DE1064049B - Process for the preparation of N-substituted beta-oxybuttersureamides with analgesic activity - Google Patents

Description

GERMAN

It has been found that new, analgesic compounds of the formula

CH ₃ -CH-CH ₂ -CO-NH-R

OH

obtained, in which pure 4 to 8 carbon atoms, aliphatic hydrocarbon radical with an attached to the Tertiary carbon atom bonded to nitrogen atom means when one uses corresponding N-substituted amides the acetoacetic acid is reduced in a manner known per se or /? - oxybutyric acid or its functional derivatives or reacts salts in a manner known per se with appropriately substituted amines.

A particularly advantageous method is to use N-substituted acetoacetic acid amides !! start out, which can be obtained in particular by reacting primary amines of the formula R - NH ₂ with diketene. As amines z. B. the following into consideration: tert. Butylamine, l, l-dimethyl-propyl- (l) -amine, 1,1-dimethyl-n-butyl- (1) -amine, 1,1-direthyl-n-amyl- (1) -amine, 1 , 1 -Dirne thyln-hexyl- (l) -amine, l, l-diethyl-propyl- (l) -amine, 1,1-diethyl-n-butyl- (1) -amine, 1,1 -dipropyl- ethyl- (1) -amine, 1-methyl-1-ethyl-propyl- (1) -amine, 1-methyl-1 -ethyl-n-butyl- (l) -amine, l-methyl-1-ethyl- n-amyl- (l) -amine, whereby the branched butyl-, amyl- and hexylamines can also be used instead of the normal ones. There can also be other tert. Alkylamines are used which contain the above-mentioned alkyl radicals in a combination other than that already mentioned.

The reduction of the keto group can, for. B. catalytically with the help of metals of the VIII. Group of the periodic System, preferably with nickel catalysts, in the presence of solvents customary for this purpose, e.g. B. aqueous Alcohols, alcohols or water. Noble metals or Raney catalysts can also be used be used. You can also use nascent hydrogen, e.g. B. with aluminum amalgam and Reduce alcohol, sodium amalgam, lithium aluminum hydride or sodium borohydride. The reduction is also can be carried out electrolytically.

As a starting compound is also the /? - Butyrolactone, which by known methods, for. B. by catalytic hydrogenation of diketene. By implementing with the aforementioned Amines form the desired / J-oxybutyric acid amides directly in a manner known per se. This implementation takes place by the action of both components without or in the presence of solvents, e.g. B. water or organic solvents such as alcohols, benzene, toluene or ethers. The reaction is usually spontaneous, and the products of the process can be isolated from the reaction mixture by fractional distillation.

of analgesic effective,

N-substituted ß-oxybutyric acid amides

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr.-Chem. Gustav Ehrhart, Bad Soden (Taunus),

Dr.-Chem. Ingeborg Hennig, Kelkheim (Taunus),

Dr. Ernst Lindner, Frankfurt / M.-Höchst,

and Heinrich Ott, Eppstein (Taunus),

have been named as inventors

You can also use methods known per se, for. B. / 3-Oxybutyric acid ester with the above convert primary amines. As / 3-oxybutyric acid ester are advantageously lower aliphatic esters such. B.

the methyl, ethyl and propyl esters.

The products of the process have very favorable therapeutic properties, and indeed they stand out with surprisingly good analgesic properties. The analgesic effectiveness was determined according to the focal beam method tested by Wolff-Hardy and Goodell by exposing mice to the heat stimulus until they showed a defensive reaction. First, the normal reaction time was determined using a group of 60 mice in the control experiment reacted to the pain stimulus after an average of 7.2 seconds. In the following The table shows the dosage required to achieve the analgesic for two process products, the mean value found for the 20 treated mice was an increase in reaction time of 25.3 seconds became. The low toxicity of the products of the process is of particular importance for use as medicinal products. In the table below is also the Dos. let. min. for the two specified connections indicated after intravenous administration.

Tabel

No. link For analgesia
required dose DOS. let.
min. iv 1. ß-oxybutyric acid tert. butylamide 750 mg / kg s.c. 1.5 g / kg 2. / S-oxybutyric acid [1,1-diethyl-propyl- (l)] - amide 250 mg / kg s.c. 350 mg / kg 909 609/426

The mentioned in the German patent 918926 Ν, Ν-diethylhydracrylsäureamid has after same method and in the same dose as when using jß-oxybutyric acid-tert. butylamide for analgesia has proven to be completely ineffective in analgesic terms.

From the published documents of the patent 964 057 the ß-oxy-butyric acid-p-phenetidide is known. A major advantage of the process products over this compound is their considerably better solubility in water, which allows subcutaneous injections, * while the known compound only
can be administered. But also applied per os s
the products of the process have a better analgesic effect
For example, 500 mg / kg / I-oxy-butyric acid [l, l-diethyl-propyl- (l)] - amide per os have as strong an analgesic effect as 1250 mg / kg of the known compound per os. With 250 mg / kg of the product of the process, applied subcutaneously, the same analgesic effectiveness is achieved as with 1250 mg / kg of the known compound per os.

The products of the process can be administered either orally or parenterally.

example 1
ιβ-oxybutyric acid tert. butylamide

Acetoacetic acid tert. butylamide, prepared from equivalent amounts of tert-butylamine and diketene in water, is dissolved in methanol and hydrogenated at 60 to 70 ° C in the presence of Raney nickel. After filtration and concentration of the filtrate, the oily residue is distilled. It is / S-oxybutyric acid-tert. butylamide obtained from _{b.p. 0j45} 102 ° C; Melting point 88 to 89 ° C (after recrystallization from ethyl acetate).

Example 2

/ 9-oxybutyric acid tert. butylamide

A solution of 9 g of ß-butyrolactone in 300 ecm of ether

is with a solution of 8 g of tert-butylamine in 30 ecm

Ether was added while cooling and the mixture was left to stand at room temperature for 24 hours. After distilling off of the solvent and the unreacted reagents, the residue solidifies. It will be 10 g / S-oxybutyric acid tert. butylamide melting point 87 ° C obtain.

Example 3

/? - Oxybutyric acid [l, l-diethyl propyl (l)] amide
33 g of acetoacetic acid [l, l-diethylpropyl (l)] amide with a melting point of 96 to 97 ° C., obtained from equivalent amounts of l, l-diethylpropyl (l) amine and diketene in benzene, are converted into 100 ecm of methanol and 20 ecm of water are dissolved and 1.9 g of sodium borohydride are added in portions. After the exothermic reaction has subsided, this becomes

Methanol is distilled off under reduced pressure. After etherifying the residue and washing the ethereal solution The ether residue crystallizes with dilute hydrochloric acid. There are 28 g of jS-oxybutyric acid [l, l-diethyl-propyl- (l)] - amide obtained from melting point 67 to 68 ° C (from cyclohexane).

Example 4

β-Oxybutyric acid [3-methyl-pentyl- (3)] -amide
po , 30 g of acetoacetic acid 3-methyl-pentyl- (3) -amide, prepared from equivalent amounts of 3-methyl-pentyl- (3) -amine ufM diketene in benzene, are dissolved in 100 ecm of methanol and ljj ^ cm of water and 3 g of sodium hydride are added in portions. After neutralization with 2N hydrochloric acid, the alcohol is distilled off under reduced pressure and the residue is extracted with ether. After drying and distilling off 18 g ^ -Oxybuttersäure- [3-methylpentyl (3)] - arnid from Kp _0i05 95 to 96 ⁰ C obtained..

In an analogous manner, 14 g of acetoacetic acid [2-methyl-butyl- (2)] amide, prepared from equivalent amounts of diketene and 2-methyl-butyl- (2) amine in benzene, are hydrogenated with 1.5 g Sodium borohydride 10 g /? - Oxybutyric acid- [2-methyl-butyl- (2)] - amide of Kp. _Oi07

"95 ⁰ C obtained.

² > Example 5

/ S-oxybutyric acid [2-ethyl-hexyl- (2)] amide

22 g of acetoacetic acid [2-ethyl-hexyl- (2)] - amide, prepared from equivalent amounts of 2-ethyl-hexyl-2-amine and Diketene in benzene, are in 100 ecm methanol and 2 ecm Dissolved water and hydrogenated according to the instructions given in Example 4 with 1.2 g of sodium borohydride. The work-up is also carried out according to Example. The ether residue crystallizes from cyclohexane. It 18 g /? - oxybutyric acid- [2-ethyl-hexyl- (2)] - amide

obtained 64 ⁰ C of melting point.

Claims (1)

Claim: Process for the preparation of analgesic, N-substituted / 3-oxybutyric acid amides general formula CH ₃ - CH - CH ₂ - CO - NH - R OH wherein R is an aliphatic hydrocarbon radical having 4 to 8 carbon atoms with one attached to the Tertiary carbon atom bonded to nitrogen atom means, characterized in that one corresponding N-substituted amides of acetoacetic acid reduced in a manner known per se or that one ß-oxy-butyric acid or its functional derivatives or reacts salts in a manner known per se with appropriately substituted amines. © 909 609/426 8. 59