DE2627425C3 - Antipyretic with analgesic properties - Google Patents

Description

In the Archives of Pharmacy Vol. 308/1975, pp. 700-712 is 3-Hydroxyinden-2-carboximidic acid ethyl ester of the formula 1 and its preparation are described:

OH

NH

OC ₂ H _s

No indication of possible usability is given for the new compound.

The search for non-steroidal antipyretics has become increasingly important in recent years. The interest is directed towards compounds that exceed the previously commercially available preparations of this indication area, especially with regard to their tolerability. As for the treatment of various inflammatory diseases of the rheumatic Long-term therapy is usually required, comes the problem of tolerability and the side effects of particular importance. Above all, the irritation of the observed in many cases The gastrointestinal tract limits the use of many anti-inflammatory drugs.

It has now been found that ethyl 3-hydroxy-indene-carboximidate (compound I) and its pharmacologically acceptable salts in addition to the antipyretic active component also valuable analgesic Have properties and are also characterized by a remarkably good compatibility. Because of these properties, the medicament according to the invention is also suitable in anti-inflammatory therapy.

The subject of the present application is therefore a medicament with an antipyretic effect and analgesic properties for oral and rectal administration, characterized by a content of 3-Hydroxy-indene-carboximidic acid ethyl ester or its pharmacologically acceptable salts.

The conversion of the free base of the active ingredient into its pharmacologically acceptable salts is carried out by Neutralization with an appropriately applicable organic or inorganic acid, such as. B. Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, fumaric acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid.

Due to its favorable therapeutic quotient, the compound of the formula I can be used widely Dosage limits in liquid or solid form can be administered orally or rectally.

Such Zusatzve for liquid forms are such. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic see salts) as well as high molecular weight polymers (like liquid polyethylene oxide) for viscosity regulation. Solid carriers are z. B. starch, lactose, mannitol, Methyl cellulose, talc, highly disperse silicic acids, higher molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycol); for oral application suitable preparations can if desired

ίο contain flavorings and sweeteners.

The single dose of the compounds according to the invention should, depending on the indication, be in the range of 10-500 mg, preferably 50 mg-150 mg. Comparative toxicity studies were carried out

π carried out with aminophenazone and also comparative experiments with acetylsalicylic acid and tilidine. the The results are summarized below:

Comparative experiments

1. Acute toxicity

method

The determination of the acute toxicity was carried out on male mice (NMRI) with a body weight from 20-23 g carried out. All test animals were fasted for 16 to 18 hours before the start of the test held. Water was available ad libitum. There were 4 animals in each dose group. The can sequence was logarithmic. The substances were called

Intragastric suspension in 10% tragacanth mucus administered The application volume was 2 ml / 100 g body weight.

The LDn values after 7 days of observation of the animals are given in Table I below:

Table I.
Results
Acute toxicity Mice mg / kg substance Application URL > 1 600
475 Compound I
Aminophena / on intragastric
inlragastral

As can be seen from Table 1, the toxicity of the compound I according to the invention is very low. Aminophenazone is significantly more toxic than compound I.

2. Antipyretic effects in comparison to acetylsalicylic acid

Test animals were male, fasted rats (SlV 50) with a body weight of 120-160 g. To generate an increased body temperature, the animals received 2 ml / 100 g of body weight 18 hours before administration of the test substance 12% dry yeast suspension injected subcutaneously in 2-3 depots. A control group received that appropriate volume of physiological NaCl solution is injected subcutaneously. 10 animals were grazed per dose.

After 3 preliminary measurements of the body temperature on the day of the experiment at 30-minute intervals, the The test substance was administered intragastrically to animals treated with yeast. The application volume was 2 ml / 100 g body weight. A second treated with yeast

th control group and the control group treated with physiological Na-CL solution the day before instead of the test substance (compound I = 3-hydroxy-indene-2-carboximidic acid ethyl ester) the corresponding vehicle was administered as a comparison substance Acetylsalicylic acid, a known strong antipyretic substance, was also examined

temperature of the test animals was examined after 30, 60 minutes and then every hour, up to Measured rectally using a thermocouple probe a total of 5 hours after administration of the substance.

The test results are shown in Table II below:

substance

Temperature C " Minutes after application

30 60

180

240

NaCl 2 ml / 100 g s.c. Tragacanth 2 ml / 100 g i.g.

12% yeast 2 nii / 100 g sc tragacanth 2 ml / 100 g ig

12% flefe 2 ml / 100 g s.c. Acetylsalicylic acid 150 mg / kg i.g.

12% yeast 2 ml / 100 g s.c. Acetylsalicylic acid 300 mg / kg i.g.

12% yeast 2 ml / 100 g s.c.

Compound I 125 mg / kg i.g.

12% yeast 2 ml / 100 g s.c.

Compound I 250 mg / kg i.g. LD 50 of acetylsalicylic acid: 1878 mg / kg i.g.

37.0 36.8 36.8 37.0 37.0 36.8 38.0 38.1 38.1 38.0 37.9 37.6 37.9 37.7 36.8 36.7 37.5 37.6 37.9 37.3 36.5 36.7 36.9 37.1 36.4 35.7 35.7 35.7 36.2 36.3 36.4 35.8 34.4 34.6 34.4 35.0

As can be seen from Table II, the compound I has a very good dose-dependent antipyretic effect. 125 mg / kg I lower the increased Body temperature to a greater extent than 300 mg / kg acetylsalicylic acid. The effects of I also last longer than that of the reference substance. Because while the body temperature is the with Acetyisalicylic acid treated animals approaches the body temperature of the control animals without yeast-induced fever after 240 minutes, the temperature is that of I treated animals is still considerably below this and only shows a slightly increasing tendency in the further course. The substance I according to the invention is therefore the standard substance with regard to its antipyretic effect Clearly superior to acetylsalicylic acid.

3. A comparison of anti-inflammatory effects to aminophenazone

The rat paw edema was used to investigate the anti-inflammatory effect. As a phlogistic

r. Native hen's egg protein, yeast and carrageenin were used here.

method

Test animals were male rats of the SlV 50 strain, which had been fasted for 16 hours, with one Body weight of 120-160 g. After determining the initial value of the paw volume of the right The test substance was administered intragastrically to the rear extremities. 10 animals were used per dose. That The application volume was 2 ml / 100 g body weight. The paw volume was determined by means of mercury displacement. When trying different Phlogistics, which were injected subplantar into the right posterior photo, were applied of the test substances and the measurement of the paw volume according to the schedule according to Table HI

Table III I'hlogislikiim Application of the test subslun / PIOtenvnliimcniiicssung Egg white, 0.1 ml / paw

Dry suspension 5% 0.05 ml / plole

Oirrageenin I% 0.1 ml / paw

45 minutes before the protein injection and 60 minutes after the

Protein injection

Immediately / hurriedly with the oleine injection 3 hours after the oleic injection

60 minutes before carrageenin injection

1 and 1 hours after carragninin injection

In the case of protein edema, the average increase in paw volume was the treated and of the control animals 60 and 120 minutes after injection of the Phlogistics calculated in% of the mean value of the initial measurements The mean value from the percentage The increase in the paw volume of the control group after 60 and 120 minutes was set equal to r00% and the corresponding values for the treated groups in% of these calculated. The difference between these values 100% of the control group gives the relative inhibition of the paw edema by the test substance.

Table! V Results: Anti-inflammatory effects on rat paw edema In the yeast and carrageenin modem, the

percentage increase in paw volume for the treated and for the control animals 3 hours after

Injection of the phlogistics determines the percentage Increase in paw volume in the control group

was set equal to 100% and the corresponding

Values for the treated groups in% thereof

Calculated from these values was as above indicated the relative inhibition of the paw edema

κι determined by the test substance

The results are summarized in Table IV:

Substance (Intragastr. dose I'hlogistikum Inhibition of LHs ₁ , Application) Folenedema thcrap. effective (mg / kg) (%) dose Aminophenazone 150 protein 17th 3.2 Compound I 125 protein 17th > 12.8. Aminophenazone 150 yeast 27 Compound I 50 yeast 53 Aminophenazone 150 yeast 34 Compound I 125 yeast 62 Aminophenazone 150 yeast 53 Compound I 250 yeast 71 Aminophena / on 150 C'arragecnin 68 3.2 Compound I 250 ("arragecnin 69 > 6.4

In yeast edema, compound I shows a stronger anti-inflammatory activity than the standard substance aminophenazone in all doses investigated. Since in In the event of yeast edema neither ED 50 values are available nor equieffective values have been determined, a the quotient LDso / thei apeutically effective dose corresponding value cannot be specified. For protein and carrageenin modem, 125 mg / kg or 250 mg / kg of compound I anti-inflammatory as strongly effective as 150 mg / kg of aminophenazone.

If one takes into account the difference between the therapeutically effective dose and the respective LD »of the two for compound I and aminophenazone with the same anti-inflammatory effect Substances, there is a clear substance advantage for compound I even with these types of edema versus aminophenazone.

4. Analgesic effects in comparison zuTilidine (WHO-Nan5e)

To characterize the analgesic effect of the Compound, common methods such as the phenyl-p-quinone and hotplate tests were used.

A) Phenyi-p-quinone test method

Male mice (NMRI) with a body weight of 20-25 g were fasted for 16 hours used. 30 minutes after intragastric administration of the test substance, 0.25 ml / 20 g of body weight of a 0.02% solution of phenyl-p-quinone in 5% alcohol applied intraperitoneally. in the course of a further 20 minutes it was observed at how much of a total of 12 animals in each dose group die typical pain reactions occurred after administration of phenyl-p-quinone.

The results can be found in Table V below:

Table V control Dt) SiS 30th Applica- Use Animals with if I
substance Tilidine 250 ion type dete more positive Compound I Animal number pain control (nig / kg) reaction "" Tilidine ν » Compound I - ■ g · 12th 12th 30th ■ right 12th 2 125 si, 12th 9 - •G· 12th Il •G· 12th I. si, I? 4th

In the Phcnyl-p-quinone test, the compound I shows a clear and dose-dependent analgesic effect. The effect of one of the strong analgesics Tilidins, however, is not reached.

B) Hot plate test method

Test animals were male mice (NMR1) with a body weight, which had been fasted for 16 hours from 21 to 26 g. The animals were placed on a copper plate kept constant at 55 ° C. and the time until measured for licking the front paws. After three The initial measurements were the test substance intragastra! administered. The application volume was 2 ml / 100 g body weight. The measurements according to SubTable VI

10

Punch applications took place after 15, 30, 60, 90 by 120 minutes. 10 animals were used per dose The mean values were formed from the respective reaction times of the preliminary measurements and the! Average values of the reaction times after administration of the substance ii percent of it calculated.

The results can be found in the following table VI zi:

substance

dose

(mg / kg)

Application variant Output value Change of the reaction in%

after min.

15th

30th

90

control _ i.g. 100 0 + 2 + 2 - 6 + 4 Tilidine 50 ig · 100 + 220 + 156 + 142 + 108 + 148 Compound I 50 ig- 100 + 136 + 113 + 100 + 66 + 74 control - i.g. 100 + 16 + 15 + 13 + 14 + 19 Tilidine 50 ig- 100 + 69 + 76 + 69 + 77 + 71 Compound I 125 i.g. 100 + 115 + 89 + 80 + 69 + 58 control - i.g- 100 + 19 + 18 + 25 + 23 + 36 Tilidine 50 i.g. 100 + 122 + 123 + 124 + 92 + 88 Compound I 250 i.g. 100 + 105 + 113 + 117 + 100 + 96

Similar to the phenyl-p-quinone test, the compound I also has a pronounced analgesic effect in the hotplate test, which is used to examine strong analgesics. 125 mg / kg of compound I are about more powerful, 250 mg / kg about as effective as 50 mg / kg of tilidine. The large distance between the therapeutically effective dose and the LD _{50 of} the substance is also particularly favorable for compound I.

The good analgesic effect of the compound I can also be seen in the analgesia test on the edematous Detect rat paw (Randall-Selitto test) in Because after the administration of the compound I there is one

significant increase in pressure pain wave dei

oedmatous rat paw comes

The pronounced analgesic component

with the possibility of using it as an anti-inflammatory facility the compounds I especially for use ir

Medicinal products suitable for the treatment of de;

rheumatic form circle should be used

len.

The following examples are intended to explain the invention in greater detail:

example 1

1 kg of ethyl 3-hydroxy-indene-2-carboximidate is dried with 440 g of lactose and 240 g Corn starch mixed intimately and with a mixture of 500 g of 4% strength aqueous gelatin solution and 10 g Granulated glycerine.

140 g of corn starch, 70 g of cellulose, 50 g of talc and 10 g are added to the granules obtained in this way Magnesium stearate is added and mixed well. Then the mixture is made into kernels with one Weight of 246 mg pressed, which in the usual way mi be coated with a sugar solution. You get

Dragees with an active ingredient content of 100 mg.

Example 2

1 kg of ethyl 3-hydroxy-indene-2-carboximidate is mixed with 210 g of colloidal silica and 4.2 g of butylhydroxyanisole and 9.8929 kg each of a mixture of triglycerides of natural saturated vegetable fatty acids the chain length C12-Ci8 with an addition Partial glycerides of the same fatty acids mixed unc warmed The melted mass is in usual: Processed into suppositories with a weight of 2.1 g, which contain 100 mg of active ingredient.

Claims (1)

Claim: Orally or rectally administered antipyretic, with analgesic properties, characterized by a content of 3-hydroxy-indene-2-carboximidic acid ethyl ester or its pharmacologically acceptable salts.