DE1693031B1 - DIPROPYL ACETANILIDE AND DIPROPYL ACETYL SALICYL ACID DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

a) R ₁ = H, —OH, -OC ₂ H ₅ , -CF ₃ or -NH-CO-CH ₃ with R ₂ = R ₃ = R ₄ = R ₅ = H,

ß) R ₂ = -CF ₃ , R ₅ = H or -CF ₃ with Ivj ⁼⁼⁼ 1V3 = JK4 ^ rl,

_γ ) R ₃ = -CF ₃ with R ₁ = R ₂ = R ₄ = R ₅
= Dog

ö) R ₅ = -CF ₃ , R ₃ = -Cl with R ₁ = R ₂ = R ₄ = H or

b) if Y is an oxygen bridge,

R ₁ = R ₂ == H, R ₃ = —COOH and R ₄ , R ₅ = H or part of a fused benzene nucleus,

2. Process for the preparation of the compounds of claim 1, characterized in that one dipropylacetyl chloride with an optionally substituted according to claim 1 compound the formula

YH

in which Y has the meaning already given, alone or in the presence of solvents, preferably pyridine or dioxane, in particular reacting with heating of the reaction mixture. 3. Agents with analgesic, antipyretic and anti-inflammatory effects, marked by a content of at least one of the compounds of claim 1.

The invention relates to acetanilide and compound of the all-acetylsalicylic acid derivatives substituted by the above definition the general formula common formula

Y-CO-HC

C ₃ H ₇

C ₃ H ₇

40

(D

45

in which Y is an oxygen bridge or the NH group and the ligands on the benzene nucleus

a) if Y is the NH group,

a) R ₁ = H, —OH, -OC ₂ H ₅ , -CF ₃ or —NH-CO — CH ₃ with R ₂ = R ₃ = R ₄

= R ₅ = H,
ß) R ₂ = -CF ₃ , R ₅ = H or -CF ₃ with Rj

= R ₃ = R ₄ . = H,
_γ ) R ₃ = -CF ₃ with R ₁ = R ₂ = R ₄ = R ₅ = H

and
d) R ₅ = -CF ₃₇ R ₃ = -Cl with _{R 1} = R ₂ = R ₄ = H or

b) if Y is an oxygen bridge,

R ₁ = R ₂ = H, R ₃ = —COOH and R ₄ , R ₅ = H or part of a fused benzene nucleus,

The manufacture of the new acetanilide and acetylsalicylic acid derivatives takes place by reacting dipropylacetyl chloride with an optionally according to YH

in which Y has the meaning already given, alone or in the presence of solvents such as pyridine or dioxane, preferably with heating of the reaction mixture.

The compounds corresponding to the general formula (1) are particularly distinguished by a analgesic or reliever, antipyretic and anti-inflammatory or anti-inflammatory effects and corresponding pharmaceutical compositions containing these compounds are also included the subject of the invention. However, the new compounds also prove to be the starting material for chemical syntheses as useful and the derivatives of dipropylacetanilide are with success as Food preservatives applicable.

The invention relates in particular to the products from the dipropylacetanilide series listed in the table below as well as dipropylacetylsalicylic acid (hereinafter referred to as B.34.65), dipropylacetylsalicylic acid amide (hereinafter referred to as B.G. 12 P.F.) and α-dipropylacetyloxyjo-naphthoic acid (hereinafter referred to as B.G. 12 P.B.). :

ORIGINAL INSPECTED

product

Referred to as

Alcohol concentration

for recrystallization:

percentage

nature

Melting point after recrystallization

(Fp.)

yield

Percentage of the main elements

C. % H % N be
calculates ge
found be
calculates ge
found be
calculates 71.95 71.03 8.99 8.86 5.95 72.96 72.88 9.57 9.65 5.32 62.72 62.66 7.02 7.03 4.88 68.39 69.35 9.08 8.86 10.55

found

4-hydroxydipropyI-acetanilide

4-ethoxydipropylacetanilide

4-trifluoromethyldipropylacetanilide

4-acetylamidodipropylacetanilide

B.G.ll G.B.

B.G.ll GA.

B.G.ll J.G.

B.G.ll M.V.

96

60

80

60

beige pink crystalline powder

white crystalline powder

white crystalline powder

white crystalline powder

104 °

153 °

157 °

250 °

4.97

10.27

= NH

R ₃ R ₂ R ₁ R ₅ R ₄ H H OH H H H H C ₂ H ₅ O H H H H CF ₃ H H H H CH ₃ -CO-NH H H

product Designated
as alcohol
concentrate
for the order
crystallize;
percentage Procure
Ness Enamel
Point
after
Around
crystalline
sate
(Fp.) the end
prey
% Pr
C.
be
calculates ocentual
%
ge
found he share
H
be
calculates the house
%
ge
found ptelemer
N
be
calculates ite
%
ge
found 3-trifluoromethyl
dipropylacetanilide BGll
JF 80 white
crystalline
nes Pul
ver 64 ° 70 62.72 62.56 7.02 6.97 4.88 4.97 3,5-di- (trifluorom-
thyl) -dipropyl-acet-
anilide BGll
JI 95 the same 153 ° 89 54.08 54.36 5.39 5.42 3.94 3.86 2-trifluoromethyl
dipropyl acetanilide BGll
JE 80 the same 100 ° 76 62.72 62.60 7.02 7.12 4.88 4.98

R ₃ R ₂ Ri R ₅ R ₄ H CF ₃ H H H H CF ₃ H CF ₃ H CF ₃ H H H H

5 alcohol
concentration
for the order
crystallize:
percentage R ₃ 1 693 03 1 R ₂ R ₁ the end
prey
% Prc
C ⁰
be
calculates jcentual
ge
found 6th R ₄ the house
%
ge
found ptelemer
N
be
calculates ite
%
ge
found product Designated
as 70 Cl Procure
Ness Enamel
Point
after
Around
crystalline
sate
(Fp.) H H 49 55.00 55.91 he share
H
be
calculates H 6.12 4.35 4.45 2-chloro-5-trifluoro-
methyldipropyl
acetanilide BGll
JH white
crystalline
nes Pul 77 ° 5.95 ver Y = NH R ₅ CF ₃

External texture

The products according to the invention are mostly in the form of a crystalline powder, which in general white, sometimes also beige-pink.

Method of manufacture
of the products according to the invention

In the following, the production of the products according to the invention is described by means of examples, specifically with reference to the preparation of dipropylacetylsalicylic acid, p-hydroxy-dipropylacetanilide and 2-chloro-5-trifluoromethyl-dipropylacetanilide. The other derivatives can be analogous Way to be obtained.

1. Preparation of dipropylacetylsalicylic acid

4.89 g of dipropylacetyl chloride (30 mmol) are with 3.66 g salicylic acid (30 mmol) in the presence of pyridine (50 ml) freshly distilled over potassium hydroxide Heated to reflux for 2 hours.

The precipitate which forms is separated off and the filtrate with 20 ml of 5% aqueous hydrochloric acid added and extracted twice with 50 ml of ethyl ether. The ethereal phase is dried with sodium sulfate and evaporated.

The evaporation residue is obtained by precipitating the product from alcoholic solution by adding purified by water. After three or four consecutive treatments you get a product whose aqueous-alcoholic solution with ferric chloride no longer gives any color.

Α-Dipropylacetyloxy - /? - naphthoic acid in particular was used in the same way and the dipropylsalicylamide.

2. Preparation of p-hydroxy-dipropylacetanilide

4.89 g of dipropylacetyl chloride (30 mmol) and 6.54 g of p-aminophenol (60 mmol) are dissolved in 100 ml refluxed anhydrous dioxane for 1 hour.

The reaction mixture is evaporated and the residue is then dissolved in 20 ml of warm 96% alcohol. The hot solution is filtered and the filtrate is ^{cooled to 0} ° C .; crushed ice is then added very slowly until the precipitation is complete. This measure is repeated several times.

3. Preparation of 2-chloro-5-trifluoromethyldipropylacetanilide

4.89 g of dipropylacetyl chloride (30 mmol) are mixed with 11.76 g of 2-chloro-5-trifluoromethylaniline at room temperature for 10 minutes (60 mmol) mixed.

A precipitate forms and is separated off.

The precipitate is washed with water by shaking in a separatory funnel until the with Nitric acid-acidified aqueous phase no longer provides turbidity with silver nitrate.

The organic precipitate is evaporated to dryness. The residue is precipitated with Purified water from alcoholic solution.

Pharmacological properties
and therapeutic applications

The products according to the invention have, in particular, pain relievers or pain relievers, antipyretic ones and anti-inflammatory or anti-inflammatory properties, which are usually stronger than at the same dose those of aspirin.

These properties have been demonstrated in particular by the following tests.

I. Measurement of analgesic effectiveness

A. Measurement method

Mice were placed on a metal grid connected to an electrode of a device for generating electrical excitations of known duration and amperage. The tail of the animals was connected to the second electrode in such a way that the current was connected through the body of the animals. The device was regulated in such a way that a direct current surge lasting 1.5 seconds with a variable current intensity could be sent via a high-frequency relay and monitored with a connected oscilloscope.
Groups of ten mice were used for the experiments, and each animal was examined separately. After placing it on the grid in the manner described, a current impulse of low intensity was applied, starting with a voltage of 10 V, which was then increased by 5 V each time until the treated mouse uttered a short scream. This experiment was repeated every 10 minutes for 1 hour and after averaging the voltages at which the ten animals performed on each

Γ 693

Attempts to utter their scream, these values were plotted graphically. The mean value thus obtained the voltage in the animals fluctuates between 20 and 22 V, depending on the animal group.

On the following day, these "measured" animals were treated with the product to be examined, that was administered buccally. The same measurements were carried out again, namely initially every 10 minutes and then, if necessary, every 15 or 30 minutes until the effects wear off of the product and reaching the voltage threshold observed the day before.

If the product entered has analgesic properties, the animals tolerate as long as xeine Effect lasts, much greater currents without yelling than the untreated animals.

Through this process, the speed of the effect of a product and can be simultaneously the strength and duration of its effect can be determined.

called. These appear after about 3 to 5 minutes and are characterized by a bending of the mouse's spine with spreading or stretching of one of the hind paws in a very characteristic way. ■■ -

For the evaluation, the number of these is characteristic Movements within 20 minutes of injection are counted. .. "■ -.

Groups of 12 mice each and the number of pain attacks were used for the investigations in the treated mice with the behavior of untreated or known products treated animals compared.

The products to be examined were administered to the animals in suspension in gum or gum resin ¹ Z ₂ hours before the test by the buccal route.

Results (with the same doses)

B. Scored Results 'with the same doses) Time in minutes,
after which the Latency Maximum
of the Mice the
normal
Tension Examined
product after
recording
of
Prndiikfp "! Animals
without
scream swell again Γ ί UUUhlCj
in Kn.nntm * i tolerated reach in IVUnuts tension (V) Acetylsalicylic 120 acid 10 40 300 B. 34.65 .. 0 60 180 B.G. 12. P.F. 10 27 200 B.G. 11th GA. 60 34 260 B.G. 11. G.B. 0 38 180 B.G. 11. M.V. 0 32 260 B.G. 11. J.E. 0 40 240 B.G. ll.J.F. 0 35 240 B.G. ll.J.G. 0 40 440 B.G. 11 J H. 0 53 500 B.G. 11.J.I. 0 47 240 B.G. 12. P.B. 0 36 N-acetyl p-amino- 195 phenol 10 38

product Middle number
the spreading 25th Acetylsalicylic acid 2.5
15.6
8.6
7.8
9.2
8.7
8.2
2.2
2.4
4th
3.5
2.5
3.5
34 N-acetyl-p-aminophenol ....
B. 34.65 B.G. 12. P.F 30th B.G. 11th GA B.G. 11. G.B BG. ll.M.V. B.G. 11. J.E 35 BG. 11.J.F B.G. ll.J.G B.G. ll.J.H B.G.ll.J.I 40 B.G. 12. PB

As can be seen, the analgesic effect found in these experiments is that according to the invention Products by nature mostly with those of acetylsalicylic acid and N-acetyl-p-aminophenol comparable and sometimes better and in all cases the duration of action is longer than that of acetylsalicylic acid. Other investigations (writhing test) with benzoquinone, acetic acid and analgesimeter test according to R a η d a 11 and S e 1 i 11 ο confirm these results.

The "writhing test" and its results using acetic acid are discussed in more detail below described in detail.

Measurement of the analgesic effectiveness according to the "writhing test" with acetic acid.

In this test, mice are injected intraperitoneally with 300 mg / kg of a 3% aqueous Acetic acid solution produced typical attacks of pain- This experiment shows that the analgesic effect of the products according to the invention are mostly comparable and sometimes with that of acetylsalicylic acid is even better; in all cases the analgesic effect is that of N-acetyl-p-aminophenol think.

50 II. Determination of the antipyretic effect

A. Measurement method

As test animals rabbits were used, in which by intraperitoneal injection of an aqueous 10% suspension of brewer's yeast in amounts of 1 ml / kg weight caused hyperthermia became.

After this injection, the temperature of the animals was regularly rectal using every 30 minutes a thermocouple measured and the mean value of the temperature of a group of test animals at determined at each temperature reading.

It was worked with groups of four rabbits, which the products to be examined in a Dose of 165 mg / kg buccally 1 hour and 30 minutes after the brewer's yeast injection was administered.

309 507/595

B. Results

In the comparison animals and in the animals treated with the products to be examined, the maximum temperature was reached 5 hours and 30 minutes after injection of the brewer's yeast. However, they showed an increase of 2.1 in the control animals - C, whereas the analogous figures were treated with aspirin animals at 1.9 ° C and treated as animals 34.65 at 1.2 ° C.

In addition, the temperature curve for the comparison animals is based on this maximum value a plateau that was 2 hours and 30 minutes before the very slow decline to normal temperature began exists because the hyperthermia is still 1.5 ° C 10 hours after the injection.

In the case of the animals treated with acetylsalicylic acid, there is an immediate slight temperature drop of 0.2 ^° C. and by the tenth hour the temperature of the treated rabbits is the same as that of the comparison animals.

The treated as animals 34.65 finally an immediate sharp drop by 1 ° C will take place, and at the tenth hour, the temperature of the animals has virtually reached its initial value again as hyperthermia then amounts to only 0.15 ^0C.

35

III. Determination of anti-inflammatory
or hostile effect

A. Measurement method

The determination was made on groups of ten mice. These mice became subcutaneous 0.05 ml of a 4% formole solution was injected into the back of the right hind paw. In the same Way, for the purpose of comparison, the same volume of physiological saline solution was used in injected the left hind paw.

Each animal then received 0.10 ml of a 0.5% Evans blue solution in physiological in the tail vein Saline solution.

After one hour, the animals were checked and the difference in coloration became apparent found in both hind paws (the right opposite the left), those in the inflamed paws more pronounced was.

The following notation was specified for the evaluation:

0: no difference compared to the control paw,

+: easily noticeable difference,
+ +: clear difference,
+ + 4-: very strong difference. .

The animals were then sacrificed and their paws cut off at knee joint level and the whole all right and left paws weighed. The difference in weight between the one on the right or left paws determined mean value gives a measure of the strength of the udem.

The test animals were given acetylsalicylic acid 3 hours before the test and 2 hours after the formol injection or the product to be examined is administered buccally in the form of a suspension in gum or gum resin in variable doses.

B. Results

The results obtained are summarized in the following table:

D. IO Comparison animals .... coloring Edema weight Percentage Acetylsalicylic acid (Total (middle inflammation 200 mg / kg x 2 all + for weight opposite to Examined product Phenylbutazone ten of the edema the 50 mg / kg x 2 Mice) per mouse) Comparison B. 34.65 (mg) animals 200 mg / kg x 2 17th 33 (%) ²⁰ B. 34.65 100 100 mg / kg x 2 10 31.1 B. 34.65 91.2 50 mg / kg x 2 20th 20.7 25 B.G. 11.J.H. 62.7 200 mg / kg x 2 11th 22.6 68.4 G 24 72.7 11th 33 100 8th 21.2 64.2

55 As you can see, the B. 34.65 shows a more pronounced anti-inflammatory effect at the same dose for edema weight as acetylsalicylic acid. It is extremely interesting to note that the dose reduced to half for B. 34.65 gives essentially constant results. Against it at a dose of 50 mg / kg there is no longer any noticeable effectiveness in terms of edema weight established, which suggests that the action of B. 34.65 is dominated by a swelling phenomenon.

The effectiveness of the B.G. 11. J.H. was essentially identical to that of B. 34.65.

Additional measures of anti-inflammatory effectiveness were made with various others Products according to the invention carried out according to different test methods.

All of the anti-inflammatory substances were given to the animals in all experiments in the form of a Suspension in a 4 to 6% tragacanth gum solution administered buccally, namely in the Way that the total dose in mice contained in a volume of 0.15 ml and in rats of 0.30 ml was.

A. Kaolin test

For this test, mice weighing 20 to 24 g were used, each in groups of about thirty animals were divided. The products to be examined were given to animals 48 and Administered buccally 24 hours before kaolin injection and a third (the preceding same) dose on the third day together with the kaolin injection. The latter was subcutaneously at the The sole of one of the hind paws is injected. A 10% kaolin solution was used for this; that of a mouse injected volume was 0.10 ml. In the other hind paw, 0.10 ml became physiological at the same time Saline injected.

The product to be tested was finally given a final time 2 hours before the animals were killed

administered with gas or chloroform, which is done 20 to 24 hours after the kaolin injection became. The two hind paws of the animals were cut off at the level of the "knee joint" and those with

Kaolin-treated and untreated paws were weighed separately for each animal. The percentage of Edema formation was calculated according to the following equation:

(Mean weight of paws treated with kaolin - mean weight of paws not treated with kaolin) Mean weight of paws not treated with kaolin

100.

The results obtained were compared with results obtained with groups of control animals which were merely injected with kaolin without any preparation.

B. Formaldehyde test

For the study, adult mice of any sex were divided into groups of approximately 30 animals are used.

The animals were administered orally for 4 days using an esophageal probe (esophageal probe) treated with the products to be examined suspended in rubber or gum resin, the latter being Administration took place 2 hours before the formaldehyde injection. The latter was done in the following way: Each mouse was subcutaneously 0.05 ml of a 4% formaldehyde solution in the sole of the foot the left hind paw and at the same time 0.05 ml of physiological saline solution in the right hind paw injected. 1 hour after the formaldehyde injection, the animals were sacrificed with gas or chloroform.

The paws were cut off at the level of the "knee joint" and weighed separately for each animal.

The percentage of edema formation was calculated in the following way:

(Weight of paws treated with formaldehyde - weight of paws not treated with formaldehyde) Weight of paws not treated with formaldehyde

100.

The results obtained were compared with results obtained in comparison animals, those only formaldehyde was injected without any pretreatment.

C. Carrageenin test

The test was carried out on male rats weighing 150 to 200 g.

The animals were pretreated daily for 8 days with the product to be tested based on oral Ways was administered. On the 8th day, the animals received a simultaneously with the product to be tested subcutaneous injection of 1 ml of a 1.5% carrageenin solution in physiological saline solution one side of your back. The daily treatment of the animals (with the product to be examined) was continued until the animals were killed by gas or chloroform, which was the 5th day after the carrageenin injection took place. The granuloma formed was dissected out and weighed.

The results obtained were compared with results obtained with untreated control animals were achieved, which therefore only received the carrageenin.

Results of the exams
the anti-inflammatory effects
(with the same doses by weight)

The following notation was specified for the evaluation:

0: no inflammation inhibition compared to the comparison animals,
+: 10 to 30% inhibition of inflammation

compared to the comparison animals,
+ +: 30 to 50% inhibition of inflammation

compared to the comparison animals and
+ + +: more than 50% inhibition of inflammation compared to the comparison animals.

product

Acetylsalicylic acid
Phenylbutazone ...

B. 34.65

B.G.11.J.H

Formaldehyde-
test

Kaolin test

Carra-

genin-

test

These various experiments show that the anti-inflammatory Effectiveness of B. 34.65 with that of acetylsalicylic acid and phenylbutazone is comparable, while the anti-inflammatory effectiveness of B.G. 11. J.H. is always stronger than that of acetylsalicylic acid and phenylbutazone.

toxicity

After various test methods it was found that the lethal dose of the products according to the invention is higher in all cases than with aspirin. While the DL ₅₀ value for acetylsalicylic acid is 1.5 g / kg, it is always higher than 2.5 g / kg for the products according to the invention.

Clinical examinations

Results of some clinical examinations are given below as examples, which show the application of products according to the invention.

A. B. 34.65 (Dipropylacetylsalicylic acid)

1. A 33 year old female patient suffers from a forehead headache on awakening. One 500 mg tablet of the Product begins to work after 15 minutes. The pain disappears and occurs on Days not up again.

No intolerance; no secondary phenomena.

2. A 42-year-old female patient suffers from flu-like conditions with runny nose and forehead and back of the head pain if there is no fever. The patient is "nervous" (malade normotendue).

One 500 mg tablet of the product was administered. The headache disappears ¹ I ₄ . Hour after ingestion and only sets in again after 2 hours. A further administration of a tablet when the pain recurs is therefore appropriate, or successfully makes the pain disappear.

No intolerance; no secondary phenomena.

3. A 42 year old patient has alveodental arthritis. The algia includes the right upper and Lower jaw; Mastication impossible.

A 500 mg tablet of the product suppresses the painful paroxysm after 15 minutes and the abnormal sensitivity to jaw pressure. On the other hand, it remains a background of pain. The effects last for 3 hours.

No intolerance; no secondary reactions.

B. B.G. 11th year (3,5-bis [trifluoromethyl] dipropylacetanilide)

1. A 52 year old female patient suffers from frequent forehead headaches on days.

One 250 mg tablet of the product will work after a few Minutes and the pain does not return throughout the day.

Excellent tolerance.

2. A 26 year old female patient suffers from severe forehead and back of the head pain, which undoubtedly affects one apyretic flu-like affect decreases.

Two 250 mg tablets will make the pain go away in 10 minutes. After However, it begins to return in 3 hours, after which two tablets are given again. Of the Pain then disappears completely and does not recur.

No secondary symptoms; very good tolerance.

C. B.G. 11. J.H. (2-chloro-5-trifluoromethyl-

dipropylacetanilide)

1. A 46 year old patient suffers from osteoarthritis of the right knee joint as a result of a previous one Injury. Walking is very difficult.

One 250 mg tablet will significantly reduce the pain of walking after 15 minutes. After 4 hours the pain reappears; a second tablet allows you to calm down again.

No secondary phenomenon; very good tolerance.

2. A 32-year-old female patient suffers from tendinitis on the left elbow as a result of a relatively short posterior humerus fracture.

Treatment with four tablets a day for 8 days can suppress the pain while the patient is healing.
No secondary symptoms; no intolerance.

D. The other products of the invention
give similar results

Pharmaceutical forms and dosage

The products according to the invention can be diluted in the form of tablets, troches, coated tablets, capsules, etc. with conventional and, depending on the selected pharmaceutical form, suitable excipients in Doses of 100 to 1000 mg per unit are taken. In general, they can be in any suitable Administered in a manner (orally, rectally, parenterally or otherwise), individually or in combination and in the presence of the usual excipients which are necessary for the preparation of the chosen form of administration.

Claims (1)

Patent claims: 1. Acetanilide and acetylsalicylic acid derivatives of the general formula in which Y is an oxygen bridge or the NH group and the ligands on the benzene nucleus a) if Y is the NH group,