Pamidronic acid

Pamidronic acid is a drug used to treat a broad spectrum of bone absorption diseases.

Solid

Pamidronate is a phosphonoacetic acid.|Pamidronic acid is a second generation, nitrogen containing bisphosphonate similar to [neridronic acid] and [alendronic acid]. Pamidronic acid was first described in the literature in 1977. The second generation bisphosphonates are less common as third generation bisphosphonates, such as [ibandronic acid], [zoledronic acid], [minodronic acid], and [risedronic acid] are becoming more popular. Pamidronic acid was granted FDA approval on 31 October 1991.|Pamidronic acid is a Bisphosphonate.|Pamidronic Acid is an amino- bisphosphonate with anti-resorptive and anti-hypercalcemic activities. Pamidronic acid binds to and adsorbs onto hydroxyapatite crystals in the bone matrix, thereby preventing osteoclast resorption. This agent also binds to and inhibits farnesyl pyrophosphate synthase, an enzyme that plays an important role in the mevalonate pathway. This inhibits the formation of isoprenoid metabolites that are substrates for protein prenylation. This prevents farnesylation and geranylgeranylation of proteins essential for osteoclast function, leading to the induction of apoptosis of osteoclasts. By preventing osteoclast-mediated bone resorption, pamidronic acid decreases bone turnover rate, stabilizes the bone matrix and reduces hypercalcemia.|An aminobisphosphonate that inhibits BONE RESORPTION and is used for the treatment of osteolytic lesions, bone pain, and severe HYPERCALCEMIA associated with malignancies.

(3-Amino-1-hydroxypropane-1 , 1-diyl)bis(phosphonic acid) (pamidronic acid) A mixture of 3-aminopropionic acid (1.00 g, 1 1.2 mmol, 1 equiv.) and phosphorous acid (0.920 g, 1 1.2 mmol, 1 equiv.) in methanesulfonic acid (4.7 mL) was heated at 65 °C. Phosphorus trichloride (2.06 ml_, 23.6 mmol, 2.1 equiv.) was added slowly under stirring. After completion of the addition, the temperature was raised to 70 °C and the reaction mixture was stirred overnight under an argon atmosphere at the same temperature. The clear, colorless solution was cooled to 25 °C and quenched at 0-5 °C with water (4 mL) under vigorous stirring. The mixture was then refluxed for 5 h. The solution was cooled to 20 °C and the pH was adjusted to 2 with 1 N sodium hydroxide solution. Methanol was added to the mixture and a precipitate was formed. The mixture aged overnight at 4 °C. The precipitate was filtered off and washed with methanol. The white solid was then solubilized in water and loaded onto a cation exchange column (Si- Tosic acid 40-63 μηι, 0.55 mmol/g) which was beforehand rinsed with 100percent MeOH and then 100percent water. It was eluted with water and the resulting solution was then freeze- dried to get pamidronic acid as a free acid (2.619 g, 99percent) as a white solid. In a 1, 000 mL three-neck flask provided with magnetic stirring, surmounted with a condenser and with nitrogen inertization and placed in a thermostated oil bath and connected to a vacuum pump, 91 g (1 mole) of 3-aminopropionic acid, 123 g (1.5 moles) of phosphorous acid and 500 mL of anhydrous chlorobenzene are added. 2.2 g (0.025 mol) of β-Alanine (1) and 4.3 g (0.053 mol) phosphorous acid were added into 3 mL (0.015 mol) of 1-butyl-3-methylimidazolium hexafluorophosphate on stirring. Then, 7 mL (0.080 mol) of phosphorous trichloride was added dropwise in ca. 30 min, and the contents of the flask were stirred at 75 °C for 3 h. After cooling the mixture to 26 °C, 10 mL (0.53 mol) of water was added and the mixture was stirred further at 105 °C for 1 h. Then, the mixture was stirred at 26 °C for 12 h, and finally at 0-5 °C for 3 h. The precipitate was removed by filtration to give ~5 g of the crude product that was suspended in 15 mL of methanol, and the mixture was digested by stirring at 65 °C for 30 min. The solid product was filtered off to furnish 4.2 g (72percent) of pamidronic acid (2) in a purity of >99percent. 2.2 g (0.025 mol) of β-Alanine (1) and 4.3 g (0.053 mol) phosphorous acid were added into 3 mL (0.015 mol) of 1-butyl-3-methylimidazolium hexafluorophosphate on stirring. Then, 7 mL (0.080 mol) of phosphorous trichloride was added dropwise in ca. 30 min, and the contents of the flask were stirred at 75 °C for 3 h. After cooling the mixture to 26 °C, 10 mL (0.53 mol) of water was added and the mixture was stirred further at 105 °C for 1 h. Then, the mixture was stirred at 26 °C for 12 h, and finally at 0-5 °C for 3 h. The precipitate was removed by filtration to give ~5 g of the crude product that was suspended in 15 mL of methanol, and the mixture was digested by stirring at 65 °C for 30 min. The solid product was filtered off to furnish 4.2 g (72percent) of pamidronic acid (2) in a purity of >99percent. Preparation of pamidronic acid A suspension of 3-aminopropionic acid (25g, 0. 280mol) and phosphorous acid (34. 5g, 0. 421mol) in sulfolan (90ml) is heated to 75° C for 30 min. The mixture is cooled to 35- 40° C and then gradually introduced phosphorous trichloride (83ml, 0. 954mol) while maintaining the temperature at 35-45° C. The mixture is heated to 63-67° C for 3 hrs, whereby white solid results. It is then cooled to 0-5° C and quenched by slow addition of water (250ml) at 0-5° C over a period of 1 hr. The resulting clear solution is charcoalized and is heated at 100° C for 3 hrs, cooled to ambient temperature. Cooled the charcoalized solution and stirred for 4hrs at 0-5° C. The crystallized product is filtered, washed sequentially with chilled water (100mol), rectified spirit (75ml) and dried in air oven at 55-60° C until water content is less than 0.5percent w/w. Yield 41.4g, (62.7percent), appearance: white crystalline solid, purity >99.0percent.To a mixture of 12.3 g (0.15 mol) phosphoric acid, 8.9 g (0.9 mol) beta-aminopropyonic acid and 50 ml chlorobenzene 33.0 g (0.24 mol) PCl3 was added by dropping under stirring at 100° C. The two-layer mixture was heated at 105-110° C. for 2 h. nder those conditions the bottom layer became thick and finally became solid. The reaction mixture was cooled down to 60-65° C. At this temperature 20 ml of water was added drop by drop. The layers were stirred for 15 mm., cooled down to room temperature and then they were separated. The bottom aqueous layer was filtered through paper filter. To the solution was added to 100 ml isopropanol drop by drop (60-65° C.) under stirring. The warm solution was filtered and 100 ml of ethanol was added. After 12 hours at room temperature, precipitate was filtered off generating a yield 12.7 g (62percent) t.m. 232-234° C. To obtain a homogeneous product the solid material was boiled with 50 ml of water and insoluble substance was filtered off yield 10.8 g (53percent) m.p. 234-236° C.EMBODIMENT 3 Excepting that 200 ml of methanol was added to the aqueous phase separated after the hydrolysis in order to promote the crystallization, the same procedures as the embodiment 1 were repeated to give a final productproduct. From IR and NMR measurements, the final productproduct was identified as 3-amino-l-hydroxypropane-1, 1-diphosphonic acid and the yield was 72.0%.wherein said bisphosphonic acid is selected from the group consisting of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid; N-methyl-4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid; 4-(N, N-dimethylamino)-1-hydroxypropylidene-1, 1-bisphosphonic acid;

anticancer

Molecular Weight:235.07
XLogP3:-6.9
Hydrogen Bond Donor Count:6
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:4
Exact Mass:235.00107569
Monoisotopic Mass:235.00107569
Topological Polar Surface Area:161
Heavy Atom Count:13
Complexity:243
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes