DE1620407B - S-Hydroxy-o-oxo-N-phenyläthylmorphinan- (cis) compounds and their salts and processes for their preparation - Google Patents

Description

OH

IO

I '5

wherein A denotes a single or a double bond and their salts.

2. Process for the preparation of 3-hydroxy-6 - oxo - N - phenylethylmorphinan - (ice) - connec- 30

II

-CH ₂ CH ₂

wherein A denotes a single or a double bond, in a manner known per se, an alkylphenyl ether cleavage subjected and optionally treated the base obtained with an acid. 3. Pharmaceutical preparation consisting of a compound of the general formula I and customary auxiliaries or carriers.

The invention relates to 3-hydroxy-o-oxo-N-phenylethylmorphinan (cis) compounds of the general formula I.

OH

nyläthylmorphinan- (cis) compound of the general formula II

N-CH ₂ -CH ₂ ^ >

60

in which A denotes a single or double bond, and its salts and a process for their preparation lung.

The inventive method is characterized in that a 3-methoxy-OTOxo-N-phe-

45

I 50

55

N-CH ₂ CH ₂

wherein A denotes a single bond or a double bond, in a manner known per se, an alkylphenyl ether cleavage and the base obtained is optionally treated with an acid.

The 3-methoxy-6-oxo-N-phenyläthylmorphinan- (cis) used as starting material (II) can be made from - methoxy - 6 - oxo - N - methylmorphinane - (ice) (cf.

USA.-Patent 3,085,091) by reaction with cyanogen bromide, replacing the N-methyl group with a cyano group, treatment of the obtained N-cyano compound with hydrochloric acid to eliminate the N-cyano group and reaction of the N-unsubstituted compound obtained with phenylethyl bromide (cf. Japanese patent specification 20 863 [September 16, 1965] or Chem. Abstracts, 64 [1966], P 2070 e).

According to the invention, the 3-methoxy-6-oxo-N-phenyläthylmorphinane- (cis) used as starting material of the formula II hydrolytic cleavage in a manner known per se, as used for Cleavage of alkylphenyl ethers applied is subjected. Some examples of such a way of working are the following:

1. Treatment with a mineral acid (e.g. hydrobromic acid, hydroiodic acid) with heating,

2. Treatment with an aluminum halogen compound (e.g. aluminum chloride, aluminum bromide, Aluminum iodide) or a boron halide (e.g. boron fluoride, boron bromide, boron chloride) in the presence or the absence of an inert solvent (e.g. benzene, toluene) with heating and subsequent treatment with water or an acid,

3. Treatment with a salt of a pyridine base (e.g. pyridine hydrochloride, pyridine hydrobromide) under warming,

4. Treatment with alkali hydroxide (e.g. potassium hydroxide, sodium hydroxide) in an inert Solvent (e.g. triethylene glycol, diethylene glycol) with heating, preferably in the presence an anti-oxidant (e.g. hydrazine).

3 - Hydroxy - 6 - oxo - N - phenyläthyl - 7 -dehydromorphinan - (ice) or 3 - Hydroxy - 6 - oxo - N - phenyläthylmorphinan- (cis) form salts with organic and inorganic acids, e.g. hydrochloride, Hydrobromides, hydroiodides, sulfates, phosphates, tartrates, salicylates, benzoates, malates, citrates and acetates.

The 3-hydroxy-6-oxo-N-phenylethylmorphinane (ice) compounds obtainable according to the invention of the general formula II and their salts have a remarkable analgesic activity. In the following table shows the analgesic activity and toxicity compared to levorphanol *) - tartrate (3 - hydroxy - N - methylmorphine antartrate), a commercially available analgesic agent, specified.

*) Non-proprietary name proposed by the WHO.

connection

Analgesic activity

Haffner-Hesse method

D'Amour Smith Method

Toxicity LD ₅₀
(mg / kg)

Addiction generation

(Physical
Dependency)

Levorphanol

3-Hydroxy-6-oxo-N-phenethyl-7-dehydromorphinan- (cis) -sali-
cylate

S-Hydroxy-o-oxo-N-phenethylmorphinan (cis) salicylate

3.9

18.0
68.0

9.1

66.0
150.0

189.8

570.2
> 800.0

6 to 9

0.166 to 0.25
1.0

Explanation:

The analgesic activity was measured by the Haffner-Hesse method (Hesse: Arch. Exp. Path, and Pharm., Vol. 158 [1930], p. 233) Mice and according to the D'Amour-Smith method (D'A mou r et al: J. Pharmacol., Vol. 1 [1946], p. 255) determined and is determined as the action ratio given for morphine, to which the value 1 is assigned. Toxicity was assessed by subcutaneous administration of the test compound tested on mice. The physical dependence (addiction generation) was after Deηeau and Seevers on rhesus monkeys (Macaca mulatta) and is given as the effect ratio to morphine, which is assigned the value 1.

3 - hydroxy - 6 - oxo - N - phenylethyl - 7 - dehydromorphinan- (cis) and 3-hydroxy-6-oxo-N-phenylethylmorphinan (cis) and their salts can be used alone or in combination with pharmaceutically acceptable Carriers are administered, the choice of which in view of the preferred method of administration, the solubility of the substance and standard pharmaceutical practice is carried out. In general, the Dose on these substances '/ 20 to' / 3 of the doses Levorphanol tartrate (3 - hydroxy - N - methylmorphinan). The substances obtainable according to the invention are suitable for treating the types of painful conditions that are common with the specified known analgesic. The substances are particularly effective against pain, caused by tumors and surgery. Pharmaceutical preparations are for example tablets, capsules, pills, suspensions and solutions. In the manufacture of Tablets e.g. B. the substances can be filled with fillers (e.g. lactose, potato starch, wheat starch) or binders (e.g. gum tragacanth, acacia gum, corn starch, gelatin) are combined. Furthermore it is expedient to use a dissolving agent, e.g. B. to use corn starch, potato starch or alginic acid.

In addition, lubricants, e.g. B. stearic acid, magnesium stearate or talc, together with sweeteners, e.g. B. saccharin, is desirable. Furthermore, one can taste and flavorings, e.g. B. Use peppermint flavor, wintergreen oil or cherry flavor. In the In the manufacture of capsules, fillers such as those listed above for tablets can also be used became. If the substances obtainable according to the invention in the form of suspensions or Solutions are used, they can be used with aqueous, sugar or substances of the sorbitol type containing Combine carriers which contain an agent for controlling viscosity, e.g. B. Magnesium aluminum silicate, Methyl cellulose or carboxymethyl cellulose and a suitable preservative, e.g. B. sodium benzoate or methyl and propyl esters of p-hydroxybenzoic acid. In these liquid preparations It may also contain coloring and flavoring substances and buffers.

The following examples illustrate the invention. Parts by weight are equivalent to parts by volume Ratio like grams to milliliters.

example 1

A solution of 8.4 parts by weight of aluminum bromide in 84 parts by volume of anhydrous benzene is added dropwise with stirring to a solution of 3.38 parts by weight of 3-methoxy-o-oxo-N-phenylethyl-7-dehydromorphinane (cis) in 40 parts by volume of anhydrous benzene . The resulting mixture is heated under reflux for half an hour and 3 hours, cooled to 10 ⁰ C. The benzene layer is decanted off and the residue is dissolved in 300 parts by volume of chloroform containing 5% methanol. The chloroform solution is washed twice with 100 parts by volume of 10% strength aqueous sodium carbonate solution each time, dried over anhydrous potassium carbonate and concentrated to 50 parts by volume. After the precipitated crystals have been filtered off and recrystallization from methanol, 1.42 parts by weight of 3-hydroxy-6-oxo-N-phenylethyl-7-dehydromorphinan-(cis) crystals, melting point 183 to 184 ° C. (decomp.), receive.

[«] L ³ · ⁵ - 127.7 ° (C ₂ H ₅ - OH, c = 1.012).

The salicylate of this substance is recrystallized from methanol to give crystals, melting point 217 to 218 ° C. (decomp.).

Example 2

A solution of 1.58 parts by weight of 3-methoxy-6-oxo-N-phenylethylmorphinan (cis) in 15 parts by volume of 48% hydrobromic acid is refluxed for 15 minutes. The reaction mixture is concentrated under reduced pressure. The residue is mixed with water, made alkaline with aqueous ammonia and extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous potassium carbonate. After the chloroform has been distilled off, 3-hydroxy-6-oxo-N-phenylethylmorphinan- (cis) is obtained as an oil. By recrystallizing the substance from a mixture of 0.62 parts by weight of salicylic acid and 20 parts by volume of methanol, 2.078 parts by weight of 3-hydroxy-6-oxo-N-phenylethylmorphinan- (cis) salicylate are obtained which, after recrystallization from methanol, crystals from Melting point 28O ⁰ C (decomp.) Supplies.

Example 3

50 g S-hydroxy-o-oxo-N-phenylethyl ^ -dehydromorphinan- (cis) -salicylate, 6.52 kg of lactose, 3.00 kg of corn starch and 210 kg of carbomethoxy cellulose are mixed together to form lumps. The lumps are broken up and forced through a sieve with a mesh size of 1.4 mm. The Granules obtained are mixed with 200 g of talc and 20 g of magnesium stearate and in the usual way processed into tablets to obtain 50,000 tablets. Each tablet weighs 200 mg and contains 1.0 mg of the active ingredient.

Example 4

20 g S-hydroxy-o-oxo-N-phenylethylmorphinan (cis) salicylate, 14.00 kg of lactose and 4.90 kg of wheat starch are mixed with potato starch paste granulated and dried. The granulate is sieved through a DIN No. 6 sieve (1.0 mm mesh size) and then mixed with 360 g of talc and 40 g of magnesium stearate. By tableting the obtained Mixing in the usual way 100,000 tablets are obtained. Each tablet weighs 200 mg and contains 0.2 mg of the active ingredient.

Example 5.

By dissolving 0.75 g of 3-hydroxy-6-oxo-N-phenylethylmorphinan (cis) salicylate in physiological saline solution, 10 l of solution are prepared and filtered. The solution obtained is filled into 5000 ampoules under nitrogen, and the ampoules are sterilized ^{at 115 ° C. for 30 minutes.} Each ampoule (2 ml) contains 0.15 mg of the active ingredient.

Claims (1)

Patent claims: 1. S-hydroxy-o-oxo-N-phenylethylmorphinan (cis) compounds of the general formula I 5 Fertilize according to claim 1, characterized in that a 3-methoxy-6-oxo-N-phenylethylmorphinane (cis) compound is used of the general formula II