DE2113259A1 - Carbonyldioxy-morphinans - Google Patents

Abstract

Carbonyl dioxy-morphinans. Compds. (I), their salts and medicaments contg. them where R is alkyl or N methylmorphinan-3-yl are useful as antitussives having a lower toxicity than dextromethorphane (d-3-methoxy-N-methylmorphinane) or codeine phosphate. (I) are prepd. from 3-hydroxy-N-methyl morphinan and R'-CO-X where R' is alkoxy or halogen and X is halogen.

Description

Novel carbonyldioxymorphinane derivatives The present invention relates to novel carbonyldioxymorphinan derivatives and their non-toxic acid addition salts. More precisely, the invention relates to new carbonyldioxymorphinane derivatives having the general formula wherein R represents a lower alkyl group or N-methylmorphinan-3-yl group and its non-toxic acid addition salts, The compounds of this invention are novel compounds and have an excellent antitussive effect. Also, the compounds of this invention have lower toxicity and a broader safety threshold than those of d-3-methoxy-N-methylmorphinan (commonly called dextomethorphan) and codeine phosphate, which are known as antitussive agents. In particular, the d-isomer of this invention does not cause habituation and is therefore particularly useful as an antitussive agent.

The compounds of this invention according to the general formula (I) can by reacting 3-hydroxy-N-methylmorphinan with a carbonyl halide compound with the general formula R '- CO - X (II), wherein X represents a halogen atom and R 'represents a lower alkoxy group or a halogen atom: are prepared.

Particularly, the compounds of this invention are made according to the general Formula (1> in which R represents a lower alkyl group, prepared by the reaction of 3-hydroxy-N-methylmorphinan and one equimolar or one excess Polar amount of the carbonyl halide compound having the general formula (II) in which Rl is a lower alkoxy group, the reaction being carried out in an organic solvent such as chloroform, tetrahydrofuran or the like, preferably in the presence a base such as triethylamine, potassium carbonate, sodium carbonate or the like. On the other hand, compounds of this invention with the general formula (I), in which R represents an N-methylmorphinan-3-yl group prepared by the reaction of 3-hydroxy-N-methylmorphinan and an excess amount of the carbonyl dihalide compound with the general formula (II), in which R 'represents a halogen atom, where the Reaction in an organic solvent such as chloroform, tetrahydrofuran or the like takes place.

The reactions proceed satisfactorily at room temperature.

The product can be removed from the reaction mixture in a conventional manner Separation process can be isolated s * B. by extraction, if necessary, the product can be obtained by recrystallization, column chromatography or na according to others Methods to be cleaned.

The acidic addition salt of the product thus obtained can be treated by treatment of the product with a pharmaceutically non-toxic inorganic acid, e.g. Hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid or a pharmaceutically non-toxic organic acid such as acetic acid or tartaric acid can be obtained by a known method.

One of the starting materials, 3-hydroxy-N-methylmorphinan, can do that d-isomers, the 1-isomer or a mixture thereof.

The antitussive effect and the toxicity of d-N, N1-dimethyl-3,3 '- (carbonyldioxy) dimorphinan hydrochloride, which is one of the compounds of this invention with those of dextromethorphan * hydrobromide and codeine phosphate compared in Experiment 1 below.

Experiment 1: The antitussive effect was measured with an electric Stimulation method (see Naunyn - Schmiedeberg's Arch.

Pharmacol. Exptl, Pathol., 2t.0, 19 (1952)) as indicated below, checked; The test sample was given to a cat weighing 2.5-3.5 kg by means of administered intravenous injection. The cat then went electric after 10 minutes stimulated and the percentage of inhibition was derived from the reduction in amplitude (Intensity) of the act of coughing and then ED50 (mgfkg) from the reaction of the Test sample amount and inhibition percentage calculated.

The toxicity was determined using a Kärber method (see Arch.

Pathol. Pharmakol., 162, 482-483, (1931)) as indicated below, certainly. The test compound was administered subcutaneously to a 6 week old ICR - JCL mouse Injection given.

The mortality rate was determined after 7 days and LD50 (mg / kg) was calculated from the relationship of the amount of test sample used and the mortality rate. The results are shown in Table I.

Table I. Test sample ED50 LD50 safety threshold value (LD50 / ED50) dN, N'-dimethyl-3,3'- (carbonyldioxy) di-2.45 405 165 morphinan.hydrochloride Dextromethorphan.Hydro- 2.33 150 64 bromide Codeine phosphate 1.59 183 115 Then the formation of habituation to dN, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan.hydrochloride which is one of the compounds of this invention was compared with that of codeine phosphate in the following Experiment 2, Experiment 2 According to the method of FIG Hosoya et al. (See Folia Pharmacol. Japan,, 120 (1958) 3, the test sample was administered intraperitoneally to rats intraperitoneally for 2 months in a constant amount daily or twice daily with increasing the amount from day to day The test sample was interrupted and a physiological saline solution and levallorphan, which is a narcotic antagonist, were administered in place of the test sample, and thereafter the phenomena of abstinence syndromes such as decreased weight, abnormal behavior and the like were observed and the habit formation was examined. The results are shown in Table II below .

Table II Test sample amount (mg / kg / day) abstinence syndrome (A) (B) (C) (D) dN, N'-dimethyl-3,3'- (carbonyldioxy) di- 50 30 - 60 none none morphinan.hydrochloride Codeine phosphate 40 20 - 80 ob- respect Physiological Saline - no no (Control) (A): constant amount administered; (B): increased amount every day; (C): decrease in weight; (D): Abnormal behavior From Table In above, it can be seen that codeine phosphate caused habituation, but dN, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan did not induce habituation.

The compounds of this invention can be administered orally in the form of tablets, Capsules, powder, syrup and the like, or parenterally in the form of an intramuscular Injection, subcutaneous injection and the like. The clinical Dose for an adult is 30 to 150 mg per day for oral administration, which is usually 3 to 4 times a day, while the dose is 5 to 15 mg daily in the case of parenteral administration, which takes place 1 to 2 times. The clinical The dose will be correct according to the condition of the patient, the age and the like customized.

Example 1 Preparation of d-N, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan In a mixture of 2.5 ml of tetrahydrofuran and 4 ml of chloroform was added 0.45 g of d-3-hydroxy-N-methylmorphinane dissolved. While stirring the solution, phosgene was added to the solution for about 30 minutes initiated, the temperature of the reaction mixture rose to 40 to 500 C. After stirring the batch for a further hour, the pH of the solution was increased to 10 adjusted by adding 2 normal aqueous sodium hydroxide solution while cooling with ice, The oily product thus formed was dried with 50 ml of potassium carbonate. By Distilling off the ether gave the desired compound as a colorless oily material obtained in a yield of 0.54 g.

Elemental analysis as C35H44N2O3. 2H2O C% H% N% calculated: 72.88 §, 39 4.6 found: 72.7t 8.33 4.51 = + 42.5 (C = 2, methanol) Further, by treating the product with 1 normal aqueous hydrochloric acid solution saturated with chloroform by a conventional method, crystal needles were obtained from dN, N'-dimethyl-3,3 '- ( carbonyldioxy) dimorphinana.Hydrochloride with a melting point of 2400C (with decomposition).

= + 21.7 (C = 1, methanol) Example 2 Manufacture of d1-N, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan By doing the same Procedure as indicated in Example 1, dl-3-hydroxy-N-methylmorphinane is used instead used by d-3-hydroxy-N-methylmorphinan. The desired connection was saved as a colorless oily material obtained. The yield was 0.54 g.

Elemental analysis as C35H44N2O3. H2O C% H% N% calculated: 75.24 8.30 5.01 found: 75.15 g, 22 5.01 Example 3 Preparation of 1-N, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan In a mixture of 24 mol of tetrahydrofuran and 13 ml of chloroform, 7.7 g of l-3-hydroxy-N-methylmorphinane was obtained dissolved. Then, while stirring the solution, phosgene was added to the solution for about 30 Minutes initiated. After further stirring for one hour, the reaction product solution became concentrated and the residue obtained was dissolved in chloroform. After washing the Solution with 5% aqueous sodium carbonate solution and then with water the solution was dried over anhydrous sodium sulfate. The chloroform was distilled off. 1.75 g of the desired product (as trihydrate) was found as a white, obtained caramel-like material.

Elemental analysis as C35H44N203. 3H20 0% H% Nf calculated: 70.67 8.47 4.71 found: 70.98 7.83 4.63 When the product was dried for 6 hours at 70 to 750 C, a white, caramel-like material (monohydrate) obtained, elemental analysis as C35H44N203 8 H20 0% H% calculated: 75.24 8.30 5.01 found: 75.97 8.35 4.95 - ei4.8 (C = 1, methanol) Example L Preparation of d-3-ethoxycarbonyloxy-N-methylmorphinan 2.0 g-d-3-hydroxy-N-methylmorphinan was dissolved in 30 ml of anhydrous tetrahydrofuran and then 17 g anhydrous potassium carbonate suspended in the resulting solution. Then, a solution of 1.2 g of ethyl chlorocarbonate in 5 ml of anhydrous tetrahydrofuran was added dropwise to the suspension over about 30 minutes with stirring. A crystalline precipitate was formed immediately. After the batch had been stirred overnight, the solvent was distilled off.

The residue was mixed with 50 ml of ether and 50 ml of water under sufficient Working through mixed. Then the formed ether layer was decented separated and washed three times with 10 ml of 1 normal aqueous hydrochloric acid solution extracted. The extracts were combined together and the solvent became made alkaline with anhydrous potassium carbonate. Then was twice with each 50 ml of ether extracted.

The extracts were combined and the combined solution was washed with water and dried over anhydrous sodium sulfate.

When the ether was distilled off, 2.5 g of a light yellow became oily product obtained. When the product of a silica gel column chromatography treatment using methanol as an eluate, it became desirable Product obtained as a slightly yellowish oily material.

Elemental analysis as C2oH27N03 C% H% N% calculated: 72.92 8.26 4.25 found: 72.39 8.25 4.21 = +, 51.5 (C = 0.75, methanol) Example 5 Production of tablets dN, N'-dimethyl-3,3 '- (carbonyldioxy) -dimorphinan 1.0 g lactose f °, ° 8 starch 3, 5 g talc 0.5 g A mixture of the above ingredients was made into 100 tablets using a flat 7.0 mm tablet punch.

The tablets can be coated according to a known method, if this is desired.

Example 6 Preparation of an injection solution In 100 ml physiological Saline was dissolved in 0.5 g of d-N, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan. The solution thus obtained was aseptically divided and filled into 1 ml ampoules containing 5 mg of active compound.

Claims (4)

Patent claims: 1.) Carbonyldioxymorphinanderivate with the general formula wherein R represents a lower alkyl group or N-methylmorphinan-3-yl group and their non-toxic acid addition salts. 2.) d-N, N'-dimethyl-3,3 '- (carbonyldioxy) dimorphinan according to claim t. 3.) Cough suppressant pharmaceutical preparations, characterized by a content of the compounds mentioned in claim 1 or 2 or a pharmaceutical usable acid addition salt thereof as an active ingredient. 4.) Use of the compounds mentioned in claim t or 2 or a pharmaceutically acceptable acid addition salt as an active ingredient for the preparation of cough suppressants,