IT8922427A1 - COMPOUNDS WITH ANTITUSSIVE ACTIVITY, PROCESS FOR THEIR PREPARATION THEIR PHARMACEUTICAL COMPOSITIONS. - Google Patents

Description

Patent Application for Industrial Invention entitled:

Activity compounds antitussive, process for their preparation, their pharmaceutical compositions.

Summary

Does Promethazine in optically active or racemic form have activity? antitussive in addition to the known activity? antihistamine, the processes for separating the optical isomers of Promethazine are also described.

Description of the invention

The present invention relates to the new use as antitussive of Promethazine in optically active or racemic form, the relative pharmaceutical compositions and the processes for separating the two optical isomers of this active principle.

Promethazine characterized by the following formula (I):

where does the asterisk indicate the presence of an asymmetric carbon atom? an antihistamine agent and has long been used in racemic therapy.

It has now been surprisingly found by the Applicant that racemic Promethazine or in the form of an optical isomer possesses a marked activity. antitussive.

This activity? antitussive of the aforementioned active ingredient? particularly advantageous for the treatment of cough of any kind and in bronchial complications due to flu, and with irritative and convulsive cough of all kinds.

The present invention therefore relates to active pharmaceutical compositions antitussives suitable for oral, injectable and rectal administration in combination with excipients conventionally used in pharmaceutical preparations.

For oral administration, the pharmaceutical compositions according to the present invention can be formulated in the form of syrup, ready-made or extemporaneous solutions.

For oral administration in solid form in the form of capsules, tablets, single-dose sachets, fast-acting or delayed-acting dragees.

In the case of injectable administrations, the pharmaceutical compositions according to the present invention can be formulated in ready or extemporaneous liquid form; for rectal administration they can be formulated in suppository form.

The pharmaceutical compositions according to the present invention can contain from 10 to 100 mg of active principle and can be administered three or four times a day, depending on the severity. of symptomatology.

The results of the activity tests? antitussive agents conducted with the compounds according to the present invention and by comparison with codeine, carried out on the guinea pig, after electrical stimulation of the vagus nerve and exposure for 5 minutes to an aqueous solution containing 5% of citric acid in the form of aerosol according to what described by R.M. Pierknig et al in Arzn Forsch, 29,287,1979. Are illustrated in Table 1.

In particular, the compounds under examination are administered intravenously 5 minutes after electrical stimulation and orally 60 minutes after the 5% citric acid aerosol -Table 1- Antitussive effect of (?) Promethazine, (+) dextroisomer, (-) levoisomer and codeine. '

Ammonia aerosol test

Male albino guinea pigs weighing an average of 350 g were used, divided into groups of 10 animals each.

Three groups of batches of animals were treated respectively with Promethazine in optically active dextrorotatory and levorotatory form and in racemic form orally at doses of 2 and 4 mg / kg respectively; two groups of animals were treated with codeine at doses of 2.5 and 5 mg / kg respectively; two groups of? mimals were treated with diphenhydramine orally at a dose of 5 and 10 mg / kg respectively, a last group? been held as a control.

After 30 minutes from the administration of each single dose of drug, the animals were placed individually in a glass container into which ammonia vapors were introduced.

The evaluation of the activity? of the product concerned? was performed by calculating the coughs of the animals in thirty minutes of observation.

The results show that racemic, levo and dextrorotatory promethazine have a very strong antitussive action comparable to that of codeine.

Histamine aerosol test

The histamine aerosol test on guinea pigs weighing an average of 400 g by administering to the animals respectively doses of 5 mg / kg of dextrorotatory promethazine, 5 mg / kg of left-handed promethazine and 5 mg / kg of racemic promethazine, shows that Promethazine, is in racemic form which in the form of optical isomer, produces a remarkable inhibition of the bronchospasm induced by histamine.

The optical isomers of Promethazine are obtained by conventional methods of optical resolution.

In particular, according to the present invention, the separation of the two enantiomers is obtained with two different methods.

The first method involves the following steps:

1) a) is added to an organic solution of one or a mixture of polar solvents, preferably a mixture of ethyl acetate and ethanol, containing the racemic form of the active principle of formula (I), the acid d, l - a- (isopropylene aminooxy) propionic and the corresponding salt of the left-handed form of Promethazine is precipitated at temperatures between 0 and 5 ° C, which is recovered and treated with an aqueous solution of an alkali metal hydroxide. purpose of obtaining (-) Promethazine in free form;

b) from the mother liquors coming from the filtration of the salt of the levorotatory form of Promethazine, the corresponding salt containing the dextrorotatory form of Promethazine is recovered by precipitation at temperatures between 0 and 5 ° C, which is hydrolyzed with a basic solution of a hydroxide of an alkali metal preferably sodium hydroxide in order to obtain the free form of the dextrorotatory isomer of Promethazine.

The second method involves the following steps:

2 a) racemic Promethazine is added to a boiling solution of a polar organic solvent, preferably methanol, containing (+) tartaric acid, thus precipitating the levorotatory form of Promethazine (+) tartrate, the precipitated salt is hydrolyzed with an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, to obtain (-) Promethazine in free form,

b) the mother liquors deriving from the filtration of (+) Promethazine (-) tartrate are dried and hydrolyzed with an alkali metal hydroxide, preferably sodium hydroxide, to obtain (+) Promethazine in free form.

The following examples are reported for illustrative but not limitative purposes of the present invention.

Example 1-Levorotatory Promethazine

A solution of 20.44 g of racemic Promethazine in 400 ml of ethyl acetate containing 6% 95% ethanol is placed in a 1 liter beaker.

14.5 g of d, 1-a- (isopropyleneaminooxy) -propionic acid are added and the mixture is stirred until solution. POSTILLA 1

The crystals are dissolved by heat in 125 ml of ethyl acetate. The solution is covered and cooled at 0-5 ° C for 8-16 hours, the precipitate is collected and transferred to 50 ml of water; it is stirred until solution and alkalized with sodium hydroxide up to pH 10.

The emulsion obtained is extracted with 3 portions of 50 ml of chloroform which are separated and combined and dried. The solvent is evaporated and 11 g of levorotatory Promethazine are obtained [a] D = -57? (in chloroform).

Example 2 - Dextrorotatory promethazine.

The mother liquors obtained from the filtration of the left-handed Promethazine salt of Example 1 are combined and diluted with an equal volume of petroleum ether (b.p. 30? -60?); it is cooled at 5 ° C for 8-16 hours.

The precipitate recrystallizes from ethyl acetate.

cool at 5 ° C for 8-16 hours.

The precipitate recrystallizes from ethyl acetate.

Then it is dissolved in 50 ml of water and is alkalized to pH 10 with sodium hydroxide.

The obtained emulsion is extracted with a portion of 50 ml of chloroform.

The chloroform solutions are combined, anhydrified with anhydrous sodium sulphate and dried.

About 10 g of dextrorotatory Promethazine are obtained

+56? (In chloroform).

Example 3 - Levorotatory promethazine

A mixture of 31-25 g of (+) tartaric acid in 450 ml of methanol? placed in a flask and heated until boiling. 59-98g of racemic form Promethazine are added to the hot solution.

The resulting solution is cooled and after 24 hours, the salt precipitates and is separated by filtration.

The salt is hot dissolved in 350 ml of ethanol.

The salt precipitates in the form of crystals at room temperature in 12 hours and is separated by filtration.

The product obtained is dissolved in hot with 90 ml of water, the solution is brought to pH 10 with sodium hydroxide and extracted with 3 portions of 50 ml of chloroform.

The chloroform extracts are combined, anhydrified on anhydrous sodium sulphate and dried.

At the end 14 g of levorotatory Promethazine are obtained with [a] D =

- 57 ?.

Example 4 - Dextrorotatory promethazine

The mother liquors of the previous example and coming from the filtration of (+) Promethazine (-) tartrate, gather and dry up.

A solid product is obtained consisting of the (+) tartrate of {+) Promethazine which is dissolved in 150 ml of hot water; the pH is brought to 11 with sodium hydroxide and then extracted 3 times with 50 ml portions of dichloroform.

The combined chloroform layers are dried with sodium sulphate and then dried.

Thus 16 g of crude dextrorotatory Promethazine are obtained.

Raw dextrorotatory Promethazine is dissolved in 90 ml of 95% ethanol: 180 ml of ethanolic solution containing sufficient sulfuric acid (0.03-0.035 moles of concentrated sulfuric acid) is added to the ethanol solution. In this way the (+) Promethazine sulphate crystals precipitate.

The crystals obtained are dissolved in the minimum quantity? of water (45 ml of warm water), and the resulting warm solution? diluted with acetone until saturation at the boiling point. The solution is cooled and the pure (+) Promethazine sulphate crystals are separated after 6 hours, which are dissolved in water and treated with an aqueous solution of sodium hydroxide at pH 10, thus obtaining the free form of {+) Promethazine which is extracted with chloroform,

the chloroform extracts are dried and 8 g are obtained. of dextrorotatory Promethazine ml = di56?.

Claims (5)

Claims 1 Pharmaceutical compositions with activity? antitussives including the compound of formula (I): (I) where the asymmetric carbon indicates the presence of an asymmetric carbon, said compound being present in optically active left-handed or right-handed form, or in racemic form, as an active principle in combination with pharmaceutically acceptable carriers and / or excipients. 2. The pharmaceutical compositions according to claim 1 containing from 10 to 100 mg of active principle. Process for separating the optically active left-handed and right-handed forms of the active ingredient in racemic form according to claim 1 comprising the following steps: polar organic, containing (+) tartaric acid the compound of formula (X) is added in racemic form, in this way the (+) tartrate salt of the left-handed form of the compound of formula (I) precipitates the precipitated salt is hydrolyzed with a solution aqueous of a POSTILLA 2 hydroxide of an alkali metal, preferably sodium hydroxide, to obtain the left-handed form of the compound of formula (I) b) the mother liquors deriving from the filtration of the (+) tartrate of the left-handed form of the compound of formula (I) are dried and hydrolysed with hydroxide of an alkali metal, to obtain the dextrorotary form of the compound of formula (I). 4. Process according to claim 3 where the polar solvent in which the (+) tartrate of the left-handed form of the compound of formula (I) is precipitated? methanol, and hydroxide used to obtain the corresponding optically active free forms, both left-handed and right-handed, of the compound of formula (I)? Sodium hydroxide. 5. Process for separating the optically active left-handed and right-handed forms of the active ingredient in racemic form according to claim 1 comprising the following steps: a) is added to an organic solution of one or more? polar solvents, containing the racemic form of the active principle of formula (I), the d, 1 -a (isopropylene aminooxy) propionic acid and the corresponding salt of the left-handed form of the compound of formula precipitates at temperatures between 0 and 5 (I), which is recovered and treated with an aqueous solution of an alkali metal hydroxide, in order to obtain in free form the left-handed isomer of the compound of formula (I); b) from the mother liquors coming from the filtration of the salt of the left-handed form of the compound of formula (!) of step (a), the corresponding salt containing the right-handed form of the compound of formula is recovered by precipitation at temperatures between 0 and 5 ° C (I) which is hydrolyzed with a basic solution of an alkali metal hydroxide in order to obtain the free form of the dextrorotatory isomer of the compound of formula (I). Process according to claim 5 wherein the polar solvents in which the salt of the left-handed form of the compound of formula (I) is precipitated are a mixture of ethyl acetate and ethanol, and the hydroxide used to obtain the corresponding optically active free forms is left-handed which dextrorotation of the compound of formula (I)? sodium hydroxide.