Pyrazoline derivatives, their preparation and application as medicaments

(Entry 1 of the Tables)

1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-(4-metylphenyl)-3-trifluoromethyl-1H-pyrazole

Preparation of (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (Method E-1)

Into a flask with dry inert atmosphere, 15 ml of anhydrous THF is introduced and the flask cooled to −70° C. A solution of 2 M LDA in THF-hexane (5 ml, 10 mmoles) and diethylmethyl phosphonate (0.75 ml, 5 mmoles) dissolved in 5 ml of THF are added and the flask shaken for 30 minutes. Then, N-phenyltrifuoroacetimidoyl chloride (1.04 g , 5 mmoles) is added dropwise, (prepared according to Tamura, K.; Mizukami, H. et al.; J. Org. Chem., 1993, 58, 32-35) while continuing the shaking in the same conditions for 1 hour. P-tolualdehyde (0.6 g, 5 mmoles) is added, the cold bath removed and the flask left with shaking at room temperature for 16 hours. 10 ml of 2N HCl are added with shaking for a further 4 hours. The THF is eliminated with a rotavapor, the mixture extracted with ethyl ether (3×20 ml) and the combined organic extracts washed with 5% sodium bicarbonate solution and with saturated sodium chloride solution until reaching a pH˜6. The mixture is dried over anhydrous sodium sulphate and evaporated. The crude oil obtained is purified using column chromatography through silica gel under pressure (eluting with AcOEt-petrol ether 1:9) to obtain (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.8 g, yield: 75%) in the form of a clear oil.

IR (film, cm −1 ): 1715, 1601, 1201, 1183, 1145, 1056, 811, 703

1 H-NMR (CDCl 3 ): δ2.4 (s. 3H); 6.97 (d, J=18 Hz, 1H); 7.25 (d, J=9 Hz, 2H); 7.54 (d, J=9 Hz, 2H); 7.95 (d, J=18 Hz, 1H).

Thin layer chromatography (TLC) (Petrol ether): Rf=0.16

Preparation of 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (METHOD A)

A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.82 g, 3.69 mmoles) and (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.79 g, 3.69 mmoles) in 15 ml of acetic acid is refluxed for 3 hours under a nitrogen atmosphere. It is cooled, poured over water and extracted with AcOEt. The organic solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude product thus obtained is crystallised from EtOH-petrol ether to give 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (0.65 g, yield: 45%).

m.p.=140-3° C.

IR(KBr, cm −1 ): 3356, 3268, 1594, 1326, 1170, 1139, 1120, 1097.

1 H-NMR (CDCl 3 ): δ2.34 (s, 3H); 2.99-3.06 (dd, J=6.9 y 14 Hz; 1H); 3.66-3.73 (dd, J=12.6 and 14 Hz, 1H); 4.69 (broad s, 2H); 5.38-5.45 (dd, J=6.9 and 12.6 Hz, 1H); 7.04-7.11 (2d, J=8.1 y 9.3 Hz, 4H); 7.17 (d, J=8.1 Hz, 2H); 7.70 (d, J=9.3 Hz, 2H).

13 C-NMR (CDCl 3 ): 20.9; 41.2; 64.5; 113.4; 120.5 (q, J=268 Hz); 125.3; 127.6; 130.1; 133.2; 136.7; 138.3; 138.8 (q, J=38 Hz); 146.0.

TLC (AcOEt): Rf=0.89

(Entry 2 in the Tables)

1-(4-Aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole

Preparation of (E)-1,1,1-trifluoro-4-methyl-4-phenyl-3-butene-2-one (METHOD E-2)

To a solution of boron dimethyl-trifluoro sulphide (3.9 g, 30 mmoles) in 75 ml of dichloromethane cooled to −60° C. trifluoroacetic anhydride (6.3 g, 30 mmoles) is added slowly. The mixture is shaken for 10 minutes and a solution of α-methylstyrene (3.54 g, 30 mmoles) in 15 ml de dicloromethane added slowly, maintaining the temperature at −60° C. Then the temperature is allowed to rise to −50° C., and kept at this value for 15 minutes, then allowed to rise to 0° C. and the mixture shaken under these conditions for 30 minutes. 50 ml of ethyl ether and 50 ml of an aqueous solution of 10% sodium bicarbonate solution are added. The phases are separated and the aqueous phase washed with more ether. The combination of the ether phases is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness with a rotavapor. The crude product thus obtained is purified using column chromatography through silica gel under pressure eluting with petrol ether. 2.0 g (51%) of unreacted starting α-methylstyrene and 2.35 g of (E)-1,1,1-trifluoro-4-phenyl-3-butene-2-one (yield: 75%) were recovered in the form of colourless oil.

IR (film, cm −1 ): 1709, 1596, 1204, 1142, 1072.

1 H-NMR (CDCl 3 ): δ2.71 (s, 3H); 6.8 (s, 1H); 7.45 (m, 3H); 7.6 (m, 2H).

Preparation of 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoro methyl-1H-pyrazole (METHOD A)

In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-methyl-4-(4-methylphenyl)-3-butene-2-one (1.75 g, 8.2 mmoles), 4-(aminosulphonyl)phenylhydrazine chlorohydrate (2 g, 9 mmoles) and piperidine (0.85 g, 10 mmoles) are added, dissolved in 100 ml of ethanol, and heated under reflux for 5.5 hours. The mixture is cooled, the solvent eliminated with a rotovapor, water added to the residue and the solution extracted with AcOEt. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The crude product is purified using column chromatography through silica gel under pressure, eluting with AcOEt-petrol ether (4:6) obtaining 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole in the form of a white solid (1.46 g, yield: 47%) with a

m.p.=60-6° C.

IR (KBr, cm −1 ): 3384, 3266, 1593, 1498, 1327, 1151, 1099, 703.

1 H-NMR (CDCl 3 ): δ1.6 (s, 3H); 2.8 (m,1H); 3.1 (m, 1H); 4.5 (broad s, 2H); 7.2 (m, 3H); 7.4-7.55 (m, 4H); 7.7 (d, 2H).

13 C-NMR (CDCl 3 ): 27.6; 54.2; 63.1; 114.6; 124.0 (q, J=268 Hz); 125.6; 127.4; 127.8; 129.1; 131.0; 142.0 (q, J=38 Hz); 142.6; 147.5.

(Entry 3 in the Tables)

1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoro methyl-1H-pyrazole

Preparation (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (Method E-3)

In a flask 2,4-difluorobenzaldehyde (20 g, 0.14 moles), glacial acetic acid (12.2 g, 0.2 moles) and piperidine (12.2 g, 0.14 moles) are dissolved in THF (300 ml). The solution is cooled to 5-10° C. and CF 3 COCH 3 (8 g, 0.07 moles) bubbled through it. It is removed from the cold bath, the temperature increased to room temperature and the mixture kept at this temperature for 1.5 hours with continuous shaking. CF 3 COCH 3 (5 g, 0.045 moles) is added once again and the mixture left for 1.5 hours with shaking. Once again 5 g is added and the mixture shaken for a further 1.5 hours. This step is repeated until a total of 35 g (0.31 moles) of CF 3 COCH 3 have been added. A solution of 20% (50 ml) is added and the solvent eliminated under reduced pressure. 50 ml of water are added and the solution extracted with AcOEt. The organic phase is washed with water, 5% H 2 SO 4 , water and the mixture dried over anhydrous sodium sulphate. The solution is filtered and evaporated. The resulting crude product is distilled, obtaining 18.1 g of (E)-1,1,1-trifluoro-4-(2,4-difluorohphenyl)-3-butene-2-one with a m.p. of 50-1° C.

IR (KBr, cm −1 ): 1717, 1602, 1583, 1277, 1146, 1059, 706

1 H-NMR (CDCl 3 ): δ6.9 (m, 2H); 7.05 (d, J=16 Hz, 1H); 7.6 (m, 1H); 8.0 (d, J=16 Hz, 1H).

Preparation of 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole (METHOD A)

A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (47.8 g, 0.21 moles) and (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (53.1 g of 95%, 0.21 moles) in 315 ml of acetic acid is refluxed for 24 hours under a nitrogen atmosphere. The mixture is cooled, poured over water and filtered. It is washed with toluene and the crude product thus obtained crystallised from isopropanol. 46.2 g are obtained. The mother waters of crystallisation from crystallisation, once concentrated, give another 12.6 g of product. In total 58.8 g (68%) of 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)4,5-dihydro-3-trifluoromethyl-1H-pyrazole with a melting point of 160-2° C.

The following procedure can also be followed:

In a flask with an inert atmosphere sodium ethoxide (0.53 g, 7.72 mmoles) is dissolved in 45 ml of ethanol. 1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-butene-2-one (prepared according to method E-1) (0.913 g, 3.86 mmoles) and 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.87 g, 3.87 mmoles) are added and the mixture was refluxed for 16 hours. The mixture was cooled, evaporated to dryness, cold water added, and the mixture acidified by adding acetic acid and the precipitated solid filtered. This solid was redissolved in ether, treated with active C, filtered and the solvent eliminated with a rotovapor. The resulting residue was crystallised from ethyl ether-petrol ether (50:50) to give 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole (1.02 g, yield: 65%) in the form of a solid m.p.=160-2° C.

IR (KBr, cm −1 ): 3315, 3232, 1617, 1593, 1506, 1326, 1179, 1099, 1067.

1 H-NMR (CDCl 3 ): δ3.0 (dd, J=6.3 and 11.4 Hz, 1H); 3.80 (dd, J=11.4 and 12.6 Hz, 1H); 4.79 (broad s, 2H); 5.70 (dd, J=6.3 and 12.6 Hz, 1H); 6.8-6.95 (m, 2H); 7.01-7.09 (m, 3H); 7.74 (d, J=8.7 Hz, 2H).

(Entry 4 of the Tables)

4,5-dihydro-1-(4-methylphenyl)-5-(4-methylsulphonylphenyl)-3-trifluorometyl-1H-pyrazole (METHOD A)

In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-(4-methylsulphonylphenyl)-3-butene-2-one (prepared according to the method E-1) (1.83 g, 6.58 mmoles) and 4-methylphenylhydrazine chlorohydrate (1.04 g, 6.58 mmoles) are dissolved in 50 ml de ethanol. A few drops of hydrochloric acid are added, and the mixture refluxed under an inert atmosphere for 4 days. The mixture is cooled and the product crystallised. The solution is filtered and the product recrystallised from ethanol. 4,5-dihydro-1-(4-methylphenyl]-5-(4-methylsulphonylphenyl)-3-trifluoromethyl-1H-pyrazole (0.8 g, yield: 32%) is obtained in the form of a solid with a melting point of 140-3° C.

IR (KBr, cm −1 ): 1516, 1310, 1148, 1131, 1060, 774

1 H-NMR (CDCl 3 ): δ2.2 (s, 3H); 2.9(dd, J=7.8, 17.1 Hz, 1H); 3.05(s, 3H); 3.7(dd, J=12.9, 17.1 Hz, 1H); 5.45(dd, J=7.8, 12.9 Hz, 1H); 6.8(d, J=8.4 Hz, 2H); 7(d, J=8.4 Hz, 2H); 7.45(d, J=8.4 Hz, 2H); 7.9(d, J=8.4 Hz, 2H)

(Entry 39 in the Tables)

methyl 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxylate (METHOD B)

4,5-dihydro-5-(4-methylphenyl))-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxylic acid (6.9 g, 19.3 mmoles) and thionyl chloride (3.5 ml, 48 mmoles) are dissolved in 50 ml of tetrahydrofuran and the mixture shaken at room temperature for 16 hours. The mixture is evaporated to dryness with a rotavapor and the crude acid chloride so obtained is dissolved in 150 ml of methanol in a flask with inert atmosphere, and 8 ml (58 mmoles) of triethylamine added and the mixture shaken at room temperature for 2 hours. Water is added, the solid filtered and washed with abundant water and methanol. The desired methyl ester is thus obtained (5.8 g, yield: 82%) in the form of a cream coloured solid with a m.p.=155-160° C.

IR(KBr, cm −1 ): 1741, 1561, 1260, 1226, 1135, 1089

1 H-NMR (CDCl 3 ): 2.3(s, 3H); 3(s, 3H); 3.1(dd,J=6, 18.3 Hz, 1H); 3.75(dd, J=12.6, 18.3 Hz, 1H); 5.4(dd, J=6, 12.6 Hz, 1H); 7-7.25(m, 6H); 7.7(d, J=8.7 Hz, 2H)

(Entry 41 in the Tables)

Preparation of 1-(4-aminosulphonylhphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxamide (METHOD C)

1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-1H-pyrazole-3-carboxylic acid (3.7 g, 10.3 mmoles) and thionyl chloride (3 g, 25.8 mmoles) are dissolved in 70 ml of tetrahydrofuran and shaken at room temperature for 16 hours. The mixture is evaporated to dryness with a rotavapour and the crude acid chloride so obtained dissolved in 30 ml of methanol in a globe of inert atmosphere and cooled to 0° C. 9 ml of concentrated ammonium hydroxide solution dissolved in 20 ml of THF is added. The mixture is shaken at room temperature for 16 hours and the solvent eliminated with the rotavapor. Water is added to the residue and the mixture extracted with ethyl acetate, which is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The crude residue so obtained is crystallised from ethyl acetate-petrol ether to give 2.6 g (yield: 72%) of the desired compound with a m.p.=210-5° C.

IR (KBr, cm −1 ): 3450, 3337, 1656, 1596, 1345, 1141

1 H-NMR (d 4 -CH 3 OH): δ2.4(s, 3H); 3.05(dd, J=6, 17.7 Hz, 1H); 3.8(dd, J=12.9, 17.7 Hz, 1H); 5.6(dd, J=6, 12.9 Hz, 1H); 7.2-7.3(m, 6H); 7.75(d, J=8.7 Hz, 2H)

(Entry 43 in the Tables)

Preparation of 3-cyano-4,5-dihydro-5-(4-methylphenyl)-1-(4-methyl sulphonylphenyl)-1H-pyrazole (METHOD D)

In a flask with inert atmosphere 6.3 ml of anhydrous DMF is placed, the flask cooled to 0° C. and 2.1 ml of thionyl chloride slowly added. The flask is shaken for 2 hours in these conditions. A solution of 4,5-dihydro-5-(4-methylphenyl)-1-(4-methylsulphonylphenyl)-1H-pyrazole-3-carboxamide (3.8 g, 10.6 mmoles) in 30 ml of DMF is added and the mixture shaken for 5 hours at 0° C. and, then, for 16 hours at room temperature. The contents of the flask are poured onto ice and the solid precipitate filtered. 3.35 g (yield: 93%) of crude product are obtained which is crystallised from ethyl acetate giving a yellow solid with a m.p.=162-4° C.

IR (KBr, cm −1 ): 2220, 1593, 1500, 1389, 1296, 1143

1 H-NMR (CDCl 3 ): δ2.3(s, 3H); 3-3.1(s+dd, 4H); 3.75(dd, J=12.6, 18 Hz, 1H); 5.5(dd, J=6.3, 12.6 Hz, 1H); 7-7.2(m, 6H); 7.7(d, J=8.7 Hz, 2H)

(Entry 64 of the Tables)

1-(4-acetylaminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole (METHOD F)

0.58 g (1.43 mmoles) of 1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole and 2 ml acetyl chloride are heated under reflux for 2 hours. The mixture is cooled, evaporated to dryness under reduced pressure and the resulting residue dissolved in AcOEt, washed with water, dried over Na 2 SO 4 and evaporated to dryness. 0.49 g (76%) of 1-(4-acetylaminosulphonylphenyl)-5-(2,4-difluorophenyl-4,5-dihydro-3-trifluoromethyl-1H-pyrazole were obtained in the form of a white solid with a m.p.=172-4° C.

IR (KBr, cm −1 ): 3302, 1723, 1593, 1506, 1337, 1165

1 H-NMR (CDCl 3 ): δ2.0 (s, 3H); 3.0 (dd, J=6.6, 18.0 Hz, 1H); 3.8(dd, J=12.9, 18.0 Hz, 1H); 5.7(dd, J=6.6, 12.9 Hz, 1H); 6.9 (m, 2H); 7.05 (m+d, 3H); 7.85 (d, J=8.7 Hz, 2H); 8.1 (s, 1H)

EXAMPLES 9 AND 10

(Entries 75 and 76 in the Tables)

(+)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole y (−)-1-(4-amino sulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoro methyl-1H-pyrazole

The racemic mixture (±)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole is resolved into its enantiomers by high performance liquid chromatography using a CHIRALPAK AS column with 10μ particles and dimensions of 25×2 cm (Daicel), mobile phase 0.1% diethylamine in methanol and a flow rate of 8 ml/min. At a retention time of 7.4 minutes (+)-1 -(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole is obtained as a white solid with a melting point of: 173-4° C.; enantiomeric purity 99.9%; [α] D =+183.9 (c=1 CH 3 OH). At a retention time of 9.2 minutes (−)-1-(4-aminosulphonylphenyl)-5-(2,4-difluorophenyl)-4,5-dihydro-3-trifluoromethyl-1H-pyrazole is obtained as a white solid with a m.p.: 173-4° C.; enantiomeric purity >99.9%; [α] D =−189.4 (c=1 CH 3 OH).

Following the same procedure the examples corresponding to entries 77 and 78 in the tables are obtained.

Table 1 shows some examples that are encompassed by the general formula (I) and in Table 2 the data are indicated for identification of these compounds. The examples 1-36, 44-63 and 65-74 have been prepared according to method A, examples 37-39 according to method B, examples 40-42 according to method C, example 64 according to method F and the enantiomerically pure compounds 75-78 by resolution of the racemic mixture.

The products object of the invention are potent, orally active, anti-inflammatory agents, and selective inhibitors of COX-2, with a notable analgesic activity, lack ulcerogenic effects and are very active in the experimental arthritis test. With a view to demonstrating these activities, by way of example, some pharmacological assays are now indicated.

Inhibition of the Synthesis of Prostaglandins in Inflammatory Exudate and Mucus Membrane in Rat

In this assay, as well as demonstrating the selective inhibition of COX-2, the anti-inflammatory activity is also demonstrated, along with the absence of effects on gastric prostaglandins, after oral administration. The assay was carried out by modification of a method described by O. Tofanetti et al. ( Med. Sci. Res. 1989, 17, 745-746). The products under study are administered orally at an initial screening dose of 40 mg/kg. One hour after treatment the rats were anaesthetised and a sponge soaked in carrageenan was implanted subcutaneously in the interscapular zone. Six hours after implantation the rats were sacrificed and the interscapular sponges extracted as well as gastric mucuous. Next the PGE 2 content was determined by immunoassay for each one of the samples, in the sponge exudate on the one hand and in the gastric mucus on the other. The inhibition of PGE 2 in the inflammatory exudate demonstrates anti-inflammatory activity, both of COX-2 and COX-1 inhibitors, whereas inhibition of PGE 2 in the gastric mucus is considered a COX-1 inhibitory effect.

Table 3 summaries the results obtained with the compound of examples 3 and in table 4 the ED-50 (effective dose-50) is shown, as well as its selectivity. It is a more potent anti-inflammatory that the reference product.

Analgesic Activity Against “Hyperalgesia” by Thermal Stimulus of Pre-inflamed Rat Paw

In this assay the analgesic activity in rat was monitored following the method described by K. Hargreaves et al. ( Pain, 1988, 32, 77-78). Firstly, a suspension of carrageenan was injected into the back right paw of each rat. After two hours the products under study were administered orally at a screening dose of 40 mg/kg. Two hours after treatment a heat source was applied to the sole of each back paw of the rats and the time measured that they took to remove the paw measured. Hyperalgesia was determined by comparing the percentage of algesia of the paw injected with carrageenan to the other back paw. The analgesic activity was calculated comparing these hyperalgesia values of the groups treated with product with those of the group treated with the vehicle only.

In table 5 the results obtained with the compound of example 3 and summarised and in table 6 the ED-50 is presented, showing that this product is more active that other selective inhibitors of COX-2 in the assay of activity against thermal hyperalgesia.

Gastrointestinal Effects (GI): Induction of Ulcers in Rats Submitted to Cold Stress

In this assay possible ulcerogenic effects at a gastrointestinal level were determined after oral administration. To do this a modification of the method described by K. D. Rainsford ( Agents and actions, 1975, 5, 553-558) was followed. Firstly the rats received the products under study orally at different doses. After two hours had elapsed the rats were placed in a chest freezer at −15° C. for 1 hour. Afterwards they were left for 1 hour at room temperature. The animals were then sacrificed and the stomach extracted. The stomach was kept in saline solution for 15 minutes. After this time the percentage of surface area with gastric ulcers was determined using a Project C.S.V. vs 1.2 image analyser for each stomach. For each product the maximum dose that did not lead to ulcerogenesis was determined by linear regression analysis of the dose-response.

The results obtained with the compound of example 3 are summarised in table 7. It has been shown not to have ulcerogenic effects, even at very high doses, as was to be expected from a COX-2 selective product. On the other hand, both dichlorophenac and piroxicam, selective COX-1 inhibitors, exhibited ulcerogenic effects at very low doses.

Anti-arthritic Activity in Rat

In this study the anti-arthritic activity in rat of the compound of example 3 has been studied. To do so the method described by B. J. Jaffee et al. ( Agents and Actions, 1989, 27, 344-346) was followed. Firstly, the Freund adjuvant was injected ( Mycobacterium butiricum suspended in soy-bean oil) through the sub-sole of the back left paw of the rats. After 14 days, when the secondary inflammation had developed in the uninjected paw, which is considered the experimental arthritis, treatment with the product under study or with the vehicle for the control group was started. The compound of example 3 was administered orally at a dose of 10 mg/kg/day for 11 days. The volume of the paw with secondary inflammation in the last days of treatment was measured. The anti-arthritic activity was calculated by comparing the average volume of the paw with secondary inflammation of the group treated with the compound of example 3 and the control group for 5 days.

The results obtained show that the compound of example 3 has a high anti-arthritic activity, as treatment with 10 mg/kg/day, po, led to an inhibition of secondary inflammation, i.e. of an anti-arthritic activity, of 71%.

On the basis of their good pharmacodynamic properties, the derivatives of pyrazolines in accordance with the invention, can be used in satisfactory manner in human and animal therapy, in particular as anti-inflammatory agents for the treatment of inflammation and for the treatment of other disorders associated with inflammation, such as anti-arthritics, analgesics for the treatment of pain and migraine, or as antipyretics in the treatment of fever.

In human therapy, the administration dose of the compounds of the present invention varies as a function of the seriousness of the affliction to treat. Normally the dose will lie between 100 and 400 mg/day. The compounds of the invention will be administered, for example, in the form of capsules, tablets, or injectable solutions or suspensions.

Below, by way of example, two pharmaceutical compositions containing the compounds object of the present invention are shown.

Pharmaceutical Formulations