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Pyrazoline derivatives, their preparation and application as medicaments

a technology of pyrazoline and derivatives, applied in the field of new pyrazoline derivatives, can solve the problems of the beneficial effects, the gastric toxicity of the classic nsaid, and the absence of significant effects of these modifications on the incidence of serious adverse reactions such as perforation and hemorrhaging

Inactive Publication Date: 2006-01-31
ECUPHAR
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to new pyrazoline derivatives that can be used as medicines in humans and animals. These compounds have been found to have anti-inflammatory, antipyretic, and analgesic properties. They can be used to treat inflammation, fever, and pain. The new compounds have been found to have a higher preference for the lateral cavity of cyclooxygenase-2, which makes them more effective inhibitors of this enzyme. The patent text also describes the discovery of the induced prostaglandin-synthetase, cyclooxygenase-2, and the potential use of selective inhibitors of this enzyme to reduce inflammation without causing the side effects of traditional non-steroid anti-inflammatory drugs."

Problems solved by technology

The gastric toxicity of the classic NSAIDS, as well as their beneficial effects, is due to the suppression of prostaglandin synthesis by inhibition of the COX enzyme.
Although several strategies have been followed (enteral Coating to prevent adsorption in the stomach, parenteral administration, pro-drug formulation, etc) to reduce the gastrointestinal lesions provoked by the NSAIDS, none of these modifications have provided a significant impact on the incidence of serious adverse reactions such as perforation and haemorrhaging.

Method used

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  • Pyrazoline derivatives, their preparation and application as medicaments
  • Pyrazoline derivatives, their preparation and application as medicaments
  • Pyrazoline derivatives, their preparation and application as medicaments

Examples

Experimental program
Comparison scheme
Effect test

example 1

(Entry 1 of the Tables)

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

[0041]

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

[0042]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...

example 2

(Entry 2 in the Tables)

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

[0052]

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

[0053]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 sulphat...

example 3

(Entry 3 in the Tables)

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

[0061]

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

[0062]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 CF3COCH3 (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. CF3COCH3 (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 CF3COCH3 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 solut...

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Abstract

The present invention relates to new pyazoline derivatives of formula and to physiologically acceptable salts thereof, to the method for their preparation and to their application as medicaments.

Description

[0001]This application is a 371 of PCT / ES99 / 00156 filed on May 27, 1999.FIELD OF THE INVENTION[0002]The present invention relates to new pyrazoline derivatives, of general formula (I), and to physiologically acceptable salts thereof, to the procedures for their preparation, to their application as medicaments in human and or veterinary therapy and to the pharmaceutical composition that contain them. [0003]The new compounds object of the present invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.BACKGROUND OF THE INVENTION[0004]Non-steroid anti-inflammatory drugs (NSAIDS) are traditionally classified as anti-inflammatory, antipyretic and analgesic agents for the symptomatic alleviation of inflammation, fever and light to moderate pain. The main indications for these drugs are osteoarthritis, rheumatoid arthritis and other inflammatory diseases of articulations, as well as for the treatment of inflammations associated with smal...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D231/06A61K31/41A61K31/415A61P29/00A61P43/00
CPCC07D231/06A61P1/04A61P11/06A61P15/00A61P17/06A61P19/02A61P25/06A61P29/00A61P35/00A61P43/00A61K31/415
Inventor CUBERES-ALTISENT, MARIA ROSABERROCAL-ROMERO, JUANA MARIAMONTSERRAT-CONTIJOCH-LLOBET, MARIAFRIGOLA-CONSTANSA, JORDI
Owner ECUPHAR
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