NO830745L - LEFT-TURN ISOMS OF MEKITAZINE AND PROCEDURE FOR THEIR PREPARATION - Google Patents

Description

The present invention relates to the levorotatory isomer corresponding to racemic 10-[(1-aza-bicyclo(2,2,2)oct-3-yl)-methyl]10H-phenothiazine or mekitazine (internationally recognized nomenclature), a method for the preparation hence and the compound's use as a drug, especially as an anti-histiamine drug.

Mekitazine corresponding to the formula:

is an antihistamine, particularly useful for treating allergies. Mekitazine is described e.g. in FR-PS 2,034,605.

As formula I has an asymmetric carbon atom (the carbon atom in the 3-position in the 1-aza-bicyclo(2,2,2)octane ring system), mekitazine can be dissolved into two optical isomers or enantiomers.

The compound according to the invention which is the levorotatory enantiomer corresponds to the formula:

in which the absolute configuration of the carbon atom in the 3-position of the 1-aza-bicyclo(2,2,2)octane ring system is sinister (S)

and thus has the designation 10-[(1-aza-bicyclo(2,2,2)oct-3(S)-yl)methyl]10H-phenothiazine. The compound Ia can be prepared by condensation of 3(S)-chloromethyl-[1-aza-bicyclo-(2,2,2)octane] with phenothiazine in the presence of an inert solvent (e.g. an aromatic hydrocarbon such as toluene or xylene, or a polar solvent such as hexamethylphosphoric triamide or a mixture of these compounds), in the presence of an alkaline condensing agent, according to a process analogous to that described in FR-PS 2,034,605 for the preparation of mekitazine from racemic 3- chloromethyl[1-aza-bicyclo(2,2,2)octane] and phenothiazine. 3(S)-chloromethyl-[1-aza-bicyclo(2,2,2)octane] can be obtained by the action of thionyl chloride on [1-aza-bicyclo(2,2,2)oct-3(S)-an ]methanol according to a procedure identical to that described by CA. Grob and E. Renk, "Heiv.

Chim. Acta", 37 (1954), 1689-1698 for the preparation of racemic 3-chloromethyl[1-aza-bicyclo(2,2,2)octane] from racemic [1-aza-bicyclo(2,2,2)oct- 3-an]methanol.

[1-aza-bicyclo(2,2,2)octa-3(S)-an Jmethanol can be obtained by dissolving racemic [1-aza-bicyclo(2,2,2)oct-3-an]methanol. Such a resolution can be carried out e.g. by reacting racemic [1-aza-bicyclo(2,2,2)octa-3-methanol with an optically active acid or a derivative of an optically active acid to form a mixture of diastereomeric salts or esters and then separating said diastereomers from their mixtures by classical processes such as e.g. recrystallization, and from each diastereomer to regenerate the starting base or alcohol in optically pure form, i.e. in the form of a pure enantiomer. Optically active acids and derivatives of acids which may be used include those described by S.H. Wilen, "Tables of Resolving Agents and Optical Resolutions", University of Notre Dame Press, Notre-Dame, Indiana (1972).

The compound Ia, which is obtained in a crude state by the procedure previously described, can be purified by classical methods, either physically (crystallization or chromatography) or chemically (salt formation and regeneration of the base by treating the salt in an alkaline medium).

The compound Ia in the form of the pure base can be converted into

an addition salt with a mineral or organic acid, by adding such an acid in the presence of a suitable solvent.

The compounds Ia show an antihistaminic activity superior to that of mekitazine and a cholinolytic action distinctly lower than that of mekitazine. This has the result that, at equi-active antihistamine doses, compound Ia will produce fewer cholinolytic effects and therefore fewer secondary effects (mydriasis, dry mouth and constipation) than mekitazine, and this is a significant advantage. Such a result was certainly unexpected.

The following example illustrates the invention without limiting it.

EXAMPLE: Preparation of 10-[(1-aza-bicyclo(2,2,2)oct-3(S)-yl)methyl]10H-phenothiazine

1) Preparation of [1-aza-bicyclo(2,2,2)oct-3(S)-an Jmethanol To 26.2 g of racemic [l-aza-bicyclo.(2,2,2)oct-3-ane ]-methanol

in 100 ml of an ethanol/f^O mixture (80/20 by volume)

27.9 g natural tartaric acid (L) was added. The mixture is then brought to the boiling point to dissolve the reactants and then cooled. The crystals obtained are separated by filtration, washed twice, each time with 20 ml of an ethanol/r 2 O mixture 80/20 and then with 50 ml of diethyl oxide.

24 g of product is obtained in this way and this is recrystallized twice from an 80/20 ethanol/H 2 O mixture. 8.6 g of product is obtained in this way and taken up in 400 ml of chloroform and 15 ml of a concentrated ammonia solution. The organic phase is dried over magnesium sulphate and the chloroform is removed by evaporation under reduced pressure. The remainder is taken up in 200 ml

diethyl oxide, the solution is filtered and evaporated to dryness under reduced pressure. In this way, 3.35 g of [1-aza-bicyclo(2,2,2)oct-3(S)-an]methanol are obtained which melts at 56-58°C and for which the specific rotation measured at a 3% -ig solution of the product in a 1N aqueous solution of methanesulfonic acid) is

The optical purity of the product obtained, determined by the method of J.A. Dale et al, "J. Org. Chem.", 34 (1969), 2543, is 99%.

2) Preparation of 3 (S)-chloromethyl-j_l-aza-bicyclo (2, 2, 2) octane]. The hydrochloride of 3(S)-chloromethyl-[1-aza-bicyclo(2,2,2)octane] is prepared by the action of thionyl chloride on [1-aza-bicyclo-(2,2,2)oct-3(S) -an]methanol in a chloroform medium and melts at a temperature above 260°C, whereby the specific rotation (measured on a 1% aqueous solution of the product) is

By treating the above hydrochloride in an aqueous medium with a mineral base such as sodium hydroxide and then extracting the product formed with diethyl oxide and removing the diethyl oxide by evaporation, 3(S)-chloromethyl[1-aza-bicyclo(2,2 ,2)octane]. 3) Preparation of 10-[(1-aza-bicyclo(2,2,2)oct-3(S)-yl)-methyl]-10H-phenothiazine. 6 g of phenothiazine, 2.9 g of potassium tert-butylate, 3 ml of hexamethylphosphoric triamide and 30 ml of anhydrous xylene are placed in a nitrogen atmosphere. The mixture is brought to the boiling point, 10 ml of solvent is distilled off and, over the course of one hour, a solution of 2.4 g of 3 ( S )-chloromethyl-[1-aza-bic-cyclo ( 2 , 2 , 2 )-octane is added ] in 30 ml anhydrous xylene. Boiling is continued for one hour and after cooling the reaction mixture, 20 ml are added

water, after which the aqueous phase is removed by decantation,

the whole is then extracted three times, each time with 20 ml of chloroform. The chloroform phase is dried over magnesium sulfate and the chloroform is removed by evaporation under reduced pressure. Thus, 10 g of a crude product is obtained which is fixed on a column of silica gel. Elution is carried out with a mixture of 95 parts by volume toluene and 5 parts by volume diethylamine. The fractions containing the desired product (these fractions are located using a thin-layer chromatographic test on silica, the presence of the desired product in a fraction is indicated in this sample by a spot located at the same point as that given by mekitazine reference -the product), evaporates. In this way, 5 g of product is obtained, which is again fixed on a column of silica gel. Elution is carried out with a mixture of 90 parts by volume of chloroform,

5 parts by volume methanol and 5 parts by volume acetic acid. The fractions containing the desired product (the fractions located as indicated above) are evaporated. 2.4 g of product is obtained in this way and this is dissolved in water. The aqueous solution is made alkaline by the addition of a concentrated ammonia solution and the insoluble material is extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated under reduced pressure. 1.15 g of product is obtained which is recrystallized from acetone, which gives 0.7 g of 10-[(1-aza-bicyclo(2,2,2)-oct-3(S)-yl)methyl]10H-phenothiazine which melts at 139-140°C and the rotation for the product (measured on a 1% solution of the product in ethanol) is

The optical purity of the product obtained, determined by the calorimetric method as described by C. Fouquey and J. Jacques in "Tetrahedron", 23 (1967) 4009, is 97.5%.

The antihistamine activity of the compounds (compound Ia and mekitazine) is assessed by measuring the affinity for H-2-histamine receptors. This affinity was measured by capacitance

thete for the products to displace tritiated pyrilamine

( 3H pyrilamine) from the binding points, and is expressed by a value IC^q which is the concentration of the product (in nanomoles per litre) which is necessary to achieve a 50% inhibition of the binding of<3>H-pyrylamine. The products were tested according to the procedure described by V.T. Tran et al. in "Proe. Nat. Acad. Sei., (USA), 75 5290 (1978) using membranes from guinea pig brain.

The cholinolytic effect of the compounds was assessed

by measuring the affinity for muscarinic receptors of acetylcholine. This affinity was measured by the capacity of the product to displace the benzylate of tritiated 3-quinuclidinol ( 3 H QNB) from the binding points and is expressed by a value IC^q which is the concentration of the product (in nanomoles per litre) which is necessary to achieve inhibition of

50% of the binding of H QNB. The product was tested according to the procedure described by H.I. Yamamura et al. in "Proe. Nat. Acad. Sei., (USA) 71_, 1725, (1974 ) using the membranes from the striatium in rat brains.

The results obtained are summarized in the following table:

The compound of formula Ia therefore has 1.4 times greater antihistamine activity and 4 times lower cholinolytic activity than racemic mekitazine, i.e. at equiactive doses, compound Ia being approximately 5 times less cholinolytic than the racemate.

The acute toxicity of compound Ia and mekitazine to mice is approximately the same.

The compounds of formula Ia and salts thereof with a pharmaceutically acceptable acid can be used in human therapy, as active substances in drugs, especially antihistamine drugs.

Such a drug contains, next to the active substance, a pharmaceutically acceptable carrier such as those usually used in the pharmaceutical field, and may take the form of tablets, capsules, gelatin-coated pills, suppositories, injectable solutions, etc.

The dosage depends on the desired effect and the method of administration. E.g. is the general dose by oral administration for adults between 10 and 200 mg per day active substance.

Claims (3)

1. Compound, characterized by the "formula: where the absolute configuration for the carbon atom in the 3-position in the 1-aza-bicyclo(2,2,2)octane ring system is sinister (S). 2. Process for preparing the compound according to claim 1, characterized in that 3(S)-chloromethyl-[1-aza-bicyclo(2,2,2)octane] is condensed with phenothiazine in an inert solvent in the presence of an alkaline condensing agent. 3. Medicine, particularly usable as an antihistamine medicine, containing an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance is the compound according to claim 1 or a salt of this compound with a pharmaceutically acceptable acid..