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鏂伴椈鍔ㄦ?

Tivicay|Dolutegravir synthesis
2015-05-10 07:03:01

Tivicay|Dolutegravir|搴﹂瞾鐗归煢

Dolutegravir (trade name:  Tivicay, also known as S/GSK1349572, GSK1349572, Chinese Name:搴﹂瞾鐗归煢锛屽痉缃楁牸闊? was approved by the US Food and Drug Administration (FDA) in August 12, 2013 for use in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children aged 12 years and older weighing at least 40 kg (approx. 88 lbs).

A once-daily integrase inhibitor, dolutegravir was developed by ViiV Healthcare, a joint venture between GlaxoSmithKline, Pfizer and Shionogi. Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller.

Chemical Structure of Tivicay_Dolutegravir_integrase inhibitor_HIV_Shionogi_Pfizer_GSK 钁涘叞绱犲彶鍏嬩笌鏃ユ湰鐩愰噹涔夊埗鑽?叕鍙歌壘婊嬬梾鑽?墿搴﹂瞾鐗归煢_寰风綏鏍奸煢鐨勫寲瀛︾粨鏋刓

Background:

The new once-daily drug Dolutegravir, which belongs to a novel class known as integrase inhibitors that block the virus causing AIDS from entering cells, is owned by ViiV Healthcare, a joint venture focused on HIV in which GSK is the largest shareholder. Dolutegravir may challenge the world’s best-selling AIDS medicine Atripla, made by Gilead Sciences Inc. The drug, combined with one of ViiV’s older treatments, reduced the HIV virus to undetectable levels in more people than Gilead’s Atripla in a clinical trial released in July ,2012. (See the Full Conference Report Here).

Gilead’s Atripla (Emtricitabine/Tenofovir/efavirenz), approved in 2006 with loss of patent protection in 20121, is the top-selling HIV treatment. The $3.2 billion medicine combines three drugs in one pill, two compounds that make up Gilead’s Truvada (Emtricitabine/Tenofovir) and Bristol- Myers Squibb Co.’s Sustiva (Efavirenz, 渚濆彂闊︿粦).

A three-drug combination containing dolutegravir and ViiV’s older two-in-one treatment Epzicom(Abacavir/Lamivudine, marketed outside US as Kivexa) proved better than Gilead’s market-leading Atripla  in a clinical trial released in July, suggesting it may supplant the world’s best-selling AIDS medicine as the preferred front-line therapy.

The result was the second positive final-stage clinical read-out for dolutegravir, following encouraging results against U.S. company Merck & Co’s rival Isentress in April, 2012. (See the Conference Abstract Here).

Generic Name:dolutegravir
Trade Name:Tivicay
Synonym:GSK1349572, S-349572, GSK572
Chinese Name: 搴﹂瞾鐗归煢锛屽痉缃楁牸闊?br /> Date of Approval: August 12, 2013 (US)
Indication:HIV infection
Drug class: Integrase strand transfer inhibitor
Company: ViiV Healthcare,GlaxoSmithKline
CAS number: 1051375-16-6
Chemical Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
Patent: US8129385 (PDF File Here)
Patent expiration date: Oct 5, 2027
PCT patent application: W02006116764

Synthesis of Tivicay (Dolutegravir), HIV/AIDS Drug From Shionogi and GlaxoSmithKline 鑹炬粙鐥呴噸纾呮柊鑽?害椴佺壒闊︾殑鍒跺?鏂规硶

Synthesis of Tivicay_Dolutegravir_integrase inhibitor_HIV_Shionogi_Pfizer_GSK 钁涘叞绱犲彶鍏嬩笌鏃ユ湰鐩愰噹涔夊埗鑽?叕鍙歌壘婊嬬梾鑽?墿搴﹂瞾鐗归煢_寰风綏鏍奸煢鐨勫寲瀛﹀悎鎴怽

Full Experimental Procedures for the Preparation of Dolutegravir (S/GSK1349572, GSK1349572), HIV/AIDS Drug From Shionogi and GlaxoSmithKline

1) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound YP-2). To a slurry of 2000 g of 3-Hydroxy-2-methyl-4-pyrone (Compound YP-1, 1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K CO (1.2 eq.). The mixture was stirred at 80 C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound P-2 as oil. Without further purification, compound YP-2 was used in the next step. H NMR(300 MHz, CDCl) δ 7.60 (d, J = 5.7 Hz, 1 H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7 Hz, 1 H), 5.17 (s, 2H), 2.09 (s, 3H).

2) Synthesis of 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound P-3). To 904 g of the crude compound YP-2 was added 5.88 L of THF and the solution was cooled to -60 C. 5.00 L of 1.0 M of Lithium bis(trimethylsilylamide) in THF(1.25 eq.) was added dropwise for 2 h to the solution of compound 2 at -60 0C. Then, a solution of 509 g of benzaldehyde(1.2 eq.) in 800 ml. of THF was added at -60 C and the reaction mixture was aged at -60 C for 1 h. The THF solution was poured into a mixture of 1.21 L of conc.HCl, 8.14 L of ice water and 4.52 L of EtOAc at less than 2 C. The organic layer was washed with 2.71 L of brine (twice) and the aqueous layer was extracted with 3.98 L of EtOAc. The combined organic layers were concentrated. To the mixture, 1.63 L of toluene was added and concentrated (twice) to provide toluene slurry of compound P-3. Filtration, washing with 0.90 L of cold toluene and drying afforded 955 g of compound YP-3 (74% yield from compound P-1 ) as a solid. H NMR(300 MHz, CDCl) δ 7.62 (d, J = 5.7 Hz, 1 H), 7.5-7.2 (m, 10H), 6.38 (d, J = 5.7 Hz, 1 H), 5.16 (d, J = 11.4 Hz, 1 H), 5.09 (d, J = 11.4 Hz, 1 H), 4.95 (dd, J = 4.8, 9.0 Hz, 1 H), 3.01 (dd, J = 9.0, 14.1 Hz, 1 H), 2.84 (dd, J = 4.8, 14.1 Hz, 1 H).

3) Synthesis of 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound YP-4). To a solution of 882 g of compound YP-3 (1.0 eq.) in 8.82 L of THF were added 416 g of Et N(1.5 eq.) and 408 g of methanesulfonyl chloride(1.3 eq.) at less than 30C. After confirmation of disappearance of compound P-3, 440 ml. of NMP and 1167 g of DBU(2.8 eq.) were added to the reaction mixture at less than 30C and the reaction mixture was aged for 30 min. The mixture was neutralized with 1.76 L of 16% sulfuric acid and the organic layer was washed with 1.76 L of 2% Na2SOaq. After concentration of the organic layer, 4.41 L of toluene was added and the mixture was concentrated (tree times). After addition of 4.67 L of hexane, the mixture was cooled with ice bath. Filtration, washing with 1.77 L of hexane and drying provided 780 g of compound YP-4 (94% yield) as a solid. H NMR(300 MHz, CDCl) δ 7.69 (d, J = 5.7 Hz, 1 H), 7.50-7.25 (m, 10H), 7.22 (d, J = 16.2 Hz, 1 H), 7.03 (d, J = 16.2 Hz, 1 H), 6.41 (d, J = 5.7 Hz, 1 H), 5.27 (s, 2H).

4) Synthesis of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid (compound YP-5). To a mixture of 822 g of compound YP-4 (1.0 eq.) and 1 1.2 g of RuCl-nH2O(0.02 eq.) in 2.47 L of MeCN, 2.47 L of EtOAc and 2.47 L of H2O was added 2310 g of NalO(4.0 eq.) at less than 25C. After aging for 1 h, 733 g of NaCIO(3 eq.) was added to the mixture at less than 25C. After aging for 1 h, precipitate was filtered and washed with 8.22 L of EtOAc. To the filtrate, 1.64 L of 50% Na aq, 822 ml. of H2O and 630 ml. of coc.HCl were added. The aqueous layer was extracted with 4.11 L of EtOAc and the organic layers were combined and concentrated. To the residue, 4 L of toluene was added and the mixture was concentrated and cooled with ice bath. Filtration, washing with 1 L of toluene and drying provided 372 g of compound YP-5 (56% yield) as a solid. H NMR(300 MHz, CDCl) δ 7.78 (d, J = 5.7 Hz, 1 H), 7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J = 5.7 Hz, 1 H), 5.6 (brs, 1 H), 5.31 (s, 2H).

5) Synthesis of 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylic acid (compound YP-6). A mixture of 509 g of compound YP-5 (1.0 eq.) and 407 g of 3-amino-propane-1,2-diol(2.5 eq.) in 1.53 L of EtOH was stirred at 65 C for 1 h and at 80 C for 6 h. After addition of 18.8 g of 3-Amino-propane-1,2-diol(0.1 eq.) in 200 ml. of EtOH, the mixture was stirred at 80 C for 1 h. After addition of 18.8 g of 3-amino- propane-1 ,2-diol (0.1 eq.) in 200 ml. of EtOH, the mixture was stirred at 80 C for 30 min. After cooling and addition of 509 ml. of H O, the mixture was concentrated. To the residue, 2.54 L Of H O and 2.54 L of AcOEt were added. After separation, the aqueous layer was washed with 1.02 L of EtOAc. To the aqueous layer, 2.03 L of 12% sulfuric acid was added at less than 12 C to give crystal of compound YP-6. Filtration, washing with 1.53 L of cold H O and drying provided 576 g of compound YP-6 (83% yield) as a solid. H NMR(300 MHz, DMSO-d6) δ 7.67 (d, J = 7.5 Hz, 1 H), 7.5-7.2 (m, 5H), 6.40 (d, J = 7.5 Hz, 1 H), 5.07 (s, 2H), 4.2-4.0 (m, 1 H), 3.9-3.6 (m, 2H), 3.38 (dd, J = 4.2, 10.8 Hz, 1 H), 3.27 (dd, J = 6.0, 10.8 Hz, 1 H).

6) Synthesis of methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylate (compound YP-7). To a slurry of 576 g of compound YP-6 (1.0 eq.: 5.8% of H2O was contained) in 2.88 L of NMP were added 431 g of NaHCO(3.0 eq.) and 160 ml. of methyl iodide(1.5 eq.) and the mixture was stirred at room temperature for 4 h. After cooling to 5 C, 1.71 L of 2N HCI and 1.15 L of 20% NaClaq were added to the mixture at less than 10 C to give crystal of compound YP-7. Filtration, washing with 1.73 L of H O and drying provided 507 g of compound YP-7 (89% yield) as a solid. H NMR(300 MHz, DMSO- d6) δ 7.59 (d, J = 7.5 Hz, 1 H), 7.40-7.28 (m, 5H), 6.28 (d, J = 7.5 Hz, 1 H), 5.21 (d, J = 5.4 Hz, 1 H), 5.12 (d, J = 10.8 Hz, 1 H), 5.07 (d, J = 10.8 Hz, 1 H), 4.83 (t, J = 5.7 Hz, 1 H), 3.97 (dd, J = 2.4, 14.1 Hz, 1 H), 3.79 (s, 3H), 3.70 (dd, J = 9.0, 14.4 Hz, 1 H), 3.65-3.50 (m, 1 H), 3.40-3.28 (m, 1 H), 3.26-3.14 (m, 1 H).

7) Synthesis of methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2- pyridinecarboxylate (compound YP-8). To a mixture of 507 g of compound YP-7 (1.0 eq.) in 5.07 L of MeCN, 5.07 L of H O and 9.13 g of AcOH(0.1 eq.) was added 390 g of NaIO (1.2 eq.) and the mixture was stirred at room temperature for 2 h. After addition of 1.52 L of 10% Na aq., the mixture was concentrated and cooled to 10 C. Filtration, washing with H O and drying provided 386 g of compound YP-8 (80% yield) as a solid. H NMR(300 MHz, DMSO-d ) δ 7.62 (d, J = 7.5 Hz, 1 H), 7.42-7.30 (m, 5H), 6.33 (d, J = 6.0 Hz, 2H), 6.29 (d, J = 7.5 Hz, 1 H), 5.08 (s, 2H), 4.95-4.85 (m, 1 H), 3.80 (s, 3H), 3.74 (d, J = 5.1 Hz, 2H).

8) Synthesis of (4R,12aS)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H– pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (compound YP-9). After dissolution of a mixture of 378 g of compound YP-8 (1.0 eq.) in 3.78 L of MeOH by heating, the solution was concentrated. To the residue, 1.51 L of toluene was added and the mixture was concentrated. To the residue, 1.89 L of toluene, 378 ml. of AcOH and 137 g of {R)-3-Amino-butan-1-ol(1.3 eq.) were added and the mixture was heated to 90 C, stirred at 90 C for 2.5 h and concentrated. To the residue, 1.89 L of toluene was added and the mixture was concentrated. The residue was extracted with 3.78 L and 1.89 L of CHCI3 and washed with 2 x 1.89 L of H O. The organic layers were combined and concentrated. To the residue, 1.89 L of EtOAc was added and the mixture was concentrated. After addition of 1.89 L of EtOAc, filtration, washing with 1.13 L of EtOAc and drying provided 335 g of compound YP-9 (83% yield) as a solid. H NMR(300 MHz, CDCl) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d, J = 7.5 Hz, 2H), 6.47 (d, J = 7.5 Hz, 1 H), 5.35 (d, J = 10.2 Hz, 1 H), 5.28 (d, J = 10.2 Hz, 1 H), 5.12 (dd, J = 3.9, 6.3 Hz, 1 H), 5.05-4.90 (m, 1 H), 4.07 (dd, J = 3.9, 13.5 Hz, 1 H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1 H), 1.48 (ddd, J = 2.4, 4.5, 13.8 Hz, 1 H), 1.30 (d, J = 6.9 Hz, 3H).

9) Synthesis of (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione (compound YP-10). To a slurry of  332 g of compound YP-9 (1.0 eq.) in 1.66 L of NMP was added 191 g of NBS(1.1 eq.) and the mixture was stirred at room temperature for 2 h. After addition of 1.26 L of H2O, the mixture was stirred for 30 min. After addition of 5.38 L of H O and aging of the mixture at 10 C for 30 min and at 5 C for 1 h, filtration, washing with 1.33 L of cold H O and drying provided 362 g of compound YP-10 (89% yield) as a solid. H NMR(300 MHz, CDCl) δ 7.69-7.63 (m, 2H), 7.59 (s, 1 H), 7.38-7.24 (m, 3H), 5.33 (d, J = 10.2 Hz, 1 H), 5.25 (d, J = 9.9 Hz, 1 H), 5.12 (dd, J = 3.9, 5.7 Hz, 1 H), 5.05-4.90 (m, 1 H), 4.1 1 (dd, J = 3.9, 13.2 Hz, 1 H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1 H), 1.49 (ddd, J = 2.4, 4.5, 14.1 Hz, 1 H), 1.31 (d, J = 6.9 Hz, 3H).

10) Synthesis of (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7- [(phenylmethyl)oxy]-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1 ,3]oxazine-9-carboxamide (compound YP-11). Under carbon monooxide atmosphere, a mixture of 33.5 g of compound YP-10 (1.0 eq.), 34.8 ml. of i-Pr2NEt(2.5 eq.), 14.3 ml_ of 2,4- difluorobenzylamine(1.5 eq.) and 4.62 g of Pd(PPh3)(0.05 eq.) in 335 ml. of DMSO was stirred at 90 C for 5.5 h. After cooling, precipitate was filtered and washed with 50 ml. of 2-propanol. After addition of 502 ml. of H O and 670 ml. of AcOEt to the filtrate, the organic layer was washed with 335 ml. of 0.5N HClaq. and 335 ml. of H2O and the aqueous layer was extracted with 335 ml. of AcOEt. The organic layers were combined and concentrated. To the residue, 150 ml. of 2-propanol was added and the mixture was concentrated. After addition of 150 ml. of 2-propanol, concentration, cooling to 20 C and filtration, crude crystal of compound P-11 was obtained. After dissolution of the crude crystal in 380 ml. of acetone by heating, precipitate was filtered and the filtrate was concentrated. After addition of 200 ml. of EtOH, concentration, addition of 150 ml. of EtOH, concentration, cooling and filtration, crude crystal of compound P-11 was obtained. After dissolution of the crude crystal in 450 ml. of acetone by heating, the solution was concentrated. To the residue, 150 ml. of 2-propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 2-propanol and drying provided 34.3 g of compound YP-11 (84% yield) as a solid. H NMR(300 MHz, CDCI ) δ 10.40 (t, J = 6.0 Hz, 1 H), 8.35 (s, 1 H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J = 9.9 Hz, 1 H), 5.26 (d, J = 10.2 Hz, 1 H), 5.15 (dd, J = 3.9, 5.7 Hz, 1 H), 5.05-4.90 (m, 1H), 4.64 (d, J = 5.4 Hz, 2H), 4.22 (dd, J = 3.9, 13.5, 1 H), 4.09 (dd, J = 6.0, 13.2 Hz, 1 H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1 H), 1.50 (ddd, J = 2.4, 4.5, 14.1 Hz, 1 H), 1.33 (d, J = 7.2 Hz, 3H).

11) Synthesis of (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (Dolutegravir) Under hydrogen atmosphere, a mixture of 28.0 g of compound P-11 (1.0 eq.) and 5.6 g of 10% Pd-C in 252 ml. of THF and 28 ml. of MeOH was stirred for 1 h. After precipitate (Pd-C) was filtered and washed with 45 ml. of THF, 5.6 g of 10% Pd-C was added and the mixture was stirred for 1.5 h under hydrogen atmosphere. After Pd-C was filtered and washed with 150 ml. of CHCI 3/Me0H(9/1 ), the filtrate was concentrated. After dissolution of the residue in 1.38 L of EtOH by heating, the solution was gradually cooled to room temperature. After filtration, the filtrate was concentrated and cooled. Filtration, washing with EtOH and drying provided 21.2 g of compound 1a (92% yield) as a solid. H NMR(300 MHz, DMSO-d6) δ 12.51 (s, 1 H), 10.36 (t, J = 5.7 Hz, 1 H), 8.50 (s, 1 H), 7.39 (td, J = 8.7, 6.3 Hz, 1 H), 7.24 (ddd, J = 2.6, 9.5, 10.8 Hz, 1 H), 7.12-7.00 (m, 1 H), 5.44 (dd, J = 3.9, 5.7 Hz, 1 H), 4.90-4.70 (m, 1 H), 4.65-4.50 (m, 1 H), 4.54 (d, J = 5.1 Hz, 2H), 4.35 (dd, J = 6.0, 13.8 Hz, 1 H), 4.10-3.98 (m, 1 H), 3.96-3.86 (m, 1 H), 2.10-1.94 (m, 1 H), 1.60-1.48 (m, 1 H), 1.33 (d, J = 6.9 Hz, 3H).

12). Synthesis of (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt (Dolutegravir Sodium salt). After dissolution of 18.0 g of dolutegravir (1.0 eq.) in 54 ml_ of EtOH by heating, followed by filtration, 21.5 ml. of 2N NaOHaq.(1.0 eq.) was added to the solution at 80 C. The solution was gradually cooled to room temperature. Filtration, washing with 80 ml. of EtOH and drying provided 18.8 g of Dolutegravir Sodium salt (99% yield) as a solid. H NMR(300 MHz, DMSO-d) δ 10.70 (t, J = 6.0 Hz, 1 H), 7.89 (s, 1 H), 7.40-7.30 (m, 1 H), 7.25-7.16 (m, 1 H), 7.06-6.98 (m, 1 H), 5.22-5.12 (m, 1 H), 4.87-4.74 (m, 1 H), 4.51 (d, J = 5.4 Hz, 2H), 4.35-4.25 (m, 1 H), 4.16 (dd, J = 1.8, 14.1 Hz, 1 H), 4.05-3.90 (m, 1 H), 3.86-3.74 (m, 1 H), 2.00-1.72 (m, 1 H), 1.44-1.32 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3H).

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http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=e1c18d5b-830f-4b4e-8671-35bcfb20eed5&cKey=af219b7d-2171-46b2-91ef-b8049552c9e5&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d
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Raffi F et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral-naive adults: 48 week results from SPRING-2 (ING113086). 19th International AIDS Conference. 22-27 July 2012, Washington. Late breaker oral presentation THLBB04.
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National Institutes of Health (U.S.). A trial comparing GSK1349572 50 mg plus abacavir/lamivudine once daily to Atripla (also called the SINGLE trial). Available from: http://clinicaltrials.gov/ct2/show/NCT01263015.

钁涘叞绱犲彶鍏嬫棗涓嬭壘婊嬬梾鏂拌嵂dolutegravir鑾稦DA浼樺厛瀹¤瘎璧勬牸  III鏈熶复搴婄暐鑳滃悏鍒╁痉Atripla

2013骞?鏈?5缇庡浗椋熷搧鑽?搧绠$悊灞?FDA)鎺堜簣钁涘叞绱犲彶鍏嬬敤浜庢不鐤楄壘婊嬬梾(HIV/AIDS)鐨勮瘯楠岃嵂鐗ヾolutegravir浼樺厛瀹¤瘎璧?鏍硷紝FDA搴旇?浼氬湪浠婂勾8鏈?7鏃ヤ箣鍓嶏紝瀵规槸鍚︽壒鍑哾olutegravir涓婂競鍋氬嚭瑁佸畾銆傚垎鏋愪汉澹??涓篸olutegravir鏄?競鍦洪?鍏堢殑鍚夊埄寰风?瀛?鍏?徃鑹炬粙鐥呮不鐤楄嵂鐗╃殑寮哄姴绔炰簤瀵规墜銆傚垎鏋愪汉澹??涓鸿?鑽?墿鍙?兘鎴愪负骞撮攢鍞??鍑犲崄浜跨編鍏冪殑浜у搧銆?/p>

鑻卞浗鍒惰嵂鍏?徃钁涘叞绱犲彶鍏嬩笌鏃ユ湰鐩愰噹涔夊埗鑽?叕鍙革紙Shionogi锛夊悎浣滃紑鍙戠殑鎶楀嚮鑹炬粙鐥呯殑鏂拌嵂锛屽湪鍚庢湡闃舵?鐨勪复搴婅瘯楠屼腑鐨勮〃鐜拌秴杩囦簡鍚夊埄寰风?瀛﹀叕鍙?锛圙ilead Sciences锛夌殑涓夊悎涓?殑鍙f湇鑽?搧Atripla(渚濇硶闊︽仼鑼?鎭╂洸浠栨花/鏇胯?绂忛煢瀵岄┈閰哥墖,Efavirenz/Emtricitabine /Tenofovir Disoproxil Fumarate)銆傝憶鍏扮礌鍙插厠鍒惰嵂鍏?徃鍜屾棩鏈?洂閲庝箟鍒惰嵂鍏?徃鍘诲勾涓冩湀浠藉叕甯冧簡鑹炬粙鐥呮柊鑽疍olutegravir鐨勪笁鏈熶复搴婅瘯楠岀粨鏋?鍦ㄦ帴鍙?dolutegravir鑽?墿浠ュ強鍏朵粬涓ょ?鑰佺増鑹炬粙鐥呰嵂鐗╂不鐤?8鍛ㄤ箣鍚?鎮h?浣撳唴88%鐨勭梾姣掕?鎴愬姛鎶戝埗,鑰屾湇鐢ㄥ悏鍒╁痉绉戞妧鎶?湳鍏?徃Atripla鑽?墿 涔嬪悗,鎮h?浣撳唴81%鐨勭梾姣掕?鎶戝埗,鐢辨?鍙?互鐪嬪嚭,钁涘叞绱犲彶鍏嬪埗鑽?叕鍙哥殑dolutegravir鑽?墿鐣ヨ儨涓??銆傛嵁鐮旂┒浜哄憳琛ㄧず,鍦ㄦ瘮瀵硅瘯楠屼腑,鐢变簬鑽?墿 鐨勫壇浣滅敤,10%鐨勬偅鑰呮渶缁堝仠姝㈡湇鐢ㄤ簡鍚夊埄寰风?鎶?妧鏈?叕鍙哥殑Atripla,鑽?墿,浣嗘槸浠呮湁2%鐨勬偅鑰呭仠姝㈡湇鐢ㄨ憶鍏扮礌鍙插厠鍒惰嵂鍏?徃鐨?dolutegravir鑽?墿,鐢辨?鍙??钁涘叞绱犲彶鍏媎olutegravir鑽?墿鐨勫畨鍏ㄦ?鐣ラ珮銆?/p>

鍘诲勾鍥涙湀浠芥椂,钁涘叞绱犲彶鍏嬪埗鑽?叕鍙稿皢dolutegravir鑽?墿鍚岄粯娌欎笢鍒惰嵂鍏?徃鐨処sentress鑽?墿杩涜?浜嗚嵂鏁堟瘮瀵硅瘯楠?骞朵笖鑾峰緱浜嗘垚鍔?姝ゆ?鍚屽悏鍒╁痉绉戞妧鍏?徃涔嬮棿鐨勬瘮瀵硅瘯楠屾槸绗?簩娆℃垚鍔熶簡,鍥犳?璇ヨ嵂鐗╃殑浼樺娍宸茬粡鏄?‘瀹氱殑銆?/p>

閫氱敤鍚嶏細Dolutegravir
鍟嗗搧鍚嶏細Tivicay
鍒?悕锛欸SK1349572, S-349572, GSK572
涓?枃鍚嶏細搴﹂瞾鐗归煢锛屽痉缃楁牸闊?br /> 鑽?墿鍏?徃锛氳憶鍏扮礌鍙插厠鍏?徃
閫傚簲鐥囷細鑹炬粙鐥?br /> 鑽?墿绫诲瀷:鏁村悎閰舵姂鍒跺墏
鎵瑰噯鏃ユ湡: 2013骞?鏈?2鏃?(缇庡浗锛?br /> CAS鐧诲綍鍙? 1051375-16-6
鍖栧?鍚嶏細(4R,12aS)-N-[(2,4-浜屾盁鑻?熀)鐢插熀]-3,4,6,8,12,12a-鍏?阿-7-缇熷熀-4-鐢插熀-6,8-浜屾哀浠?2H-鍚″暥骞禰1′,2′:4,5]鍚″棯骞禰2,1-b][1,3]鍣佸棯-9-鐢查叞鑳?br /> 缇庡浗涓撳埄锛?129385 (PDF 鏂囦欢涓嬭浇)
涓撳埄鍒版湡鏃堕棿锛?027骞?0鏈?鏃?br /> 鍥介檯涓撳埄锛歐02006116764


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