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Brinzolamide Basic information
Brinzolamide Chemical Properties
  • Melting point:130.0 to 134.0 °C
  • Boiling point:586.0±60.0 °C(Predicted)
  • Density 1.50±0.1 g/cm3(Predicted)
  • storage temp. -20°C
  • solubility DMSO: ≥10mg/mL
  • pka9.62±0.40(Predicted)
  • form powder
  • color white to beige
  • Merck 14,1376
  • CAS DataBase Reference138890-62-7(CAS DataBase Reference)
Safety Information
  • WGK Germany 3
  • RTECS XJ9095055
  • HS Code 2935904000
Brinzolamide Usage And Synthesis
  • DescriptionBrinzolamide was introduced as Azopt in the US for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or openangle glaucoma. Brinzolamide is a potent inhibitor of human carbonic anhydrase Ⅱ lowering IOP after topical administration . It is the second of this class after dorzolamide (1995). Brinzolamide can be prepared in an eight-step sequence from 3-acetyl-2,5-dichlorothiophene. In patients with primary open-angle glaucoma or ocular hypertension, brinzolamide produced significant reductions in IOP and showed less ocular discomfort than dorzolamide.
  • Chemical PropertiesCrystalline Solid
  • OriginatorAlcon (US)
  • UsesCarbonic anhydrase inhibitor. Antiglaucoma agent
  • Usesantihypertensive, beta-blocker, antianginal
  • UsesFor the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
  • IndicationsBrinzolamide, a heterocyclic sulfonamide, is a topical CAI suspension that has a high affinity for the carbonic anhydrase II isoenzyme.Because the ocular hypotensive effect of the drug is equivalent whether dosed twice or three times daily, brinzolamide 1% may be administered twice daily.
  • Manufacturing ProcessTo a solution of 3-(2,5,5-trimethyl-1,3-dioxane-2-yl)thiophene (2.5 g, 11.7 mmol) in hexane (30 mL) cooled to 0°C was added via syringe n-butyl lithium in hexane (2.5 M, 10.3 mL, 25.7 mmol) over 5 min. The mixture was stirred at 0°C for 20 min, the ice bath was removed and the stirring was continued for 30 min. At this time a white precipitate formed. The mixture was cooled to -60°C and THF (20 mL) was added. Sulfur dioxide was then passed through the surface of the mixture for 30 min. The mixture was warmed to ambient temperature and stirred for an additional 15 min. The volatiles were evaporated and to the residue was added water (50 mL) and sodium acetate trihydrate (9.55 g, 70.2 mmol). The solution was cooled on an ice bath and hydroxylamine-O-sulfonic acid (4.62 g, 40.9 mmol) was added. The mixture was stirred at ambient temperature for 1 h, extracted with ethyl acetate (3x100 mL) and the combined extracts were washed with a sodium bicarbonate solution, brine and dried over molecular sieves. Evaporation to dryness gave a viscous liquid (4.93 g), which was chromatographed (silica, eluting with 33% ethyl acetate-hexane) to give a solid 3-(2,5,5-trimethyl-1,3- dioxane-2-yl)-2-thiophenesulfonamide (2.47 g, 72%): m.p. 200°-202°C. The last compound (9.45 g, 32.5 mmol) and 1 N HCl (100 mL) in THF (100 mL) was heated at reflux for 1 h. The THF was evaporated and the aqueous solution was made basic by the addition of sodium bicarbonate. The mixture was cooled using an ice bath and the precipitate was filtered, washed with cold water and dried in vacuo to give 5.83 g (88%) of a solid 3-acetyl-2- thiophenesulfonamide: m.p. 193°-196°C.
    The last product (5.73 g, 28.0 mmol) was dissolved in hot THF (200 mL). The solution was cooled to 10°C and pyridinium bromide perbromide (10.73 g, 33.5 mmol) was added. The mixture was allowed to stir at ambient temperature for 1 h. The volatiles were evaporated and the residue was mixed with water. The precipitate was filtered, washed with cold water and dried in vacuo overnight to give 7.77 g of a solid. A portion of this solid (3.49 g, 12.3 mmol) was suspended in ethanol (100 mL) and treated with sodium borohydride (266 mg, 7.04 mmol). The suspension turned clear after 10 min and was heated at reflux for 1 h. The ethanol was evaporated and the residue was extracted with ethyl acetate, washed with brine and evaporated to give 3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (1.80 g, 71%): m.p. 138°-140°C.
    A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103 mol) in DMF at 006. When the addition was completed the ice bath was removed and the reaction 20 mixture stirred at ambient temperature for 1 h. The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6 mL, 0.14 mol) was added. The reaction mixture was stirred at ambient temperature for 18 h after which time it was evaporated to dryness. The residue was suspended in brine (100 mL) and extracted with methylene chloride (4x80 mL). The combined extracts were dried (MgSO4), filtered and evaporated to a solid which was recrystallized from ethyl acetate to give the desired subject (17.4 g). Chromatography of the mother liquor (silica, 3% ethanol/methylene chloride) furnished more subject which was combined with the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2- methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide.
    3,4-Dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1- dioxide (4.9 g, 50 18.6 mmol) was converted to the 4-(1-ethoxy)ethoxy-3,4- dihydro-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (6.2 g, 99%) using the reaction with p-toluensulfonic acid and ethylvinyl ether at 0°C in tetrahydrofuran for 2 hrs.
    The last one (6.2 g, 18.4 mmol) was converted into 3,4-dihydro-4-hydroxy-2- (2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (4.87 g, 77%) m.p. 187°C by using the reaction with n-butyl lithium in anhydrous THF at -40°C for 40 min, and then bubbling sulfur dioxide gas for 20 min after which time the mixture was warmed to room temperature. After 30 min at room temperature the mixture was concentrated the residue was dissolved in water, cooled (0°C), sodium acetate trihydrate was added followed by hydroxylamine-O-sulfonic acid. The reaction mixture was stirred at room temperature for 18 h after which time was basified with solid sodium bicarbonate and extracted with ethyl acetate.
    3,4-Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-1,2-thiazine- 6-sulfonamide-1,1-dioxide hydrochloride was obtained by the reaction of 3,4- dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6- sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at -16°C and the next stirring for 18 hrs at room temperature. After which time the mixture was cooled to 0°C and propylamine was added, the desired product (0.57 g, 46%) was obtained: m.p. 178°-181°C. The desired 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]- 1,2-thriazine-6-sulfonamide-1,1-dioxide was prepared according to described above procedure for 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2Hthieno[ 3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide substituting 2- bromoethylmethylether for 2-(bromomethyl)ethyl-methylether.
  • brand nameAzopt (Alcon).
  • Therapeutic FunctionAntiglaucoma
  • Clinical UseBrinzolamide is indicated for the treatment of elevated IOP in patients with ocular hypertension or open-angle glaucoma.The drug is commercially available as a sterile 1.0% aqueous suspension with a pH of approximately 7.5. BAC 0.01% is added as a preservative.
    The efficacy and safety of brinzolamide 1%, either two or three times daily, were evaluated in 572 patients with open-angle glaucoma or ocular hypertension against timolol 0.5% twice daily and dorzolamide 2.0% three times daily. Mean IOP changes were -3.8 to -5.7 mm Hg, -4.2 to -5.6 mm Hg, and-4.3 to-5.9 mm Hg for two- and three-times-daily brinzolamide and dorzolamide dosing, respectively. The mean IOP changes for timolol 0.5% ranged from -5.6 to -6.3 mm Hg (Figure 10-15). Brinzolamide was well tolerated, with 1.8% (twice daily) and 3% (three times daily) of patients reporting ocular discomfort versus 16.4% with dorzolamide. Complaints of blurred vision were higher with brinzolamide (5–6%) than dorzolamide (1%) or timolol (0%).
    A meta-analysis of randomized clinical trials reported peak ocular hypotensive effect on IOP of 17% (19% to 15%) and trough effect of 17% (19% to 15%).
  • Side effectsBoth brinzolamide and dorzolamide exhibit similar taste abnormalities. A single case report of the development of metabolic acidosis from topical brinzolamide has been described after twice-daily dosing. Other adverse events are negligible for brinzolamide except for some blurring of vision, attributable to its suspension vehicle.
  • Veterinary Drugs and TreatmentsBrinzolamide is chemically similar to dorzolamide and reduces aqueous humor production by altering H+/Na+ active transport mechanisms associated with aqueous humor production in the ciliary epithelial cells. It can be used as a substitute for dorzolamide and some patients that exhibit excessive topical irritation following application of dorzolamide drops, tolerate brinzolamide better or vice versa. Cats seem to be particularly sensitive to irritation from topical dorzolamide and often brinzolamide can be used in these patients. Comparative data is available suggesting that brinzolamide and dorzolamide are equally effective in animal patients.
  • PrecautionsBrinzolamide has the same contraindications and precautions as dorzolamide.
Brinzolamide Preparation Products And Raw materials
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