DE1693031C2 - - Google Patents

Description

QH ₇

in the Y an oxygen bridge or the NH group means 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. = R ₄

- R = 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, = R ₂ = R ₄ = R ₅

= Dog 6) Rj = -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 _s = H or part of a fused Benzolkeras,

2. Process for the preparation of the compounds of / jispruchs 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, aHein 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 awideetens one of the compounds of claim 1.

The invention relates to acetanilide and acetylsalicylic acid derivatives of the general formula Above definition substituted compound of the general formula

C ₃ H ₇

Y-CO-HC

(D

C ₃ H ₇

in Y an oxygen bridge or the NH group means 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

- KJ = H., ß) R ₂ = -CF ₃ , R ₅ = H or -CF ₃ with R ₁

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

and A) R ₅ = -CF ₃₁ R ₃ = -Cl with R, = 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 preparation of the new acetanilide and acetylsalicylic acid derivatives takes place by reacting dipropylacetyl chloride with an optionally according to

40

45 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 agents with a Contents of these compounds are thus also part of the subject matter of the invention. However, the new compounds also prove useful as starting materials for chemical syntheses and the Derivatives of Dipropylacetanilids are with success as

Food preservatives applicable.

The invention relates in particular to the products listed in the table below from the Dipropylacetaniiidzeile as well as Dipropylacetylsailicyläure (hereinafter referred to as B.34.65), the di- propylacetylsalicylic acid amide (hereinafter referred to as B.G.! 2 P.F.) and α-dipropylacetyloxy - / <- naphthoic acid (hereinafter referred to as B.G. 12 P.B.).

product Designated Alcohol-
concentral ion
for the order Procure Enamel
Point
after Out Percentage
I. be f ge H be the main elements ge N be V. ge as crystallize: Salvation Around prey c calculates found calculates % found calculates found • Percentage salt crystalline 71.95 71.03 8.99 8.86 5.95 6.21 sate (Fp.) V. • 4-hydroxydipropyl B.G.11 % beige pink 104 ° 64 acetanilide G.3. crystalline 72.96 72.88 9.57 9.65 5.32 5.60 nes Pul ver 4-ethoxydipropyl B.G.11 60 white 153 ° 92 acetanilide GA crystalline 62.72 62.66 7.02 7.03 4.88 4.97 nes Pul ver 4-trifluoromethyl B.G.ll 80 white 157 ° 74 dipropylacetanilide JG. crystalline 68.39 69.35 9.08 8.86 10.55 10.27 nes Pul ver 4-acetylamidodipro- B.G.ll 60 white 250 ° 71 pylacetanilide M.V. crystalline nes Pul ver

Y = NH

R ₃ R ₃ R. R ₅ R * 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

3-trifluoromethyl dipropylacetanilide

3,5-di- (trifluoromethyl) -dipropyl-acetanilide

2-trifluoromethyl dipropyl acetanilide

Referred to as

Alcohol coniceatration

Ki recrystallization;

percentage

BGU J.F.

B.G.11 JI.

BGU J.E.

80

95

80

Besdialfcaheit

white crystalline powder

desgi.

(fcsgl.

Melting point after ■ recrystallization

(Fp.)

Ausseute

64 °

153 °

100 °

70

89

Percentage of the main elements

calculated

62.72

54.08

62.72

found

62.56 54.36

62.60

H%

calculates

7.02

5.39

7.02

found

6.97

5.42

7.12

NV.

calculated

4.88

3.94

4.88

found

4.97

3.86

4.98

= NH

R » R ₁ R,. R ₁ H H CF ₃ H H H H CT ₃ H CF ₃ H CF, H H H

■ product 5 alcohol R ₃ 1 693 03 1 Procure Enamel R ₂ R, f Out 6th be ge R ₃ H be ■ V the main elements ge N% be ge concentration
for the order Cl Ness Point
after H H prey Percentage calculates found CF ₃ calculates H found calculates found Designated crystallize:
percentage Around
crystalline 55.00 55.91 5.95 % 6.12 4.35 4.45 as sate % C% 2-chloro-5-trifluoro- white (Fp.) 49 roethyldipropyl 70 crystalline 77 ° acetanilide B.G.11 nes Pul J.H. ver Y = NH

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 wild the production of the invention Products described with the aid of examples, specifically with reference to the manufacture of dipropylacetylsalicylic acid, p-hydroxy-dipropylacetanilide and 2-chloro-5-trifluoromethyl-dipropylacetanilide. The other derivatives can be obtained in an analogous manner.

1. Preparation of dipropylacetylsalicylic acid

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

The precipitate which forms is separated off and the filtrate with 20 ml of 5% aqueous hydrochloric acid added and twice with 50 ml of ethyl? ther extracted. 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.

In the same way, a-Dipropylacetyloxy - ^ - naphthoic acid in particular 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 nil refluxed anhydrous dioxane for 1 hour.

The reaction mixture is evaporated and the residue is then dissolved in 20 ml of warm 96% alcohol solved. The hot solution is filtered and the filtrate is cooled to OC; then you give the chopped up very slowly Add ice 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 shaken in one

Separating funnel washed with water until the aqueous phase acidified with nitric acid is not cloudy supplies more 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 st. ! im heart calming or relieving, antipyretic 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 controlled in such a way that a direct current surge of 1.5 seconds of 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 on the gitteri in the manner described, a current impulse was applied low strength, starting with a voltage of 10 V, which was then increased by 5 V each time until the treated mouse uttered a short cry. This experiment was for 1 hour every Repeated 10 minutes and after calculating the mean values of the tensions at which the ten animals in the individual eggs

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 made 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 simultaneously the strength and duration of its effect can be determined.

B. Scored results [at the same doses) Time in minutes,
after which the Latency Maximum
of the Mice the
normal Examined after
admission Animals
without Tension product of
Prnrl ti Ir 11 * «; scream swell again rrOUUK ICa tolerated reach in minutes voltage (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. ll.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 ll.J.H. 0 53 500 B.G. ll.J.I. 0 47 240 B.G. 12. P.B. 0 36 N-acetyl p-amino- 195 phenol 10 38

As can be seen, the analgesic effect of the products according to the invention found in these tests is essentially the same as that of acetylsalicylic acid and N-acetyl-p-aminophenol comparable and sometimes better and in all In some cases, the duration of action is longer than that of acetylsalicylic acid. Other examinations (curvature resp. Stretching test (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.

This test is performed on mice by intraperitoneal Injection of 300 mg / kg of a 3% aqueous acetic acid solution caused typical attacks of pain. These appear after about 3 to 5 minutes and are characterized by bending of the Spine of the mouse with spreading out or stretching one of the hind paws in a very characteristic way Wise.

For the evaluation, the number of these characteristic movements is shown within 20 minutes of the injection.

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 I ₂ hours before the test by the buccal route.

Results (with the same doses)

product

Acetylsalicylic acid

N-acetyl-p-aminophenol

B. 34.65

B.G. 12. P.F

B.G. 11th GA

B.G. 11. G.B

B.G. ll.M.V.

B.G. 11. J.E

B.G. ll.J.F

B.G. ll.J.G

B.G. ll.J.H

B.G. ll.J.I

B.G. 12. P.B

Average number of spreads

2.5 15.6 8.6 7.8 9.2 8.7 8.2 2.2 2.4 4

3.5 2-5 3.5 34

This experiment shows that the analgesic effect of the products according to the invention mostly corresponds to that of acetylsalicylic acid is comparable and sometimes even better; in all cases the analgesic Effect of those 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 quantities hyperthermia was produced by 1 ml / kg weight.

After this injection, every 30 minutes

utes rectally the temperature of the animals nrit help of a thermocouple and the mean value the temperature of a group of test animals determined at each temperature reading.

Groups of four rabbits were used.

puts the products to be examined in one

Dose of 165 mg / kg buccally for 1 hour

and 30 minutes after the brewer's yeast injection

was administered. · ·

309644/193

B. Results

B. Results

In the comparison animals and in the animals treated with the products to be investigated, the maximum temperature reached 5 hours and 30 minutes after the brewer's yeast injection. she showed however, an increase of 2.1 ° C in the comparison animals, while the analogous values in those with Acetylsalicylic acid treated animals at 1.9 ° C and the animals treated with B. 34.65 at 1.2 ° C lay.

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 animals treated with acetylsalicylic acid, there is an immediate slight drop in temperature of 0.2 "C. and at the tenth hour the temperature of the treated rabbits is the same as that of the Comparison animals.

In the animals treated with B. 34.65, there is an immediate strong decrease in TC, and by the tenth hour the temperature of the animals has practically reached its starting value again, since the hyperthermia is then only 0.1 5 ^C C.

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.
+ + +: very strong difference.

The animals were then killed and cut off their paws in the amount of the knee joint and weighed the totality of all right and all left paws. The difference in weight between the mean value determined for the right and left paws is a measure of the strength of the odema.

The test animals were given acetylsalicylic acid 3 hours before the test and about an hour after the formol injection or the product to be examined buccally in the form of a suspension in rubber or Gum resin administered in variable doses.

The results obtained are summarized in the following table:

3 Examined product coloring Edema weight Percentage (Total (middle inflammation all + for Weight opposite to ten of the Odems the Comparison animals .... Mice) per mouse) Comparison Acetylsalicylic acid (mg) animals 10 200 mg / kg x 2 17th 33 (%) Phenylbutazone 100 50 mg / kg x 2 10 31.1 B. 34.65 91.2 15th 200 mg / kg x 2 20th 20.7 B. 34.65 62.7 100 mg / kg x 2 11th 22.6 B. 34.65 68.4 20th 50 mg / kg x 2 8th 24 B.G. ll.J.H. 72.7 200 mg / kg χ 2 11th 33 100 8th 21.2 64.2

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. On the other hand 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. In doing so, the animals were all anti-inflammatory Substances in all experiments in the form of a suspension in a 4 to 6% tragacanth gum solution administered by the buccal route in such a way that the total dose in mice in one volume of 0.15 ml and in rats of 0.30 ml.

A. Kaolin test

For this test, mice with a weight of 20 to 24 g were used, which were divided into groups of j <

about thirty animals were divided. The too under

Searching products were administered to the animals by buccal route 48 and <24 hours prior to the kaolin injection and a third (the preceding i

same) dose on the third day together with the kaolin injection. The latter was injected subcutaneously into the sole of one of the hind paws . Use was added a 1 0% reference kaolin; the volume injected into one mau was 0.10 ml. In the other Hin

The 6th paw became 0.10 ml physiological at the same time

Saline injected.

The product to be tested was finally tested one last time 2 hours before the killing of the tiei

administered with gas or chloroform, which is done 20 to 24 hours after the kaolin injection would. 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 manner : 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 of 150 carried out up to a weight of 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) continued until the animals were killed by gas or chloroform, which occurred on 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:

product

Acetylsalicylic acid
Phenylbutazone ...

B. 34.65

B.G. ll.J.H

Formaldehyde-
test

Kaolin test

Carrageenin
test

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.

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

In the following, results of some clinical investigations are given as examples, which show the use of products according to the invention.

A. B. 34.65 (Dipropylacetylsalicylic acid)

1. A 33 year old patient has a frontal head

6s pain on waking. A 500 mg tablet de

Product starts after 15 minutes zi

works. The pain disappears and begins

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 for an hour after ingestion and only sets in again after 2 hours. Another administration of a Tablet when the pain recurs is therefore appropriate, or brings the pain successfully to 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. 11. JLI. (3,5-bis [trifluoromethyl] dipropylacetanilide)

1. A 52-year-old patient suffers from frequent forehead headaches during the day.

A 250 mg tablet of the product takes effect 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 after 3 hours, after which another two tablets are administered. 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 reduce the pain while it is healing of the sick are oppressed.

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 Acctylsalicylic Acid Derivatives the general formula C ₃ H ₇ Y-CO-HC (D