SK42293A3 - New enantiomers derived from (s)-2-amino-2-(3,4-dichlorobenzyl)- -propanol - Google Patents

Abstract

Enantiomers of absolute (S) configuration of formula (I) <IMAGE> in which R is H or methyl, with antiallergic, especially antihistamine activity, usable in the form of medications.

Description

Fodststa_vynálezu

The present invention provides novel enantiomers derived from 2-amino-2- (3,4-dichlorobenzyl) -1-propanol with the (s) -configuration according to the Cahr-Ingold-Prelog rule of formula 1

(1) wherein R represents a hydrogen atom or a methyl group, and their addition salts with non-toxic organic or inorganic acids. The invention also relates to the use of these substances as an antiallergic and in particular an antihistaminic drug.

Acid addition salts of the abovementioned compounds include salts with therapeutically acceptable acids, such as acetic acid, benzenesulfonic acid, safrsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, hydrogen bromide, and examples thereof. hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, pampic acid ,; phosphoric acid, salicylic acid Csicjl, stearic acid, succinic acid, sulfuric acid and tartaric acid.

The salts are prepared by methods known to those skilled in the art, such as by base addition of a product of formula I with some of these acids in a solution in a water-miscible solvent such as ethanol or acetone or which is immiscible. with water such as chloroform or dichloromethane, after which safsic? the formed salt * is separated by concentration and / or cooling of the reaction medium or precipitation with a solvent in which; the salt * is insoluble, such as diethyl ether.

The subject of the invention is also a process for producing the compounds O τ '. IN* formula T, whose essence is that it be splits iepi corresponding racemates of these compounds which are described in SF no. Or G 237 355, or that chemical synthesis performs for what ^, ov''tis enantiorních precursors with (S) -confi- guráciou. In a production process which: consists in cleavage

racemic compounds, an optically active acid is used to treat the racemic compound to form two diastereomeric addition salts, or two optically active esters, which are separated. From the separated products, the enantiomer with the (S) -configuration of the present invention, also referred to herein as the eutomer, and in addition its antipode with the (R) -configuration, which is considered to be inactive and Also, direct resolution of the racemic compound by high performance liquid chromatography (HPLC) can also be used. In particular, the above procedures are carried out as follows:

The method of resolution via diastereoisomeric salts is carried out by reacting a racemic compound containing a mixture of eutomer and distomer in a ratio of 1: 1 in a suitable solvent with an optically active acid to form two diastereoisomeric salts which are separated. they are separated based on the solubility difference in the solvent used. Under these conditions, the lower solubility diastereoisomer precipitates and is isolated by filtration.

The separated salts may be sacrificed from selective solvents to obtain satisfactory optical purity or otherwise treated, usually in a basic environment, to recover the corresponding erantiomeric aminoalcohol. The amine alcohols can then be purified by recrystallization or subjected to a second purification step by re-formation of diastereoisomeric salts. Optionally, an optically active acid other than that used in the first stage is used in this second step.

Non-limiting examples of the enantiomer of acids typically used to prepare diastereomeric salts in the process of the present invention include the enantiomer of the? -Phenylene glycine,? -Phenylalanine and their N-carboxylated derivatives, malic acid, mandelic acid, and the like. tartaric acids and derivatives thereof, which are esterified with acids, or alternatively -afric acid, acids

3-bromo-S-camphorsulfonic acid and their positional isomers with d-methoxy-d-trifluoromethylphenylacetic acid,

The known enantiomers of these acids are commercially available and their use is well known to those skilled in the art, so this method is well suited for resolution of racemates containing eutomers of formula I which rely on the preparation and separation of diastereoisomeric salts or the preparation of diastereoisomers to purify the product. which has previously been enriched in the eutomer of formula (I) which is the subject of the present invention.

In the manufacture of diastereoisomeric salts, 0.25 to 2.00 moles of the enantiomer of the acid in solution in an aqueous solvent or solvent mixture which are preferably fully or partially miscible with water are used per mole of amino alcohol to be separated or purified. are usually selected from the group consisting of alcohols, ketohols, low molecular weight ethers and also acetonitrile.

The reaction is preferably carried out in solution in ethanol,

while is left to re C, δ to eliny s one mole with sophisticated ranging in from 20 ° C to boiling point swarm and o Usually gives orednost *. creation

minutes to about 3 hours. After about 5 moles of salt is complete after about this time, the reaction mixture is allowed to stand, first at room temperature, and then until the less soluble diastereoisomer has crystallized. Crystallization can be aided by inoculating the solution with several crystals of the chopped salt if the salt has already been produced. Upon completion of crystallization or at a time deemed appropriate to achieve the desired optical purity, the diastereoisomer is filtered off. Two phases, of _ <_

each containing more or less purified diastereoisomer, are treated separately, either in the diastereoisomer purification step or in the enantiomeric amino alcohol release step from its salt. The release of the enantiomeric aminoalcohol is carried out by alkaline treatment in. aqueous medium, after which the released enantiomer is filtered or alternatively extracted with an organic solvent which is immiscible with water.

b) An alternative method of resolving a racemic compound or a mixture comprising an eutomer of formula I is carried out by esterification with an optically active carboxylic acid to form a mixture of diastereoisomeric esters which are separated and saponified to give separated enantiomers of the aminoalcohol, i. eutomer of formula I and a corresponding distomeric antipode.

In this process, the racemic or partially enriched compound is subjected to an esterification reaction with an optically pure carboxylic acid or one of its derivatives, such as a halide, anhydride or ester. For example, the C ⁴ - and (-) - enantiomers are used. N -methoxy-α-trifluoromethylphenylacetic acid or derivatives thereof. The reaction is carried out in an inert solvent, which may be selected from toluene, tetrahydrofuran, or alternatively dichloromethane or chloroform and coprice, preferably in the presence of an organic or inorganic base, to catalyze the reaction, if optically derivative. of the active acid using an ester, or neutralizing the acidic by-products of the reaction. The catalysts are suitably selected from the group consisting of sodium and its alkoxides, such as sodium methoxide (preferred) and alkoxides of metals other than aluminum. The bases used for neutralization may be of an inorganic nature, such as alkali metal or alkaline earth metal hydroxides or salts, from which sodium carbonate is betrayed, or alternatively of an organic nature, such as amines such as trialkylamine, Ν, dial-dialkylanilines or aromatic amines. Of these amines, triethylamine and pyridine are preferred.

The diastereoisomers obtained after the reaction are separated and purified by methods known to those skilled in the art, such as fractional crystallization or chromatographic separation, and then hydrolyzed by treatment with a strong base such as an alkali metal hydroxide and usually in an aqueous-alcoholic environment to The separated and purified aminoalcohol amines in the context of the present invention then obtained, in particular, the (S) -configuration having the general formula (I).

c / Stiezenie racemic ieoo detection eutomer of Compound of formula I enriched in WSOK vykonzmesi _t nou .kvapalinovou chromatography is performed

The nantiomers also separate from each other on a column which, as a stationary phase, contains an acidic glycosrotein of the name &quot; AGP, immobilized with a non-porous silica filler,

G, O -

z. 'o t; e

-O / 's o c xv have a mean diameter of δ / µm [column CHPAL-AGF (?.) - tirma yield

·) 7 p o n in C · “P P T a« h J

J lL w * », /. M. w »t · * ^Ί mobi as R and t s * for DC amp ELEI composition buffer, pH 6 (ο, Ο '.' Ί sodium dihydrogen mor.odraselr.ého KHpPO ^, the pH adjusted solution IN Potassium hydroxide and a water-miscible solar solvent selected from the group consisting of aliphatic alcohols containing up to 3 carbon atoms and acetonitrile are preferred, and acetonitrile and isopropyl alcohol are preferred, and these solutions are mixed to elute the enantiomers from the stationary phase. solution in an amount of 0.1 to 25 ^s of the volume, LLUC is performed under conditions that c _ _ are suitable for good separation of the isomers, namely between 10 and 40 ° ^C with a flow rate patibílna the resistance of the material, lead to J7 to create a pressure of the order of 10 Pa.

at a temperature in that which is but which can

However, the preferred method of preparing enantiomers with the (S) -configuration of formula (I) is by using enantiomeric precursors with the (S) -configuration according to the Cahn-Ingold-Prelog rule.

In a preferred procedure, the allyl halide is reacted with a amino alcohol precursor with the (S) -configuration of formula II

An alternative procedure consists in reducing the carbonyl functionality of the aminoester precursor with the (3) -configuration of formula III

a complex hydride derived from boron or aluminum, wherein in formulas II and III P represents a hydrogen atom or a methyl group and P4 represents a hydrogen atom or a lower alkyl group such as a methyl or ethyl group,

Concerning the (S) -configuration of the compounds of the invention and their precursors of formulas II and III, the common precursor was methyl (S) - (-) -3- (3,4-dichlorophenyl) -2-methylalanine of formula 17

CH ₂ - / ^COO - ^{CH 3} -C.

CH ⁵ (IV) whose enantioselective synthesis was carried out as described by U. Schollkopf, Synthesis, p. 969, 19S1, in which * (2R, oSR) - (-) - 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-nitro-pyrrolidine / product of Merck - catalog number 818314,4 3 is alkylated 4-dichlorobenzyl chloride, and then the (2R, 5S) -5- (3,4-dichlorobenzyl) -2,5-dihydro-3,5-dimethoxy-2-isopropyl- ^, δ-methylpyrazine formed is hydrolysed to form of the methyl ester of formula IV. N-alkylation of the methyl ester of formula IV with allyl iodide affords a precursor of formula III wherein R is hydrogen: reduction of the methyl ester of formula II with ormanomethyl hydride yields a precursor of formula II wherein R is hydrogen or methyl and compounds of formulas II and III then obtain the eutomer of formula I »

In accordance with the invention, the process of making the compounds of which the formula I is particularly preferred is

reacting the formula (TI), wherein R of the eutomer of formula (I) is hydrogen and then the allyl halide is an atom of the invention, with an aminoalcohol of hydrogen to form wherein R represents the methylation of this eutomer of formula (T) by formaldehyde and formic acid to form a eutomer of formula I according to the invention wherein P is methyl.

In a particular embodiment of this preferred variant of the process of the invention, (S) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol, which is a compound described in Example IC of the European patent, is first no. 0 237 366, is reacted with an allyl halide, such as allyl chloride or allyl iodide, but preferably allyl bromide, in an inert solvent such as toluene or acetonitrile. Optionally, a basic agent, which may be of an organic nature, such as sodium carbonate, or an organic nature, such as triethylamine, may be added to the reaction mixture to stimulate the reaction. In practice, 0.5 to 1.0 mole of allyl halide per mole of amino alcohol used is used, the reaction being carried out in solution in 2 to 3 liters of the selected solvent. Depending on the solvent and the halide used, a satisfactory result is obtained after a reaction time ranging from 1 to 24 hours at a temperature of from 20 to 110 ° C. Preferred conditions to be considered in the case of the use of allyl bromide include a reaction time of 2 to 5 hours 'dot' and

100 C. The obtained amino alcohol of the formula I is isolated and purified by conventional means:

the compound mentioned above.

the compound of formula (I ') is subjected to fractional crystallization. The? -Methylation of fsic] is then obtained,

The reduction methylation is carried out with an aqueous solution of formaldehyde and formic acid according to the Zschweiler-Clarke procedure.

A mole of the ammonium alcohol of the formula I to be N-methylated is used in an amount of aqueous solution corresponding to 1.2 to 3.5 ~ 6 '.

of formaldehyde with up to 5 moles of pure acid;

In practice, formaldehyde is first added to the product, then, after the exothermic reaction, formic acid is added and the reduction is carried out by heating the reaction mixture at 90 to 100 ° C for one to two hours.

To carry out this procedure, the eutomer of formula I wherein F. is methyl is purified by conventional, in particular chromatographic methods.

With regard to the preparation of (S) - (-) -2-amino-2- (3,4-dichlorobenzyl) -1-propanol, the prior art; 2 37S 745, Example 2-d. includes [sicl synthesis of dextrorotatory 1-3- (3,4-dichlorophenyl) -2-methylalanine in degrees from methyl 2-isocyanatopropionate; and

3,4-dichlorobenzyl bromide. In addition, 3F 0 237 355, Example 1-C describes the reduction of this acid with a borane-dimelylsulfide complex.

Compared to this process, which comprises a total of 5 steps, the preferred process of the invention is faster and more economical since it allows the synthesis of (S) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1'-propsol in 4 steps. synthetic steps from 3,4-dichlorophenylacetone. The process essentially comprises reacting the ketone by a Sucherer-Qerg reaction with potassium cyanide and ammonium carbonate to give (7 - / -) - O- (3,4-dichlorobenzyl) -5-methylhydantoin, which is further subjected to alkaline water hydration of the stereospecific adion salt

-P + conversion to the salt using (R) - ( ⁺ ) - d-methylbenzylamine to the (5) - (-) - enantiomer of hydantoin.

This substance is insoluble and can therefore be filtered off and converted by treatment in acidic solution to (Sj (3,4-dichloro:

benzyl) -5-methylhydantoin in optical purity higher than 98 (S) -enant by conventional procedure of [lacur.g] hydantoin ss hydrolyzes to <0 VO in alkaline aqueous medium

p. m (s) - (-) - 2- (3,4-Dichlorobenzyl) saline, which is reduced with the reed described in Example 1 of the European Patent No. 0 237 borane-dimethylsulfide complex (f) -1- (2-amino-2- (3,4-dichlorobenzyl) -1-propanol

These preferred pre-fed procedures are illustrated in the Preparative Procedure and Examples below. The examples are illustrative only and do not limit the scope of the invention in any respect.

 (S) - (R) -2-amino-2- (3,4-dichlorobenzyl) -1-propanol [(1e);

P = H]

- Step 1: (N -) - 6 - (3,4-dichlorobenzyl) - 6-methylhydantoin

ID, 0 g (0.79 mol) of 3,4-dichlorophenylacetone in 700 ml of ethanol is introduced into. of the reactor and the mixture is heated to dC'O until completely dissolved. 73.0 g (0.81 mol) of potassium cyanide, 149.0 g of ammonium carbonate and 700 ml of water are then added thereto.

The mixture was heated to 6 ° to 70 ° C for 17 hours and the resulting suspension was cooled to 10 ° to 10 ° C with stirring and allowed to stand at this temperature for 16 hours. The insoluble material is filtered off and washed with water and diisopropyl ether and then under reduced pressure by weight.

Product weight: 155.0 g; Melting point: 2kQ ° C «“ X at 50 ^J C dried to constant yield: 72 ¾ j

- step 2: (s) - (-) - 5- (h, 4-dichlorobenzyl) -5-meteylhydantoin

100 ml of demineralized water are mixed with 150 ml of acetone in a reflux-adjusted reactor, and 3.7 g (0.091 ml) of sodium hydroxide in cubes are added.

Then 50.0 g (0.1%) of racemic hydrate 2 of the previous step with 22.2% (0.153 mol) of (R) - (+) - d-methylbenzylamine are added successively.

The mixture is warmed to teclotu fur's with stirring

and kept under refl ux until dissolution reactionary evil -items. Then to the mixture adds water / total 100 ml / min butt blending up to 70 ° C. Created the solution is added stirring slowly.

• Start crystallization is observed U V ~ V at about 60 ° C and then with a mixture of 1.5 kept at 50 ° C for hours, and bv sa krevštβ- Lizac completed. Finally, the mixture is in progress ΙΟ minutes och- tunes to approximately 2 T * ´ 7 4 ´ 4 J7 * ^ Q ^ O ^ **** O v U i / .7 vÄxXvEa 2-i O-jb; ... is filtered off and 2x rre washes with 100 ml from acetone: water in a volume ratio 2 - 1.

without further processing, the suspension is acidified to pH 1 with tritiated acid solution, the filter substance is filtered off and the product obtained, found

95.5%.

The insoluble material is suspended in 250 ml of water and the addition of hydrogen peroxide (d = 1.1S) is gradually added. The stainless steel is washed with water. The optical purity of an HPLC aliquot is

The wet product was recrystallized under reflux from 200 mL of a 1: 1 v / v acetone mixture. After cooling to 15 ° C for 2 hours, the insoluble material is filtered off, washed with a mixture of acetone and water and dried at 50 ° C under reduced pressure. 18.79 g of (S) - (-) - 5- (3,4-dichlorobenzyl) -5-methylhydantoin are obtained.

Yield: 75 optical purity: 100% (HPLC); mp: 276 ° C; [.alpha.] @ 25.4 DEG C.-1, ethanol] - Step 3: (S) - (-) - 2- (3,4-dichlorobenzyl) alanine

Dissolve 4.7 g (115 mmol) of sodium hydroxide in 25 ml of water in an autoclave and add 7.0 g (25.6 mmol) of (s) - (-) - hydantoin, prepared according to Step 2, to the resulting solution. The autoclave is sealed and the mixture is heated to 140-145 ° C under a pressure of 0.3 to 0.4 MFa with stirring for 1 hour.

/ I

The mixture is then cooled to 20-25 ° C and the resulting chestnut-brown solution is acidified with stirring with concentrated hydrochloric acid to a pH of 5.5 to 6.2. After cooling to 10 minutes for 30 minutes, the insoluble material was filtered off, washed with water and then with toluene and dried at 50 ° C under reduced pressure.

Product weight: 5.5 methanol)

VV ’difficult: £ 56 out of * -Z

- ABOUT ,

- Step 4: (S) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol

62.5 ml of tetrahydrofuran (ΤΗΡ, ^Ζ and then 2.45 g / 10 mmol) of (s) - (-) - 2- (3,4-dichlorobenzyl) alanine are introduced into a reactor protected against nitrogen under a nitrogen atmosphere. humidity.

3.80 g (50 mmol) of borane-dimethylsulfide complex (3MS) are added dropwise over 30 minutes at 2 ° C. The mixture was stirred at room temperature for 15 minutes and then heated to reflux for 4.5 hours. After cooling to 5 ° C, 7.5 ml of methanol are gradually added to the mixture such that the temperature does not exceed 20 ° C, and 7.5 ml of 1K sodium hydroxide solution are then added in the same manner. The resulting suspension was allowed to stand overnight with insoluble matter filtered off and discarded. The filtrate was evaporated under reduced pressure in a water bath and the resulting white residue was taken up in 50 ml of water. The mixture was □ oxygenated to pH 1 by addition of concentrated hydrochloric acid (d = 1.18).

- The resulting solution is extracted twice with 15 ml of ether. The ether phases are discarded and the acid phase is basified to pH 12 by cold addition of a concentrated sodium hydroxide solution (d = 1.3%) and then saturated with sodium chloride.

The alkaline mixture is extracted 3 times with 20 ml of water and the combined ether phases are washed with saturated sodium chloride solution and then dried. Evaporation of the ether yields the aminoalcohol in the form of a white and amorphous raw material.

Weight yield: 90% [t]? ;; Melting point: 8β ^Ό (c = 5, methanol)

Example (3) - (-) - N-allyl-2-amino-2- (3,4-dichlorobenzyl) -1-propanol [(D;

35.0 g (0.15 mol) (s) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol / [4] + = -1.8 ° (c = 5, methanol) is dissolved in. 350 ml of anhydrous acetonitrile in a moisture-protected reactor.

To the resulting solution was added 12.9 mL / 18.05 g with stirring at 20-25 ° C over approximately 5 minutes; 0.15 mol / allyl bromide. The solution is stirred at the same temperature for 1 hour and then gradually warmed to 5Ό to 60 ° C. This temperature is maintained for 2.5 hours and a precipitate develops over time. The suspension is cooled to 5 ° C with ice-cold bath and then filtered off, poured into 800 ml of water, basified to pH 11 with 10N sodium hydroxide solution and extracted three times with 250 ml of diethyl ether.

The combined ether phases are extracted with saturated sodium chloride solution and then freed from water. The ether was evaporated under reduced tl by drying with a mask in a water bath. The crude solid was refluxed in 500 ml of hexane mixture. The extract was cooled and the crystalline white precipitate of purified (S) -f-1,4-allyl-2-amino-2- (3,4-dichlorobenzyl) -1-proparole was filtered off and dried in a vacuum oven at 40 ° C. ^J C constant weight

Weight Yield: Thanks Product: 25.4 ° C 20 ° C; <<Xj g; melting point:

- ·?

* 7 to 88 (c = 0.5, 1 N chloroic acid:

OVO -

Note: Observed (c = 5, ethanol) and (c = 1 deviation is not ethanol / 1N acid specific for: a hydrochloric acid 1 HNMR (CDCl ₇ TMS): ex. D20 [sicj; 2 (m, 2H) 5.65-5.15

(Ppm) 1.00 (s, 3H); 1.00-2.90 (m, 2Hy)

fs, 2H); 3.10-3.40 (e, 4H); 5.00-5.35 (m, 1 H); 5.90-7.45 (m, 3H).

(S) - (+) - N -Allyl-2-methylsmino-2- [3,4-dichlorobenzyl-1-propanol [1 ']; R = ch ₃ 1

0.5 g (49 mmol) of (S) -N-allylaminopropanol prepared as described in Example 1 are mixed with 3.5 ml of a formaldehyde solution of 3.0 g / l corresponding to 5.0 gp of 133 mmol of formaldehyde. in a reactor equipped with a strong stirrer.

The mixture is heated with stirring to about 40 to 50 ° C to encourage homogenization and then cooled to 15 ° C. Next, 9.3 ml of 100 formic acid / d = 1.22 is added dropwise to the mixture, corresponding to 11.35 g; 247 mmol formic acid. The resulting clear solution was kept in a boiling water bath for 2.5 hours with stirring. It is then cooled, 200 ml of water are added and the mixture is acidified to pH 1 by addition of concentrated hydrochloric acid. The mixture was then extracted 3 times with 100 ml diethyl ether. The ether phase is discarded and the acid phase is basified to pH 11 with 10 N hydroxide solution.

Ľ '»' · '' • J?? J_ «. N 29 S ⁴ ct ΙΧΌ2S

Q? ' C. Then mix

It is extracted three times with 150 ml of ether.

The combined ether phases of cn.oricu crude sodium and dried over sodium sulphate, Ster evaporates the residue (14.0 s / s and contaminates it with flash chromatography)

on a silica gel column.

The column was eluted with 95: 5 dichloromethane: methanol to give purified (S) - (+) - N-allyl-2-methylamino-2- (3,4-diohlorobenzyl) -1-propanol in oily form , which slowly crystallizes to a low melting product.

Product weight: 11.5 g; Yield: 81: δ ²⁰ °: + 13 ° (c = 1, 1N hydrochloric acid) 1 H NMR (CDCl ₃ TM ₃ ): δ (ppm) 0.95 (s, 3H), 2.30 (s, 3H) 2.70 (s, 2H); 2.95 (s, 1Hexch.D2O fsicj); 3.05-3.45 (m, 4H); 5.00-5.35 (m, 2H); 50-5.05 (m, 1H); 6.95-7.40 (m, 3H);

- According to HPLCC optical purity determination on a Chiral-AGP (?) Column (supplier Chromteeh), eluting with a mixture containing 0.01 M potassium dihydrogen phosphate solution, adjusted to pH δ and isopropyl alcohol, the product purity is above 98

- Production of hydrochloride

The eutomer of formula (I) obtained above is dissolved in 150 ml of dichloromethane. The temperature is kept below 25 ° C and excess ethereal hydrogen chloride is added to the solution, then the mixture is allowed to stand for 1 hour while protecting it from moisture.

The solvents were evaporated in vacuo in a water bath. The solid residue ss is dissolved in a minimum amount of methanol pr.

and the purified hydrochloride is precipitated by the addition of '0 C - Ή anhydrous diethyl ether.

172 ° C.

Melting point: 171:

Elemental analysis for C ^ HH ^Cl ClNO (324.59) Calculated: C 51.79 ;: H 5.21; Cl 32.76; N, 4.31; 1 4.93

Found: C, 51.71; H, 6.30;

IR (K3r): 3250, 2500, 1470,

32.72; N, 4.20; 0 5.22 .½

030, 950, 830 ^cm:

Distomeric antipodes of the compounds of the example are:

- (R) - (+) -N-Allyl-2-amino-2- (3,4-dichlorobenzyl) -1-propanol (Example 1) mp: 89 ° C;

~ θ ^: + 11 ° (c = 0, δ, 1N hydrochloric acid)

- (F - (-) - N-allyl-2-methylamino-2- (3,4-dichlorobenzyl) -1-propanol (Example 2) melting point: above 50 ° C;

-14 ° (c = 1,1N hydrochloric acid?

These compounds were prepared as described in the above examples from (R) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol described in Example 1B of the European Patent

no. 0 237 356

The low toxicity of the products of the invention and their unexpected pharmacological properties which have been discovered confirm the value of these compounds in the preventive or curative treatment of allergic manifestations, in particular for histamine-induced events.

Acute toxicity (oral) of compounds of general formula. For this purpose the ucts of the invention are administered in the form of an aqueous solution of elesre ^- "weight. Animals boi ^ i ooia studied at us

T b - About 2 ml per 100: ozone:

nosinv

ABOUT

Days after which they were killed and subjected to autopsy.

every day for 14 days

The LD 50 values (lethal dose causing the death of O0 »animals) are of the order of 1000 mg / kg, which can be interpreted as oomerically low, toxicity.

The antiallergic properties of the eutomers of formula (I ') have been demonstrated by their ability to inhibit an anaphylactic bronchoconstriction reaction induced by an aerosol containing egg albumin in guinea pigs which have been previously sensitized to the allergen.

The above test is carried out as follows: Guinea pigs weighing 250 to 200 g are pre-sensitized by two intraperitus injections of 0.5 ml sterile suspension of 20 µg egg albumin / Grade V; Sigma (a) 100 mg of aluminum hydroxide Al (GH) 2 in physiological saline solution (0.9% NaCl), administered at 24 hour intervals.

At the same time, non-sensitized control animals were treated with 2 injections of the same suspension, but containing no egg albumin.

The actual experiment is carried out after the time necessary for the sensitization of the animals; this period varies from 14 to 21 days. The experiment is usually started after 18 days and the animals are first administered an increasing dose of the test product in the form of an aqueous solution. Administration is oral and groups of five animals are used, each animal receiving a dose of 0.5 to 1.0 ml, corresponding to 1 to 10 µm f / kg of product.

C Λ 4 M, Λ A from V.1111 * L * L · in this cod, animals are anesthetized by intraperitorial injection of urethane solution and undergoing the following surgical operation:

- in the left carotid artery was placed no continuous method to monitor blood cannula to bo-o ro · s ~ T ».- * ³ I

- a cannula is placed in the right jugular vein for intravenous administration of solutions;

- after upper cervical tracheotomy, a polystyrene cannula (internal diameter 2.65 mm, length 9-11 mm) is inserted to vent the animal / Harvard pump 50-1725; Kent, United Kingdom /, operated at a rate of 50 breaths per minute, each breath having a volume of 1.2 ml / kg.

After this operation and stabilization of the intratracheal pressure and blood pressure, the animals are treated with an ultrasonic nebulizer / Pulmosonik Apparatus; The 25'1 model administers an egg albumin aerosol. With this device, during a given 30 30 inzufláci3 ^{from the} valve through the tracheal objectives in a total volume of 30 / om ovalbumin suspension of a concentration of 5 mg / ml. After 60 minutes, the intratracheal pressure is recorded for each animal from both the test and control groups, as reported in Torr. These measurements make it possible to determine the extent of inhibition of bronchoconstriction achieved by the test substance. The results are expressed in terms of the product value, which is the effective dose, expressed in jumol per kilogram (µl [sicl / kg), which can be inhibited by 50% of the albumin-induced bror.chok ^ tritium in sensitized animals. conditions of this test.

iD: - _n , determined after

In these conditions, the inhibition of noc, the eutomer hydrochloride of Formula 1 of Example 2 is 1.84 µM / kg.

In addition, antihistaminic properties in guinea pigs were studied using the bronchocyte tricone assay performed as described by H. Konzett and R. Rossler, Ar. 3XP. Fath. Pharmak. Naur.ym Schiedeberg, 1971, 71-74.

In this test, the products of the invention were studied after administration in the form of a solution or suspension administered by the intravenous and intraduodenal route, as well as in the form of a powder administered by the intranasal route.

Regardless of which route of administration has been chosen, the preparation of the animals used in the test includes the following steps: first, a male guinea pig weighing 350 to

400 g are synthesized by intraperitoneal injection of an isotonic solution containing 250 g / l of ethylcarbamate at a rate of 5.0 ml / kg. The animals are then fitted with a tracheal cannula allowing measurement of pulmonary pressure and a cannula in the right jugular vein for intravenous administration of the solution. A cannula is also introduced into the carotid artery to monitor blood pressure qualitatively.

The animals are then connected to the pump / Harvard ref. 50 - 17 ¹ 8 / s are kept under artificial ventilation at a frequency of 50 breaths per minute. The intratracheal pressure is recorded in a kit including an operator, amplifier and recorder (Gould, ref. PL93Z, 13-4615-50 and 81S8-G4400-06).

After this equipment, the animals are left undisturbed for 10 minutes, then a real experiment is started, which is carried out in various ways, depending on which route has been chosen for administration.

a / i.v.

The test products in the form of a base are dissolved in an isotonic solution (0.9% sodium chloride solution containing 10% by weight). % by volume of Trar.scutol. Dilution is performed by adding isotonic solution. When products in the form of salts, in particular hydrochlorides, are used, the solutions are incorporated in isotonic solution.

Treatment of the animals consisted of a series of histamine dihydrochloride l10 CO pM [sic] / kg} renr with the test product solution, following the following timing.

administration of the solution before and after the treatment.

t = -20 minutes - histamine / 100 fsLsicl / kg / t = -1 0 minutes - dtto / control / t = 0 minutes - injection of the test product t = + 10 minutes - histamine / 100 pM (sic) / kg / t = +20 minutes - dtto t = + 30 minutes - dtto t = +40 minutes - dtto t = + 50 minutes - dtto t = +50 minutes - dtto

The test results are shown in Table 1.

b / Administration i.d.

When used in the form of bases, the test products are suspended in a solution containing TO g (1 carboxymethylcellulose (CMC)). When used in the form of salts, they dissolve in isotonic solution. The resulting suspensions or solutions are administered via a cannula, the end of which is inserted into the duodenum of the animal.

Timing of subsequent histamine administration i. in. by the route and administration of the test solution i.d. the route is identical to the schedule described in paragraph a /.

The results of these tests are shown in Table 2.

c) Administration as intrarasal powder (In.P./)

The test product is administered by nasal insertion of a powder containing 20 mg of lactose which is mixed with an appropriate amount of the test product. Artificial ventilation is stopped for a moment prior to insertion to facilitate penetration of the compound into the lungs. Histamine i.v. route and test product In.p. the way is as follows:

t = -1? minutes - histamine / 100 pMfsicJ / kg / t = - 5 minutes - dito / control / t = C minutes - irrigating test product t = 5 minutes - histamine / 100 μΜ [sic] / kg /

The results of these tests are shown in Table 3.

- Calculation and expression of results:

For each route of administration and for each histamine administration dose b, the efficacy of the test products is expressed as a percentage change in the bronchoconstriction amplitude calculated with respect to the bronchoconstriction amplitude that occurs following the histamine control prior to administration of the test product. The percentage change is calculated using the following formula:

Bc / tx / - Sat / tx / change /% / = ICO - - x 100

Sc / to / - Bo / to / where

Bc (tx) represents the amplitude of bronchoconstriction in mm at time x, Bo (tx) represents the amplitude of the baseline respiratory value in mm at time x, Bc (to) and Bo (10 o) amplitude in mm after control administration.

histamine, which inhibits histamine-induced chokonstriction at various times in the form of a value that represents the effective γ in the duct, expressed in pM [sic] / kg, which is capable of hibernating histamine-induced bronchoconstriction in the bronchial dose of pro50 induced by histamine.

Unless this term is used, the results are expressed as a percentage change at a given time at a given concentration of the test product. Under these conditions, a positive percentage corresponds to a potency of the effect on bronchiconstriction and, conversely, a negative value of the inhibitory effect of the bronchoconstriction.

Statistical analyzes of the results were performed using the Student's [sicl T-test]. A p value of <0.05 is considered statistically significant.

In these tests, the compounds described in Examples 1 and 2 were used. In addition, as the comparator product for the eutomer of Example 1, the corresponding racemic (R, S) compound described in Example 7 of Bvrop patent no. As far as the eutomer of Example 2 and its hydrochloride are concerned, the rscemic (R, S) compound hydrochloride described in Example 13 of Rvrbp patent no. As well as the corresponding R-configuration distomeric antipode, prepared as described above.

In these tests, the following compounds were + * Ä 7 A · 1 ~ 4 Ä Z * A ~ O * 7 T C C ΓΠ * Γ C. Ή - lu r ... 'j j -..- j----- - _in - ----- j of antagonists allergens that are effective in the airways and Cromakolimu / INN /, which is a compound known as bronchodilators.

Inhibitory effect by i.v. for bronchoconstriction induced by the histamine-induced ICO. Results are reported as μΜ / kg [sic]

compound .konfigurácia t = 1C ' t = 20 ' t = 30 ' from the example 1 by / S / 4.89 2.88 2.54 invention illustrates a comparative racemate (R, S) 6.65 4.10 4.36 from the example 2 according to invention - base /WITH/ 1, 27 0.93 0.7 * - .hydrochl: orid / 3 / 1, 68 0.70 n c In j illustrates a comparative racemate.HCl (R, S) 3.72 2.11 1, 88 illustrates a comparative distomer (R) +6,3 * 18.4 +28.2 reference substance fenspiride /INN/.HC1 4.25 4.99 ň 24 Table 1 - Mon kračovani about compound configuration t = 40 * + “Sp ¹ in ~ J t = 60 ' from the example 1 by / Sz ^z 2 ao 3.17 3.55 invention illustrates a comparative racemate (R, S) 3.39 J p * 3.52

of Example 2 of the invention

- base / 3 / 0.95 1, 01 0.76 - Hydrochl: chloride /WITH/ O, O7 0.51 0.53 trovnávací racemát.H Cl / R, S / 2.07 2.34 2.22 illustrates a comparative distomer / R / +35.4 +36.7 +41.1 reference substance fenspiride /INN/.HC1 - 8.90 8.01 1 1, 03

percent potency. the bronchoconstriction effect is statistically insignificant for 3.5 pM [sic] / kg l 'k and

Inhibitory effect on id administration of 100 µM / kg [sic] histamine. 3Dc ₀ in pM / kg [sic1 on bronchoconstriction] The results are shown as

compound kor. • P 4 ^Λ o 4--, a ' IN "* . in T = 2 θ ' T = 30 " from the example 1 according to /with/ - 1 00 in 78 invention from the example 2 according to invention - base /with/ - 1 , ^á 5 about , 59 - Hydrochlo I '? and 4 / 3 / B59 42 0 Ή r - illustrates a comparative di stomer / R / +5.8 + 14 / * +32 4

- 24 η fi

Table ¹ and 2 - continued

compound configuration t = 40 ' t = 50 ' t = 50 ' from Example 1 according to /with/ 0.59 1, 28 2.17 invention .. from Example 2 according to invention - base /WITH/ 0.55 M3 0.52 - hydrochloride /with/ 0.48 0.51 0.56 straightening distomer * /?./ + 4Δ, 5 -35.5 +30.0

* Percent potency not statistically significant for effect on bronchoconstriction

3,5 µM [sic] / kg Art

Inhibitory boat when administered as intranasal powder (In, P) for bronchoconstriction induced by tamin. The results are shown as y in

100 µM [sic] / kg bi εν µM / kg sic compound configuration o9 at t = 5 min from Example 2 of the invention

- base / S /

- hydrochloride (3)

Cromakalim (SHIT), 28 1, 77, 88, in these assays, convincingly the egg albumin-induced compounds of the invention have been induced by the egg album.

In addition, these results demonstrate the specificity of the antihistaminic activity of the compounds of Examples 1 and 2 having the S configuration and are within the scope of this invention. It has been shown that, in comparison with the racemic (R, S) -alogues, the compounds of the invention are nearly two-fold more effective.

Fri i.v. or In. administration, the compounds of the invention exhibit the same efficacy / if not higher than the reference compounds with which they are compared.

It is particularly surprising that in the case of the present invention cut down the product of Example 2, has a suitable configuration distomer R evident, although not statistically significant ^one, potenciaeny effect on the activity of histamine, and is provided in the route of administration, and the ID administration.

These antiallergic and, in particular, antihistaminic properties, which have been demonstrated by bronchoconstriction tests, cannot be considered obvious from the prior art. In addition, there is a remarkable difference between the efficacy of the eutomers of formula I and their antipodes. In summary, the cited properties justify the patentability of the S-configuration enantiomers of the compounds of formula I as novel products. Thus, these new products are:

(S) - (-) - N-Al-yl-2-amino-2- (3,4-dichlorobenzyl) -1-propanol and (S) - (+) - N-Hept-2-methylamino-2- ( 3,4-dichlorobenzyl) -1-propane 1 and salts thereof. The invention also relates to a process for the manufacture of these substances and their use in the form of medicaments for preventive or therapeutic treatment of allergic conditions, in particular those caused by histamine.

Due to their antiallergic activity, the compounds of the invention are useful in the form of pharmaceutical compositions for the treatment of asthmatic conditions and in particular for inhibiting bronchoconstriction or bronchospasm in allergic asthma or for treating similar conditions [sicj] resulting from acute or chronic bronchitis. The histamine activity of the compounds of the invention justifies their use in symptoms caused by histamine release, such as nasal or conjunctival mucosal allergies, allergic rhinitis and certain forms of edema, dermatosis, pruritus or eczema.

Low toxicity

of these products uses in oral daily dose-a Viθ Σθ vi V ΡΟΖΙΏ, ΘΟΖ from 50 o p o 'u δ / s t sub-doses. ’Can be

The salt-containing products of the DCs are administered by a free method of administration and prea.

of these products allows to achieve the expected effect up to even COO mg. However, this dose is usually 50C mg per day / in the case of oral need, divided into several inventions with their pharmaceutical suitability formulations suitable for the nature and extent of the drug. For example, tablets, dragees, capsules, powders, lace, gels, suspensions or alternatively also solutions which can be injected or orally.

The pharmaceutical preparations are made by methods well known to those skilled in the art. From 1 to .¾ w active ingredient consisting of a compound of formula I or one of its salts and 99 to ^50: h w pharmaceutically suitable carrier which is compatible with the active ingredient and that has a physical form suitable for the intended route Sian formulation.

Neaaedzujúce As examples of methods of making tablets and injectable isotonic solutions based on compounds of the present invention include ^1:

tablets

Composition of a tablet weighing 200 mg Active ingredient of the formula I of Example 2 polyvinylpyrrolidone and carbamyclohexyl magnesium stearate. okryst a l i c c e lul ó z a

5 until 75 mg 2 mg P mg 60 until 75 p σ 20 until 76 mg

Production

Folyvinylpyrrolidone is dissolved in water, a low molecular weight alcohol, such as ethanol, or a mixture thereof to a solution having a concentration of 0.1 to 1%. A homogeneous mixture is produced separately. . . % of the weight additive, carboxymethyl-written solution, granules of pellets, the mixture weighed 200 mg.

of lactose and half the amount of cellulose with starch, which is then moistened up. The resulting paste is processed into granules and sieved and screened. The fractions are thoroughly mixed and processed into tablets of

Injection solution

Composition active ingredient of the formula I / hydrochloride of example 2 / sodium chloride distilled water q.s.

0 mg mg

1.0 ml

Production

The solution is divided into injections which can be heat sterilized in the usual manner after sealing. The solution may also be sterilized by filtration then distributed to injection and these operations are transferred to tions _of which are sealed under sterile.

Claims (3)

PATENT CLAIMS 4-dichlórpodía 1. Enantiomers derived from 2-amino-2-, 3-benzyl-1-propanol with absolute configuration (S) of Cahn-Ingold-Prelogyl of formula I (1) wherein R is hydrogen or methyl and not salts with non-toxic acids . their addition kt (s) -1 The configuration according to claim 1 is (S) - (+) - N-allyl-2-methylamino-2-propanol or its non-toxic acid addition (3,4-dichlorobenzyl) salt. of claim 1 or 2 for the histamine treatment of an enantiomer with the (S) -configuration according to the manufacture of an antiallergic and in particular an anti-allergic product. A process for the preparation of compounds according to claim 1, characterized in that the alcohol with the absolute configuration (s) of the intermediate amino acid of formula II (11) wherein R is hydrogen or methyl is N-allylated with a hlyl halide. A process for the preparation of a compound according to claim 2, wherein in the first step (S) - (-) -2-amino-2- (3,4-dichlorobenzyl) -1-propanol N-allyl is allyl bromide, to form a compound of formula I according to the invention wherein R is hydrogen and then N-methyl is reacted with formaldehyde and formic acid. Claim 6 - before repair A process for the preparation of (S) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol, characterized in that (+/-) - 5- (3,4-dichlorobenzyl) ) -5-methylhydantoin, is cleaved in an alkaline solution of (R) - (+) - D-metylbenzylamíhom to separate (S) - (-) - 5- _(3,4-t dichiórbenz yl) -5-methylhydantoin, who The mixture is hydrolyzed in an alkaline aqueous medium to give (S) - (-) - 2- (3,4-dichloroenzyl) bacon and this is reduced with an organic metal hydride. Claim 5 - after repair 5. A process for the preparation of (s) - (-) - 2-amino-2- (3,4-dichlorobenzyl) -1-propanol, characterized in that (+/-) - 5- (3,4-dichlorobenzyl): ) -5-methylhydantoin cleaves in alkaline aqueous-acetone medium with (R) - (-) - <d -methylbenzylamine to separate (S) - (-) - 5- (3,4-dichlorobenzyl) -5-methylhydantoin, which is hydrolyzed in an alkaline aqueous medium to give (s) - (-) - 2- (3,4-dichlorobenzyl) alanine and this is reduced with a borane-dimethylsulfide complex.