DE1935172C3 - Salts of N-phenyl-N- (2-pyridylmethy)> 2- (N-piperidino) ethylamine with straight-chain saturated fatty acids - Google Patents

Description

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30th

The invention relates to salts of N-phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) ethylamine with straight-chain saturated fatty acids that have an even number of 14 to 22 carbon atoms.

These salts are useful as cough suppressants. They are crystalline, tasteless, stable, non-hydroscopic and have low toxicity.

It is already known that N-phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) -äthylamiri Has antitussive effectiveness. However, this compound is oily, tends to discolour and is also bitter with a persistent unpleasant taste. The crystalline hydrochloride of this compound is still bitter. Neither the connection itself nor that Hydrochloride are therefore suitable for use in powder form.

It has been found that among the salts of N - phenyl - N - (2 - pyridylmethyl) - 2 - (N - piperidino) ethylamine with various organic acids those sake with saturated straight-chain fatty acids, having an even number of 14 to 22 carbon atoms for use in pharmaceutical Preparations are suitable because they are not hygroscopic and stable enough to last a long time Withstand storage, also have no taste and only low toxicity.

Surprisingly, it has been found that salts with saturated fatty acids containing 12 or fewer carbon atoms (e.g. lauric acid, capric acid and caprylic acid), are not crystalline, while salts Saturated fatty acids with 24 or more carbon atoms (e.g. lignoceric acid) have a haemolytic effect are, salts with unsaturated fatty acids (e.g. linolenic acid) are unstable, salts with aliphatic dicarboxylic acids (e.g. maleic acid, fumaric acid, and lemons

40

45

50 acid) have a bitter taste and salts of a large number of aromatic carboxylic acids have one or more disadvantages such as non-crystallinity, instability and bitter taste.

The invention therefore relates to salts of N - phenyl - N - (2 - pyridylmethyl) - 2 - (N - piperidino) ethylamine with straight chain saturated fatty acids that have an even number of 14 to 22 carbon atoms exhibit.

The salts according to the invention are obtained in a manner known per se by reacting N-phenyl-N- (2-pyridylethyl) -2- {N-piperidino) -ethylamine or one of its mineral acid salts with a saturated straight-chain fatty acid with an even number of 14 to 22 carbon atoms or a salt of this acid.

Suitable fatty acids with an even number of 14 to 22 carbon atoms are: myristic acid. Palmitic acid, stearic acid, arachidic acid, and hehenic acid. Such salts with fatty acids can generally be obtained as salts with 3 moles of the fatty acid will.

The following experimental data show the properties of the products according to the invention:

Attempt 1

Stability test

The test was carried out to check the color change and the hygroscopic character.

1. N-Phenyl-N- {2-pyridylmethyl) -2- (N-piperidino) -ethylamine-tri-palmitate.

2. N-phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) -ethylamine-tristearate.

3. N-Phenyl-N- {2-pyridylmethyl) -2- (N-piperidino) -ethylamine-tri-myristate.

4. N-phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) -ethylamine-tri-behenate.

5. N-Phenyl-N- (2-pyridylmethy]) - 2- (N-piperidino) -ethylamine (control).

6. N-Phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) ethylamine hydrochloride (Control).

7. N-Phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) -ethylamine-tri-oleate (Control).

Conditions: 40 ^c C, 90% relative humidity.

The above samples were allowed to stand under these conditions, and the changes that occurred over time have been observed. The results are shown in Table 1 (color changes) and Table 2 (degree of swelling).

Table of color changes

connection 3 7th time in
10 Days
14th 21 28 Connections according to the
invention
number 1 No. 2 No. 3 - ■ - - I. I. Nf. 4th -

I 935 172

continuation

connection j 7th £ eji in
II) Η 2K control
No. 5. ,,, : + -γ- No. 6 + + + No. 7 + +

- = No change.

H- = Little change. • + H- = weak change. + H- + = noticeable change.

Table T, degree of swelling

connection 3 7th time in
10 Days
14th 21 28 number 1 + i M I MIM - - - No. 2
No. 3
No. 4
No. 6 (control) -

- = No change. + = Little change. + + ■ = Weak change. + + + = Noticeable change.

From Tables 1 and 2 '.lervor. that the control compounds 5, 6 and 7 underwent discoloration before the lapse of 14 days and the control compound 6 swelled on the third day, while the compounds according to the invention showed neither discoloration nor swelling after 28 days.

Attempt 2
Determination of the antitussive effectiveness (on the dog)

An aqueous suspension of the compound to be tested was introduced into the stomach of a coughing and non-anesthetized male dog (weight 8.5 kg) through a previously inserted tube, and the 50% antitussive dose (AtD ₅₀ ) was measured according to the "Coughing dog method "By Y. Käse, see Selected Pharmacological Testing Methods, 363, A. Burger eds., Marcel Dekker, Inc., New York (1969). The results are shown in Table 3.

Table 3

Table 3 shows that the inventive method

bindings are just as effective as control and

Starting compound No. 5 on an equivalent basis.

but superior to the commercially available noscapine

Preparations.

Attempt 3

Taste test

The powdery compounds were orally administered to ten adults, and their bitterness The taste was assessed as having a persistently unpleasant taste.

Table 4 connection connection

number 1

No. 2

No 3

No. 4

No. 5 (control)
Noscapine (control)

AlD ₅₀ on dogs (mg kg)

38.5 (10.7)

41.6 (10.7)
35.8 (10.8)

47.7 (10.7)
10.8

100 compound according to the invention

number 1

No. 2

No. 3

No. 4

control
No. 5 ..
No. 6 ..

Number of people

10 10 10 10

0 0

0 0 0 0

0 0

0 0 0 0

0 0

The numbers in brackets are the equivalent values based on control compound no. - = No perception at all.

+ = Minor perception. -I- + = noticeable perception. -t- + = very monotonous perception.

t 935172

Table 4 shows that the compounds of the invention in contrast to the control connections, the al? felt extremely bitter, none at all produce a bitter taste with a persistent unpleasant aftertaste.

Attempt 4

Table 5

Mice
Rats

intravenous

9.6 (8.6)
8.3 (7.5)

orally

195 (175.5)
820 (738.0)

a) Average acute toxicity of compound no. 6 l0 b) Average acute toxicity of compound no. 1 _{Carrying out the test Carrying out the test}

Compound No. 6 was administered orally or intravenously to groups of 10 male mice each (ICR-JCL T strain, 4 weeks old) and groups of 10 male rats each (SD-JCL / T strain, 6 weeks old). The animals were kept under observation for 4 days and the LD _{50 was} then determined by the Litchfield-Wilcoxon method. The results are shown in Table 5.

Compound No. 1 was administered intraperitoneally, subcutaneously or orally to groups of 10 mice (ICR-JCL / T strain, 4 weeks old) and groups of rats (SD-JCL / T strain, 6 weeks old), the animals were kept under observation for 7 days and the LD _{50 was} again determined by the Litchfieid-Wilcoxon method. The results are shown in Table 6.

table

At the administration

Intraperitoneally
Subcutaneous ....
Orally

LO _ä "(mg kg)

mouse
male ι female

300 (87)
660 (191.4)
700 (203)

200 (81.1) 690 (200.1) 750 (217.5)

(145) D ₅₁ ) (mg kg) Female (127.6 (348) rat 440 (362.5 (841) ___ 1250 (870) 3000 male 500 1200 2900

The numbers in brackets indicate the control connection no. 5 converted values.

Tables 5 and 6 show that the compounds according to the invention are less toxic than that Compound No. 6.

Pharmaceutical mixtures containing salts according to the invention can be prepared according to known Methods of making powders. Tablets. Capsules, syrups or injections can be made.

In the following examples, parts are parts by weight unless otherwise specified. Part by weight behaves to part of space as grams to cubic centimeters.

15.9 parts of palmilic acid in 100 volume dividers of ethanol admitted. The mixture was stirred for a while and then concentrated. After adding ether to the Colorless crystals precipitated from the concentrate, which were filtered off, washed with petroleum ether and recrystallized from acetone became. The yield was 14.2 parts of N-Phemi-N - (2 - pyridylmethyl) - 2 - (N - piperidino) - ethylamine tri-palmitate from melting point 59 to 61 C.

Analysis (for C ₁₉ H ₂₅ N ₃ 3C, _h H ₃₂ O ₂ ):

Calculated ... C 75.58, H 11.46. N 3.95:
⁴ - found .... C 75.48. H 11.42, N 3.91.

example 1

1.5 parts of N-phenyl-N- (2-pyridylmethyl) -2- (N-piperidino) ethylamine were dissolved in 5 parts by volume of ether and "to this a solution of 4.2 parts of stearic acid in 60 parts of ether is added. After standing the mixture and constriction, colorless crystals fell which were filtered off and dried. The yield was 4.9 parts of N-phenyl-N- (2-pyridylmethyl) -2 - (N-piperidino) ethylamine tristearate with a melting point of 51 to 55 ° C

Analysis (for C ₁₉ H ₂₅ N ₃ · 3C ₁₈ H ₃₁₁ O ₂ ):
Calculated ... C 76.32. H 11.67, N 3.66:
found .... C 75.92, H 11.98. N 3.69.

Example ?

1.5 parts of N-phenyl-N- (2-pyridy! Mclhyl) -2- (N-piperidino) ethylamine were dissolved in 5 parts of ether and then with a solution of 3.3 parts Myristic acid added in? 0 parts by volume of ether. After a while the mixture was concentrated, whereupon colorless crystals precipitated, which were filtered off and dried. The yield was 3.6 parts of N-phenyl-N - (2 - pyridylmethyl) - 2 - (N - piperidino) - ethylamine myristai from melting point 48 to 51 ° C.

Analysis (for C ₁₉ H ₂₅ N ₃ 3C _U H _2K O ₂ ):

"° Calculated ... C 74.72, H 11.20, N 4.29:
found .... C 74.64, H 11.48. N 4.24.

Example 2

4.5 parts N-Phen *, I-N- (2-pyridylmethyl) -2- (N-piperidino-ethylamine were dissolved in 5 parts by volume of ethanol, followed by a solution of

fts example 4

1.5 parts of N-phenyl-N- (2-pyridylmethyl (-2- (N-pipcridino) ethylamine) were dissolved in 5 parts by volume of ethanol and the solution then with the solution

of 5.1 parts of acidic acid in HH) Kuumlcilcn Alhanol added, the ethanolic solution at 50 ° C had been made. The mixture obtained was stirred at 40 ° C. for some time and then concentrated, whereupon colorless crystals precipitated. After addition of Pctrolülhcr, 5.2 parts of N-Phcnyl-N - (2-pyridylmclhyll-2-IN-pipcridino) -äiihylami tri-behcnat from melting point 74 to 76 ° C obtained

Analysis (for C ₁₁₁ H ₂₅ N., 3C ₂₂ II ₄₄ O,):

Calculated ... C 77.51. Il 12.01. N 3.19; found .... C 77.26. Il 11.86, N 3.37.

Claims (2)

Patent claims: 1. Salts of N - Plier · ;; . N > (2- pyridylraethyth 2- (H * piperidino) -äthylarnros contains straight-chain saturated fatty acids which have an even number of Have 14 to 22 carbon atoms, 2. Pharmaceutical preparation, characterized by a content of a compound according to Addressed 1 as the only active ingredient in connection ip with pharmaceutically acceptable carriers or thinners.