LU83497A1 - AMIDE DERIVATIVES OF P-ISOBUTYLPHENYLPROPIONIC ACID, ITS PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

I 1 (! - 2 -! The present invention relates to amide derivatives of i p-isobutylphenylpropionic acid of the general formula:

I CH -.- CH-CONHX

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v CH

I / 3

CH -CH

^ \

1 °. CH

3 in which X represents the rest e} j} es puljst ^ tui ^ rtçh amine from the group of lysine, m-trifluorotoluidine, glutamic acid and aspeasginic acid.

15 <· · j The anti-inflammatory properties of p-isobutylphenyl-i propionic acid are known. It is also known that this acid - like most of the drugs used in the therapy of inflammatory illnesses - has undesirable side effects! 20 kungen shows how low stomach tolerance and not inconsiderable toxicity, these factors being essential for long-term therapy.

: i j It has now been found that the amide derivatives according to the invention in addition to those typical for p-isobutylphenylpropionic acid see anti-inflammatory properties a lower

Show toxicity and greater stomach tolerance.

To prepare the amide derivatives of the formula (I), the | The process according to the invention comprises the following steps: a) the hot chlorination of p-isobutylphenylpropionic acid with an excess of a chlorinating agent, preferably thionyl chloride or phosphorus pentachloride; j b) the reaction of the chloride of p-isobutylphenylpropion-35 acid in a reaction medium from the group of 'alkalinized water and pyridine at low temperature with the appropriately substituted amine, i 7} Tm-trifluoromethylaniline)! ί - - ------ - —- - - - .....- \ - 3 - and optionally as a further step the salt formation of the free acid functions of the amides obtained by means of a pharmacologically acceptable, organic or inorganic 5 see Base,

The following examples illustrate the process according to the invention. ;

Example_1_ 120 ml of thionyl chloride was added to 50 g of p-isobutylphenylpropion-

J acid was added and the reaction mixture gradually increased to 75 ° C

j | heated. To monitor the reaction pattern, | gas evolution from the reaction mixture using gas j! 15 traps were observed until it stopped, indicating the end of the reaction. The excess thionyl chloride was removed ", whereupon the chloride of p-isobutylphenylpropionic acid was obtained by vacuum distillation. b2_Glutamin ^ id_der_p-Isobutylphenylpr2pi2nsäure l | 20 A solution of 1 h, 7 g glutamic acid in 20 ml water was I with a solution of 8 g solid NaOH in 20 ml of water. The mixture was cooled by adding ice (2 cubes),

and with stirring the chloride became the p-isobutylphenylpro-; | dropped pionic acid. The temperature was raised to about 0C

I 25 and the mixture was stirred until after a few hours the pH became acidic. Additional sodium hydroxide (1.6 g in aqueous solution) was added and the mixture was left to stand for 2 days. Acidification with dilute HCl precipitated a white, pasty product, whereupon Cvclohexane 30 was added and mixed thoroughly.

29 g of a product which was insoluble in water, dilute HCl and cyclo-hexane were obtained. The disodium salt of the like! The product obtained was prepared in ethanol / acetone using a J 35 aqueous NaOH solution.

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The amides of aspartic acid and lysine were prepared by the same process, with lysinamide used for this purpose. was ensured that the lysine was present as copper complex 5 before the reaction.

Example_2 27 g of the chloride prepared as in Example 1 were dissolved in 50 ml of chloroform and 9> 5 ml of pyridine were added to the solution. 16.1 g of m-trifluorotoluidine in 50 ml of chloroform were added to this solution with stirring. The reaction was exothermic and the temperature rose spontaneously to 60 ° C; then the reaction mixture was cooled to room temperature and left to stand overnight. After washing the reaction mixture thoroughly with water, the chloroform extract was concentrated to dryness, whereupon an oil was obtained which crystallized.

j, After crystallization, 51 g of p-isobutylphenyl-i were obtained; 20 propionamide of m-trifluorotoluidine as a powder that was insoluble in water and soluble in most organic solvents and had a melting point of 84-86 ° C.

The compounds according to the invention were subjected to pharmacological tests and showed moderate or even negligible toxicity. In fact, an LD ^ q above 900 mg / kg was found for all four compounds in mice per os.

The anti-inflammatory activity was tested through the classic kaolin and protein-induced edema tests, which repeat two crucial and different phases in the pathogenesis of the inflammatory process.

35 The kaolin injected into the tibia tarsal canal of rats | leads to chronic inflammation, while the protein injected into the j subplantar region of rats leads to an acute | inflammatory condition.

/ '\ - 5 - 100 mg / kg per os the kaolin test protein test; Connection_increase! Lysinamide of p-isobutylphenyl-I 5-propionic acid 7.1 + 5.3 11 + 5.6 I o-1 'p-isobutylphenyl-propionamide of m-trifluorotoluidine 7 +5.5 10 + 5.1

Controls 13 20 I Finally, the compounds according to the invention also showed good stomach tolerance.

1 10 j 'On the basis of the results of the preliminary pharmacological tests described above, the inventions | Compounds according to the invention carried out further pharmacological tests, of which the tests relating to the p-isobutyl-15phenylpropionamide of m-trifluorotoluidine (hereinafter abbreviated as BP-03) are listed below.

This compound has a very low acute toxicity when administered orally and intraperitoneally. Although oral! I could not be determined in rats even with doses of 4000 mg / kg, LD ^ Q was determined intraperitoneally in males! Animals have an LD ^ q value of 1620 mg / kg and in females

Animals of 1765 mg / kg found. No LD ^ q could be determined orally in mice Ί 25, while it was intraperitoneal in male animals at 940 and in female animals at 1190 mg / kg.

i: In rats, the repeated administration of doses up to 100 mg / kg for 28 days did not change the body growth of the animals or the haema- | tological and hematochemical parameters. Only one

Dose of 200 mg / kg 2 animals died during the test period.

j 35 The following table 1 gives the data of acute toxicity -3 in rats compared to free acid (denoted by the trivial name "ibuprofen").

3 fl i '• - 6 -

Table 1 | Acute toxicity from BP-03 and ibuprofen

Rats when administered by i.p.

Injection 5 compound dose rats per mortality LD ^ q ms / ^ g _mg / kg dose after 7 days + f <0t05) BP-03 700 6 1/6 1010 6 1/6 1196 + 264 '1455 6 5/6 - 10 _2100 6_6 / 6_

Ibuprofen 250 6 0/6 360 6 2/6 415 + 80! 520 6 5/6 | 750 6 6/6 15 * l.f. = Confidence range.

! Table 2 describes the subacute toxicities in rats (TD ^ q) in the 28-day test compared to ibuprofen and j 20 naproxen (i.e. d-2- (6 * -methoxy-21-naphthyl) propionic acid).

j i ï J 25 30 j 35!

P

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B / --- "- —1 1" "" '—— - J

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Table 2

All-cause mortality in male and female

Rats 5 treatment mortality TDqn TD -, -.

_ln 28 Ia ^ mg / * g mÄ ° s 3T-D3 25 mg / kg 0/10 186.69: öT-03 50 mg / kg 0/10 229.74 ^ 0.66 10 ^ 282.72 BT-03 100 mg / kg 0/10 BT-03 200 mg / kg 3/10

Naproxen 25 mg / kg 2/10 I 15 30.50 I Naproxen 50 mg / kg 6/10 40.69 ^ I - 54.08 * | Naproxen 100mg / kg 10/10? I |! Ibuprofen 25 mg / kg 0/10 I 84.29 jçi 20 ^ * I Ibuprofen 50 mg / kg 3/10 123.11 0.59 | ^ 179.83 | Ibuprofen 100mg / kg 4/10

Ibuprofen 200mg / kg 5/10 25

A comparison with the compound naproxen, which is known for its anti-inflammatory activity and is frequently used for therapeutic purposes, shows that it is significantly more toxic, namely a toxicity of about 3.8 times that of the compounds according to the invention.

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|| The studies carried out on mice and rabbits; ! showed no teratogenic or embryotoxic effects.

. 'S! ! * 35 The pharmacodynamic tests showed a clear anti-inflammatory and analgesic effect j of the test compounds. The following data were obtained: || ; ft /? il / i ï * ~ ... ..... - ..... - ...... - i - 8 -; A) Inhibition of carrageenin-induced edema of the rat rat paw (R.Coubon et al Arch.Int.Pharmacodyn. 99,474, (1954)) '5 The anti-inflammatory activity of the compound according to the invention was compared to known anti-inflammatory; Compounds, namely ibuprofen and naproxen, for percentage inhibition of the edema induced by carrageenin in the! Evaluation compared to control animals. The edema was at | io induced and induced rats in the control animals; Paw volume increase of 57.55% · I I The ED ^ q value for the connection BT-03 was calculated according to jung 103 mg / kg, while the ED ^ q values of naproxen and ibuisprofen were 47.9 and 170 mg / kg, respectively. However, if the molecular weight of the test compounds is taken into account, i; '; the ED ^ q values for Naproxen, Ibuprofen and BT-03 at! 0.21, 0.82 and 0.29 mM / kg, respectively.

\ i i j '20 From this point of view, BT-03 is about 1.4 times less effective than naproxen, but 2.8 times more effective than ibuprofen.

However, it must be mentioned that repeated doses of naproxen used in this test are 1.8 times more toxic than BT-03, the latter also having a lower toxicity than ibuprofen.

I B) Inhibition of those induced by Freund’s adjuvant

Arthritis in rats (B.B. Newbould, Brit.J. of Pharmacol. 21, 127 (1963))

Both compounds, namely BT-03 and the reference substance 30 ibuprofen, inhibit the lesions induced directly by Freund's Adjuvant! «In the injected paw. The ED ^ q value, | namely the dose, which is a 50-? 6ige reduction in volume! increases the paw, for BT-03 is 87 mg / kg.

û On a molar basis, this corresponds to 0.25 mM / kg for BT-03, I 35 while for ibuprofen the ED ™ value is 0.30 mM / kg.

i Although both BT-03 and the reference substance | the development of the i |. characteristic of Freund's adjuvant Inhibiting secondary lesions is the | / »- 9 -

Derivative proportional to the administered doses superior to ibuprofen in terms of activity and lower toxicity, i C) Analgesic activity on the acetic acid-induced, j 5 th "stretching" in mice (Fennessy, MR et al. "Methods of Narcotic Research" Eds. Honorary Awards Neidle Dekker, | New York (1975)) j The compound BT-03 inhibits acetic acid-induced stretching ("stretclsing") in proportion to the dose administered. The value calculated for ED, ^ is 123 mg / kg, j while the ED ^ value of ibuprofen is 105 mg / kg.

j Taking into account the different molecular weights, the ratio between the respective ED ^ q values 15 showed that BT-03 is about 1.4 times more effective than ibuprofen, because on a molar basis the ED ^ q of BT-03 was 0.35 mM / kg, v while it was 0.50 mM / kg in the comparative compound ;; lies.

D) Analgesic effect in the Flinch jumping test in rats; 20 Both compounds BT-03 and ibuprofen cause an increase in the algogenic ("algogenic") threshold value in proportion to the dose administered (RA Turner "Screening Methods; i in Pharmacology" Academie Press, New York, (1965)) ij ji |] 25 The ED ^ q value of BT-03 »defined as the dose which causes an I '50% increase in the algogenic stimulus is jj 129 mg / kg, while the ED ^ q for ibuprofen 108 mg / kg j! lies. A comparison of these values on a molar basis (namely, 0.37 mM / kg for BT-03 and 0.52 mM / kg for ibuprofen) I '30 leads to the conclusion that the activity of BT-03 is about 1, 4 j times larger than that of the reference substance. Is further

Ijj i | with repeated administration of the used in this test; doses of ibuprofen more toxic than the compound BT-03.

35 The pharmacological and pharmacodynamic properties of the compound BT-03 shown above confirm the clear, unpredictable improvement over the free acid.

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The following Table 3 gives the therapeutic index obtained by comparing the toxic dose TD ^ q found in the 28 day subacute toxicity test 5 and the effective ED ^ q dosers determined in the above tests. The constant clear advantage of the connection according to the invention is visible.

Table 3

BT-03 TEST IBUPROFEN

10 DT5Q 0.66 0.59 _ _ = 2.27 (A) _ = 0.72 DE5Q 0.29 0.82 15 DT 0.66 0.59 _ _ = 2.64 (B) _ = 1, 97 DE3Q 0.25 0.30 20 DT50 0.66 0.59 _ = 1.88 (C) _ = 1.16 DE50 0.35 0.51 25 DT 0.66 0.59 _ _ = 1.78 (D. ) _ = 1.13 DE5t) 0.37 0.52 30 35 // F'S \

Claims (4)

1.- Amide derivatives of p-isobutylphenylpropionic acid with the general formula: CH3-C! I-CONHX! 5 Φ (I) j CH -CH jj 2 \, l „in which X stands for the residue of a substituted amine from fj in the group of lysine, m-trifluorotoyuidine, glutamic acid and H aspartic acid. '! 15 2, - Lysine-p-isobutyl-phenylpropionamide. 3.- p-isobutylphenyl-propionamide from m-trifluorotoluidine. 4. p-isobutyl-phenyl-propionamide of glutamic acid. ! 20 t; 5. p-1sobutylpheny 1-propionamide of aspartic acid. : ίί »j jjl ifj '6.- Process for the preparation of the compounds according to Claim i 1, characterized in that p-isobutyl-phenylpropionic acid: ¾ 25 chlorinates with excess chlorinating agent and the chloride obtained is reacted with the correspondingly substituted amine. ! is set. 7. The method according to claim 6, characterized in that J '30 is the chlorinating agent thionyl chloride or phosphorus penta- I chloride. 8, - Method according to claim 6, characterized in that the reaction of the chloride of p-1sobutyl-phenyl-35-propionic acid with the substituted amine is carried out in an alkaline aqueous medium and at a low temperature. j; ; , i! I t 1 t * - 2 - 9. The method according to claim 8, characterized in that the reaction of the chloride of p-isobutyl-phenyl-propionic acid with the substituted amine is carried out in pyridine. 5 10, - medicament containing a compound according to claim 1 to 5 and conventional carriers and auxiliaries. I The patent attorney:!. * l k I i m s I i i i 15] 20 - 25 i i 'j ji | 30! $ n '1 .1 35 i