Abstract:
New chemical compounds, which are pyrrolidinoethylamine amides, in the form of free bases and salts thereof, which are useful as antitussives, pharmaceutical compositions thereof, and method of treating therewith. 
     In the form of their salts, the compounds have the formula: ##STR1## wherein ##STR2## is an acyl radical of a phenylacetic, 60 -phenyl-α-(1 to 5 C atoms) acetic, (1 to 5 C atoms) diphenylacetic, benzilic, diphenyl-α-chloroacetic, α-lower-alkoxy-α,α-diphenylacetic, 3-coumarincarboxylic, 9-xanthenecarboxylic, phenoxyacetic, phenoxyisobutyric, halophenoxyisobutyric, or 9-flourene carboxylic acid, and wherein R&#39;H represents an inorganic or organic acid. 
     Medicaments containing these active principles may be used, inter alia, in the treatment of coughs and respiratory complaints.

Description:
BACKGROUND OF INVENTION 
     (1) Field of Invention 
     New chemical compounds, pyrrolidinoethylamine amides, antitussives, compositions thereof, method of treating therewith. 
     (2) Prior Art 
     Much research work has been carried out in the search for nonmorphine derivatives which have antitussive properties. In this field, many structures have been studied and numerous patents and publications exist covering terpene molecules, dialkylamino-alkoxyethanol esters, and piperazine and piperidine derivatives. Numerous of these have been published during the last few years. On the other hand, few patents or articles mention pyrrolidine derivatives, especially of the type presently concerned, although new and useful antitussives, especially of a nonaddicting nature, would surely still be highly desirable. 
     SUMMARY OF THE INVENTION 
     The present invention relates to certain new chemical compounds, which are pyrrolidinoethylamine amides, in the form of free bases and salts thereof, which are useful as antitussives, pharmaceutical compositions thereof, and method of treating therewith. 
     In the form of their salts, the compounds have the formula: ##STR3## wherein ##STR4## is an acyl radical of a phenylacetic, α-phenyl-α-lower-alkyl (1 to 5 C atoms) acetic, diphenylacetic, diphenyl-α-chloroacetic, benzilic, α-lower-alkoxy-α,α-diphenylacetic, 3-coumarincarboxylic, 9-xanthenecarboxylic, phenoxyacetic, phenoxyisobutyric, halophenoxyisobutyric, or 9-fluorene carboxylic acid, and wherein R&#39;H represents an inorganic or organic acid 
     OBJECTS 
     It is accordingly an object of the present invention to provide certain novel pyrrolidinoethylamine amides, acid addition salts thereof, pharmaceutical compositions of the same in the form of either the free base or an acid addition salt thereof, and a method of treating therewith, especially a method of treating or ameliorating cough therewith. Another object is the provision of novel antitussive agents, compositions thereof, and method of treating therewith. Still other objects will become apparent hereinafter and additional objects will be obvious to one skilled in the art. 
     THE INVENTION 
     The invention, then, comprises (a) pyrrolidinoethylamine amides of the formula: ##STR5## wherein RCO is as previously defined, and (b) acid addition salts therof. R is preferably a 9-xanthenyl, diphenyl--CH--, diphenyl--C(OH)--, or phenyl--CH(C 2  H 5 )-- radical, being derived respectively from 9-xanthenecarboxylic, diphenylacetic, diphenylhydroxyacetic, and alphaphenyl-alpha-ethylacetic acids. The acid addition salt may be of any of the usual types of acid, organic or inorganic, but from the standpoint of improved lipid solubility and flavor is preferably of the lipophilic type, e.g., a fatty acid of 14-22 carbon atoms, inclusive, e.g., palmitic, linoleic, linolenic, or oleic, or of the naphthoic type, especially pamoic, particularly when R has one of the preferred meanings assigned in the foregoing. When R has formula II as previously assigned, then R 2  is preferably allyloxy, hydroxy, or carboxy, R 1  is preferably methyl or hydrogen, and X is preferably bromine or hydrogen, or all three are methoxy. 
     These new chemical compounds forming an object of the invention can be obtained by the following methods, as illustrated by the following examples: 
     1st method 
     The acid chloride ##STR6## is reacted with the pyrrolidinoethylamine in an organic solvent, for instance benzene or acetone. 
     2nd method 
     The pyrrolidinoethylamine is heated in the presence of a loweralkyl ester, for insance ##STR7## sodium is used as catalyst. 
     For sake of convenience, the compounds are at times designated by their code number. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following Examples are given by way of illustration only and are not to be construed as limiting. 
     EXAMPLE 1 (illustrates method 2) 
     Synthesis of N(2&#39;-pyrrolidino-ethyl)-9-fluoroene-carboxamide hydrochloride (F 1532) 
     One mol (238 g) of ethyl 9-fluorene carboxylate is treated with 1.6 mol of 2-amino-ethyl pyrrolidine. Heated for 2 hours at 150° C., the ethanol distills over as it is formed. The reaction mass obtained is dissolved in methylene chloride, washed three times with water, dried, filtered, and distilled to dryness. 
     The base is then hydrochlorided in solution in a mixture of ethanol and methylene chloride. 
     The hydrochloride is precipitated by the addition of ether. The yield of hydrochloride (F 1532) referred to the ethyl ester is 85%. ##STR8## 
     Empirical formula: C 20  H 23  ClN 2  O 
     Molecular weight: 342.9 
     White crystals 
     Melting point: 198° C. 
     Plate chromatography: support: silica Merck G 254, solvent: butanol/acetic acid/water 6/2/2, development: ultraviolet lamp or iodine vapors, Rf: 0.64 
     Infrared spectrography: absorption band ν C ═O amide at 1675 cm -1  ν C ═C aromatic at 1610 cm -1  ν C--H  aromatic at 3070 cm -1   Solubility characteristics: very soluble in water, ethanol and propylene glycol. 
     EXAMPLE 2 (illustrates the 1st method) 
     N(2&#39;-pyrrolidino-ethyl)-9-xanthene carboxamide hydrochloride (F 1534) 
     The chloride of 9-xanthene carboxylic acid is obtained by treating 1 mol of acid, suspended in benzene, with thionyl chloride and then distilling to dryness. The crude acid chloride, dissolved in ether, is treated with a stoichiometric amount of N-2-pyrrolidinoethyl amine. The F 1534 precipitates as it is formed. Purification is effected by treatment with an excess of bicarbonate to form the base of 1534, which is extracted by methylene chloride, and then rehydrochlorided by an ethanolic solution of hydrochloric acid. 
     The yield of crude product is 85% and of pure product 70%. ##STR9## 
     Empirical formula: C 20  H 22  ClN 2  O 2   
     Molecular weight: 357.9 
     Melting point: 195° C. 
     White crystals 
     Plate chromatography: support: silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: ultraviolet lamp and iodine vapors Rf: 0.65 
     Infrared spectrography: ν NH  3230 and 3200 cm -1  ν C ═O sintered to 1645 cm -1  Solubility characteristics: very soluble in water. 10% soluble in ethanol and propylene glycol. 
     EXAMPLE 3 
     Synthesis of N(2&#39;-pyrrolidino-ethyl)-α-phenyl-α-ethyl acetamide hydrochloride (F 1419) 
     To a solution of 1 mol of α-phenyl-α-ethyl acetyl chloride in 2 liters of benzene add, with agitation, a benzene solution of 1 mol of 2-pyrrolidino -ethyl amine. The hydrochloric acid formed during condensation attaches itself to the pyrrolidine group and the expected derivative crystallizes out in the reaction medium. 
     In order to favor the precipitation, ether may be added. 
     The yield of the reaction is quantitative for product of the formula: ##STR10## 
     Empirical formula: C 16  H 25  ClN 2  O 
     Molecular weight: 296.8 
     White crystals, slightly hygroscopic 
     Melting point: 160° C. 
     Plate chromatography: support: silica gel Merck G 254 solvent: butanol/acetic acid/water 6/2/2 development: untraviolet lamp or iodine vapor Rf: 0.44 
     Infrared spectrography: absorption band at 1645 cm -1  of the C═O amide. Solubility characteristics: very soluble in water, insoluble in ether. 15% soluble in ethanol, 25% in propylene glycol and 7% in N-methyl pyrrolidone. 
     EXAMPLE 4 
     N(2&#39;-pyrrolidino-ethyl)-10-phenothiazine carboxamide hydrochloride (F 1461) 
     To a suspension of 1 mol of 10-chlorocarbonyl-phenothiazine in 2 liters of acetone there is slowly added a solution of 1 mol of 2&#39;-pyrrolidino-ethyl amine in acetone. After several hours at room temperature, the crystalline suspension is filtered, the crystals are treated with an aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride; the organic phase is then distilled; the residue is taken up in an ethanolic solution of hydrochloric acid. The F 1461 precipitates upon the addition of ether. 
     The yield is about 70% of a derivative of the formula: ##STR11## 
     Empirical formula: C 19  H 22  ClN 3  OS 
     White crystals 
     Melting point: 207° C. 
     Plate chromatography: support: silica gel solvent: butanol/acetic acid/water 6/2/2 development: ultraviolet lamp Rf: 0.55 
     Infrared spectrography: absorption bands: ν NH  to 3480 cm -1  and ν C ═O to 1660 cm -1 . Solubility characteristics: 10% soluble in water, ethanol, propylene glycol and N-methyl pyrrolidone. 
     EXAMPLE 5 
     N(2&#39;-pyrrolidino-ethyl)-α,α-diphenyl acetamide hydrochloride (F 1459) 
     Into a solution of 1 mol of diphenyl acetyl chloride in acetone there is gradually introduced with agitation 1 mol of pyrrolidino-ethyl amine in acetone solution. After 8 hours at room temperature, the acetone is distilled to dryness. 
     The residual oil is treated with an aqueous bicarbonate solution and extracted with chloroform; the organic phase is distilled to dryness, and the residue is taken up in an ethanolic solution of hydrochloric acid. The yield is 60% of a derivative of the formula: ##STR12## 
     Empirical formula: C 20  H 25  ClN 2  O 
     Molecular weight: 344.9 
     White crystals 
     Melting point: 179° C. 
     Plate chromatography: support: silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: iodine vapors Rf: 0.51 
     Infrared spectrography: Absorption bands: δ NH  at 3240 and 3200 cm -1  δ C ═O at 1675 cm -1   
     Solubility characteristics: 25% soluble in water, 5% in ethanol, 3% in propylene glycol. 
     EXAMPLE 6 
     N(2&#39;-pyrrolidino-ethyl)-α,α-diphenyl-α-chloroacetamide hydrochloride 
     An acetone solution of 1 mol of diphenyl-α-chloroacetyl chloride is treated at 0° C. with an acetone solution of pyrrolidinoethylamine. 
     The derivative of the formula: ##STR13## crystallizes out as it is formed. 
     Empirical formula: C 20  H 24  Cl 2  N 2  O 
     Molecular weight: 379.3 
     Melting point: 160° C. 
     EXAMPLE 7 
     N(2-pyrrolidino-ethyl)-α,α-diphenyl-α-ethoxy-acetamide hydrochloride (F 1460) 
     The derivative obtained in accordance with Example 6 is treated in suspension in absolute ethanol. 
     After refluxing for 4 hours and concentration under vacuum, the F 1460 precipitates upon the addition of ispropyl ether. 
     For purification it is possible to dehydrochlorinate by reaction of an aqueous bicarbonate solution and then after extraction with chloroform, distillation and treatment with an ethanolic solution of hydrochloric acid; the purified derivative is recovered with a yield of 80%. ##STR14## 
     Empirical formula: C 22  H 29  ClN 2  O 2   
     Molecular weight: 389 
     White crystals 
     Instantaneous melting point: 130° C. 
     Plate chromatography: support: silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: iodine vapors Rf: 0.63 
     Solubility characteristics: 1% soluble in water, 4% in ethanol, insoluble in ether. 
     EXAMPLE 8 
     N(2&#39;-pyrrolidino-ethyl)-2-allyloxy-5-bromo-3-methyl benzamide hydrochloride (F 1479) 
     By treating the acid chloride of the formula: ##STR15## with a solution of pyrrolidino-ethyl amine and, after customary treatment there is recovered, in quantitative yield, the derivative of the formula: ##STR16## 
     Empirical formula: C 17  H 24  ClBrN 2  O 2   
     Molecular weight: 403.7 
     White crystals 
     Melting point: 118° C. 
     Plate chromatography: support: silica gel solvent: butanol/acetic acid/water 6/2/2 development: ultraviolet lamp and iodine vapors Rf: 0.62 
     Solubility characteristics: very soluble in water. 
     EXAMPLE 9 
     N(2&#39;-pyrrolidino-ethyl)-5-bromo-3-methyl-salicylamide hydrochloride 
     Methyl-5-bromo-3-methyl salicylate, suspended in pyrrolidino-ethylamine, is treated at 90° C. for 4 hours. The methanol is distilled off as it is formed. The reaction mixture is then treated with 6N hydrochloric acid, and the initial methyl ester is extracted with ether; the aqueous phase is treated with ammonia, extracted with ether, washed, dried, evaporated to dryness, and then hydrochlorided by an ethanolic solution of hydrochloric acid, precipitated with ether, filtered, and washed. 
     The derivative of the formula: ##STR17## is recovered in a yield of 80%. 
     Empirical formula: C 14  H 20  BrClN 2  O 2   
     Molecular weight: 363.7 
     White crystals 
     Melting point: 184° C. 
     Plate chromatography: support: silica gel solvent: butanol/acetic acid/water 6/2/2 development: ultraviolet lamp and iodine vapors 
     Rf: 0.75 
     Solubility characteristics: very soluble in water, 3% soluble in ethanol, 7% in propylene glycol, insoluble in ether. 
     The following derivatives were also obtained by Methods 1 and 2. 
     EXAMPLE 10 
     N(2&#39;-pyrrolidino-ethyl)-α,α-diphenyl-hydroxy-acetamide hydrochloride (F 1535) ##STR18## 
     Empirical formula: C 20  H 25  ClN 2  O 2   
     Molecular weight: 360.9 
     White crystals 
     Melting point: 209° C. 
     Plate chromatography: support: silica gel Merck G 254 solvent: BuOH/AcOH/H 2  O 6/2/2  development: UV and iodine Rf: 0.64 
     Infrared spectrography: δ NH  and δ OH  wide absorption band at 3250 cm -1  δ C ═O at 1665 cm -1 . Solubility characteristics: very soluble in water. 
     EXAMPLE 11 
     N(2&#39;-pyrrolidino-ethyl)phenyl piperidino-acetamide (F 1533) ##STR19## 
     Empirical formula: C 19  H 29  N 3  O 
     Molecular weight: 315.5 
     Beige crystals 
     Melting point: 80° C. 
     Infrared spectrography:  NH  at 3350 cm -1  and  C ═O at 1665 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: UV and iodine Rf: 0.13 
     Solubility characteristics: insoluble in water. Very soluble in ethanol. 
     EXAMPLE 12 
     N(2&#39;-pyrrolidino-ethyl)-2-carboxy-benzamide (F 1537) 
     This derivative is obtained from phthalic anhydride in solution in acetone treated with 2-amino-ethyl-pyrrolidine. The F 1537 crystallizes out in the form of a monohydrate. ##STR20## 
     Empirical formula: C 14  H 20  N 2  O 4   
     Molecular weight: 280.3 
     Crystals of impure white color 
     Instantaneous melting point: 130° C. 
     Infrared spectrography: ν NH  at 3240 cm -1  ν C ═O (acid) low at 1710 cm -1  ν C ═O (amide) at 1645 cm -1  ν C ═O (internal salt COO -- ) intense at 1550 and 1600 cm -1 . 
     Plate chromatography: support: Merck silica gel solvent: methylethylketone/N-propanol/EtOH/NH 4  OH 34% 90/9/36/64 development: ultraviolet lamp or iodine vapors Rf: 0.69 
     Solubility characteristics: very soluble in water, ethanol and propylene glycol. 
     EXAMPLE 13 
     N(2&#39;-pyrrolidino-ethyl)cinnamide, HCl (F 1542) ##STR21## 
     Empirical formula: C 15  H 21  ClN 2  O 
     Molecular weight: 280.8 
     White crystals 
     Melting point: 202° C. 
     Infrared spectrography: ν N--H  3260 cm -1  ν C ═O (amide) 1670 cm -1  ν C ═C (ethylene) 1630 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: ultraviolet lamp or iodine vapors Rf: 0.81 
     Solubility characteristics: very soluble in water, ethanol and propylene glycol. 
     EXAMPLE 14 
     N(2&#39;-pyrrolidino-ethyl)-3-coumarin-carboxamide hydrochloride ##STR22## 
     Empirical formula: C 16  H 19  ClN 2  O 3   
     Molecular weight: 322.8 
     Beige crystals 
     Melting point: 220° C. 
     Infrared spectrography: ν NH  at 3330 cm -1  ν C ═O (lactone) 1700 cm -1  ν C ═O amide 1660 cm -1  ν C ═C at 1610 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: ultraviolet lamp or iodine vapors Rf: 0.53 
     Solubility characteristics: very soluble in water. 4% soluble in ethanol, 7% in propylene glycol. 
     EXAMPLE 15 
     N(2&#39;-pyrrolidino-ethyl)-4-chloro-phenoxy-isobutyramide hydrochloride (F 1541) ##STR23## 
     Empirical formula: C 16  H 24  Cl 2  N 2  O 2   
     Molecular weight: 347.3 
     White crystals 
     Melting point: 140° 
     Infrared spectrography: salification bands 2500 to 3500 cm -1  ν N--H  3230 cm -1  ν C ═O (amide) 1660 cm -1  ν C ═C 1600 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: ultraviolet lamp or iodine vapors Rf: 0.57 
     Solubility characteristics: Soluble in water, ethanol, and propylene glycol. 
     EXAMPLE 16 
     N(2&#39;-pyrrolidino-ethyl)phenoxy-isobutyramide hydrochloride (F 1540) ##STR24## 
     Empirical formula: C 16  H 25  ClN 2  O 2   
     Molecular weight: 312.8 
     White crystals 
     Melting point: 94° 
     Infrared spectrography: salification bands 2500 to 3500 cm -1  ν NH  at 3250 cm -1  ν C ═O at 1660 cm -1  ν C ═C at 1600 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: UV and iodine Rf: 0.58 
     Solubility characteristics: soluble in water, ethanol and propylene glycol. 
     EXAMPLE 17 
     N(2&#39;-pyrrolidino-ethyl)-4-chloro-phenoxy-acetamide hydrochloride (F 1539) ##STR25## 
     Empirical formula: C 14  H 20  Cl 2  N 2  O 2   
     Molecular weight: 319.2 
     White crystals 
     Double melting point: 95° and 144° C. 
     Infrared spectrography: salification bands at 2500 to 3500 cm -1  ν NH  3260 cm -1  ν C ═O (amide) 1660 cm -1  ν C ═C 1600 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: ultraviolet lamp or iodine vapors Rf.: 0.45 
     Solubility characteristics: soluble in water, ethanol, and propylene glycol. 
     EXAMPLE 18 
     N(2&#39;-pyrrolidino-ethyl)-3-4-5-trimethoxy-benzamide hydrochloride (F 1538) ##STR26## 
     Empirical formula: C 16  H 25  ClN 2  O 4   
     Molecular weight: 344.8 
     Beige crystals 
     Melting point: 158° C. 
     Infrared spectrography: Salification bands 2500 to 3550 cm -1  ν NH  3290 cm -1  ν C ═O (amide) 1650 cm -1   
     Plate chromatography: support: Merck silica gel solvent: BuOH/AcOH/H 2  O 6/2/2 development: UV and iodine Rf: 0.5 
     Solubility characteristics: soluble in water, ethanol, and propylene glycol. 
     Obtaining of New Salts 
     The hydrochloride derivatives described in the above examples can be treated by the following techniques in order to obtain new therapeutically acceptable salts whose organoleptic properties, and more particularly flavor, are however improved. 
     Salification Experimental Record 
     Method A - transalification 
     The water insoluble salts are prepared by addition of an aqueous solution of one equivalent of the hydrochloride of the base to an aqueous solution of one equivalent of the sodium salt of the acid. 
     The salt is centrifuged, washed with water until disappearance of the chloride. Dry under vacuum to constant weight. 
     Method B - direct salification 
     The hydrochloride of the amine is treated with an aqueous solution of sodium bicarbonate and the base is extracted with chloroform. Dry. Filter. This solution is added to a solution or suspension of the acid in chloroform. 
     Dissolve. Concentrate the solution and crystallize the salt by addition of ether. 
     EXAMPLE 19 (illustrates Method A) 
     N(2-pyrrolidino-ethyl)-α,α-diphenyl-acetamide pamoate (F 1629) 
     A solution of 0.15 mol of N(2 -pyrrolidino-ethyl)diphenylacetamide hydrochloride in 2.5 liters of water is added to a solution of 0.075 mol of sodium salt of pamoic acid in 1 liter of water. 
     The precipitate obtained is centrifuged, washed with water until disappearance of the chloride and dried under vacuum to constant weight. 
     The yield of the product of the following formula is 95%. ##STR27## 
     Empirical formula: C 63  H 64  N 4  O 8   
     Molecular weight: 1005.23 
     Yellow crystals 
     Instantaneous melting point: 145° 
     Infrared spectrography: Salification band 2500 to 3500 cm -1  ν C ═O (amide) 1645 cm -1  ν C ═O (COO - ) 1565 cm -1   
     Plate chromatography: support: silica gel solvent: Butanol/acetic acid/water 6/2/2 development: ultraviolet lamp or iodine vapors Rf: acid: 0.70 (UV - FeCl 3 ) base: 0.35 (UV) 
     Solubility characteristics: Insoluble in water and alcohol. Soluble in methyl pyrrolidone and dimethyl acetamide. 
     EXAMPLE 20 (Method A) 
     N(2-pyrrolidino-ethyl)-α,α-diphenyl-acetamide palmitate (F 1630) ##STR28## 
     Empirical formula: C 36  H 56  N 2  O 3   
     Molecular weight: 564.82 
     White crystals 
     Instantaneous melting point: 55° 
     Infrared spectrography: salification bands 2500 to 3500 cm -1   NH  3270 cm -1   C ═O (amide) 1645 cm -1   
     Plate chromatography: support: silica gel solvent: butanol/acetic acid/water 6/2/2 development: ultraviolet lamp or iodine vapors Rf: base: 0.35 (UV) acid: 0.85 (rhodamine + UV) 
     Solubility characteristics: Insoluble in water. Poorly soluble in alcohol, dimethyl acetamide, methyl pyrrolidone, and propylene glycol. 
     The new derivatives obtained in the foregoing manner, which are bases, can be converted into addition salts with acids, which form part of the invention. The addition salts can be obtained by the reaction of the new derivatives with acids in suitable solvents such, for example, as shown by the examples. As acids used for the formation of these addition salts there may be mentioned, in the mineral series: hydrochloric, hydrobromic, methanesulphonic, sulphuric and phosphoric acid; in the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic acid, to name a few. 
     The invention accordingly also relates to the salts with organic or inorganic acids, especially lipophilic acids, e.g., fatty acids having 14 to 22 carbon atoms, inclusive, which are linear or branched, saturated or unsaturated, including palmitic, linoleic, linolenic, and oleic acids, and the like, as well as of the naphthoic type, especially pamoic acid, in addition to the usual organic and inorganic acids of the type already mentioned. 
     Moreover, in addition to the substituents R 1  and R 2  as specifically illustrated by the Examples for Formula II, the same and/or additional substituents as specifically shown for R 1  and R 2  may be present, and R 1  may be present in a different ring position, e.g., in a different position of the benzene ring with respect to the R 2  and X substituents present therein. X may, for example, be fluoro, bromo, chloro, or iodo. Either or both of R 1  and R 2  may be, for example, methyl, ethyl, propyl, amyl, methoxy, ethoxy, propoxy, amyloxy, propenyloxy, butenyloxy, propynyloxy, butynyloxy, hydroxyethoxy, hydroxypropyloxy, hydroxybutyloxy, or hydroxyamyloxy or the like, &#34;lower&#34; in each case meaning a maximum of (5) carbon atoms in such group. The nature and location of these substituents depends only upon the selected starting compound employed in the preparation thereof, as will be apparent and fully within the ability of one skilled in the art, as will selection and preparation of the desired acid addition salt of such compound in any particular case. 
     EXPERIMENTAL 
     The high order of activity of the active agents of the present invention has been evidenced by tests in lower animals and representative of these are reported herein. 
     A - Toxicology 
     The chemical compounds previously described were subjected to toxicity tests. 
     The acute toxicity, determined by the 50% lethal dose (DL 50), is reported in the following table. 
     It is determined on mice, the products being administered orally, intraperitoneally, and intraveneously in isotonic aqueous solution. 
     
         ______________________________________   DL 50 (mg/kg)               intraperi-Compounds oral      toneal      intravenous______________________________________F 1419    660       200         76F 1459    562       178         48F 1460    750       178         40F 1461    560       178         26______________________________________ 
    
     
         ______________________________________     DL 50 (en mg/kg)Compounds   oral        intraperitoneal______________________________________F 1532       178         75F 1533       750        178F 1534       750        178F 1535       562        237F 1536      1000        300F 1537      1000        500F 1538       562        300F 1539      1000        178F 1540      1000        237F 1541       562        178F 1542      1000        178F 1543      1000        178F 1629      2000        750F 1630      1500        500______________________________________ 
    
     B - Pharmacology 
     The pharmacological experiments to which these new compounds were subjected disclosed interesting antitussive properties upon using the citric acid aerosol method on guinea pigs. 
     The animals were subjected to a 20% citric acid aerosol for 15 minutes. 
     The coughs were recorded by a microphone. 
     The products were administered intraperitoneally 20 minutes before the exposure to the aerosol. 
     The results are summarized in the following table. 
     
         ______________________________________ Citric Acid Aerosol Method(on guinea pigs)                     % reduction of     dose in mg/kp   no. of coughsLots      i.p.            in 15 minutes______________________________________Controls  --               22                      20F 1532    25              - 15%F 1533    50               -7%F 1534    50              - 63%F 1535    50              - 43%F 1536    50                0F 1537    50               -8%F 1538    50               -1%F 1539    50              - 18,5%F 1540    50              - 22%F 1541    50              - 26%F 1542    50              -19,5%F 1543    50              -19%F 1630    50              - 60%F 1629    50              - 60%F 1419    50              - 35%F 1459    50              - 65%F 1460    50              - 20%F 1461    50              - 56%______________________________________ 
    
     Some derivatives were also tested orally. By way of example, we cite a few results as compared with the citric acid aerosol. 
     
         ______________________________________     orally         % decrease in no.Compounds doses in mg/kg coughs in 15 mins.______________________________________F 1419    100            -40     50             -22F 1459    50             -31F 1461    50             -12     100            -25F 1629    100            -50     50             -30______________________________________ 
    
     A second method using a different type of stimulation of coughs made it possible to note, as compared with codeine, the antitussive properties of the main components claimed. 
     The technique employed is derived from Takagi&#39;s technique, and consists in causing coughing by mechanical stimulation of the tracheal bifurcation in the unanesthetized guinea pig. 
     The cough is evaluated by the research worker in accordance with the following scale: 
     1: heavy cough 
     0.5: light cough 
     0: no cough 
     The products are administered intraperitoneally and the stimulation is effected 10 and 20 minutes after the injection. 
     The results are set forth in the following table: 
     
         __________________________________________________________________________Takagi&#39;s Technique             Cough rating             before treatment                       after treatmentLots   weight      parameters             to  to + 5 mn                       t + 10 mn                             t + 20 mn__________________________________________________________________________CONTROLS  310 no. of animals               12                   12    12    12      m      1,0 0,96  0,83  0,83      s2     0    0,020                        0,060                              0,106      Em     0   0,03  0,07  0,09F 1459 330 no. of animals               12                   12    12    1250 mg/kg   m      1,0 0,96  0,67  0,33      s2     0    0,020                        0,106                              0,151      Em     0   0,03  0,09  0,11      % variation      -32% S.                             -66%                             H.S.F 1461 310 no. of animals               12                   12    12    1250 mg/kg   m      0,87                 0,79  0,54  0,37      s2      0,051                  0,067                        0,248                              0,233      Em     0,06                 0,07  0,14  0,14      % variation      -35% N.S.                             -55% S.Reference  310 no. of animals               12                   12    12    12CODEINE    m      0,96                 0,96  0,75  0,6750 mg/kg   s2      0,020                  0,020                        0,113                              0,151      Em     0,03                 0,03  0,03  0,11      % variation      -22% N.S.                             -30% S.__________________________________________________________________________ m = average of the ratings; S2 = variance; Em = difference from mean S.: result significant N.S.: result not significant H.S.: result highly significant 
    
     The determination of fungistatic bacteriostatic properties was carried out by two methods on four strains: 
     Diffusion Method 
     The microorganisms are introduced into nutrient agar. On the surface, paper disks soaked with the products to be tested are deposited, after 18 hours incubation. The diameter of the growth inhibition zones is measured. 
     Measurement of the Minimum Inhibitory Concentration (M.I.C.) 
     Halved serial dilutions are formed in a hemoylsis tube, in each case to a volume of 1 ml; each dilution is inoculated with 10 6  micro-organisms per ml. After 48 hours in the oven, the minimum inhibitory concentration is determined. A subculture of the negative tubes (bacteriostatic), makes it possible to note the bactericidal concentration. A significant action with respect to Staphylococcus aureus and Escherichia coli was obtained with the products F 1459, F 1532, F 1533, F 1534 with MICs of the order of 625μg; a more moderate but significant effect was obtained with Pseudomonas aeruginosa and Candida albicans. These products are accordingly not major antiseptics, but their bactericidal action is real and significant at concentrations of 1 g percent. 
     Additional Properties 
     Furthermore, certain derivatives showed a high order of local anesthesia activity comparable to that of procaine; these were F 1534, F 1535 and F 1541. 
     The antalgic properties with respect to a decrease in contortions caused by phenyl benzoquinone, as measured in mice, are very clear from the 150 mg/kg by mouth in the case of F 1534 (40% decrease), F 1539 (75% decrease), and F 1541 (60% decrease). 
     Compositions and Method of Treating 
     The foregoing properties taken together, and the low toxicity of these compounds, confirmed by a subacute toxicity study for six weeks on two species of animals, namely rats and dogs, make it possible at the present time to test these derivatives clinically for their use in respiratory therapy and in the treatment of certain pains. The new derivatives thus show antitussive and, in certain cases also local anesthesia, properties sufficient to permit their use in therapy for the treatment of laryngotracheitis, stubborn tracheitis, nervous cough, and smoker&#39;s cough. These therapy treatments were carried out by means of suitable pharmaceutical forms, using either the product in its initial free basic form or in the form of a therapeutically acceptable salt. The novel compounds are preferably used in the form of their pharmaceutically-acceptable acid addition salts, e.g., their hydrochlorides, hydrobromides, or the like. The salt form is also the best form for pharmaceutical formulations. Innumerable other pharmaceutically-acceptable acid addition salts can be prepared from the hydrochlorides via the free bases in conventional manner. For oral use, the compounds are usually administered as tablets, solutions, or suspensions, in which they are present together with usual pharmaceutical carriers, excipients, binders, and the like. For example, tablets may be prepared conventionally by compounding one of the new compounds, preferably in the form of an acid addition salt thereof, with customary carriers and adjuvants, e.g., talc, magnesium stearate, starch, lactose, gelatin, gums, and the like. In their most advantageous form, then, the compositions of the present invention will contain a non-toxic pharmaceutical carrier in addition to the active ingredient. Exemplary carriers are: 
     Solids: lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium phosphate, sucrose, talc, stearate acid, gelatin, agar, pectin, acacia, or other usual excipient; 
     Liquids: peanut oil, sesame oil, oliver oil, water, elixir, or other usual excipient. The active agents of the invention can be most conveniently administered in such compositions containing about 0.01 to 67 percent, preferably 0.04 to 12.15 percent, by weight of the active ingredient. Such formulations are representatively illustrated in U.S. Pat. No. 3,402,244. 
     A wide variety of pharmaceutical forms suitable for many modes of administration and dosages may be employed. For oral administration, the active ingredient and pharmaceutical carrier may, for example, take the form of a granule, pill, tablet, lozenge, elixir, syrup, or other liquid suspension or emulsion; and for rectal administration, a suppository. 
     The method of using the compounds of the present invention comprises internally administering a compound of the invention, usually in the form of a non-toxic, pharmacologically-acceptable acid addition salt, and preferably admixed with a pharmaceutical carrier, for example, in the form of any of the above-mentioned compositions, or filled into a capsule, to alleviate one or more of the foregoing enumerated conditions and symptoms in a living animal body, whether human or domestic animal, for example, the aforementioned cough. The compounds, and especially their non-toxic salts, may be advantageously employed in amounts of about 1 to 50 milligrams per unit dose, preferably about 2.5 to 25 milligrams per unit dose, preferably and usually in admixture with the conventional carrier. The unit dose is preferably given a suitable number of times daily so that the daily dose may vary from about 5 to about 100 milligrams. However, the compounds are subject to usual variations in optimum daily and unit dosages, due to patient body weight, condition, and ancillary factors, and the invention therefore should not be limited by the exact ranges stated. The exact dosage, both unit and daily, will of course have to be determined according to established veterinary and medical principles. The doses for administration usually vary for oral and rectal administration from about 5 to about 100 mg over a period of 24 hours, and the active substances are generally administered orally in the form of capsules, tablets of normal or delayed action, syrups and drops, and rectally in the form of suppositories or rectal capsules. 
     The active principles of the present invention may be used alone or together with or in combination with other or supplementary active principles for the particular treatment involved, such as antihistamines, expectorants and bronchic fluidizers, antibiotics, corticoids, vitamins, analgesics, anticholinergics, sedatives, stimulants, buffering agents, antacids, or the like. By way of illustration, but not of limitation, we cite a few representative galenical preparations, which are representative for all of the pharmacologically active compounds of the invention, but which have been particularly designed to embody as active ingredient the particular compounds embodied therein, especially in the form of a pharmaceutically acceptable salt thereof: 
     (a) tablets 
     50 mg of F 1535 
     excipient q.s.p. 
     (b) syrup 
     F 1639 -- 200 mg 
     Na guiacol sulfonate -- 600 mg 
     terpene hydrate -- 1 g 
     excipient q.s.p. 
     (c) suppositories 
     F 1534 -- 10 mg 
     Promethazine -- 30 mg excipient g.s.p. 
     (d) long-action tablets 
     F 1629 -- 50 mg 
     excipient q.s.p. 
     (e) syrup 
     F 1419 
     vitamin C 
     antibiotic 
     (f) suppository 
     F 1459 -- 10 mg 
     General 
     The free bases of the invention may generally by extracted with a suitable organic solvent, e.g., ether, methyl-butyl ketone, or the like, if desired. Salts with pharmaceutically acceptable acids, e.g., hydrochloric, hydrobromic, fumaric, citric, maleic, tartaric, or lactic, or the like, may also be precipitated with acid from a dried solution of the free base in a conventional manner and recrystallized, if desired (See Example 7), instead of directly, as also shown herein. One acid salt, even if not pharmaceutically acceptable, is still useful, since it can readily be converted to another salt which is pharmaceutically acceptable in known manner, e.g., by alkalization and then acidification with a different acid, if desired. 
     Where the foregoing examples produce a compound having a methyl or other lower-alkyl group, it is to be understood that compounds containing other lower-alkyl groups of straight or branched nature and containing up to five carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyl, amyl and isoamyl, are prepared in the same manner by substitution in the process of the appropriate different lower-alkyl starting material. Likewise, where chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material. Similarly, where methoxy or other lower-alkoxy group is present, compounds having other lower-alkoxy groups containing various lower-alkyl groups having up to five carbon atoms inclusive are prepared in the same manner from the appropriate different lower-alkoxy starting material. In the same manner, ortho and meta products are produced instead of the para by utilizing the selected ortho or meta substituted starting material and vice versa. Similarly, other molecular changes within the scope of the invention are readily made. 
     It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds, compositions, or procedures shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.