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Tivicay|Dolutegravir|度鲁特韦 的合成
2015-05-10 07:03:01

Tivicay|Dolutegravir|度鲁特韦

Dolutegravir (trade name:  Tivicay, also known as S/GSK1349572, GSK1349572, Chinese Name:度鲁特韦,德罗格韦) 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 葛兰素史克与日本盐野义制药公司艾滋病药物度鲁特韦_德罗格韦的化学结构

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, 依发韦仑).

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: 度鲁特韦,德罗格韦
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 艾滋病重磅新药度鲁特韦的制备方法

Synthesis of Tivicay_Dolutegravir_integrase inhibitor_HIV_Shionogi_Pfizer_GSK 葛兰素史克与日本盐野义制药公司艾滋病药物度鲁特韦_德罗格韦的化学合成

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).

References:

Johns, Brian Alvin; Kawasuji, Takashi; Taishi, Teruhiko; Taoda, Yoshiyuki ; Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity and their preparation; PCT Int. Appl., WO2006116764, 02 Nov 2006

Johns, Brian Alvin; Weatherhead, Jason Gordon;Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection; PCT Int. Appl., WO2010011812, 28 Jan 2010

Johns, Brian Alvin; Weatherhead, Jason Gordon; Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection;PCT Int. Appl., WO2010011819, 28 Jan 2010

Yoshida, Hiroshi; Taoda, Yoshiyuki; Johns, Brian Alvin; Synthesis of fused tricyclic carbamoylpyridone HIV integrase inhibitors and intermediates;PCT Int. Appl., WO2010068253, 17 Jun 2010

Johns, Brian Alvin; Duan, Maosheng; Hakogi, Toshikazu;Processes and intermediates for fused tricyclic carbamoylpyridone HIV integrase inhibitors;PCT Int. Appl., WO2010068262, 17 Jun 2010

Sumino, Yukihito; Okamoto, Kazuya; Masui, Moriyasu; Yamada, Daisuke; Ikarashi, Fumiya; Preparation of compounds having HIV integrase inhibitory activity; PCT Int. Appl., WO2012018065, 09 Feb 2012

Kawasuji, Takashi; Johns, Brian A.;Discovery of dolutegravir and S/GSK1265744: Carbamoyl pyridone HIV-1 integrase inhibitors;Abstracts, 64th Southeast Regional Meeting of the American Chemical Society, Raleigh, NC, United States, November 14-17 (2012), SERM-176.

Kawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Weatherhead, Jason G.; Akiyama, Toshiyuki; Taishi, Teruhiko; Taoda, Yoshiyuki; Mikamiyama-Iwata, Minako; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Garvey, Edward P.; Fujiwara, Tamio;Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles;Journal of Medicinal Chemistry (2013), 56(3), 1124-1135

Walmsley S et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467). 52nd ICAAC, 9-12 September 2012, San Francisco. Abstract H-556b.
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
http://www.natap.org/2012/ICAAC/ICAAC_06.htm
http://i-base.info/htb/20381

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.
http://pag.aids2012.org/abstracts.aspx?aid=20990

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.

葛兰素史克旗下艾滋病新药dolutegravir获FDA优先审评资格  III期临床略胜吉利德Atripla

2013年2月15美国食品药品管理局(FDA)授予葛兰素史克用于治疗艾滋病(HIV/AIDS)的试验药物dolutegravir优先审评资 格,FDA应该会在今年8月17日之前,对是否批准dolutegravir上市做出裁定。分析人士认为dolutegravir是市场领先的吉利德科学 公司艾滋病治疗药物的强劲竞争对手。分析人士认为该药物可能成为年销售额几十亿美元的产品。

英国制药公司葛兰素史克与日本盐野义制药公司(Shionogi)合作开发的抗击艾滋病的新药,在后期阶段的临床试验中的表现超过了吉利德科学公司 (Gilead Sciences)的三合一的口服药品Atripla(依法韦恩茨/恩曲他滨/替诺福韦富马酸片,Efavirenz/Emtricitabine /Tenofovir Disoproxil Fumarate)。葛兰素史克制药公司和日本盐野义制药公司去年七月份公布了艾滋病新药Dolutegravir的三期临床试验结果,在接受 dolutegravir药物以及其他两种老版艾滋病药物治疗48周之后,患者体内88%的病毒被成功抑制,而服用吉利德科技技术公司Atripla药物 之后,患者体内81%的病毒被抑制,由此可以看出,葛兰素史克制药公司的dolutegravir药物略胜一筹。据研究人员表示,在比对试验中,由于药物 的副作用,10%的患者最终停止服用了吉利德科技技术公司的Atripla,药物,但是仅有2%的患者停止服用葛兰素史克制药公司的 dolutegravir药物,由此可见葛兰素史克dolutegravir药物的安全性略高。

去年四月份时,葛兰素史克制药公司将dolutegravir药物同默沙东制药公司的Isentress药物进行了药效比对试验,并且获得了成功,此次同吉利德科技公司之间的比对试验是第二次成功了,因此该药物的优势已经是确定的。

通用名:Dolutegravir
商品名:Tivicay
别名:GSK1349572, S-349572, GSK572
中文名:度鲁特韦,德罗格韦
药物公司:葛兰素史克公司
适应症:艾滋病
药物类型:整合酶抑制剂
批准日期: 2013年8月12日 (美国)
CAS登录号: 1051375-16-6
化学名:(4R,12aS)-N-[(2,4-二氟苯基)甲基]-3,4,6,8,12,12a-六氢-7-羟基-4-甲基-6,8-二氧代-2H-吡啶并[1′,2′:4,5]吡嗪并[2,1-b][1,3]噁嗪-9-甲酰胺
美国专利:8129385 (PDF 文件下载)
专利到期时间:2027年10月5日
国际专利:W02006116764


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