CT4.7
Brinzolamide
CAS: 138890-62-7;138890-50-3;154127-19-2
Molecular Formula: C12H21N3O5S3
CT4.7 - Names and Identifiers
CT4.7 - Physico-chemical Properties
| Molecular Formula | C12H21N3O5S3 |
| Molar Mass | 383.51 |
| Density | 1.50±0.1 g/cm3(Predicted) |
| Melting Point | 130.0 to 134.0 °C |
| Boling Point | 586.0±60.0 °C(Predicted) |
| Flash Point | 308.2°C |
| Solubility | DMSO 77 mg/mL Water <1 mg/mL Ethanol <1 mg/mL |
| Vapor Presure | 1.03E-13mmHg at 25°C |
| Appearance | White to beige powder |
| Color | white to beige |
| Merck | 14,1376 |
| pKa | 9.62±0.40(Predicted) |
| Storage Condition | -20°C |
| Sensitive | Sensitive to heat and humidity |
| Refractive Index | 1.625 |
| MDL | MFCD08067749 |
| Use | Heterocyclic sulfa Carbonic anhydrase inhibitors |
CT4.7 - Risk and Safety
| WGK Germany | 3 |
| RTECS | XJ9095055 |
| HS Code | 2935904000 |
CT4.7 - Introduction
Brinzolamide is a potent carbonic anhydrase-II inhibitor with an IC50 of 3.19 nM.
Last Update：2022-10-16 17:13:46
CT4.7 - Reference Information
| ophthalmic drugs | brinzolamide is a new type of topical heterocyclic sulfonamide carbonic anhydrase inhibitor, which has a strong affinity and inhibitory effect on the carbonic anhydrase isoenzyme II(CAII) in the human ciliary body. It can be selective, high affinity and significantly inhibit the activity of carbonic anhydrase isoenzyme II, effectively reduce intraocular pressure, and has the advantages of high efficiency, low toxicity and small side effects, its physiological pH value and suspension design make the drug eye comfort strong characteristics are favored by patients. It can be used as a separate treatment for patients who are ineffective or contraindicated to β-blockers, or as a synergistic treatment for β-blockers. This product can quickly enter the eye tissue after eye drops, in the iris, ciliary body, Choroid, retina, lens and blood have a longer half-life. The use of perimine on rabbit eyes can also increase the blood flow of the optic papilla, which is beneficial to glaucoma patients with optic neuropathy. It has become the first-line drug for the treatment of open-angle glaucoma. Carbonic anhydrase (CA) is one of the main protein components of red blood cells. It is second only to hemoglobin in red blood cells and exists in many body tissues including eye tissues. Carbonic anhydrase catalyzes the hydration of carbon dioxide into carbonic acid, and the reversible reaction of carbonic acid dehydration. Inhibition of carbonic anhydrase in the ciliary body of the eye can reduce the secretion of aqueous humor. It is possible to reduce sodium and water transport by reducing the generation of bicarbonate ions, and finally reduce intraocular pressure. Intraocular pressure is an important risk factor for optic nerve damage and glaucomatous visual field defect. Brinzolamide mainly inhibits the dominant carbonic anhydrase type 2 isoenzyme in ocular tissues. In vitro tests, the effective inhibitory concentration of 50% is 3.2nM, and the Ki value for carbonic anhydrase type 2 isoenzyme is 0.13nM. |
| brinzolamide eye drops | brinzolamide eye drops (BrinzolamideEye Drops) is currently a good drug for treating ocular hypertension and relieving elevated intraocular pressure in patients with open-angle glaucoma. it was first listed in the United States in April 1998 and has been listed in nearly 30 countries in the world. it was approved for import in China in 2002 and can be used as a single drug for patients who are ineffective or contraindicated against β receptor blockers, or as a synergistic therapeutic drug for β-blockers, its trade name is Azopt. Brinzolamide eye drops is a sulfa drug, although it is used for eye drops, it can still be absorbed by the whole body. Therefore, adverse reactions of sulfa drugs may still occur during eye drops. If serious adverse reactions or allergies occur, the eye medicine should be stopped immediately. Patients with oral carbonic anhydrase inhibitors and dripping of perimine may have known systemic adverse reactions related to carbonic anhydrase inhibition. The simultaneous use of oral carbonic anhydrase inhibitors and perimine has not been studied, so the simultaneous use of these two drugs is not recommended. The current experience of perimine in the treatment of pseudocapsular exfoliative and pigmented glaucoma is limited. In the combined treatment of glaucoma, the combined application effect of periclamine and timolol was mainly evaluated. Therefore, information on the combined use of other anti-glaucoma drugs is very limited. The study of Brinzolamide eye drops in patients with acute angle-closure glaucoma and severe renal impairment has not been conducted. Since most of this product and its main metabolites are excreted through the kidneys, the above two patients are not recommended. Benzalomide is a commonly used ophthalmic preservative. It has been reported in the literature that it can cause punctate keratopathy or (and) ulcerative keratopathy. Palamine contains benzafilamide as a preservative, which may be absorbed by soft corneal contact lenses. Therefore, contact lenses must be worn after 15 minutes of brinzolamide eye drops. It is strictly prohibited to wear contact lenses at the same time. Patients with diabetes, dry eye, and corneal lesions need to be closely observed. Use with caution for pregnant women and lactating children under 18 years of age. |
| usage and dosage | shake well before use. As a single treatment or synergistic treatment, 1 drop is instilled into the conjunctival sac twice a day, and the effect is better for some patients 3 times a day. When replacing another anti-glaucoma drug, stop the drug and start using brinzolamide eye drops the next day. When using more than one drug, the interval should be at least 5 minutes. It is usually recommended to press the nasal lacrimal passage or gently close the eyes after the medicine is ordered to reduce systemic absorption. |
| adverse reactions | it is reported that the occurrence probability of clear, likely or likely treatment-related adverse reactions in clinical research of brinzolamide eye drops is less than 10% common and less than 1% rare. in the clinical use of brinzolamide eye drops alone or in combination with 0.5% of timolol in more than 1500 patients, the most common treatment-related adverse reactions and local symptoms are: taste changes (bitter taste and peculiar smell)(5.3%), transient blurred vision after drip, lasting a few seconds to a few minutes (4.8%). Pharyngitis, dermatitis, eye sensation, foreign body sensation, headache, hyperemia, eye discharge, eye discomfort, keratitis, eye pain, eye itching and rhinitis were reported in 1% ~ 5% of cases. the following very serious adverse reactions are rare: stomach pain, dark urine, easy bleeding or bruising, visual changes, persistent throat pain, fever. Brinzolamide eye drops are contraindicated to those who may be allergic to any of their ingredients. |
| use | carbonic anhydrase inhibitor is suitable for high intraocular pressure caused by open angle glaucoma or other reasons. Heterocyclic sulfonamide carbonic anhydrase inhibitors |
| production method | thiourea (1.287kg,16.93 mo1), benzyl chloride (1.858L,2.044kg,16.14 mo1), 13.5L ethanol and 4.5L water were refluxed together for 2h. In 20min, cool to 74°C. 3-acetyl -2, 5-dichlorothiophene (3.0kg,15.38 mo1) and 10 L4mol/L sodium hydroxide aqueous solution were added sequentially. Reflux for 3h until the reaction is complete, cold to room temperature overnight. Then add 10L of water, stir for 30min, then add 3L of 5.25% sodium hypochlorite solution, and stir for 30min. Filtered to collect the solid, washed with 4 × 2.5L water and 3 × 2L isopropanol, dried to constant weight in room temperature air to obtain 4.224kg compound (I), yield 97%, melting point 86~88 ℃. Compound (I)(1kg,3.53 mo1) was dissolved in 20L ethyl acetate, and chlorine gas was introduced at 2~10 ℃ and stirred until no compound (I) was detected. Blowing with a large air flow rate for 1h, then passing in ammonia gas, keeping the temperature at 5~15 ℃, and reacting until the intermediate product sulfinyl chloride is completely converted. Then blow with air for 1h, add 5L of water, and cool to 15 ℃. Add human sodium tungstate trihydrate (583g,1.77 mo1) and 8L 30% hydrogen peroxide in 5min. The mixed solution was stirred at 35 ℃ for 2h and then at room temperature for 16h. Add 5L of water, separate the organic layer, and then add 5L of water. Add sodium bisulfite until there is no peroxide detection, separate the organic layer, first wash with saturated sodium bicarbonate to Ph 8, and then wash with saturated salt. Drying, filtering, concentrating, adding tert-butyl methyl ether to the residue, filtering and collecting solids, washing with tert-butyl methyl ether, drying in air to constant weight, 597g compound (II), 71% yield, melting point 178~179 ℃. Compound (II)(1.087kg,4.55 mo1) is dissolved in 22L ethyl acetate, and 90% hydrogen bromide perbromopyridine anchor (1.305kg,3.67 mo1) is added under ice bath cooling. 544ml sulfuric acid was added in 10min to raise the temperature to 5 ℃. Stir for 1h until the reaction is complete, and then stir for 30min. Add 5L of water and stir for 5min. The organic layer is separated and washed with 4 × 5L saturated salt water until the Ph value of the lotion is 3. Drying, filtering, concentrating, adding 2L dichloromethane to the residue, freezing for 15min. Filtration to collect solids, drying to constant weight in air at room temperature to obtain 1.041kg compound (Ⅲ) with 72% yield and melting point of 147~148 ℃. Under the protection of nitrogen, compound (III)(4855g,2.68 mo1) and 12.5L tert-butyl methyl ether were added to the reaction bottle, stirred and cooled to -40 ℃. In 30min, 4.5L 1.2mol/L,(+)-β-chloro diisopine camphane alkyl boron tert-butyl methyl ether solution was added. Stir at -25 ~-20 ℃ for 3.5h until the reaction is complete, raise to 0 ℃, add 11L 1mol/L sodium hydroxide aqueous solution in 10min, and raise the temperature to 22 ℃. Stir vigorously at room temperature for 2h to separate the organic layer. The water layer is extracted with 3L tert-butyl methyl ether, and the remaining water layer is acidified with concentrated hydrochloric acid to Ph value 1, and then extracted with 2 × 4L ethyl acetate. The ethyl acetate extract was washed, dried, filtered and concentrated with 3L saturated salt. Add 2L toluene, filter to collect crystals, wash with 2L toluene, then wash with 2L dichloromethane, dry to constant weight in room temperature air to obtain 498g compound (Ⅳ), yield. 77%, melting point 126~127 ℃. Compound (Ⅳ)(5350g,1.46 mo1), 1.75L dimethyl sulfoxide and potassium carbonate (605g,4.38 mo1) were mixed, and 1-bromo-3-methoxypropane (268g,1.75 mo1) was added in 8 parts at intervals of 1h. After adding, the reaction is complete, about 1.5h. Under stirring, the reaction liquid is poured into 18L saturated salt water, and the original reactor is washed with water and tert-butyl methyl ether. The reaction solution and washing solution were combined and extracted with 2 × 4L tert-butyl methyl ether. The extract was washed with 2L 1mol/L sodium hydroxide aqueous solution, 2L 1:1 sodium hypochlorite/water and 2L saturated salt. After filtering, most of the solvent is evaporated, and then concentrated at 50 ℃ under reduced pressure. 427g compound (V) was obtained with a 94% yield and a light yellow oil. Under the protection of nitrogen, compound (V)(1.065kg,3.42 mo1) was added to 27L dry tetrahydrofuran, cooled to -70 ℃, and 3.08L2.5mol/L n-butyl lithium hexane solution was added dropwise in 2.5h to maintain the temperature of the reaction solution below -66 ℃. After 1h of reaction, sulfur dioxide was introduced to the Ph value of 4. Any temperature is raised to room temperature and left overnight. Concentrated, the remainder dissolved in 5L of water. It was added to a solution of sodium acetate trihydrate (2.796kg,20.5 mo1) and hydroxylamine-O-sulfonic acid (1.549kg,13.7 mo1) at 0 ℃ in 6L of water to raise the temperature to 25 ℃. After stirring at room temperature for 15h, it was extracted with 3 × 4L ethyl acetate. The extract is first washed with saturated sodium bicarbonate solution until the lotion is alkaline, and then washed with saturated salt. Drying, filtering, concentrating. Add 6L of dichloromethane to the residue, and add 5g of seed crystal to crystallize. Filter to collect crystals, wash with dichloromethane, and dry to constant weight in room temperature air. 748g compound (Ⅵ) was obtained with 61% yield, 111~113 ℃. Compound (Ⅵ)(28.5g,0.08 mo1), 285ml acetonitrile and 23.4ml trimethyl orthoacetate were mixed and refluxed for 16h. After cooling for 1h, the solvent is distilled, and the remainder is dissolved in 150ml of dry tetrahydrofuran. Under the protection of nitrogen, 24.5ml triethylamine and 30.5g p-toluenesulfonyl chloride were added at 4 ℃, and stirred at 4~7 ℃ for 2h. 70% ethylamine (260ml,2.80 mo1) was added dropwise in 30min to maintain the temperature below 15 ℃. After adding, stir at room temperature for 18.5h. Cold to 5 ℃, add 280ml concentrated hydrochloric acid dropwise in 1h to maintain the temperature below 30 ℃. The extract was extracted with 2 × 250ml ether, and the extract was extracted with 200ml 1mol/L hydrochloric acid. The hydrochloric acid extract was adjusted to the Ph value of 8 with solid sodium bicarbonate and frozen for 2 hours. Filter to collect crystals and wash them with water. The filtrate also contains the product, which is extracted with ethyl acetate. The crystals obtained above are dissolved in the extract, and ethyl acetate can be added. Drying, filtering, concentrating. 24.0g of product was obtained with 78% yield. It can be recrystallized with isopropanol with a melting point of 125~127 ℃. |
Last Update：2024-04-10 22:29:15
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