield: 98%.

5. N, N-Bis (2-Bromoethyl) -4-methylbenzenesulfonamide [In formula (V), X is bromo.]

The title compound was prepared according to point 4 above, except that sodium bromide was used in place of sodium iodide and the reaction mixture was refluxed in acetone for 16 days.

Melting point: 69.2 ° C.

Yield: 98.7%.

Example 3 Preparation of Enantiomers of 1 - [(4-Chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] -piperazine of Formula III. Turning (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] -plperazine

(-) - (4-Chlorophenyl) phenylmethylamine (3.4 g, 0.0156 mole) (Example 1.1) and N, N-bis (5.1 g, 0.0172 mole). A mixture of 2-chloroethyl) -4-methylbenzenesulfonamide (2.3 g, 10 da) in 6 ml (4.4 g, 0.0343 mol) of ethyl diisopropylamine was stirred in a 25 ml round-bottomed flask. The mixture was heated at reflux (127 ° C) for 4 hours, then allowed to cool to 86 ° C with stirring, and methanol (13.8 mL) was added all at once. The mixture was then cooled and stirred in an ice bath for 1 hour. The resulting precipitate was filtered, washed with methanol (10 mL) and dried in vacuo at 40 ° C. The product was recrystallized from methanol / acetone (3: 1). This gave 6 g of (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine, to the left.

Melting point: 171.1 ° C.

Yield: 87.2%.

[α] D = -40.68 ° (c = 1, toluene).

Optical purity: 100%.

Elemental analysis based on C24H25CIN2O2S:

date:

found:

C 65.37% Cl 8.04% C 65.95% Cl 8.12%

N, 6.35%

N, 6.60%

H, 5.71%

S 7.27%

H, 5.80%

S, 7.33%.

A2-A5. Investigation of the effect of the base used

Turning (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine gives N, Nbis (2-chloroethyl) -4- from methylbenzenesulfonamide according to A1. except that different bases are used in place of ethyl diisopropylamine.

The results are given in Table I, where the number of the sample in the first column, the base used in the second column, and the amount of base [in equivalents of (-) - (4-chlorophenyl) phenylmethylamine] in the third column. ] in the fourth column the reflux time in the fourth column and in the fifth column the (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine yield and the optical purity of the product in the sixth column.

/. spreadsheet

Example 3 Base Base The amount Time (H) Yield: (%) Optical purity (g) A1. ethyl-diisopropyl-amine 2.2 4 87.2 = 100 THE 2. 2,4,6-trimethylpyridine 3.0 1.5 64.2 = 100 THE 3. N-ethylmorpholine 2.2 4 61.2 98.4 A4. triethylamine 3.0 48 59.7 = 100 A5. Na ₂ CO ₃ / xylene * 3.0 28 56.7 = 100

Note: * = auxiliary solvent

It can be seen from the table that the base used has only a slight influence on the optical purity of the product. However, ethyl diisopropylamine seems to be more advantageous in terms of reaction yield.

A6-A9. Study of the activity of the N, N-diethyl-4-methylbenzenesulfonamide derivative of formula (V)

Turning (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine is prepared according to the procedure described in A1. except that, instead of starting with N, N-bis (2-chloroethyl) -4-methylbenzenesulfonamide of formula (III) wherein X is chlorine, the corresponding brominated (X is bromine), iodine ( X is iodine), tosylated [X is (4-methylphenyl) sulfonyloxy] or mesylated (X is methylsulfonyloxy) derivative which can be prepared according to Examples 2.5, 2.4, 2.1 and 2.2. . The results are shown in Table II. table

EN 224 070 Β1, where the first column is the number of the example, the second column is the X value, the third column is the amount of the compound of formula III [per equivalent of (4-chlorophenyl) phenylmethylamine]. , the fourth column the reflux time, the fifth column the yield of the resulting (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine to be turned to the left and the sixth column gives the optical purity of the product.

II. spreadsheet

Example 3 X meaning Base The amount Time (H) Yield: (%) Optical purity (g) A1. Cl 1.1 4 87.2 "100 A6. Br 1 1 88.9 "100 A7. methyl sulfonyloxy group 1 2 84.6 "100 A8. iodine 1 1 84.6 99.4 A9. (4-methylphenyl) sulfonyl alkyloxy 1 1 83.8 "100

It can be seen from the table that the type of the compound of formula (V) has only a minor influence on the optical purity of the final product. In addition, the compound of formula (V) only slightly modifies the yield of the reaction, although the best yield is obtained with the bromo derivative.

B. Right Turning (+) - 1 - [(4-Chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine g (0.2618 mol) Right Turning (+ ) - (4-chlorophenyl) phenylmethylamine (Example 1.2) and 86.4 g (0.2917 mol) of N, N-bis (2-chloroethyl) -4-methylbenzenesulfonamide (Example 2.3). A mixture of 200 ml (1.15 mol) in ethyl diisopropylamine was refluxed for 3 hours in a 500 ml 3-necked round bottom flask, poured into 400 ml of water and cooled in an ice bath and stirred for 1 hour. The resulting precipitate was filtered off, washed with methanol and dried in vacuo at 50 ° C. 88.6 g of (+) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine are obtained.

Melting point: 173.3 ° C.

Yield: 76.7%.

[α] ²⁵ D = + 43.2 ° (c = 0.5, toluene).

Optical purity: 98.35%.

Elemental analysis based on C24H25CIN2O2S:

date:

found:

C 65.38% Cl 8.04% C 64.98% Cl 7.96%

H 5.71% S 7.27% H 5.70% S 7.35%.

N, 6.35%

N, 6.40%

EXAMPLE 4 Rotating and Rotating Enantiomers of 1 - [(4-Chlorophenyl) phenylmethyl] -piperazine of Formula II 1. Rotating (-) - 1 - [(4-Chlorophenyl) phenyl] methyl] piperazine

(-) - 1 - [(4-Chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine (Example 3.A1) (370 g, 0.839 mol) and 405 g A suspension of 4-hydroxybenzoic acid in 1 liter of 30% acetic acid in hydrobromic acid was stirred at 25 ° C for 17 hours. It is then diluted with 2 liters of water and the suspension is cooled in an ice bath. The resulting precipitate was filtered and washed with water (750 mL). The filtrate was taken up in a mixture of 2 L of toluene and 0.9 L of 50% w / w aqueous sodium hydroxide solution, the organic layer was discarded and washed with 100 mL of water followed by 1 L of saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was recrystallized from 600 ml of hot hexane. The solution was filtered hot to remove insoluble residue and the filtrate was allowed to crystallize, first at room temperature and then for 24 hours in an ice bath. The crystals were filtered, washed with hexane and dried in vacuo at 40 ° C. 204.15 g of (-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine are obtained.

Melting point: 90.5 ° C.

Yield: 84.8%.

[α] D = -14.25 ° (c = 1, methanol).

Optical purity:> 99.8%.

Elemental analysis based on the formula Ο ₁₇ Η ₁₉ ΟΙΝ ₂ :

H, 6.68; N, 9.77.

Cl, 12.36%. Found: C, 71.19; H, 6.84; N, 9.55.

Cl, 11.48%.

2. Right Turning (+) - 1 - [(4-Chlorophenyl) phenylmethyl] -p45 perazine

The right-turning (+) - 1 - [(4-chlorophenyl) -phenylmethyl] -piperazine is prepared in point 1 above, except that the left-turning (+) - 1 - [(4-chlorophenyl) -phenylmethyl] ] 4 - [(4-methylphenyl) sulfonyl] -piperazine is replaced by the corresponding right-rotating enantiomer (Example 3B).

Melting point: 91.5 ° C.

Yield: 97.9%.

[.alpha.] D @ 20 = + 14.94 DEG (c = 1, methanol).

Optical purity: 100%.

Elemental Analysis for: C ₁₇ H ₁₉ CIN ₂ Calculated: C71.19; H 6.68; N 9.77.

Cl 12.36% Found: C 70.90% H 6.74% N 9.72%

Cl, 12.23%.

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Example 5

Use of 1 - [(4-chlorophenyl) phenylmethyl] piperazine enantiomers for the preparation of compounds of formula (I) having therapeutic activity

1. Rotating 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine g (0.0348 mol) rotating right (+) - 1 - [( A solution of 4-chlorophenyl) phenylmethyl] piperazine (Example 4.2) in 100 ml of n-butanol was heated to 50 ° C. 5.5 ml (0.0417 mol) of 1-chloromethyl-3-methylbenzene, 8.9 g (0.0836 mol) of sodium carbonate and 0.5 g (0.0030 mol) of potassium iodide are added. , and reflux for 3 hours. The mixture was cooled, and the solid residue was filtered and washed with toluene (200 mL). The organic layers were combined, the solvent removed and the resulting oily residue was dissolved in ethanol (500 mL) and a mixture of concentrated hydrochloric acid (15 mL) and ethanol (35 mL) was added. After cooling in an ice bath, the resulting precipitate was filtered off and the filtrate was evaporated. The residue and the precipitate were combined and suspended in 100 ml of isopropyl alcohol. The suspension is filtered, the solid washed with a little isopropyl alcohol and dried in vacuo at 50 ° C. 12.7 g of 1-[(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine dihydrochloride are obtained.

Melting point: 252.3 ° C.

Yield: 78.6%.

[?] ₃₆₅ ²⁵ = -27.96 ° (c = 1, methanol).

Optical purity: 100%.

Elemental Analysis for: C25H27ClN2.2HCl Calculated: C, 64.73; H, 6.30; N, 6.04.

Cl, 15.29% Found: C 64.45% H 6.42% N 5.93%

Cl, 15.18%.

2. Reversible 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine dihydrochloride

The procedure described in point 1 above is followed except that the left-turning 1 - [(4-chlorophenyl) -phenylmethyl] -piperazine (Example 4.1) is used instead of the right-turning enantiomer. 13 g of right-turning 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine dihydrochloride are obtained.

Melting point: 252.9 ° C.

Yield: 80.4%.

[?] ₃₆₅ ²⁵ = + 27.5 ° (c = 1, methanol).

Optical purity: 100%.

Elemental Analysis for: C25H27ClN2.2HCl Calculated: C, 64.73; H, 6.30; N, 6.04.

Cl 15.29% Found: C 64.47% H 6.32% N 5.88%

Cl, 15.18%.

3. Rotating 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] piperazine dihydrochloride g (0.0348 mol) rotating right (+) - A solution of 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.2) in 100 ml of n-butanol was heated to 50 ° C. 7.6 ml (0.0418 mol) of 1-chloromethyl-4-tert-butylbenzene, 8.9 g (0.0836 mol) of sodium carbonate and 0.5 g (0.0030 mol) of potassium iodide are added. and refluxing for 1 hour. After cooling, the solid was filtered and washed with toluene (200 mL). The organic layers were combined, the solvent removed and the residual oil dissolved in 300 mL of acetone. Concentrated hydrochloric acid (15 ml) and acetone (35 ml) were added and the mixture was diluted with an additional 200 ml of acetone. The mixture was cooled in an ice bath and the precipitate was filtered off and dried in vacuo at 50 ° C. 4.68 g of a rotating 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] -piperazine dihydrochloride are obtained. Melting point: 257.7 ° C.

Yield: 83.3%.

[aÍ365 ²⁵ = -13.26 ° (c = 0.2, methanol).

Optical purity: 100%.

Analysis calculated for C 8 H ₃₃ CIN ₂ .2HCI _2: Calcd: C 66.47% H 6.97% N 5.54%

Cl 14.01% Found: C 66.35% H 7.39% N 5.45%

Cl, 13.85%.

4. Reversible 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] piperazine dihydrochloride

The title compound was prepared as described in point 3 above, except that starting material (4) (4) was reversed (-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.1). . 4.75 g of right-turning 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] -piperazine dihydrochloride are obtained. Melting point: 273.9 ° C.

Yield: 67.4%.

[?] ₃₆₅ ²⁵ = + 11.33 ° (c = 0.2, methanol).

Optical purity: 100%.

Analysis calculated for C 8 H ₃₃ CIN ₂ .2HCI _2: Calcd: C 66.47% H 6.97% N 5.54%

Cl 14.01% Found: C 66.37% H 7.16% N 5.27%

Cl, 13.85%.

5. Rotate 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] 1-piperazinyl] -ethoxy] -ethanol dihydrochloride g (0.0348 mol) rotating to the right (+) - 1 - A solution of [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.2) in 100 ml of n-butanol was heated to 50 ° C. 2- (2-Chloroethoxy) ethanol (5 mL, 0.0464 mol) was added,

Sodium carbonate (8.9 g, 0.0836 mol) and potassium iodide (0.5 g, 0.0030 mol) were added and the mixture was refluxed for 16 hours. An additional 2 mL of 2- (2-chloroethoxy) ethanol was added and reflux continued for 4 hours. The mixture was cooled, the precipitate was filtered and washed with toluene (200 mL). The organic layers were evaporated, the resulting oil was dissolved in ethanol (100 mL), mixed with a solution of concentrated hydrochloric acid (12 mL) in ethanol (38 mL), and the solvent was removed and the residue was recrystallized from ethanol. The precipitate was filtered off and washed with a little isopropyl alcohol (portion 1). The filtrate was evaporated and the solid residue was washed with a little isopropyl alcohol (batch 2). The two portions were combined and recrystallized from isopropyl alcohol / methanol (30: 1 by volume). 10.57 g of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol dihydrochloride are obtained.

Mp 229.8 ° C.

HU 224,070 Β1

Yield: 67.8%.

[α] ₃₆₅ ²⁵ = -6.07 ° (c = 1, water).

Optical purity: about 100%.

Elemental analysis based on the formula C21H27CIN2O2.2HCI:

Calculated: C 56.32% H 6.53% N 6.26%

Cl, 15.83% Found: C, 56.32%; H, 6.79%; N, 6.08%.

Cl, 15.63%.

6. Reversible 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol dihydrochloride

The procedure described in point 5 above is followed except that the starting material is (-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.1). 11.7 g of right-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol dihydrochloride are obtained.

Melting point: 231.3 ° C.

Yield: 70.5%.

[a] ^{25 =} 65 ₃ ⁺ 5.16 ° (c = 1, water).

Optical purity: about 100%.

Elemental analysis based on the formula C21H27CIN2O2.2HCI:

Calculated: C 56.32% H 6.52% N 6.25%

Cl, 15.83% Found: C, 55.75; H, 6.54; N, 6.10%.

Cl, 15.81%.

7. Rotate 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] 1-piperazinyl] ethoxy] ethoxy] ethanol dihydrochloride g (0.0348 mol) to the right of a solution of (+) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.2) in 100 ml of n-butanol is heated to 40 ° C. 6.1 ml (0.0419 mol) of 2- [2- (2-chloroethoxy) ethoxy] ethanol, 8.9 g (0.0836 mol) of potassium carbonate and 0.5 g of 0 0030 moles) of potassium iodide. The mixture was refluxed for 6 hours, then cooled, the solid filtered and washed with a little toluene. The filtrate and washings were combined and the solvent removed. The residue was taken up in 50 ml of toluene and evaporated. The residue is taken up in 100 ml of toluene, washed with 100 ml of water and the organic phase is evaporated. The resulting oil was dissolved in 100 ml of isopropyl alcohol, mixed with 12 ml of concentrated hydrochloric acid and 38 ml of isopropyl alcohol and the solvent was removed. The solid residue is taken up in 150 ml of hot isopropyl alcohol, mixed with 100 ml of hexane and refluxed. The reaction mixture was cooled, filtered and the precipitate was washed with 50 ml of a 1: 1 mixture of isopropyl alcohol / hexane and 50 ml of hexane. The solid was dried under vacuum at 50 ° C. 12.2 g of a reversible 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] ethanol are obtained. Melting point: 198 ° C.

Yield: 71.13%.

[a] 65 ₃ ²⁵ = -10.7 ° (c = 1, methanol).

Optical purity: about 100%.

Elemental analysis based on the formula C ₂₃ H ₃₁ CIN ₂ O ₃ .2HCl:

Calculated: C, 56.16; H, 6.76; N, 5.69.

Cl 21.62% Found: C 56.34% H 7.00% N 5.67%

Cl, 21.76%.

8. Reversible 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] ethanol dihydrochloride

Follow the procedure described in point 7 above, except that the starting material is (-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.1).

Melting point: 196.1 ° C.

Yield: 73.8%.

[?] ₃₆₅ ²⁵ = + 8.94 ° (c = 1, methanol).

Optical purity: about 100%.

Elemental analysis based on the formula C ₂₃ H ₃₁ CIN ₂ O ₃ .2HCl:

H, 6.76; N, 5.69.

Cl, 21.62%.

Found: C, 56.48; H, 6.96; N, 5.65.

Cl, 22.1%.

9. Turner (-) - 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide g (0.2685 mol) Turner (-) ) -1 - [(4-Chloro-phenyl) -phenylmethyl] -piperazine (Example 4.1), 40.5 g (0.2932 mol) of 2- (2-chloroethoxy) -acetamide, 62.8 g. A mixture of sodium carbonate (0.591 mol) and potassium iodide (2 g, 0.0120 mol) in toluene (700 ml) was heated at reflux for 24 hours. 10 g of Norit are then added and the mixture is filtered hot on Dicalite. The filtrate was washed with water (500 mL) followed by saturated aqueous sodium chloride (500 mL). The organic layer was separated and dried over 250 g of sodium sulfate. The reaction mixture was filtered and the solvent was removed. The resulting oil was taken up in 1500 ml of hot diisopropyl oxide, refluxed and allowed to crystallize in an ice bath. The crystals are filtered off, washed with a little diisopropyl oxide and dried in vacuo at 40 ° C. 82.91 g of (-) - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetamide are obtained.

94.3 ° C.

Yield: 79.6%.

[?] ₃₆₅ ²⁵ = -23.5 ° (c = 1, methanol).

Optical purity: about 100%.

Elemental Analysis for: C ₂₁ H ₂₆ CIN ₃ O ₂ Calculated: C65.02; H 6.76; N 10.83.

Cl 9.14% Found: C 65.39% H 6.70% N 10.99%

Cl, 9.23%.

10. Right Turning 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide g (0.523 mol) Right Turning (+) - 1 - [( 4-chlorophenyl) phenylmethyl] piperazine (Example 4.2), 8.3 g (0.0601 mole) of 2- (2-chloroethoxy) acetamide, 12.8 g (0.1203 mole). of sodium carbonate and potassium iodide (0.5 g, 0.0030 mol) in p-xylene (100 ml) and toluene (150 ml) was heated under reflux for 17 hours. A little Norit was added and the mixture was filtered through a Dicalite pad. The filtered material was washed with a little toluene and the filtrate was combined with the washings. The solvent was removed and the residue was taken up in 100 mL of toluene. The organic layer was washed with water (100 mL) and brine (2 x 100 mL). Separates the organic phase8

The solvent was removed and the solvent was removed. The crude product obtained can be purified as described in 9. This yields the free-base (+) - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide.

If desired, the crude product can be converted to the corresponding dihydrochloride salt which is taken up in 100 ml of acetone, cooled in an ice bath and 15 ml of concentrated hydrochloric acid is added dropwise. It was diluted with 200 ml of acetone, cooled and stirred for 1 hour in an ice bath. The precipitate was filtered off and dried in vacuo at 50 ° C. This gave 19 g of a reversible 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide dihydrochloride.

Melting point: 237.4 ° C.

Yield: 78.8%.

[a] ₃₆ 5 ²⁵ = -19.64 ° (c = 1, methanol).

Optical purity: about 100%.

Analysis for C ₂ H ₂₆ CIN ₃ O ₂ .2HCI Calc'd:

H, 6.12; N, 9.12.

Cl, 23.08%; Cl, 15.38%. Found: C, 53.70; H, 6.20; N, 8.91%.

Cl 23.08% Cl 15.61%.

11. Rotary Methyl 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate Dimaleate g (0.16 mol) Rotatable (- ) -1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.1), 36.6 g (0.24 mol) methyl (2-chloroethoxy) acetate, 37.3 g A suspension of anhydrous sodium carbonate (0.35 mol) and potassium iodide (1.05 g, 0.0064 mol) in toluene (46 ml) was stirred at reflux for 18 hours, cooled to room temperature and filtered. The solid was washed with toluene (100 mL), the filtrate was combined with the wash, and the toluene was removed in a rotary evaporator at 50 ° C. The brown oil (76 g) was taken up in 80 ml of dichloromethane and the solution was purified by chromatography on silica gel (15-40 µm) eluting with pure dichloromethane, gradually diluting with methanol to a concentration of 2% methanol to give 43.5 g of methyl 2 [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate is obtained in the form of an oil. Yield: 67.5%.

The compound can be converted to the corresponding dimaleate salt by adding 15 g (0.037 mol) of methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate in 45 mL of methanol. The solution was refluxed and 9.1 g (0.078 mol) of maleic acid was added at one time. The mixture is heated to reflux until the maleic acid is completely dissolved and then allowed to cool to room temperature while stirring continuously. The crystals were filtered off and suspended in 15 ml of methanol. The suspension was stirred for 1.5 hours at room temperature and then for 1.5 hours at 0 ° C. The crystals were filtered, washed with 15 ml of methanol at 0 ° C and dried to constant weight to give 19.5 g of a rotary methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1- piperazinyl] -ethoxy] -acetate dimaleate is obtained. Melting point: 143.5 ° C.

Yield: 56%.

[?] ₃₆₅ ²⁵ = -10.09 ° (c = 1, methanol).

Optical purity: about 100%.

Elemental analysis based on C ₂₂ H ₂₇ CIN ₂ O _{3. 2} C ₄ H ₄ O ₄ :

H, 5.56; N, 4.41. Found: C, 56.81; H, 5.68; N, 4.12.

12. Rotary Methyl 2- [2- [4 - [(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate Dimaleate

14.3 g (0.05 mol) of right-turning (+) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Example 4.2), 8.4 g (0.055 mol) of methyl (2-chloro) Ethoxy) acetate, a suspension of 11.7 g (0.11 mol) of anhydrous sodium carbonate and 0.332 g (0.002 mol) of potassium iodide in 14.3 ml of toluene are refluxed for 17 hours. An additional 1.52 g (0.01 mol) of methyl 2-chloroethoxy acetate was added and the suspension was stirred at reflux for an additional 3 hours, cooled to room temperature and filtered. The solid was washed with toluene (50 mL) and the filtrate was combined with the wash. The toluene was removed in a rotary evaporator at 50 ° C. 22.8 g of a brown oil are obtained, which is taken up in 45 ml of dichloromethane. The solution was purified by chromatography on a silica gel column (15-40 µm) eluting with pure dichloromethane, diluting with methanol to a volume of 2% methanol. 11.1 g of methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate are obtained in the form of an oil.

Yield: 55.1%.

The resulting compound can be converted to the corresponding dimalate salt by dissolving 8 g (0.0198 mol) of methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] acetate in 16 ml of methanol. under reflux, 4.85 g (0.0417 mol) of maleic acid are added at once. The mixture was refluxed until the maleic acid was completely dissolved and allowed to cool to room temperature while stirring continuously. The resulting crystals were filtered, suspended in methanol (16 mL), stirred at room temperature for 2 hours, filtered, washed with methanol (10 mL) and dried to constant weight. 7.3 g of right-turning methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate dimaleate are obtained.

Melting point: 143.2 ° C.

Yield: 32%.

[ _α ] ₃₆₅ ²⁵ D + 9.8 ° (c = 1, methanol).

Optical purity: about 100%.

Elemental analysis based on C ₂₂ H ₂₇ CIN ₂ O ₃ .2C ₄ H ₄ O ₄ :

H, 5.56; N, 4.41. Found: C, 56.71; H, 5.58; N, 4.17.

13. Rotating 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid dihydrochloride, dropwise, 25 ml (0.065 mol) was added dropwise to the right a suspension of rotating (+) - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide (see point 10 above) in 70 ml of water, during which the temperature rises to 38 ° C. The mixture was heated at 50 ° C for 17 hours and then cooled in an ice bath and adjusted to pH 4-5 with 4N aqueous sodium hydroxide to give a

Extract the aliquot with 100 ml of dichloromethane, then twice with 50 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed. The residual oil was dissolved in acetone (243 mL), treated with Norit (3.5 g), filtered through celite, and washed with acetone (35 mL). The solution was heated to reflux and concentrated hydrochloric acid (198 mL, 0.13 mol) was added dropwise. The mixture was cooled in an ice bath and allowed to stand for 1 hour. The precipitate was filtered off, washed with acetone (100 mL) and dried in vacuo at 50 ° C to give 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] - 24.1 g. ethoxy] -acetic acid dihydrochloride is obtained.

Mp 229.3 ° C.

Yield: 80.3%.

[α] D = -12.79 ° (c = 1, water).

Optical purity: about 100%.

Elemental analysis for C21H25ClN2O3.2HCl:

H, 5.90; N, 6.07%.

Cl, 15.35; Cl, 23.03; Found: C, 54.67; H, 5.91; N, 6.03;

Cl 15.34% Cl 23.28%.

14. Right Turning 2- [2- [4 - [(4-Chloro-phenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid dihydrochloride

The right-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid dihydrochloride was prepared as described in point 13 above, starting from 25.2 g. (0.065 mol) of (-) - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide (see paragraph 9 above) is used. 25.6 g of the title compound are obtained.

Melting point: 227.9 ° C.

Yield: 85.3%.

[?] ₃₆₅ ²⁵ = + 12.87 ° (c = 1, water).

Optical purity: 99.87%.

Elemental analysis for C21H25ClN2O3.2HCl:

H, 5.90; N, 6.07%.

Cl, 15.35; Cl, 23.03; Found: C, 54.71; H, 5.92; N, 6.04;

Cl, 15.34% Cl, 23.19%.

15. Right Turning 2- [2- [4 - [(4-Chloro-phenyl) -phenylmethyl] -1-piperazinyl] -ethoxy] -acetic acid dihydrochloride

Methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate dimethylate (13.75 g, 0.00216 mol) (see above). (11) is added with stirring at room temperature to 54 ml of 2 π aqueous sodium hydroxide solution. The reaction mixture was extracted with diethyl ether (100 mL, then 75 mL) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate washed with 50 mL of diethyl ether. The organic layers were combined and the diethyl ether removed. The resulting oil (8.4 g) was taken up in 50 ml of ethanol and 1.3 g (0.0229 mol) of solid sodium hydroxide was added. The mixture was refluxed for 1 hour, then allowed to cool to room temperature, filtered and evaporated. The residue was taken up in 50 ml of water and the remaining ethanol was removed in a rotary evaporator. Water (10 mL) was added to the partially evaporated solution and adjusted to pH 4-5 with 10% aqueous hydrochloric acid. The resulting solution was extracted with dichloromethane (50 mL), adjusted to pH 4-5 with 10% aqueous hydrochloric acid, and extracted with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and the dichloromethane removed. The resulting viscous oil (9.8 g) was dissolved in 68.6 ml of acetone and the slightly cloudy solution treated with 1 g of activated carbon and filtered hot on diatomaceous earth. To the hot clear yellow solution was added concentrated hydrochloric acid (3.6 mL, 0.043 mol) and the resulting slurry was allowed to cool to room temperature while stirring continuously. It is filtered, washed with 50 ml of acetone and dried in vacuo at 40 ° C (6.8 g of right-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl)). Ethoxy] -acetic acid dihydrochloride is obtained.

Melting point: 227.8 ° C.

Yield: 70.8%.

[α] 36525 ^{= +} 13.7 ° (c = 1, water).

Optical purity: about 100%.

Elemental analysis for C21H25ClN2O3.2HCl:

H, 5.90; N, 6.07. Found: C, 54.18; H, 6.02; N, 5.68.

Pharmacological tests are carried out on the following compounds:

(-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Compound A, Example 4.1);

(+) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine (Compound B, Example 4.2);

Rotating 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine dihydrochloride (Compound C, Example 5.1);

right-turning 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine dihydrochloride (compound D, Example 5.2);

left-turning 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] piperazine dihydrochloride (Compound E, Example 5.3);

right-turning 1 - [(4-tert-butylphenyl) methyl] -4 - [(4-chlorophenyl) phenylmethyl] piperazine dihydrochloride (compound F, Example 5.4);

left-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol dihydrochloride (compound G, Example 5.5);

right-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethanol dihydrochloride (compound H, Example 5.6);

left-turning 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] ethanol dihydrochloride (compound I, Example 5.7);

right-turning 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] ethanol dihydrochloride (compound J, Example 5.8);

(-) -2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide (Compound K, Example 5.9);

(+) - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide], compound L), Example 5.10];

Methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate dimaleate (Compound M, Example 5.11), to the left;

right-turning methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate dimaleate [N]; Example 5.12];

left-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid dihydrochloride [Compound O, Example 5.13];

right-turning 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid dihydrochloride (compound P, Example 5.14),

1. Affinity for histamine H1 receptors

In rat histamine H affinity of the above compounds Μ _r receptor. M. Billah et al., J. Pharmacol. Exp. Ther. 252 (3), 1090-1096 (1990).

In this conventional assay, the competitive binding of the histamine H ₁ receptor to the test drug and to a radioligand, which is the ³ H-mepiramine for the histamine H-ι receptor, is measured, which is a selective angatonist of the receptor.

The binding of ³ H-mepyramine substitution ^_1 measured 10 ° to 10 ^-4 mol / l of a drug concentration, wherein the concentration of ³ H-mepyramine 4.5 * 10 ^-9 mol / l (24.8 Ci / mmol, New England Nuclear, Belgium).

The cerebral cortex removed from male Sprague-Dawley rats was homogenized in 2 ml of 20 mM Tris-HCl buffer, pH 7.4 containing 250 mM sucrose. The homogenate is centrifuged at 30,000 g for 30 minutes at 4 ° C, and the pellet is suspended in the fresh buffer above and stored in liquid nitrogen.

To measure binding to the? 1 receptor, 0.5 mg of cerebral cortex protein was incubated in 0.5 ml of 50 mM Tris-HCl buffer (pH 7.4) supplemented with 2 mM magnesium chloride for 60 minutes at 25 ° C. ³ H-mepyramine and the test substance. To separate the bound ³ H-mepyramine from the free radioligand, the sample is rapidly filtered through a Whatman GF / C filter which has been pre-impregnated with 0.1% polyethyleneimine for at least 2 hours to reduce non-specific binding of the radioligand to other proteins. The filtrate was washed four times with 2 ml of 50 mM Tris-HCl pH 7.4 and cooled in an ice bath. Radioactivity was determined by measuring β-particles on a Tri-carb 1090 scintillation counter (Camberra-Packard, Belgium). Non-specific binding is estimated in the presence of 10 pmol / L aqueous cetirizine solution and represents 30% of the total binding. The IC ₅₀ (concentration in mol / l required for 50% inhibition of radioligand binding to the H _r receptor) of the test compounds was determined by analysis of the competitive binding curve [A. De Lean et al., Mol. Pharmacol. 21, 5-16 (1982)], and the inhibition constant K1 using the Cheng and Prusoff equation [YC Cheng and WH Prusoff, Biochem. Pharmacol. 22: 3099-3108 (1973).

The pK values of the tested active substances (mean deviation, n = 2) are shown in Table III. Table.

III. spreadsheet

Compound pKi 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 8.5 ± 0.1 N 7.1 ± 0.1 SHE 7.4 ± 0.0 P 8.2 ± 0.0

The table shows that the compounds of formula (V) have good antihistaminic activity. The results also confirm that there is a significant difference in the pK1 for the two enantiomers of a given compound, which corresponds to a relative efficacy of about 2-64 fold for rat cerebral cortex receptors. This difference indicates that an enantiomer with higher affinity for this type of receptor (e.g., Compound J relative to Compound I) is useful as an anxiolytic or tranquilizer in the treatment of disorders caused by central nervous system disorders.

2. Examination of peripheral antihistamine properties

To test the peripheral antihistaminic properties of the compounds, the inhibition of histamine-induced contraction of the isolated guinea pig trachea is measured [M. H. Amiri and G. Gabella, Anat. Embryol. 178: 389-397 (1988)].

The trachea of Dunkin-Hartley guinea-pigs of any sex (250-500 g body weight) was removed and the three cartilage segments were cut into four fragments. The fragments were immersed in a Krebs-Heinseleit solution at 37 ° C containing 10 ^-7 mol / l atropine and 10 ^-5 mol / l indomethacin and stretched to a weight of 1 gram. Oxygen containing 5% carbon dioxide was introduced into the solutions. The change in tension is measured by an isometric indicator (K 30, Hugó Sachs Elektronik), to which an amplifier and a Sanborn 7700 recorder (Hewlett-Packard) are connected. The tracheal fragments are allowed to stabilize for 1 hour during which time the baseline tension is reset.

For the first contraction, 10 ^-4 mol / L histamine is added to the medium and this is taken as a reference (100%). After washing and stabilization cumulative curve

GB 224,070 Β1 adopt different hisztaminkoncentrációknál ⁽⁶ 10-, 10- ⁵ and 10- ⁴ mole / l).

For the same sample, four additional cumulative curves are plotted in which the concentration-dependent effect of histamine is examined at four increasing concentrations of the test drug.

The test drug is added to the medium 5 minutes before the histamine dose. The formulations are washed at least four times at 5 minute intervals between measurements. Each drug is tested on at least seven tracheal fragments. After plotting the last curve, additional 3.2 * 10 < ³ > and 10 ~ ³ mol / l histamine were added to determine if the antagonism was competitive or not.

For non-competitive inhibition, pD _{2 is} calculated as the logarithm of the concentration of drug required to inhibit 50% of maximal contraction [JM Van Rossum, Arch. Int Pharmacodyn. 143: 299-330 (1963)]. For competitive inhibition, pA _{2 is} calculated as the logarithm of the concentration of test compound at which the histamine dose should be doubled to induce the same contraction.

The pA ₂ or pD ₂ values (mean ± standard deviation) obtained for the test compounds are shown in Table IV. Table.

ARC. spreadsheet

Compound pA ₂ pD ₂ . THE 5.7 ± 0.4 - B 5.7 ± 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 - SHE 6.6 ± 0.3 - P - 6.3 ± 0.2

The results reveal one of the surprising properties of the investigated left-rotating and right-rotating enantiomeric pairs. With the exception of the A and B pairs of enantiomers, it has been found that one of the other pairs is a competitive inhibitor and the other is a non-competitive inhibitor. This clearly demonstrates the advantage of preparing the 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivatives in optically pure form.

The advantage of competitive inhibitors stems from the fact that they generally show less affinity for the rat cerebral cortex H _q histamine receptors, suggesting that the antiallergic effect of the compounds is very little or no effect on the central nervous system, such as sedation or drowsiness. . Non-competitive inhibitors have the advantage of being able to inhibit the effect of histamine, even when the latter is present at high local concentrations. They are therefore better suited for topical treatment, such as skin or mucous membrane disorders.

3. Inhibition of histamine-induced skin reaction in dogs

Of the animal species, dogs are those whose susceptibility to histamine is closely related to a similar human reaction. Therefore, based on the antihistamine efficacy observed in dogs, it can be concluded that the compound has similar potency in humans.

During the study Beagle dogs weighing an average of 12.6 kg and approximately 2 years old were shaved on a small area on the abdomen. In the shaved area, 50 μΙ of 0.9% w / v aqueous sodium chloride solution containing 10 pg / ml histamine is injected intradermally. Simultaneously, 60 mg / ml of Evans blue dye in 0.9% w / w aqueous saline was administered intravenously to each dog at a dose of 0.1 ml / kg. The allergic reaction develops at the site of the intradermal injection and the area of the bladder formed is measured 30 minutes after the two injections. This area is considered as a reference (100%).

The test drug is administered orally at a dose of 0.15 mg / kg (0.32 x 10 ^-6 mol / kg). At 0.5, 1.5, 3, 6, 9, 12, 24, and 32 hours after dosing, a new allergic reaction was induced at a different site by injection of histamine. In each case, the area of the formed bladder was measured 30 minutes after the injection of histamine.

To determine the antihistamine activity of the test drug in a skin allergic reaction, the reduction in the area of the blisters produced is measured and expressed as a percentage of the reference level.

Table V shows the antihistamine efficacy of Compound P. In the table, the first column represents the time elapsed after administration of the test compound, expressed in hours, the second column represents the area of histamine-formed bladder in mm ² (mean ± standard deviation for 9 dogs), the third column represents the percentage reduction in bladder area. shows, while the fourth column gives a statistically significant value for the effect tested, as determined by the Wilcoxon assay.

Table V.

Time (H) Area (mm ² ) decrease (%) Statistical value 0 76 ± 8 100 0.5 65 ± 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

HU 224,070 Β1

The table shows that after 30 minutes of compound P, the area of the bladder decreases by 15%. The maximal inhibition is measured after 3 hours and reaches 57%. After 32 hours, 33% inhibition was still observed.

4. Toxic

The compounds of formula (V) have very low toxicity. The lethal dose (which, when administered by intraperitoneal injection, causes death in 2 out of 3 mice) is significantly higher than the dose required to inhibit the histamine-induced skin reaction in dogs. VI. Table IV shows the lethal dose of the compound of formula (V) in mice.

VI. spreadsheet

Compound Lethal dose (mol / kg) C > 1x10- ³ D > 1x10- ³ E 1 * 10-3 F > 1x10-3 G 6 * 1-CH H 6 * 1 (H I ⁴ 1X10- J 1 * 1 (H K 3 * 10- ' L 1 * 10-3 SHE 3 * 10- ' P 3 * 1 (H

5. Dosing

The compounds of formula (V) are predominantly antiallergic and antihistaminic, as well as tranquillising and anxiolytic. Pharmaceutical compositions containing these compounds may be administered orally, parenterally or rectally. They may also be administered nasally in the form of a spray or aerosol, or in the form of a cream or ointment.

For oral administration, a solid or liquid preparation is used, for example, in the form of tablets, gelatin capsules, sugar coated dragees, granules, solutions or syrups.

For parenteral administration, an aqueous or oily solution, suspension or emulsion is used.

Suppositories are used for rectal administration.

These dosage forms are prepared in a conventional manner using non-toxic amounts of pharmaceutically acceptable carriers and, optionally, other pharmaceutical excipients. Examples of excipients are dispersants, stabilizers, preservatives, sweeteners and coloring agents.

The active ingredient content of the formulations may be varied within wide limits depending on the dosage and the frequency thereof. The daily dose can be varied within a wide range, generally in the range of 0.5 to 100 mg, preferably

Claims (22)

PATENT CLAIMS A process for the preparation of the left-rotating and right-rotating enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivative of formula (I) wherein R is 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. characterized by reacting the left-rotating or right-rotating enantiomer of 1 - [(4-chlorophenyl) phenylmethyl] -piperazine of formula II with a halide of formula RX R is as defined in the preamble, and X is halogen. 2. The left-turning and right-turning enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivative of formula (I) and pharmacologically acceptable salts thereof, wherein: R is methyl, (3-methyl-phenyl) -methyl, (4-tert-butyl-phenyl) -methyl, 2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethyl, 2- (carbamoylmethoxy) ethyl or 2- (methoxycarbonylmethoxy) ethyl. 3. The left-turning and right-turning enantiomers of claim 2 having an optical purity of at least 98%. 4 - [(4-Chlorophenyl) phenylmethyl] -4 - [(3-methylphenyl) methyl] piperazine, which is a left-rotator of the narrow group of enantiomers according to claim 2 or 3, and is pharmaceutically acceptable. salts. 5. The left-rotating 1 - [(4-tert-butyl-phenyl) -phenylmethyl] -4 - [(4-chlorophenyl) -phenylmethyl] - which is a narrower class of enantiomers according to claim 2 or 3 - piperazine and its pharmacologically acceptable salts. 6. The left-rotating 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy, which is a narrow group of enantiomers according to claim 2 or 3, ethanol and its pharmacologically acceptable salts. 7. The left-rotating 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide, which is a narrower class of enantiomers according to claim 2 or 3, and is pharmaceutically acceptable. salts. A left-swinging methyl-2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -acetate and its pharmacologically acceptable salts which form a narrower class of enantiomers according to claim 2 or 3. 9. A process for the preparation of a pharmaceutical composition comprising one or more left and / or right-turning enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivative of formula (I) wherein: R is 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, Or a pharmacologically acceptable salt thereof, into a composition for use as a sedative, tranquilizer or anxiolytic agent. 10. The process according to claim 9, wherein the compound is a pharmaceutically acceptable salt of the compound of formula (I) wherein R is (3-methylphenyl) methyl. 11. The process according to claim 9, wherein the compound of formula (I) is a quaternary enantiomer or a pharmacologically acceptable salt thereof, wherein R is (4-tert-butylphenyl) methyl. 12. The process according to claim 9, wherein the compound of formula (I) is a rotary enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2- (2-hydroxyethoxy) ethyl. 13. The process according to claim 9, wherein the left-swinging enantiomer of the compounds of formula (I) or a pharmacologically acceptable salt thereof, wherein R is 2- [2- (2-hydroxyethoxy) -ethoxy] is used. ethyl. 14. The process according to claim 9, wherein the compound of formula (I) is a rotary enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2- (carbamoylmethoxy) ethyl. 15. The process according to claim 9, wherein the compound of formula (I) is a rotary enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2-methoxycarbonylmethoxy-ethyl. 16. A pharmaceutical composition comprising one or more left-turning and / or right-turning enantiomers of the 1 - [(4-chlorophenyl) phenylmethyl] piperazine derivative of formula (I) wherein: R is 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, or a pharmacologically acceptable salt thereof. 17. A composition according to claim 16, which comprises a levorotatory enantiomer or a pharmacologically acceptable salt thereof, wherein R is (3-methylphenyl) methyl. 18. A composition according to claim 16, which comprises a levorotatory enantiomer or a pharmacologically acceptable salt thereof, wherein R is (4-tert-butylphenyl) methyl. 19. A composition according to claim 16, which comprises a levorotatory enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2- (2-hydroxyethoxy) -ethyl. 20. A composition according to claim 16, wherein the compound is a reversible enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2- [2- (2-hydroxyethoxy) ethoxy] ethyl-. group. 21. A composition according to claim 16, wherein the compound is a reversible enantiomer or a pharmacologically acceptable salt thereof, wherein R is 2- (carbamoylmethoxy) ethyl. 22. A composition according to claim 16, which comprises a levorotatory enantiomer of the compounds of formula (I) or a pharmacologically acceptable salt thereof, wherein R is 2- (methoxycarbonylmethoxy) ethyl.