US3073741A - Antitussive composition - Google Patents

Description

United States Patent t ,0 ,74 ANTITUSSIVE COMP'OSITIDN Alberto Vecchi and Giulio Maiiii, Milan, Italy, assignors to Lepetit S.p.A., Milan, Italy No Drawing. Filed July 1, 1959, Ser. No. 824,183

6 Claims. (Cl. 167-'-55) of N,N-dimethyl-Z-phenyLZ-benzoyloxymethylbutylamine O ll 7 O C CH3 011301120 CHQN and its non-toxic mineral acid addition salts.

The compound of the invention, which for therapeutic purposes is best used in the form of the hydrochloride, owing to its mechanism of action, is to be classified among the centrally acting antitussive agents, as it has been shown by pharmacological tests. Moreover, it lacks any narcotic action, thus proving in this respect superior to many natural or synthetic drugs commonly employed in the management of coughing.

The search for central acting, non-narcotic antitussive substances has been fairly intense in recent years, and has brought about the use of some therapeutic agents which are capable of increasing the threshold of the medullary cough center to afferent tussive impulses without the undesirable effects of narcotics. It has now been found that N,N-dimethyl-Z-phenyl 2 benzoyloxymethylbutylamine displays an antitussive effect which is favorably comparable with that of codeine and narcotine, and is free from the well known side efiects of these generally employed drugs.

The following table gives the average protecting dose, in mg./kg., of the compound of the invention against cough caused by the inhalation of acrolein in the form of aerosol in guinea pigs, by stimulation of the laryngeal nerve in cats and by inhalation of sulfuric acid in dogs. The data are compared with those obtained with codeine and narcotine under similar conditions.

The acute toxicity of the compound of the invention is also very favorable, as is shown by the following comparative table.

3,673,741 Patented Jan. 1 1953 For therapeutical purposes, N,N-dimethl-2-phenyl-2- benzoyloxymethylbutylamine and its mineral acid salts may be used as such as associated with a carrier, which may be a solid material, a sterile parenteral liquid or a syrup. When the oral administration is selected as conimonly used for this type of drugs the therapeutic administration may be providedin the form of powders, capsules, tablets or other solid dosage forms. For parenteral use, liquid diluents may be employed, such as sterile distilled water, in which the mineral acid salts are freely soluble. Although clinically appreciable effects are observed with doses as low as l-10 mg, the unit dosage is usually somewhat higher, and may safely reach 500 mg. and more in stubborn cases. Preferably the doses are maintained under 50 mg, owing to the great efiiectiveness of the compound. For preparing the actual therapeutic composition, the selected dose of the drug may be directly filled into capsules, either alone 01' associated with solid inert diluents and/or other active ingradients. Tablets may be prepared by associating the drug with the commonly used tableting materials, such as lactose, talc, cornstarch, stearic acid, magnesium stearate or the like. Ampoules are prepared by dissolving the drug, in the form of its mineral acid salts, in sterile distilled water. The composition may also advantageously take the form of a syrup, whereby the drug is dissolved in the common syrup in a concentration calculated so as to administer the proper dose, with or without the addition of suspending and/or flavoring agents and/or other drugs.

N,N-dimethyl-Z phenyl 2 benzoyloxymethylbutylamine may be prepared starting from a-carbethoxy-aphenylbutyric acid through the corresponding chloride, which in turn is converted to the dimethylamide by reaction with dimethylamine in an inert anhydrous organic solvent. By hydrogenation with lithium aluminum hydride N,N dimethyl 2 phenyl-2-hydroxymethylbutylamine is obtained which on treatment with benzoyl chloride in anhydrous pyridine gives the compound of the invention.

The following examples are illustrative of the invention.

Example 1 A mixture of 32 g. u-carbethoxy-a-phenylbutyric acid and 25 ml. thionyl chloride is refluxed for 2 hours. The excess thionyl chloride is removed in vacuo and the residue is distilled collecting at l04-l06 C. under 1 mm. Hg. Yield: 30 g. (87%) ot-carbethox-a-phenylbutyryl chloride. M.P. 35-40" C.

The above acyl chloride is mixed with ml. of a 17.5% solution of dimethylamine in benzene. After 15 minutes the solution is treated with water, made acidic with hydrochloric acid and extracted with ethyl ether.

The organic layer is separated and evaporated to dryness. The residual crude product is recrystallized from ligroin. Yield: 28 g. (90%) N,N-dimethyl-u-pheny1-acarbethoxymethylbutyramide.

Into a mixture of 17.4 g. lithium aluminium hydride in 150 ml. anhydrous ethyl ether a solution of g. ZN,N- dimethyl-a-phenyl-a-carbethoxymethylbutyramide in 90 ml. anhydrous ethyl ether is gradually dropped without exceeding 25-27 C. The mixture is then refluxed for 1.5 hours and poured cautiously after cooling into 2 volumes of cold water. The mixture is extracted with ethyl ether and the organic layer is evaporated to dryness in vacuo. The residual oil (9 g., yield 76%) is N,N- dimethyl-Z-phenyl-Z-hydroxymethylbutylamine. The hydrochloride melts at 116118 C.

To a susepnsion of 7.9 g. of the amine in 35 ml. anhydrous pyridine 8.5 g. benzoyl chloride are gradually added in about 15 minutes below 15 C. After stirring for 1 hour at room temperature the mixture is poured into 2 volumes of water. The pH is adjusted to 8.5 and the mixture is extracted with ethyl ether. The solvent and the traces of pyridine are carefully removed, then the residual oil is dissolved in ethyl ether and diluted with an ethyl ether solution of hydrogen chloride. The precipitated crystals are collected and recrystallised from ethyl acetate. Yield: 12 g. (90%) of N,N-dimethyl-2- phenyl-Z-benzoyloxymethylbutylamine, M.P. 17l173 C.

The free base may be obtained in a pure grade by dissolving the hydrochloride in water, making the solution alkaline, extracting with ethyl ether and evaporating the extract to dryness.

Example 2 Three grams of N,N-dimethy1-2-phenyl-2-benzoyloxymethylbutylamine are filled into one hundred capsules and are ready for therapeutic use.

The mixture is tabletted to one hundred tablets ready for therapeutic use.

Phosphoric acid 0.09 Syrup of lemon, to m1.

It contains about 0.05 g. of the drug in 5 ml.

We claim:

1. An antitussive composition in dosage unit form, which comprises from 0.01 to 0.5 gram of N,N-dimethyl- 2-phenyl-2-benz0yloxymethylbutylamine together with a diluent.

2. An antitussive composition in dosage unit form, which comprises from 0.01 to 0.5 gram of ILN-dimethyl- 2-phenyl-2-benzoyloxymethylbutylamine per dosage unit and a solid pharmaceutical carrier.

3. An antitussive composition in dosage unit form, which comprises from 0.01 to 0.5 gram of N,N-dimethyl- 2-phenyl 2 benzoyloxymethylbutylamine hydrochloride per dosage unit and a liquid diluent.

4. An antitussive composition as in claim 3, wherein the liquid diluent is sterile distilled water.

5. An antitussive composition in syrup form, which comprises from 0.1 to 1.0 percent of N,N-dimethyl-2- phenyl-Z-benzoyloxymethylbutylamine hydrochloride, to gether with a syrupy pharmaceutical carrier.

6. An antitussive composition containing in a dosage unit form from 0.01 to 0.5 gram of a member of the group consisting of N,N-dimethyl-2-phenyl2-benzoyloxymethylbutylamine and its non-toxic mineral acid salts, together with a diluent.

References Cited in the file of this patent UNITED STATES PATENTS 81,446 Whitlow Aug. 25, 1868 1,794,292 H0110 Feb. 24, 1931 2,421,129 Reasenberg May 27, 1947 2,486,375 Cope Nov. 1, 1949 FOREIGN PATENTS 17,085 Great Britain 1914

Claims (1)

1. AN ANTITUSSIVE COMPOSITION IN DOSAGE UNIT FORM, WHICH COMPRISES FROM 0.01 TO 0.5 GRAM OF N,N-DIMETHYL2.PHENYL-2-BENZOYLOXYMETHYLBUTYLAMINE TOGETHER WITH A DILUENT.