DE1493078B2 - - Google Patents

Description

CH ₃

IO

R ²

in R ¹ the acyl radical of one of the two acids and R ² either

or

-CH ₂ CH ₂ OH
- (CH ₂ I ₂ - CH (CH ₃ ),

20th

means.

2. Process for the preparation of the compounds according to claim 1, characterized in that one 2-aminomethyl-3-methyl-norbornane

either with a compound of the formula R ² X (where X = halogen) in a manner known per se

or, if R ² denotes the isoamyl radical, the 2-aminomethyl-3-methyl-norbornane is reacted with isovaleroyl chloride in the presence of an acid acceptor in a manner known per se and the isovaleramide derivative obtained is reduced with lithium aluminum hydride

and after purification, the ^{amine thus obtained, substituted by R 2} N, is reacted in a manner known per se with the acyl chloride R ¹ Cl of one of the two acids using a hydrogen chloride acceptor, preferably triethylamine.

3. Medicaments containing one of the compounds according to claim 1 and customary pharmaceuticals Carriers and / or formulants.

It is already known that glycinamide derivatives derived from norbornylamide have an antimicrobial effect have (cf. German Auslegeschrift 1 129 950) that 2-aminomethylbicyclo- (2.2, l) -heptene and -heptane derivatives as fungicides are useful (see. British Patent 902 637) that alkylated 2,5-endomethylene-cyclohexylmethylamines have a local anesthetic effect and for the production of bicycloheptyl aralkylureas can be used (see US Pat. No. 3,115,524) and that the bicyclically substituted Aminoalkanes of French patent specification 937 603 have an analgesic and spasmolytic effect.

However, these references do not disclose the preparation of the compounds of the present invention close, because they give the person skilled in the art neither an indication of the specific structure of the claimed Compounds still on their suitability as pharmaceuticals.

The compounds according to the invention can be represented by the following general formula:

R ¹

CH, -N

ν · ■

CH.

where R ^{1 is} the acyl radical of levulinic acid or chlorobenzoic acid and R ^{2 is} either

35 or

40 - CH, -CH, -OH

(CH ₂ ) ₂ -CH (CH ₃ ),

The invention relates to therapeutically valuable new levulinic acid and chlorobenzoic acid amide derivatives 2-aminomethyl-3-methyl-norbornans, their preparation and medicaments containing them according to the preceding claims.

means.

These compounds are in the form of white crystalline substances or as slightly yellowish viscous ones oils that are difficult to distill. It was found to have extremely low toxicity and have significant neurotropic efficacy and are therefore of great therapeutic interest Offer possible applications.

The amides of the present invention are obtained according to the above-given process according to claim 2 manufactured.

The reaction sequence can be illustrated using an example as follows:

CH ₂ -NH ₂

CH,

+ Cl-CH ₂ -CH ₂ -OH

CH ₂ -NH-CH ₂ -CH ₂ -OH

CH,

CH ₂ -NH-CH, -CH, -OH

+ R ₁ Cl-

N (EtK

CH,

CH ₂ -N-CH ₂ -CH ₂ -OH

Reaction (a) is carried out by simply heating both reagents to 160 ^° C. for 5 to 10 hours, an excess of amine in the ratio of 3 mol for each mol of chloride being used as hydrochloric acid acceptor.

The crude reaction product is made by dissolving in ether, washing in alkaline water and Purified vacuum distillation.

The excess amine is thereby recovered and the pure ^{amine substituted by R 2} N -substituted is obtained in a yield of about 90%.

It is advantageous in the procedure according to (a) as well as in the preparation of the isoamylamine compound specified as the second procedure above (claim 2) (by preparation and reduction of the isovaleramide derivative) the R ² N-substituted amines obtained before their further processing to isolate.

Reaction (b) is carried out by adding, without heating, 1 mole of acid chloride dissolved in benzene was dissolved, added to a benzene solution, the 1 mole of the N-substituted amine and 1 mole of triethylamine contains, which latter serves as a hydrochloric acid acceptor.

When the addition is complete, the whole is refluxed for 3 to 7 hours, and that The reaction mixture is then treated with 10% sodium hydroxide, 10% hydrochloric acid and finally washed with water.

After evaporation of the solvent in vacuo, the benzene solution turns slightly yellowish and Oily residue which is difficult to distil and which consists of the desired amide is obtained. The yield is about 90%.

Sometimes the amide can be obtained in crystalline form by using the above residue a small amount of ethyl acetate or a mixture of ethyl acetate / petroleum ether in proportion Treated 4: 1.

The high yields and cheapness of the solvents used for cleaning make these methods extremely suitable for industrial production.

It is surprising that the compounds according to the invention have a very low toxicity, ζ. Β. _{a DL 50} = 2500 mg / kg (mouse) was found for the levulinamide of 2-isoamylaminomethyl-3-methyl-norbornane of the present invention, while the 1-phenyl -1 - (bicyclo - [2 , 2,1] - heptyl - 2) - 3 - dimethylaminopropane has a DL ₅₀ = 335 mg / kg (mouse); the compounds of the present invention have at least as good an antispastic effect as the known compound.

example 1

55

11.6 g of 1-4 - endomethylene - 2 - aminomethyl-3-methylcyclohexane are heated for 7 hours at 16O ⁰ C with 2.25 g of ethylene chlorohydrin. By alkalization with In-NaOH, extraction with ethyl ether and distillation, 5 g of l-4-endomethylene-2-hydroxyethylaminomethyl-S-methylcyclohexane (I) are obtained, while 4 g of unreacted amine are recovered.

a) 20 g of compound (I) and 11.1 g of triethylamine, dissolved in 200 ecm anhydrous benzene becomes 19.2 g of dissolved in 50 ecm anhydrous benzene p-Chlorobenzoyl chloride is added, thereby the mixture chilled. When the addition is complete, the whole is boiled, stirring, for 4 hours and after washing with 10% hydrochloric acid solution, 10% sodium hydroxide solution, and after filtration through activated charcoal and evaporation of the solvent, 24 g of a residue are obtained obtained from the p-chlorobenzamide of 1 - 4 - endomethylene - 2 - hydroxyäthylaminomethyl-3-methylcyclohexans consists.

This residue appears as an extremely viscous, slightly yellowish Ul, and after treatment with a Mixture of ethyl acetate / petroleum ether in a ratio of 4: 1, it crystallizes, with white crystals a melting point of 98 ° C is obtained.

Analysis calculated for C ₁₈ H ₂₄ ClNO ₂ ; MG 321.5:
Calculated ... C67.15, H7.52, N4.35, Cl 11.02%; found .... C67.05, H7.61, N4.46, Cl 11.05%.

b) 7.4 g of levulinoyl chloride dissolved in 25 ml of anhydrous benzene are added to 10 g of compound (I) and 5.6 g of triethylamine in a 100 cc solution of anhydrous benzene, while the mixture is cooled.

When the addition is complete, the whole is refluxed for 5 hours and afterwards washing with 10% hydrochloric acid solution, 10% sodium hydroxide solution and filtration activated charcoal and evaporation of the solvent turn a slightly yellowish oily color A residue obtained from 11.5 g of the levulinamide of 1 ^ -endomethylene ^ -hydroxyäthylaminomethyl-3-methylcyclohexane consists.

Analysis calculated for C ₁₆ H ₂₇ NO ₃ ; MG 281:

Calculated ... C68.32, H9.61, N4.98%;
found .... C 68.30, H 9.65, N 5.02%.

Example 2

To 50 g of l ^ -endomethylene ^ -aminomethyl-3-methylcyclohexane and 36.6 g of triethylamine in 200 ecm of anhydrous benzene are 43.5 g of isovaleroyl chloride slowly mixed in 50 ecm anhydrous benzene, while cooling the mixture.

After the end of the admixture, the whole is refluxed for 5 hours and the formed Precipitate, which consists of triethylamine hydrochloride, is filtered off.

The clear benzene solution becomes after washing with acidic and alkaline water solutions and after evaporation of the solvent an oily residue is obtained, which after vacuum distillation 60 g mono-isovaleramide des l ^ endomethylene-l-aminomethyl - 3 - methyleyclohexane gives (compound II). Bp. 13170.17 mm Hg, molecular weight 223.

Analysis calculated for C ₁₄ H ₂₅ NO:

Calculated ... C75.33, H 11.21, N 6.28%;
found .... C 75.30, H 11.28, N 6.48%.

27 g of compound (II), dissolved in 100 ecm of anhydrous ethyl ether, slowly become a suspension 9.2 g of lithium aluminum hydride in 300 ecm of anhydrous ethyl ether were added. After completion After the addition, the whole is refluxed for 8 hours, after which the excess lithium aluminum hydride is destroyed with water. The ether solution is washed with a 10% sodium hydroxide solution, and the ether evaporates. The residue is distilled in vacuo, and 21 g are obtained in this way 2-isoamylaminomethyl-3-methyl-l-4-endomethylene

cyclohexane, which has the appearance of a very mobile, colorless UI (compound III). Bp 72 ° C / 1 mm Hg; MG 209.

Analysis calculated for C ₁₄ H ₂₇ N:

Calculated ... C80.38, H 12.91, N 6.70%;
found .... C 80.60, H 12.80, N 6.85%.

To 10 g of compound (III) and 4.85 g of triethylamine in a 100 cc solution of anhydrous benzene 6.45 g of levulinoyl chloride in 25 ecm of anhydrous benzene are added while cooling the mixture.

When the addition is complete, the whole is refluxed for 5 hours and washed out with a 10% sodium hydroxide solution, a 10% hydrochloric acid solution, filtration activated charcoal and evaporation of the solvent produce 11g of a slightly yellowish oily residue obtained from the levulinamide of 2-isoamylammomethyl-S-methyl-l ^ -endomethylene cyclohexane consists. Bp 145 ° C / 0.12 mm Hg; MG 307.

Analysis calculated for C ₁₉ H ₃₃ NO ₂ :

Calculated ..'. C74.26, H 10.75, N 4.58%; found .... C 74.31, H 10.85, N 4.70%.

The pharmacological investigation of the specified compounds was carried out on mice, rats, Rabbits, cats and dogs carried out, both "in vivo" and on isolated and perfused Organs "in vitro".

The following were carried out: examinations of motor activity (actography), analgesia (according to Eddy), conditioned reflexes (pole climbing test), breathing activity (spirometry), bronchospasm due to histamine, cardiac blood circulation (recording of arterial pressure and the electrocardiogram), local anesthetic effect, intestinal passage, » in vitro «reaction of the intestine and uterus to acetylcholine, histamine, 5-hydroxytryptamine and BaCl ₂ , morphological hematochemical blood count, protective effect against experimental gastric ulcer (caused by tying off the gastric outlet and by immobilization).

The toxicity of the compounds and their influence on behavior were examined with particular care.

The calming and analgesic effect of the compounds (which was investigated in mice and / or rats) was assessed quantitatively according to Eddy’s method, estimating, for each dose level, the percentage of animals with a decreasing number of movements (for 60 minutes) and an increase in the Response times to pain (in 60 minutes) that were greater than X ± 2SD (X = mean, SD = standard deviation) calculated in placebo-treated control animals of the same sex and weight.

The dose / effect curves were constructed with these percentages and the corresponding ED ₅₀ (effective dose 50) was calculated. The toxicity was derived from the LD _{50 of} the compounds examined using the Wilcoxon and Lichtfield method. The effect on the conditioned reflexes was calculated from the percentage of the inhibitory response and the comparison of the mean latency versus the controls between the elicitation of the conditional stimulus and the onset of the conditional response. The differences were analyzed according to Student's test.

The action on local anesthesia was by surface anesthesia compared with procaine and lidocaine, according to Frey's test.

The intensity / duration curves of the local anesthetic effect were plotted with the data given.

The action on the intestinal tract (according to Macht) was compared to the mice Control animals examined.

The differences in the observed values compared to the control animals were according to Student's Test examined.

The studies on the chronic toxicity of the various preparations were carried out on rats the study of growth, hematochemical analyzes, urinalysis, samples of water diuresis and histomorphological studies were carried out. On the rats, the possible teratogenic effects of the compounds examined by looking at them during the mating season administered to the males and females and for the next 21 days. Investigations about Behavior and subacute toxicity trials were both for 30 days in adult dogs Sex performed. The course of glycemia, azotemia, blood coagulation, sedimentation of erythrocytes and the electrocardiogram are examined.

The anti-ulcer effect after ligation of the gastric outlet and immobilization was studied in rats for two different daily doses. It was based on the percentage of gastric ulcer-free animals versus the incidence in the control animals, from measurements of the pH of the Gastric juice and assessed qualitatively with reference to the number and size of ulcers found.

The compounds according to the invention have the following pharmacological properties:

1. Antihistaminic and antiserotonic effects as well as general spasmolytic but not anticholingeric effect.

2. Protective effect on those caused by ligation of the gastric outlet and immobilization Experimental ulcers.

3. Local anesthetic and scarring effect.

4. Calming effect without impairing muscle performance and the related defensive reflexes.

The above compounds do not appear to have any harmful side effects on the cardiovascular system and exercise the respiratory system, blood, reproduction and progeny. The tolerance, even with constant administration, is very high. In Table 1 is a part of the therapeutically useful reproduced pharmacological effects of the products according to the invention.

The pharmacological tests show that the amides according to the invention are of interest therapeutic applications in the field of gastroenteric pathology from psychosomatic Ethiopathogenesis are given.

Table 1 (pharmacological values)

formula

effect

LD ₅₀ mg / kg (per os)

ED ₅₀ sedative, mg / kg (per os) ....

50% inhibition of intestinal spasm in g / ml perfusion fluid) by:

Acetylcholine (5 x 10 " ⁸ )

Histamine (1 · 10 ~ ⁷ )

Barium chloride (5 x 10 " ⁵ )

5-hydroxytryptamine (6 ■ 10 " ⁸ )

Local anesthetic effect
(effective concentration in
g /% for 60 m.)
Stomach ulcer prevention
50% protective dose in mg / kg sc

a) Ulcer caused by ligature of the pylorus
(Shay)

b) ulcer due to immobilization

1 · 10 " ⁶ 7-10" ⁶ 5 · 10 " ⁶ 1 ■ 10" ⁶

120 (in 24h) 240 (in 24h) CH ₂ -N-CH ₂ -CH ₇ OH

CO-CH,

CH ₂ -N-CH ₂ -CH ₅ -CH

'3 CH ₂ -CO-CH,

3,000 250

■ 10 " ⁶ 1.5-10-« · 10 " ⁶ 20 ■ 10" ⁶

(in 24 hours) (in 24 hours)

CHj-CO-CH, ι

CH ₂ -CO-CH ₃

2,500 60

8 x 10 " ⁶ 1 x HT ⁶ 1 x 10" ⁶ 1 x 10 " ⁶

(in 24 hours) (in 24 hours)

409 532/438

Claims (1)

Patent claims: 1. Levulinic acid and p-chlorobenzoic acid amide derivatives of 2-aminomethyl-3-methyl-norboraans of the general formula R ¹ CH, -N