AT278785B - Process for the production of new piperidine derivatives and their salts - Google Patents

Description

  

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  Process for the production of new piperidine derivatives and their salts
The invention relates to a process for the preparation of new piperidine derivatives with valuable pharmacological properties.



   It has surprisingly been found that piperidine derivatives of the general formula
 EMI1.1
 in which Rl is a phenyl-alkyl group with a maximum of 9 carbon atoms, and ruz denotes the allyl or propynyl group, and its addition salts with inorganic and organic acids have valuable pharmacological properties, in particular antitussive activity with a favorable therapeutic index.



   The antitussive effectiveness of the compounds of general formula I, e.g. B. the hydrochloride
 EMI1.2
 can, for example, with intravenous application to cats according to the method of R. Domenjoz, Arch. exp. Path. andPharmakol. 215, 19-24 [1952].



   Another method for demonstrating the antitussive effectiveness is the determination of the inhibition of the irritable cough caused by sulfur dioxide in guinea pigs caused by subcutaneous or oral administration of the test substances: In a preliminary experiment to select the test animals, male guinea pigs are passed through a plexiglass chamber at
 EMI1.3
 follows by inspection. The guinea pigs that react with coughs (about 2/3 of all animals) are combined in groups of 6 animals each. Such test animal groups receive the test substance about 24 hours after the preliminary test in various doses suitable for determining the ED in mg / kg

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 administered subcutaneously or orally.

   The irritant gas exposure takes place in the same way as in the preliminary test after 30 to 90 minutes after application of the test substances. The onset of a cough is assessed again by inspection. From the percentages of animals no longer reacting to SO that were determined at different doses, the dose preventing coughing in 50% of the animals = ED50 is determined by graphic interpolation.



   The new piperidine derivatives of the general formula I and their pharmaceutically acceptable acid addition salts are suitable as active ingredients for pharmaceutical preparations for the treatment of coughs, in particular for relieving and relieving the stimulus to cough. Administration can take place orally, rectally or parenterally.



   To prepare the new piperidine derivatives of the general formula I and their acid addition salts, one leaves an amide of the general formula
 EMI2.1
 
 EMI2.2
 Thionyl chloride, phosphorus trichloride and phosphorus pentoxide are mentioned among the agents. The elimination of water is accomplished, for example, by boiling an amide of the general formula II with thionyl chloride in benzene or chloroform or by heating with phosphorus pentoxide, preferably to temperatures between 140 and 200 ° C., or by heating with phosphorus trichloride.



     Starting materials of the general formula 11 are obtained, for example, by reacting the isonipecotamide with reactive esters of compounds of the general formula R-OH (III) and subsequent condensation with allyl or (2-propynyl) halides using potassium amide in liquid ammonia .



   If desired, the piperidine derivatives of the general formula I obtained by the process according to the invention are then converted in the customary manner into their addition salts with inorganic and organic acids. For example, a solution of a piperidine derivative of the general formula I in an organic solvent, such as diethyl ether, methanol or ethanol, is mixed with the acid desired as the salt component or with a solution thereof and this is separated immediately or after adding a second organic liquid, such as. B. diethyl ether to methanol, precipitated salt.



   For use as active ingredients for medicaments, pharmaceutically acceptable acid addition salts can be used instead of free bases; H. Salts with those acids, the anions of which show either no or desired pharmacological effect of their own at the dosages in question. It is also advantageous if the salts to be used as active ingredients can be readily crystallized and are not or only slightly hygroscopic. For salt formation with piperidine derivatives of the general formula I, for. B.

   Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, ß-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, naphelic acid, 5-isulphboxylic acid, mandelic acid, 5-bis-naphthalenic acid.



   The new piperidine derivatives of the general formula I and their salts are administered orally, rectally or parenterally. Daily doses of free bases or pharmaceutically acceptable salts thereof range between 0.2 and 3 mg / kg for warm-blooded animals. Suitable unit dosage forms, such as dragees, capsules, tablets, suppositories or ampoules, preferably contain 1 to 100 mg of one

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 Piperidine derivatives of the general formula I or a pharmaceutically acceptable salt thereof.



   Unit dosage forms for oral use contain as active ingredient preferably between 1 and 900/0 of a piperidine derivative of the general formula I or a pharmaceutically acceptable salt of such. To produce them, combining the active ingredient z. B. with solid, powdery carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to tablets or to dragee cores. The latter is coated, for example, with concentrated sugar solutions, which z.

   B. can contain arabic gum, talc and / or titanium dioxide, or with a paint dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, e.g. B. to identify different drug doses. Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerine, are suitable as further oral unit forms. The former contain the active ingredient preferably as granules mixed with lubricants such as talc or magnesium stearate, and optionally stabilizers such as sodium metabisulphite or ascorbic acid.

   The active ingredient is preferably in suitable liquids in soft caps. such as liquid polyethylene glycols, dissolved or suspended, and stabilizers can also be added.



   Also come for the treatment of cough z. B. lozenges as well as non-single-dose oral forms of administration, such as. B. cough syrups and cough drops prepared with the usual excipients.



   As unit dosage forms for rectal use, for. B. suppositories, which consist of a combination of a piperidine derivative of the general formula I or a suitable salt thereof with a neutral fat base, or gelatin rectal capsules, which contain a combination of the active ingredient with polyethylene glycols, into consideration.



   Ampoules for parenteral, especially intramuscular, and also intravenous administration preferably contain a water-soluble salt of a piperidine derivative of the general formula I as active ingredient in a concentration of preferably 0.5 to 5%, optionally together with suitable stabilizers and buffer substances, in aqueous solution.



   The following example explains the preparation of the new compounds of general formula I, but is not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   Example: One. Solution of 25,4gl- (2-phenylethyl) -4-allyl-isonipecotinamide in 75 ml of chloroform is carefully mixed with 30 ml of thionyl chloride, the solution heating up. It is then refluxed for 5 hours. Then chloroform and thionyl chloride are evaporated off in vacuo, the residue is decomposed while cooling with water, and it is made with conc. Ammonia is alkaline and extracted several times with ether. The combined ether extracts are dried and evaporated. The residue is distilled. The 1- (phenylethyl) -4-allyl-isonipecotonitrile boils at 126 to 1390/0.2 Torr. The hydrochloride prepared with hydrogen chloride is recrystallized from methanol, mp 293-2940.



   In an analogous way one obtains:
 EMI3.1
    (3-Phenylpropyl) -4-allyl-isonipecotonitrile, 1- (3-phenylpropyl) -4- (2-propynyl) -isonipecotonitrile, hydrochloride, m.p. 208-2100.

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Claims (1)

PATENT CLAIMS: 1. Process for the preparation of new piperidine derivatives of the general formula EMI3.2 <Desc / Clms Page number 4> in which R is a phenyl-alkyl group with a maximum of 9 carbon atoms, and EMI4.1 EMI4.2 in which R1 and R2 have the meaning given under formula (I), allows a dehydrating agent to act and, if desired, converts the compound of general formula (I) obtained into an addition salt with an inorganic or organic acid. EMI4.3