Sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion

#Human bones are subject to a constant, dynamic renovation process comprising bone resorption and bone formation. These processes are controlled by types of cells specialized for these purposes. Bone resorption is based on the destruction of bone matrix by osteoclasts. The majority of bone disorders are based on a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is a disease characterized by low bone mass and enhanced bone fragility resulting in an increased risk of fractures. It results from a deficit in new bone formation versus bone resorption during the ongoing remodelling process. Conventional osteoporosis treatment includes, for example, the administration of bisphosphonates, estrogens, estrogen/progesterone (hormone replacement therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone, growth hormone secretagogues, or sodium fluoride (Jardine et al, Annual Reports in Medicinal Chemistry 31: 211 (1996)).

#Activated osteoclasts are polynuclear cells having a diameter of up to 400 μm, which remove bone matrix. Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called “sealing zone,” the region between their cell membrane and the bone matrix. The acidic environment and the proteases cause the destruction of the bone.

#Studies have shown that the attachment of osteoclasts to the bones is controlled by integrin receptors on the cell surface of osteoclasts. Integrins are a superfamily of receptors which include, inter alia, the fibrinogen receptor αIIbβ3 on the blood platelets and the vitronectin receptor αvβ3. The vitronectin receptor αvβ3 is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the vascular smooth musculature, osteoclasts and tumor cells. The vitronectin receptor αvβ3, which is expressed on the osteoclast membrane, controls the process of attachment to the bones and bone resorption and thus contributes to osteoporosis. αvβ3 in this case binds to bone matrix proteins such as osteopontin, bone sialoprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).

#The products were identified via mass spectra (MS) and/or NMR spectra. Depending on how the last synthesis step and/or workup procedures, for example freeze-drying, were carried out, in some cases the compounds were obtained partially or completely in the form of a salt, for example in the form of an acetic acid salt, trifluoroacetic acid salt or hydrochloric acid salt.

#18.74 g (0.12 mol) of monomethyl malonate potassium salt were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring. The mixture was refluxed until the evolution of CO2 was complete (about 2 hours), then a further 60 ml of pyridine were added and the mixture was stirred under reflux for a further 1 hour. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of conc. hydrochloric acid. After addition was complete, the mixture was stirred for a further 20 minutes, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield 12.85 g.

#1H-NMR (200 MHz, d6-DMSO): δ=3.75 (s, 3H, OCH3); 6.76 (d, J=15 Hz, 1H, CHCOOCH3); 7.73 (d, J=15 Hz, 1H, Ar—CH); 7.84 (d, J=9 Hz, 2H, Ar—H); 7.98 (d, J=9 Hz, 2H, Ar—H); 13.11 (s, broad, 1H, COOH). MS (Cl+): m/e=207.2 (M+H+).