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Cabotegravir, GSK 744

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Cabotegravir (GSK744).svg

Cabotegravir, GSK 744,

PMDA APPROVED 2022/5/31, JAPAN

(3S,11aR)-N-(2,4-Difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide

OTHER ISOMER

(3R,11 aS)-N-[(2,4-Diflυorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, 11a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

VIIV HEALTHCARE …INNOVATOR

  • GSK1265744, CAS 1051375-10-0, S-265744 LAP
  • C19-H17-F2-N3-O5
  • 405.3553

2D chemical structure of 1051375-10-0

  • 744 LA
  • GSK 1265744
  • GSK 744
  • GSK-1265744A
  • GSK1265744
  • GSK1265744A
  • GSK744
  • GSK744 LA
  • GSK744 LAP
  • S-265744
  • S/GSK1265744

Product Ingredients 

 
INGREDIENT UNII CAS INCHI KEY
Cabotegravir sodium 3L12PT535M 1051375-13-3 AEZBWGMXBKPGFP-KIUAEZIZSA-M

Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.[6][9]

It is an integrase inhibitor with a carbamoyl pyridone structure similar to that of dolutegravir.[10]

In December 2021, the U.S. Food and Drug Administration approved cabotegravir for pre-exposure prophylaxis (PrEP) in at-risk people under the brand name Apretude.[11]

GSK744 (also known as S/GSK1265744) is an investigational new drug under development for the treatment of HIV infection. It is anintegrase inhibitor, with a carbamoyl pyridone structure similar to dolutegravir. In investigational studies, the agent has been packaged into nanoparticles (GSK744LAP) conferring an exceptionally long half-life of 21–50 days following a single dose. In theory, this would make possible suppression of HIV with dosing as infrequently as once every three months.[1]

S-265744 LAP is in phase II clinical development at Shionogi-GlaxoSmithKline for the treatment of HIV infection. Phase III clinical trials had been ongoing for this indication; however, no recent development has been reported for this study.

Cabotegravir, or GSK1265744, is an HIV-1 integrase inhibitor that is prescribed with the non-nucleoside reverse transcriptase inhibitor, rilpivirine.4,6,7 Early research into cabotegravir showed it had lower oral bioavailability than dolutegravir,4 which resulted in the development of long acting monthly intramuscular injection formulation for cabotegravir.4,7

Cabotegravir was granted FDA approval on 21 January 2021 in combination with rilpivirine to treat HIV-1 infection in virologically suppressed individuals.8 While previously administered once monthly only, this combination product was granted FDA approval for dosing every two months on February 01, 2022 11 and without the need for an oral lead-in period prior.7

The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AIDS”), a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor Al DS-related complex (“ARC”), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.

A required step in HIV replication in human T-cells is the insertion by virally-encoded integrase of proviral DNA into the host cell genome. Integration is believed to be mediated by integrase in a process involving assembly of a stable nucleoprotein complex with viral DNA sequences, cleavage of two nucleotides from the 3′ termini of the linear proviral DNA and covalent joining of the recessed 3′ OH termini of the proviral DNA at a staggered cut made at the host target site. The repair synthesis of the resultant gap may be accomplished by cellular enzymes. There is continued need to find new therapeutic agents to treat human diseases. HIV integrase is an attractive target for the discovery of new therapeutics due to its important role in viral infections, particularly HIV infections. Integrase inhibitors are disclosed in WO2006/116724.

(3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide, a compound of formula (I), also referred to as compound (I), has proven antiviral activity against human immunodeficiency virus (HIV).

Figure imgf000004_0001

The present invention features pharmaceutical compositions comprising the active ingredient (3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide, or a pharmaceutically acceptable salt thereof, suitable for administration once monthly or longer.

Medical uses

Cabotegravir in combination with rilpivirine is indicated for the treatment of human immunodeficiency virus type-1 (HIV-1) in adults.[1][5] The combination injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/mL) with their current antiretroviral treatment, and when the virus has not developed resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors.[5] The tablets are used to check whether a person tolerates the treatment before the injection therapy is started.[12][5]

The two medicines are the first antiretroviral drugs that come in a long-acting injectable formulation.[12]

Cabotegravir (Apretude) is indicated for use in at-risk people weighing at least 35 kilograms (77 lb) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV.[11]

Contraindications and interactions

Cabotegravir must not be combined with the drugs rifampicinrifapentinecarbamazepineoxcarbazepinephenytoin or phenobarbital, which induce the enzyme UGT1A1.[5] These drugs significantly decrease cabotegravir concentrations in the body and thus may reduce its effectiveness.[9][5] Additionally, they induce the enzyme CYP3A4, which leads to reduced rilpivirine concentrations in the body.[5][13][14][15] Additionally, patients who are breastfeeding or plan to breastfeed should not take Cabotegravir because it is not known if it will pass within the breast milk.[16]

Adverse effects

The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). For the tablets, headache and a hot feeling were slightly less frequent. Less common side effects (under 10%) for both formulations are depressive disordersinsomnia, and rashes.[9]

Pharmacology

Mechanism of action

Cabotegravir is an integrase strand transfer inhibitor. This means it blocks the HIV’s enzyme integrase, thereby preventing its genome from being integrated into the human cells’ DNA.[9] As this is a necessary step for the virus to replicate, its further spread is hampered.[9]

Pharmacokinetics

 

Cabotegravir glucuronide, the main metabolite in human bile and urine[17]

When taken by mouth, cabotegravir reaches highest blood plasma levels after three hours. Taking the drug together with food slightly increases its concentrations in the blood, but this is not clinically relevant. After injection into the muscle, cabotegravir is slowly absorbed into the bloodstream, reaching its highest blood plasma levels after about seven days.[9]

Over 99% of the substance are bound to plasma proteins. The drug is inactivated in the body by glucuronidation, mainly by the enzyme UGT1A1, and to a much lesser extent by UGT1A9. More than 90% of the circulating substance are the unchanged cabotegravir, however. The biological half-life is 41 hours for the tablets and 5.6 to 11.5 weeks for the injection.[9]

Elimination has only been studied for oral administration: Most of the drug is eliminated via the faeces in unchanged form (47%). It is not known how much of this amount comes from the bile, and how much was not absorbed in the first place. (The bile actually contains the glucuronide, but this could be broken up again in the gut lumen to give the parent substance that is observed in the faeces.) To a lesser extent it is excreted via the urine (27%), almost exclusively as the glucuronide.[9]

Pharmacogenomics

UGT1A1 poor metabolizers have 1.3- to 1.5-fold increased cabotegravir concentrations in the body. This is not considered clinically significant.[9]

Chemistry

Cabotegravir is a white to off-white, crystalline powder that is practically insoluble in aqueous solutions under pH 9, and slightly soluble above pH 10. It is slightly acidic with a pKa of 7.7 for the enolic acid and 1.1 (calculated) for the carboxamide. The molecule has two asymmetric carbon atoms; only one of the four possible configurations is present in the medication.[18]

Formulation

In studies, the agent was packaged into nanoparticles (GSK744LAP) conferring a biological half-life of 21 to 50 days[citation needed] following a single dose. The marketed injection achieves its long half-life not via nanoparticles but with a suspension of the free cabotegravir acid. The tablets contain cabotegravir sodium salt.[18]

History

Cabotegravir was examined in the clinical trials HPTN 083 and HPTN 084.[19][20] In 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vocabria intended for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with rilpivirine injection.[21] The EMA also recommended marketing authorization be given for rilpivirine and cabotegravir injections to be used together for the treatment of people with HIV-1 infection.[12] Cabotegravir was approved for medical use in the European Union in December 2020.[8]

Society and culture

Names

Cabotegravir is the United States Adopted Name (USAN)[22] and the international nonproprietary name (INN).[23]

Research

Pre-exposure prophylaxis

In 2020, results for some studies were released showing success in using injectable cabotegravir for long-acting pre-exposure prophylaxis (PrEP) with greater efficacy than the emtricitabine/tenofovir combination being widely used for PrEP at the time.[24][25]

The safety and efficacy of cabotegravir to reduce the risk of acquiring HIV were evaluated in two randomized, double-blind trials that compared cabotegravir to emtricitabine/tenofovir, a once daily oral medication for HIV PrEP.[11] Trial 1 included HIV-uninfected men and transgender women who have sex with men and have high-risk behavior for HIV infection.[11] Trial 2 included uninfected cisgender women at risk of acquiring HIV.[11]

In Trial 1, 4,566 cisgender men and transgender women who have sex with men received either cabotegravir or emtricitabine/tenofovir.[11] The trial measured the rate of HIV infections among trial participants taking daily cabotegravir followed by cabotegravir injections every two months compared to daily oral emtricitabine/tenofovir.[11] The trial showed participants who took cabotegravir had 69% less risk of getting infected with HIV when compared to participants who took emtricitabine/tenofovir.[11]

In Trial 2, 3,224 cisgender women received either cabotegravir or emtricitabine/tenofovir.[11] The trial measured the rate of HIV infections in participants who took oral cabotegravir and injections of cabotegravir compared to those who took emtricitabine/tenofovir orally.[11] The trial showed participants who took cabotegravir had 90% less risk of getting infected with HIV when compared to participants who took emtricitabine/tenofovir.[11]

In December 2021, the U.S. Food and Drug Administration (FDA) approved cabotegravir for pre-exposure prophylaxis.[11] The FDA granted the approval of Apretude to Viiv.[11]

Methods for the preparation of a compound of formula (I) are described in WO 2006/1 16764, WO2010/01 1814, WO2010/068262, and WO2010/068253

WO 2006116764 

http://www.google.com/patents/WO2006116764A1?cl=en

Figure imgf000058_0001

[Chemical formula 68]  is  UNDESIRED ISOMER………..amcrasto@gmail.com

Figure imgf000122_0001
 
 

Example Z-1:

(3R,11 aS)-N-[(2,4-Diflυorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, 11a

-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt.

Figure imgf000130_0002

(3R,11aS)-N-[(2,4-Diflυorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,

3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. To a solution of 16a (409 mg, 0.87 mmol) in dichloroethane (20 mL) was added (2R)-2-amino-1-propanol (0,14 mL, 1.74 mmol) and 10 drops of glacial acetic acid.

The resultant solution was heated at reflux for 2 h. Upon cooling, Celite was added

to the mixture and the solvents removed in vacuo and the material was purified via

silica gel chromatography (2% CH3OH/CH2CI2 gradient elution) to give

(3R),11aS)-N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6- [(phenylmethyl)oxy]-2,

3,5,7, 1 l , 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazinc-8-carboxamide (396

mg, 92%) as a glass, JH NMR (CDCIo) δ 10.38 (m, 1 H), 8.42 (s, 1 H), 7,54-7,53 (m, 2

H), 7,37-7.24 (m, 4 H), 6.83-6,76 (m, 2 H), 5.40 (d, J = 10.0 Hz, 1 H), 5.22 (d, J = 10,0

Hz, 1 H), 5.16 (dd, J – 9,6, 6.0 Hz, 1 H), 4,62 (m, 2 H), 4.41 (m, 1 H), 4.33-4.30 (m, 2

H), 3.84 (dd, J= 12.0, 10.0 Hz, 1 H), 3.63 (dd, J= 8,4, 7.2 Hz, 1 H), 1.37 (d, J= 6.0 Hz,

3 H); ES+ MS: 496 (M+1).

b)

(3R, 11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, 1la

-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8vcarboxamide sodium salt. To a

solution of

(37?, 11aS)-N-[(2,4-difluo]-ophenyl)methyl]-3-methyl-5,7-dioxo-6- [(phenylmethyl)oxy] -2,

3,5,7,11,11 a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396

mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was

bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture

was filtered through Celite with methanol and dichloromethanc. The filtrate was

concentrated in vacuo to give

(3R, l] aS)-N-f(2,4-difliιorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, υ , 11a- hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide as a pink tinted

white solid (278 mg, 86%), 1H NMR (ODCU) δ 11.47 (m, 1 H), 10.29 (m, 1 H), 8,32 (s,

1 H), 7.36 (m, 1 H), 6.82 (m, 2 H), 5.31 (dd, J – 9.6, 3.6 Hz, 1 H), 4.65 (m, 2 H),

4,47-4,38 (m, 3 H), 3.93 (dd, J= 12.0, 10.0 Hz, 1 H), 3,75 (m, 1 H), 1.49 (d, J= 5.6 Hz,

3 H); BS1 MS: 406 (M+ 1). The above material (278 mg, 0,66 mmol) was taken up

m cthanol (10 mL) and treated with 1 Nsodium hydroxide (aq) (0.66 mL, 0.66 mmol).

The resulting suspension was stirred at room temperature for 30 min, Ether was

added and the liquids were collected to provide the sodium salt of the title compound

as a white powder (291 mg, 99%).‘ 1H NMR (OMSO- do) δ 30.68 (m, 1 H), 7,90 (s, 1 H),

7.35 (m, 1 H), 7.20 (m, 1 H), 7,01 (m, 1 H), 5,20 (m, 1 H), 4,58 (m, I H), 4.49 (m, 2 H),

4.22 (m, 2 H), 3 74 (dd, J= 11.2, 10.4 Hz, 1 H), 3.58 (m, 1 H), 1.25 (d, J=- 4.4 Hz, 3 H)

DESIRED ISOMER………… ANY ERROR ………….amcrasto@gmail.com

Example Z-9-

(3£ 11aΛ^N-[(2.4-D-fluoroDhonyl)methyl] -6-hvdroxy-3-methyl-5.7-dioxo-2,3,5.7, n , 11 a

-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazino-8-carboxamide sodium salt.

Figure imgf000144_0001

The title compound was made in two steps using a similar process to that described

in example Z-I. 16a (510 mg, 1.08 mmol) and (2«5)-2-amino-1-propanol (0.17 mL, 2,17 mmol) were reacted in 1,2-dichloroethane (20 mL) with acetic acid to give

(3S, 11aR)-i\A[(2,4-diflιιorophenyl)methyl]-3-methyl-5,7-d.ioxo-6-[(phenylmethyl)oxy]-2,

3,5,7,11,1la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (500

mg, 93%). This material was hydrogenated in a second step as described in example

Z- I to give

3S, 11a R)-7N-[(2,4-Diiαuorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, 11a-

hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraziine-8-carboxamide (386 mg, 94%) as a

tinted white solid. Η NMR (CDCL3) δ 11.46 (m, 1 H), 10.28 (m, 1 H), 8.32 (s, 1 H),

7.35 (m, 1 H), 6.80 (m, 2 H), 5.30 (dd, J = 10.0, 4.0 Hz, 1 H), 4.63 (m, 2 H), 4.48-4.37

(m, 3 H), 3.91 (dd, J = 12.0, 10.0 Hz, 1 H), 3.73 (m, 1 H), 1.48 (d, J – 6.0 Hz, 3 H);

ES 1 MS: 406 (M+ 1). This material (385 mg, 0.95 mmol) was treated with sodium

hydroxide (0,95 mL, 1.0 M, 0.95 mmol) m ethanol (15 mL) as described in example Z-1

to provide its corresponding sodrum sail (381 mg, 94%) as a white solid. 1H NMR

(DMSO- Λ) δ 10.66 (m, 1 PI), 7.93 (s, 1 H), 7.33 (m, 1 H), 7.20 (m, 1 H), 7.01 (m, 1 H),

5.19 (m, 1 H), 4.59 (m, 1 H), 4 48 (m, 2 H), 4.22 (m, 2 H), 3,75 (m, 1 H), 3.57 (m, 1 H),

1.24 (d, J= 5 6 Hz, 3 H).

 
…………………..

WO 2010068253 

http://www.google.com/patents/WO2010068253A1?cl=en

Example A

The starting material of Example A is compound 8, which is identical to formula (Ia). Thus, Example A depicts a process in providing an intermediate for the compound of formula 17 below which is isomeric to the compound ZZ-2 at page 237 of WO 2006/116764 to Brian Johns et al.

Figure imgf000030_0001

14

Figure imgf000030_0002
Figure imgf000030_0003

Example Aa After dissolution of mixture of 320 g of compound 8 (1.0 eq.) in 3.20 L of MeOH by heating, the solution was concentrated. To the residue, 1.66 L of MeCN, 5.72 mL of AcOH(0.1 eq.) and 82.6 g of (S)-2-Amino-propan-1-ol(1.1 eq.) were added and the mixture was heated to 70 °C, stirred at 70 0C for 4 h and concentrated. To the residue, 1.67 L of 2-propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 500 mL of cold 2-propanol and drying provided 167 g of compound 14 (52% yield) as a crystal. 1H NMR(300 MHz1 CDCI3) δ 7.61-7.55 (m, 2H), 7.40-7.20 (m, 4H), 6.53 (d, J = 7.2, 1H), 5.46 (d, J = 10.5 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 5.20 (dd, J = 3.9, 9.6 Hz, 1H), 4.46- 4.34 (m, 1H)1 4.31 (dd, J = 6.6, 8.7 Hz, 1H)1 4.14 (dd, J = 3.9, 12.3 Hz1 1H)1 3.79 (dd, J = 9.9, 12.3 Hz1 1 H), 3.62 (dd, J = 6.9, 8.7 Hz1 1 H), 1.38 (d, J = 6.3 Hz1 3H).

Example Ab

To slurry of 156 g of compound 14 (1.0 eq.) in 780 ml_ of NMP was added 93.6 g of NBS(1.1 eq.) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was added to 3.12 L of H2O. Filtration, washing with 8.0 L of H2O and drying provided 163 g of compound 15 (84% yield) as a crystal.

1H NMR(300 MHz, DMSO-CT6) δ 8.37 (s, 1H), 7.55-7.50 (m, 2H), 7.42-7.25 (m, 3H), 5.34 (dd, J = 3.6, 9.9 Hz, 1H), 5.18 (d, J = 10.8 Hz, 1H), 5.03 (d, J = 10.5 Hz, 1H), 4.53 (dd, J = 3.6, 12.0 Hz, 1H)1 4.40-4.20 (m, 2H), 3.99 (dd, J = 9.9, 11.7 Hz1 1H), 3.64 (dd, J = 5.7, 8.1 Hz1 1 H)1 1.27 (d, J = 6.3 Hz1 3H).

Example Ac

Under carbon mono-oxide atmosphere, a mixture of 163 g of compound 15 (1.0 eq.), 163 mL of /-Pr2NEt(2.5 eq.), 68.4 ml_ of 2,4-difluorobenzylamine(1.5 eq.) and 22.5 g of Pd(PPh3)4(0.05 eq.) in 816 mL of DMSO was stirred at 90 0C for 7 h. After cooling, removal of precipitate, washing with 50 mL of DMSO and addition of 11.3 g of

Pd(PPh3)4(0.025 eq.), the reaction mixture was stirred at 90 0C for 2 h under carbon mono-oxide atmosphere again. After cooling, removal of precipitate and addition of 2.0 L of AcOEt and 2.0 L of H2O1 the organic layer was washed with 1.0 L of 1 N HCIaq. and 1.0 L of H2O (twice) and the aqueous layer was extracted with 1.0 L of AcOEt. The organic layers were combined and concentrated. Silica gel column chromatography of the residue provided 184 g of compound 16 (96% yield) as foam.

1H NMR(300 MHz, CDCI3) δ 10.38 (t, J = 6.3 Hz1 1H)1 8.39 (s, 1H)1 7.75-7.25 (m, 7H), 6.90-6.70 (m, 2H), 5.43 (d, J = 10.2 Hz, 1H), 5.24 (d, J = 10.2 Hz, 1H)1 5.19 (dd, J = 3.9, 9.9 Hz, 1H)1 4.63 (d, J = 6.0 Hz, 2H), 4.50-4.25 (m, 3H)1 3.86 (dd, J = 9.9, 12.3 Hz, 1H), , 3.66 (dd, J = 6.9, 8.4 Hz1 1 H), 1.39 (d, J = 6.0 Hz, 3H).

Example Ad

Under hydrogen atmosphere, a mixture of 184 g of compound 16 (1.0 eq.) and 36.8 g of 10%Pd-C in 3.31 L of THF and 0.37 L of MeOH was stirred for 3 h. After filtration of precipitate(Pd-C), washing with THF/MeOH(9/1 ) and addition of 36.8 g of 10% Pd-C, the mixture was stirred for 20 min under hydrogen atmosphere. After filtration of precipitate(Pd-C) and washing with THF/MeOH(9/1), the filtrate was concentrated. After 200 ml_ of AcOEt was added to the residue, filtration afforded crude solid of compound 17. The precipitates were combined and extracted with 4.0 L of CHCl3/MeOH(5/1). After concentration of the CHCI3ZMeOH solution and addition of 250 ml_ of AcOEt to the residue, filtration afforded crude solid of compound 17. The crude solids were combined and dissolved in 8.2 L of MeCN/H2O(9/1 ) by heating. After filtration, the filtrate was concentrated. To the residue, 1.5 L of EtOH was added and the mixture was concentrated (three times). After cooling of the residue, filtration and drying provided 132 g of compound 17 (88% yield) as a crystal. 1H NMR(300 MHz, DMSO-cfe) δ 11.47 (brs, 1H), 10.31 (t, J = 6.0 Hz, 1H), 8.46 (s, 1H), 7.40 (td, J = 8.6, 6.9 Hz, 1H), 7.24 (ddd, J = 2.6, 9.4, 10.6, 1H), 7.11-7.01 (m, 1H), 5.39 (dd, J = 4.1, 10.4 Hz, 1H), 4.89 (dd, J = 4.2, 12.3 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.40 (dd, J = 6.8, 8.6 Hz, 1H), 4.36-^.22 (m, 1H)1 4.00 (dd, J = 10.2, 12.3 Hz, 1H), 3.67 (dd, J = 6.7, 8.6 Hz, 1H), 1.34 (d, J = 6.3 Hz, 3H).

Example Ae

After dissolution of 16.0 g of compound 17 (1.0 eq.) in 2.56 L of EtOH and 0.64 L of H2O by heating, followed by filtration, 39 ml_ of 1N NaOHaq.(1.0 eq.) was added to the solution at 75 0C. The solution was gradually cooled to room temperature. Filtration, washing with 80 ml_ of EtOH and drying provided 13.5 g of compound 18 (80% yield) as a crystal.

1H NMR(300 MHz, DMSO-cfe) δ 10.73 (t, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.07-6.98 (m, 1H), 5.21 (dd, J = 3.8, 10.0 Hz, 1H), 4.58 (dd, J = 3.8, 12.1 Hz, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.3CM.20 (m, 2H), 3.75 (dd, J = 10.0, 12.1 Hz, 1H), 3.65-3.55 (m, 1H), 1.27 (d, J = 6.1 Hz, 3H).

………………

WO2010011814

http://www.google.st/patents/WO2010011814A1?cl=en&hl=pt-PT

Scheme 1

Figure imgf000016_0001

2a 2b

Scheme 2

Figure imgf000016_0002

Scheme 3

Figure imgf000016_0003

Scheme 4

phosphorylation

Figure imgf000017_0001
Figure imgf000017_0002

Scheme 5

Hydrogenolysis

Figure imgf000017_0003
Figure imgf000017_0004
Figure imgf000017_0005

The following examples are intended for illustratation only and are not intended to limit the scope of the invention in any way. Preparation 1 : (3S.11 af?VΛ/-r(2.4-DifluoroDhenvnmethyll-6-hvdroxy-3-methyl-5.7-dioxo- 2,3,5,7, 11 ,11 a-hexahydroM ,31oxazolor3,2-alpyridori ,2-c/1pyrazine-8-carboxamide sodium salt (compound 1 b, scheme 2).

I) MsCI, Et3N

Figure imgf000018_0001

2) DBU

P-1 P-2 P-3

Figure imgf000018_0002

a) Synthesis of 2-methyl-3-[(phenylmethvl)oxvl-4/-/-pvran-4-one (compound P-2). To a slurry of 2000 g of compound P-1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80 0C 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 P-2 was used in the next step. 1H NMR(300 MHz, CDCI3) 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).

b) Synthesis of 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound P-3). To 904 g of the crude compound P-2 was added 5.88 L of THF and the solution was cooled to -60 0C. 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 0C and the reaction mixture was aged at -60 0C for 1 h. The THF solution was poured into a mixture of 1.21 L of conc.HCI, 8.14 L of ice water and 4.52 L of EtOAc at less than 2 0C.

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 P-3 (74% yield from compound P-1 ) as a solid. 1H NMR(300 MHz, CDCI3) 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).

c) Synthesis of 2-[(£)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound

P-4). To a solution of 882 g of compound P-3 (1.0 eq.) in 8.82 L of THF were added 416 g of Et3N(1.5 eq.) and 408 g of methanesulfonyl chloride(1.3 eq.) at less than 30 0C. 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 30 0C 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% Na2S03aq. 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 P-4 (94% yield) as a solid. 1H NMR(300 MHz, CDCI3) 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). d) Synthesis of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid (compound P-5). To a mixture of 822 g of compound P-4 (1.0 eq.) and 1 1.2 g of RuCI3-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 NalO4(4.0 eq.) at less than 25 0C. After aging for 1 h, 733 g of NaCIO2(S-O eq.) was added to the mixture at less than 25 0C. After aging for 1 h, precipitate was filtered and washed with 8.22 L of

EtOAc. To the filtrate, 1.64 L of 50% Na2S203aq, 822 ml. of H2O and 630 ml. of coc.HCI 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 P-5 (56% yield) as a solid. 1H NMR(300 MHz,

CDCI3) 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).

e) Synthesis of 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1 ,4-dihydro-2- pyridinecarboxylic acid (compound P-6). A mixture of 509 g of compound P-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 0C for 1 h and at 80 0C 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 0C 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 0C for 30 min. After cooling and addition of 509 ml. of H2O, the mixture was concentrated. To the residue,

2.54 L of H2O 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 0C to give crystal of compound P-6. Filtration, washing with 1.53 L of cold H2O and drying provided 576 g of compound P-6 (83% yield) as a solid. 1H NMR(300 MHz, DMSO-de) 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).

f) Synthesis of methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1 ,4-dihydro-2- pyridinecarboxylate (compound P-7). To a slurry of 576 g of compound P-6 (1.0 eq.: 5.8% of H2O was contained) in 2.88 L of NMP were added 431 g of NaHCO3(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 0C, 1.71 L of 2N HCI and 1.15 L of 20% NaClaq were added to the mixture at less than 10 0C to give crystal of compound 7. Filtration, washing with 1.73 L of H2O and drying provided 507 g of compound P-7 (89% yield) as a solid. 1H NMR(300 MHz, DMSO- cfe) 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).

g) Synthesis of methyl 1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1 ,4-dihydro-2- pyridinecarboxylate (compound P-8). To a mixture of 507 g of compound P -7 (1.0 eq.) in

5.07 L of MeCN, 5.07 L of H2O and 9.13 g of AcOH(0.1 eq.) was added 390 g of NaIO4(1.2 eq.) and the mixture was stirred at room temperature for 2 h. After addition of 1.52 L of 10% Na2S2OsBq., the mixture was concentrated and cooled to 10 0C. Filtration, washing with H2O and drying provided 386 g of compound P-8 (80% yield) as a solid. 1H NMR(300 MHz, DMSO-d6) 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).

h) Synthesis of (3S, 11 aR)-3-methyl-6-[(phenylmethyl)oxy]-2,3, 1 1 ,1 1a- tetrahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-c/]pyrazine-5,7-dione (compound P-9). After dissolution of mixture of 320 g of compound P-8 (1.0 eq.) in 3.20 L of MeOH by heating, the solution was concentrated. To the residue, 1.66 L of MeCN, 5.72 ml. of AcOH(0.1 eq.) and 82.6 g of (S)-2-Amino-propan-1-ol(1.1 eq.) were added and the mixture was heated to 70 0C, stirred at 70 0C for 4 h and concentrated. To the residue, 1.67 L of 2-propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 500 ml. of cold 2-propanol and drying provided 167 g of compound P-9 (52% yield) as a solid. 1H NMR(300 MHz, CDCI3) δ 7.61-7.55 (m, 2H), 7.40-7.20 (m, 4H), 6.53 (d, J = 7.2, 1 H), 5.46 (d, J = 10.5 Hz, 1 H), 5.23 (d, J = 10.2 Hz, 1 H), 5.20 (dd, J = 3.9, 9.6 Hz, 1 H), 4.46-4.34 (m, 1 H), 4.31 (dd, J = 6.6, 8.7 Hz, 1 H), 4.14 (dd, J = 3.9, 12.3 Hz, 1 H), 3.79 (dd, J = 9.9, 12.3 Hz, 1 H), 3.62 (dd, J = 6.9, 8.7 Hz, 1 H), 1.38 (d, J = 6.3 Hz, 3H).

i) Synthesis of (3 S, 1 1 aR)-8-bromo-3-methyl-6-[(phenylmethyl)oxy]-2,3, 11 ,11a- tetrahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-c/]pyrazine-5,7-dione (compound P-10). To slurry of 156 g of compound P-9 (1.0 eq.) in 780 ml. of NMP was added 93.6 g of NBS(1.1 eq.) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was added to 3.12 L of H2O. Filtration, washing with 8.0 L of H2O and drying provided 163 g of compound P-10 (84% yield) as a solid. 1H NMR(300 MHz, DMSO-d6) δ 8.37 (s, 1 H), 7.55- 7.50 (m, 2H), 7.42-7.25 (m, 3H), 5.34 (dd, J = 3.6, 9.9 Hz, 1 H), 5.18 (d, J = 10.8 Hz, 1 H), 5.03 (d, J = 10.5 Hz, 1 H), 4.53 (dd, J = 3.6, 12.0 Hz, 1 H), 4.40-4.20 (m, 2H), 3.99 (dd, J = 9.9, 1 1.7 Hz, 1 H), 3.64 (dd, J = 5.7, 8.1 Hz, 1 H), 1.27 (d, J = 6.3 Hz, 3H). j) Synthesis of (3S,1 1aS)-Λ/-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6- [(phenylmethyl)oxy]-2,3,5,7, 11 ,1 1 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-c/]pyrazine-8- carboxamide (compound P-11). Under carbon mono-oxide atmosphere, a mixture of 163 g of compound P-10 (1.0 eq.), 163 mL of /-Pr2NEt(2.5 eq.), 68.4 mL of 2,4- difluorobenzylamine(1.5 eq.) and 22.5 g of Pd(PPh3)4(0.05 eq.) in 816 mL of DMSO was stirred at 90 0C for 7 h. After cooling, removal of precipitate, washing with 50 mL of DMSO and addition of 1 1.3 g of Pd(PPh3)4(0.025 eq.), the reaction mixture was stirred at 90 0C for 2 h under carbon mono-oxide atmosphere again. After cooling, removal of precipitate and addition of 2.0 L of AcOEt and 2.0 L of H2O, the organic layer was washed with 1.0 L of 1 N HCIaq. and 1.0 L of H2O (twice) and the aqueous layer was extracted with 1.0 L of AcOEt.

The organic layers were combined and concentrated. Silica gel column chromatography of the residue provided 184 g of compound P-11 (96% yield) as foam. 1H NMR(300 MHz, CDCI3) δ 10.38 (t, J = 6.3 Hz, 1 H), 8.39 (s, 1 H), 7.75-7.25 (m, 7H), 6.90-6.70 (m, 2H), 5.43 (d, J = 10.2 Hz, 1 H), 5.24 (d, J = 10.2 Hz, 1 H), 5.19 (dd, J = 3.9, 9.9 Hz, 1 H), 4.63 (d, J = 6.0 Hz, 2H), 4.50-4.25 (m, 3H), 3.86 (dd, J = 9.9, 12.3 Hz, 1 H), 3.66 (dd, J = 6.9, 8.4 Hz,

1 H), 1.39 (d, J = 6.0 Hz, 3H).

k) Synthesis of (3S,1 1aR)-Λ/-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo- 2,3,5,7, 11 ,11 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-c/]pyrazine-8-carboxamide (compound 1a). Under hydrogen atmosphere, a mixture of 184 g of compound P-11 (1.0 eq.) and 36.8 g of 10%Pd-C in 3.31 L of THF and 0.37 L of MeOH was stirred for 3 h. After filtration of precipitate(Pd-C), washing with THF/MeOH(9/1 ) and addition of 36.8 g of 10% Pd-C, the mixture was stirred for 20 min under hydrogen atmosphere. After filtration of precipitate(Pd-C) and washing with THF/MeOH(9/1 ), the filtrate was concentrated. After 200 mL of AcOEt was added to the residue, filtration afforded crude solid of compound 1 a.

The precipitates were combined and extracted with 4.0 L of CHCI3/Me0H(5/1 ). After concentration of the CHCI3/MeOH solution and addition of 250 mL of AcOEt to the residue, filtration afforded crude solid of compound 1a. The crude solids were combined and dissolved in 8.2 L of MeCN/H2O(9/1 ) by heating. After filtration, the filtrate was concentrated. To the residue, 1.5 L of EtOH was added and the mixture was concentrated

(three times). After cooling of the residue, filtration and drying provided 132 g of compound 1a (88% yield) as a solid. 1H NMR(300 MHz, DMSO-d6) δ 11.47 (brs, 1 H), 10.31 (t, J = 6.0 Hz, 1 H), 8.46 (s, 1 H), 7.40 (td, J = 8.6, 6.9 Hz, 1 H), 7.24 (ddd, J = 2.6, 9.4, 10.6, 1 H), 7.11- 7.01 (m, 1 H), 5.39 (dd, J = 4.1 , 10.4 Hz, 1 H), 4.89 (dd, J = 4.2, 12.3 Hz, 1 H), 4.55 (d, J = 6.0 Hz, 2H), 4.40 (dd, J = 6.8, 8.6 Hz, 1 H), 4.36-4.22 (m, 1 H), 4.00 (dd, J = 10.2, 12.3 Hz, 1 H), 3.67 (dd, J = 6.7, 8.6 Hz, 1 H), 1.34 (d, J = 6.3 Hz, 3H).

I) Synthesis of (3S,1 1aR)-Λ/-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo- 2,3,5,7, 11 ,11 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-c/]pyrazine-8-carboxamide sodium salt (compound 1 b). After dissolution of 16.0 g of compound 1a (1.0 eq.) in 2.56 L of EtOH and 0.64 L of H2O by heating, followed by filtration, 39 ml. of 1 N NaOHaq.(1.0 eq.) was added to the solution at 75 0C. The solution was gradually cooled to room temperature. Filtration, washing with 80 ml. of EtOH and drying provided 13.5 g of compound 1b (80% yield) as a solid. 1H NMR(300 MHz, DMSO-d6) δ 10.73 (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), 7.07-6.98 (m, 1 H), 5.21 (dd, J = 3.8, 10.0 Hz, 1 H), 4.58 (dd, J = 3.8, 12.1 Hz, 1 H), 4.51 (d, J = 5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J = 10.0, 12.1 Hz, 1 H), 3.65-3.55 (m, 1 H), 1.27 (d, J = 6.1 Hz, 3H).

updates

Figure

An Efficient and Highly Diastereoselective Synthesis of GSK1265744, a Potent HIV Integrase Inhibitor

Global API Chemistry, MDR Chemical Science,§Analytical Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States
Org. Lett., Article ASAP
DOI: 10.1021/ol503580t
Publication Date (Web): January 23, 2015……..http://pubs.acs.org/doi/abs/10.1021/ol503580t
Copyright © 2015 American Chemical Society
 
A novel synthesis of GSK1265744, a potent HIV integrase inhibitor, is described. The synthesis is highlighted by an efficient construction of the densely functionalized pyridinone core as well as a highly diastereoselective formation of the acyl oxazolidine moiety. The latter exploits the target molecule’s ability to chelate to Mg2+, a key feature in the integrase inhibitor’s mechanism of action.
 
PAPER

Abstract

Abstract Image

Bictegravir and dolutegravir are two recently approved integrase inhibitors for the treatment of HIV. A third inhibitor, cabotegravir, is in Phase 3 development. As a continuation of a series of articles on synthetic routes to newly approved drugs, the current article reviews the patent and journal literature regarding synthetic routes and final forms of these drug

Review of Synthetic Routes and Final Forms of Integrase Inhibitors  Dolutegravir, Cabotegravir, and Bictegravir | Organic Process Research &  DevelopmentReview of Synthetic Routes and Final Forms of Integrase Inhibitors  Dolutegravir, Cabotegravir, and Bictegravir | Organic Process Research &  DevelopmentReview of Synthetic Routes and Final Forms of Integrase Inhibitors  Dolutegravir, Cabotegravir, and Bictegravir | Organic Process Research &  DevelopmentReview of Synthetic Routes and Final Forms of Integrase Inhibitors  Dolutegravir, Cabotegravir, and Bictegravir | Organic Process Research &  DevelopmentReview of Synthetic Routes and Final Forms of Integrase Inhibitors  Dolutegravir, Cabotegravir, and Bictegravir | Organic Process Research &  Development

References

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External links

References

  1.  PrEP GSK744 Integrase Administered Monthly Perhaps Quarterly Prevents HIV-Infection in Monkeys. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA March 3–6, 2013.
  2. http://www.natap.org/2013/CROI/croi_38.htm

SMILES [H][C@@]12CN3C=C(C(=O)NCC4=C(F)C=C(F)C=C4)C(=O)C(O)=C3C(=O)N1[C@@H](C)CO2

Cited Patent Filing date Publication date Applicant Title
WO2006116764A1 * Apr 28, 2006 Nov 2, 2006 Shionogi & Co Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
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WO2012018065A1 * Aug 4, 2011 Feb 9, 2012 Shionogi & Co., Ltd. Process for preparing compound having hiv integrase inhibitory activity
WO2012151361A1 May 3, 2012 Nov 8, 2012 Concert Pharmaceuticals Inc. Carbamoylpyridone derivatives
WO2013038407A1 * Sep 2, 2012 Mar 21, 2013 Mapi Pharma Ltd. Amorphous form of dolutegravir
US8552187 Dec 9, 2009 Oct 8, 2013 Shionogi & Co., Ltd. Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
US8580967 Jul 23, 2009 Nov 12, 2013 Shionogi & Co., Ltd. Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate and processes for the preparation thereof
US8624023 Dec 8, 2009 Jan 7, 2014 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates

SYN

Synthetic Reference

Dolutegravir HELP . ADDED TO AID HELP

Dolutegravir HELP . ADDED TO AID HELP

Dolutegravir HELP . ADDED TO AID HELP

Dolutegravir HELP . ADDED TO AID HELP

Aoyama, Yasunori; Hakogi, Toshikazu; Fukui, Yuki; Yamada, Daisuke; Ooyama, Takao; Nishino, Yutaka; Shinomoto, Shoji; Nagai, Masahiko; Miyake, Naoki; Taoda, Yoshiyuki; Yoshida, Hiroshi; Yasukata, Tatsuro. Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis. Organic Process Research & Development. Volume 23. Issue 4. Pages 558-564. Journal; Online Computer File. (2019).

Synthetic Reference 2

Wang, Xianheng; Chen, Song; Zhao, Changkuo; Long, Liangye; Wang, Yuhe. Preparation of Dolutegravir Intermediate Diastereomer. Journal of Heterocyclic Chemistry. Volume 56. Issue 7. Pages 2063-2067. Journal; Online Computer File. (2019).

Synthetic Reference 3

Ziegler, Robert E.; Desai, Bimbisar K.; Jee, Jo-Ann; Gupton, B. Frank; Roper, Thomas D.; Jamison, Timothy F. 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Angewandte Chemie, International Edition. Volume 57. Issue 24. Pages 7181-7185. Journal; Online Computer File. (2018).

SYN 4

Synthetic Reference

Rajan, Srinivasan Thirumalai; Eswaraiah, Sajja; Reddy, Ghojala Venkat; Reddy, Sagyam Rajeshwar; Markandeya, Bekkam; Rajesham, Boge. Novel crystalline polymorph of sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate and process for preparation thereof. Assignee MSN Research & Development Center, India. IN 201641037221. (2018).

Synthetic Reference 5

Sharma, Pramodkumar; Rao, Bhatraju Srinivasa; Deo, Keshav. A process for the preparation of Dolutegravir or its pharmaceutical acceptable salts thereof. Assignee Wockhardt Limited, India. IN 2015MU01007. (2016).

Synthetic Reference 6

Weaver, Jimmie Dean. Preparation of fluoroarenes via hydrogen bond directed photocatalytic hydrodefluorination of perfluoroarenes. Assignee The Board of Regents for Oklahoma State University, USA. WO 2018187336. (2018).

SYN 7

Synthetic Reference

Li, Xuguang; Chen, Shuiku; Zhu, Songlin; Zhang, Fangjie; Fang, Shuixia; Liu, Congjun; Zhu, Huifeng; Luo, Qi; Meng, Qingyue; Cui, Hao. Method for preparation of dolutegravir. Kaifeng Pharmaceutical (Group) Co., Ltd.; Henan Furen Pharmaceutical Technology Development Co., Ltd. CN 108299466. (2018).

SYN 8

Synthetic Reference

Vellanki, Sivaram Prasad; Nadella, Madumurthy; Bhalme, Mitali; Ramabhotla, Revathi Srinivas. Process for the preparation of dolutegravir, an integrase inhibitor for HIV-1 infection therapy. Assignee Mylan Laboratories Ltd., India. IN 2015CH00588. (2016).

SYN 9

Synthetic Reference

Sankareswaran, Srimurugan; Mannam, Madhavarao; Chakka, Veerababu; Mandapati, Srirami Reddy; Kumar, Pramod. Identification and Control of Critical Process Impurities: An Improved Process for the Preparation of Dolutegravir Sodium. Organic Process Research & Development. Volume 20. Issue 8. Pages 1461-1468. Journal; Online Computer File. (2016).

Clinical data
Trade namesVocabria, Apretude
Other namesS/GSK1265744, GSK744
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa621010
License dataEU EMAby INNUS DailyMedCabotegravir
Pregnancy
category
AU: B1[1][2]
Routes of
administration
By mouthintramuscular
ATC codeJ05AJ04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1][2][3]CA℞-only [4]US: ℞-only [5][6][7]EU: Rx-only [8]
Pharmacokinetic data
Protein binding>99%
MetabolismUGT1A1
Metabolitesglucuronide
Elimination half-lifetablets: 41 hours
injection: 5.6–11.5 weeks
Excretion47% via faeces, 27% via urine
Identifiers
showIUPAC name
CAS Number1051375-10-0 as salt: 1051375-13-3
PubChem CID54713659as salt: 46215800
DrugBankDB11751as salt: DBSALT002064
ChemSpider30829503as salt: 32702138
UNIIHMH0132Z1Qas salt: 3L12PT535M
KEGGD10548as salt: D10549
ChEBICHEBI:172944as salt: CHEBI:172948
ChEMBLChEMBL2403238 as salt: ChEMBL3137330
CompTox Dashboard (EPA)DTXSID50146982 
Chemical and physical data
FormulaC19H17F2N3O5
Molar mass405.358 g·mol−1
3D model (JSmol)Interactive imageas salt: Interactive image
showSMILES
showInChI

1 Comment

  1. Lafaye says:

    Ivan ont wait

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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