Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents

Abstract

Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.

Contrast between effects of aminobisphosphonates and non‐aminobisphosphonates on collagen‐induced arthritis in mice

“…Therefore, the contrast between the sup- AA, adjuvant-induced arthritis; CA, collagen-induced arthritis; RA, rheumatoid arthritis; E, effective; NE, not effective; W, worsening. References: (1) Francis et al, 1972;(2) Flora, 1979;(3) Babier et al, 1986;(4) Francis et al, 1989;(5) Nugent et al, 1993;(6) Dunn et al, 1993a;(7) Markusse et al, 1990;(8) Ralston et al, 1989;(9) Tan et al, 1989;(10) Bijvoet et al, 1980;(11) Maccagno et al, 1994; (12) present results. pressive effect of non-aminoBPs and the ineffectiveness of aminoBPs on arthritis cannot be attributable to effects on bone resorption.…”

Synthesis of New Heterocyclic Compounds with Biological Activity against Pathogenic Microbes in the Albaha Area

“…In addition to having antiproliferative [11], Antiparasitic [12] and herbicidal properties [13]. Several pyrazoles have also been reported to have anti-inflammatory [14] and antiprotozoal effects [15,16].…”

Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

“…19 Moreover, pyrazoles and their derivatives could be considered as possible antimicrobial agents. 20 The other derivatives display antidepressant, 21 antiarthritic 22 and cerebroprotecting 23 properties. Some aryl pyrazoles were reported to be non-nucleoside human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, 24 COX-2 inhibitor, [25][26][27] activator of the nitric oxide receptor and to have soluble guanylate cyclase activity.…”