DE224197C - - Google Patents

Description

IMPERIAL

PATENT OFFICE.

PATENT LETTERING

- JVl 224197-CLASS 12j ». GROUP

Patented in the German Empire on June 19, 1909.

Acid esters of morphine are already known in large numbers, but so far only that Diacetylmorphine used therapeutically. It has now been found to be too valuable Morphine derivatives enter the Morphine molecule are introduced, in turn by chemical reagents or im Organism can be saponified more easily to phenolic hydroxyls than the ester bond between Acid and morphine is split. Such acidylated compounds are obtained Morphine of the general formula:

C ₁₇ H _ls 0 ₂ N'00C aryl O acidyl,

if you combine morphine with the halides of acidylated aromatic oxycarboxylic acids (phenol carboxylic acids) heated or these ester halides reacts with morphine in an alkaline solution.

It is well known that morphine, in contrast to all other opium alkaloids, has one specific and a selective effect on the nervous system, resulting in its narcotic see Properties expresses. This effect is carried out on the one in the morphine molecule borrowed phenolic hydroxyl, which is the anchor point for the lipoids of the nerve cells. The previously therapeutically used morphine derivatives codeine and ethylmorphine and diacetylmorphine do not show this specific morphine effect because of the substitution of phenolic hydroxyl by alkyl or acetyl the anchor point for the nerve centers of the brain obscured; these derivatives, on the other hand, leave the tetanizing effect of the opium alkaloids emerge to a greater extent and have a significant effect on morphine increased toxicity. Only through gradual saponification, with the phenolic hydroxyl becomes free, there is a slight narcotic effect; an increase in The dose does not deepen the anesthesia, but leads to tetanic symptoms.

In contrast, in the morphine derivatives to be prepared by the present process when saponification occurs, first of all the more easily split off acid group in phenol hydroxyl of the substituent attacked; a free phenylhydroxyl is formed in the substituent, the now in turn provides the anchorage point for the nerve cells of the brain, in such a way that a morphine substituted by acidyl residues has an effect, but this effect, just as it is the case with morphine itself, it affects the nerve centers of the brain extends. The success is as shown by the pharmacological and clinical testing has a substantial increase in the narcotic effect.

It has also been shown that the quaternary salts of morphine, such as morphine bromomethylate, are almost non-toxic, but at the same time have their specific morphine effect is significantly reduced. This reduction in the effect of morphine can be attributed to it that betaine formation occurs in the organism, which is necessary for anchoring Phenolic hydroxyl. This is consistent with the fact that Mor-

phinjodmethylat not due to betaine formation suffers Hofmann's cleavage with alkalis. In the case of the quaternary salts, the new Morphine derivatives can prevent this betaine formation as a result of the greater spatial distance Avoid between the quaternary nitrogen group and the phenolic hydroxyl in the substituent or if betaine formation does occur, anchoring through introduction

ίο several phenolic hydroxyl groups in the substituent enable.

The new compounds are intended to be used therapeutically as such as well as Serve starting materials for the production of other therapeutically valuable products.

Examples.

i. p-acetoxybenzoylmorphine.

16 parts of p-acetoxybenzoic acid, which by means of acetic anhydride from ρ - oxybenzoic acid is obtained in alkaline solution and from hydrous acetone in sticks from Melting point 196 ° (corr.) Crystallized, are mixed with 20 parts of phosphorus pentachloride and warmed up on the water bath. After the reaction has ended, the p-acetoxybenzoyl chloride becomes taken up with about 40 parts of warm ligroin, the solution was filtered and the solvent and that which had gone into solution Part of the phosphorus oxychloride distilled off in vacuo. The p-acetoxy then distills under a pressure of 12 mm

. benzoyl chloride at 161 to 162 ° and solidifies on cooling in long needles that melt at 30 °.

7.5 parts of this chloride are then dissolved in 100 parts of chloroform and with a Solution of 8.5 parts dry or 9.1 parts water-containing morphine base in 34 parts of normal sodium hydroxide solution and 15 parts of water some Time shaken. After adding 6 parts of sodium hydroxide solution, the chloroform solution is drained off, dried with dehydrated sodium sulfate and dried until crystallization begins constricted. When 30 parts of vinegar ether were added to the warm solution, it crystallized the p-acetoxybenzoylmorphine in colorless leaflets; by concentrating the mother liquor further amounts of this compound can be obtained.

The p-acetoxybenzoylmorphine crystallizes from vinegar in long prismatic needles, which sinter from 225 ° and melt at 232 ° with decomposition. It dissolves at 15 ° in 60 to 70 parts of acetic ether, even less in methyl and ethyl alcohol. The analysis showed: 69.77 percent C, 5.67 percent i? and 3.46 percent N, while the formula _{calls for C 26} H ₂₅ NO ₆ : 69.79 percent C, 5.89 percent H and. 3.13 percent N.

The chlorine hydrate is made from the solution of the base in methyl alcoholic hydrochloric acid Ethyl alcohol precipitated in long prisms that dissolve in 2 parts of cold water.

The chloromethylate can be caused by the action of dimethyl sulfate on the chloroform solution the base and reaction of the methylsulfuric acid salt initially formed with sodium chloride solution be won; it crystallizes from 10 parts of hot water in narrow Prisms and panels and dissolves in about 75 parts of water at ordinary temperature.

2. p-carbomethoxybenzoylmorphine.

The solution of 8.5 parts of dry or 9.1 parts of hydrous morphine base in 34 parts of normal sodium hydroxide solution and 17 parts of water is mixed with a solution of 7.5 parts of p-carbomethoxybenzoyl chloride (E. Fischer, reports d. D, former company, Vol. 41 [1908], p. 2878) shaken together for some time in 50 to 60 parts of chloroform with cooling. The emulsion which has entered is treated with 6 parts of normal sodium hydroxide solution and the chloroform solution is raised by adding about 100 parts of ether. The chloroform ether layer is then separated off, clarified by filtration and shaken first with 100 parts, then with 50 parts of normal hydrochloric acid, and finally with 50 parts of water. The combined hydrochloric acid solutions, after the addition of about 30 parts of 20 percent hydrochloric acid, precipitate the chlorohydrate of p-carbomethoxybenzoylmorphine on rubbing. The base is separated from the chlorohydrate with cooling by Potaschel solution and taken up with chloroform. The base crystallizes from alcohol in colorless prisms which ^{melt at 175 to 176 °} with decomposition. The analysis showed: 67.52 percent C, 5.49 percent H and 3.05 percent N, while the formula C ₂₉ H ₂₅ NO ₇ requires: 67.38 percent C, 5.39 percent H and 3.02 percent.

The chlorohydrate crystallizes from methyl alcohol in large prisms with one molecule of i ° 5 methyl alcohol, from ethyl alcohol with one molecule of crystal alcohol. The analysis showed 7.10 percent Cl and 9.14 percent C ₂ H ₆ O, while the formula was:

C ₂₆ H ₂₅ NO ₁ -HCl + C ₂ H ₆ O

Calculate: 7.22 percent Cl and 9.37 percent C ₂ H ₆ O. It dissolves in 2.5 parts of methyl alcohol and 4 parts of absolute ethyl alcohol. 'It does not have a fixed melting point; it tans at 165 ° and foams up at 190 °.

The p-carbomethoxybenzoylmorphine cleaves the carbomethoxy group on careful saponification and goes into the p-oxybenzoylmorphine above. Dissolve 1 part of p-carbomethoxybenzoylmorphine chlorohydrate in one

Mixture of 5 ¹ ₂ parts alcohol and ¹ _{2 2} parts water and add the amount of normal ammonia corresponding to two molecules with cooling and shaking, then after a few hours of standing at room temperature the saponification is complete and the p-oxybenzoylmorphine separates on cooling crystalline. The compound crystallizes from 22 parts of 5% alcohol in thin amounts

ίο leaflets, tan at 230 ° C and melt at 237 ⁰ with decomposition. In the analysis, _{values corresponding to the formula C 24} H ₂₅ NO _{5 were} obtained: 71.16 percent C, 5.89 percent H and 3.58 percent N ; calculated:

71.11 percent C, 5.68 percent H, and 3.46 percent N. .

The hydrochloride crystallizes from the warm solution of the base in methyl alcohol Hydrochloric acid after the addition of ethyl alcohol on cooling in prismatic needles, which are Dissolve in 2 parts of cold water. .

The bromomethylate is in a known manner using dimethyl sulfate in chloroform solution and subsequent reaction with potassium bromide and crystallized from 10 parts hot water in thin leaves.

Claims (1)

Sponsorship claim: Process for the preparation of morphine esters of acidified aromatic oxycarboxylic acids the general formula: R-OOC · aryl Acidyl O (R = radical morphine), consisting in that on morphine halides acidylated aromatic oxycarboxylic acids the general formula: _A , O-Acidvl Aryl < (X = halogen) allowed to act according to the usual acidylation methods.