New Drug Approvals

Home » Posts tagged 'Peptidomimetics'

Tag Archives: Peptidomimetics

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 3,726,874 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,675 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,675 other followers

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

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Saquinavir


Saquinavir structure.svg
Saquinavir
Saquinavir.png

Saquinavir,

Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852

(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide

(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide

(-)-cis-N-tert-butyldecahydro-2-{(2R,3S)-2-hydroxy-4-phenyl-3-{[N-(2-quinolylcarbonyl)-L-asparaginyl]amino}butyl}-(3S,4aS,8aS)-isoquinoline-3 carboxamide monomethanesulfonate

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Saquinavir mesylateUHB9Z3841A149845-06-7IRHXGOXEBNJUSN-YOXDLBRISA-N

CAS Registry Number: 127779-20-8 
CAS Name: (2S)-N1[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide 
Additional Names: (S)-N-[(aS)-a-[(1R)-2-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(1H)-isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamido succinamide; N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl](4aS,8aS)-isoquinoline-3(S)-carboxamide 
Manufacturers’ Codes: Ro-31-8959Molecular Formula: C38H50N6O5Molecular Weight: 670.84Percent Composition: C 68.04%, H 7.51%, N 12.53%, O 11.92% 
Literature References: Selective HIV protease inhibitor.Prepn: J. A. Martin, S. Redshaw, EP432695eidem,US5196438 (1991, 1993 both to Hoffmann-LaRoche); K. E. B. Parkes et al.,J. Org. Chem.59, 3656 (1994).In vitro HIV proteinase inhibition: N. A. Roberts et al.,Science248, 358 (1990). Antiviral properties: J. C. Craig et al.,Antiviral Res.16, 295 (1991); S. Galpin et al.,Antiviral Chem. Chemother.5, 43-45 (1994).Clinical evaluation of tolerability and activity: V. S. Kitchen et al.,Lancet345, 952 (1995). Review of pharmacology and clinical experience: S. Kravcik, Expert Opin. Pharmacother.2 303-315 (2001). 
Properties: White crystalline solid. [a]D20 -55.9° (c = 0.5 in methanol). Soly (21°): 0.22 g/100 ml water.Optical Rotation: [a]D20 -55.9° (c = 0.5 in methanol) 
Derivative Type: Methanesulfonate saltCAS Registry Number: 149845-06-7Additional Names: Saquinavir mesylateManufacturers’ Codes: Ro-31-8959/003Trademarks: Fortovase (Roche); Invirase (Roche)Molecular Formula: C38H50N6O5.CH3SO3HMolecular Weight: 766.95Percent Composition: C 61.08%, H 7.10%, N 10.96%, O 16.69%, S 4.18% 
Therap-Cat: Antiviral.Keywords: Antiviral; Peptidomimetics; HIV Protease Inhibitor.

Saquinavir mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 6, 1995, then approved by European Medicine Agency (EMA) on Oct 4, 1996, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Sep 5, 1997. It was developed by Roche, then marketed as Invirase® by Roche in the US and EU and by Chugai in JP.

Saquinavir mesylate is an inhibitor of HIV-1 protease. It is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of HIV-1 protease that required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. It is indicated for the treatment of HIV-1 infection in combination with ritonavir and other antiretroviral agents in adults (over the age of 16 years).

Invirase® is available as capsule for oral use, containing 200 mg of free Saquinavir. The recommended dose is 1000 mg twice daily in combination with ritonavir 100 mg twice daily for adults.

Human medicines European public assessment report (EPAR): Invirase, saquinavir, HIV Infections, 03/10/1996, 47, Authorised (updated)

EU 08/09/2021

Invirase is an antiviral medicine used to treat adults infected with the human immunodeficiency virus type 1 (HIV 1), a virus that causes acquired immune deficiency syndrome (AIDS). Invirase should only be used in combination with ritonavir (another antiviral medicine) and other antiviral medicines.

Invirase contains the active substance saquinavir.

Product details
NameInvirase
Agency product numberEMEA/H/C/000113
Active substancesaquinavir
International non-proprietary name (INN) or common namesaquinavir
Therapeutic area (MeSH)HIV Infections
Anatomical therapeutic chemical (ATC) codeJ05AE01
Publication details
Marketing-authorisation holderRoche Registration GmbH
Date of issue of marketing authorisation valid throughout the European Union03/10/1996

Invirase can only be obtained with a prescription and treatment should be started by a doctor who has experience in the treatment of HIV infection.

Invirase is available as capsules (200 mg) and tablets (500 mg). For patients already taking HIV medicines, the recommended dose of Invirase is 1,000 mg with 100 mg ritonavir twice daily. For patients who are not taking HIV medicines, Invirase is started at 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment, given in combination with other HIV medicines. After 7 days, the recommended dose of Invirase is 1,000 mg twice daily with ritonavir 100 mg twice daily in combination with other HIV medicines.

For more information about using Invirase, see the package leaflet or contact a doctor or pharmacist.

The active substance in Invirase, saquinavir, is a ‘protease inhibitor’. It blocks protease, an enzyme involved in the reproduction of HIV. When the enzyme is blocked, the virus does not reproduce normally, slowing down the spread of infection. Ritonavir is another protease inhibitor that is used as a ‘booster’. It slows the breakdown of saquinavir, increasing the levels of saquinavir in the blood. This allows effective treatment while avoiding a higher dose of saquinavir. Invirase, taken in combination with other HIV medicines, reduces the viral load (the amount of HIV in the blood) and keeps it at a low level. Invirase does not cure HIV infection or AIDS, but it may hold off the damage to the immune system and the development of infections and diseases associated with AIDS.

Invirase received a marketing authorisation valid throughout the EU on 4 October 1996.

Drug Name:Saquinavir MesylateResearch Code:Ro-31-8959; Sch-52852Trade Name:Invirase®MOA:HIV-1 protease inhibitorIndication:HIV infectionStatus:ApprovedCompany:Roche (Originator) , ChugaiSales:ATC Code:J05AE01

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2004-12-17New dosage formInviraseHIV infectionTabletEq. 500 mg SaquinavirRochePriority
1995-12-06First approvalInviraseHIV infectionCapsuleEq. 200 mg SaquinavirRochePriority

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1996-10-04First approvalInviraseHIV infectionCapsule200 mgRoche 
1996-10-04First approvalInviraseHIV infectionTablet, Film coated500 mgRoche 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-09-01New dosage formInviraseHIV infectionTablet500 mgChugai 
1997-09-05First approvalInviraseHIV infectionCapsule200 mgChugai 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2014-03-13Marketing approval因服雷/InviraseHIV infectionTabletEq. 500 mg SaquinavirRoche 
2009-07-01Marketing approval因服雷/InviraseHIV infectionCapsuleEq. 200 mg SaquinavirRoche

Route 1

Reference:1. US5196438A.Route 2

Reference:1. J. Org. Chem199459, 3656-3664.Route 3

Reference:1. WO2006134612A1.

SYN

English: DOI: 10.1021/jo00393a034

DOI: 10.1021/jo00092a026

DOI: 10.1016/S0040-4039(00)77633-7

File:Saquinavir synthesis.png

SYN

In the following, a possible route for the synthesis of Saquinavir is presented. Since Diazomethane is used, the synthesis is not suitable for a scaled up process. Roche has solved this problem with another reaction mechanism. The mechanism for laboratories starts with a ring opening substitution of an epoxid derivative of Phenylalanine with decaisohydroquinoline in dry iso-propanol with nitrogen atmosphere. The intermediate is purified by flash chromatography. In the second step of synthesis, the protection group is removed with gaseous hydrogen and a carbon/palladium catalyst. Furthermore, the new product reacts with N-Benzyloxycarbonyl-Lasparagine(Cbz AsnOH) in the solvents Cbz Asparagine L(Cbz Asn L) and 1- Hydroxybenzotriazolehydrat(HBOT). Afterwards, the protecting group of the former Asparagine is removed with another mixture of gaseous hydrogen and carbon/palladium catalyst. The final intermediate gets stirred in the last step of synthesis together with the solvents Tetrahydrofuran, HBOT and DCC. The mechanism formulated in detail can be found in the Appendix (VIII).7

Kevin E. B. Parkes; David J. Bushnell; et al. Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656–3664.

str1

SYN

he synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.

SYN

J Org Chem 1994,59(13),3656

Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.

SYN

2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.

SYN

3) The condensation of N-(tert-butoxycarbonyl)-L-phenylalaninal (XXV) with 2-(trimethylsilyl)thiazole (XXVI) by means of tetrabutylammonium fluoride gives the thiazole derivative (XXVII), which is cleaved by reaction with methyl iodide (formation of the thiazolium derivative) and treated with NaBH4 and HgCl2 to afford the protected 3(S)-amino-2(S)-hydroxy-4-phenylbutanal (XXVIII). Finally, this compound is reductocondensed with isoquinoline (XI) by means of sodium cyanoborohydride to yield the protected condensation product (XII), already obtained in scheme 16810301a.

SYN

4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.

SYN

The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III), which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V), which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI). Finally, this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).

SYN

J Label Compd Radiopharm 1998,41(12),1103

[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III), which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV). The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V), which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.

SYN

Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII), which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX). The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X), which is brominated with Br2 as before giving the tribromo derivative (XI). The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII), which is finally condensed with Ro-32-0445 (VI) as before.

SYN

Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII), which is brominated as described yielding the tribromo derivative (XIV). The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV), which is finally condensed with Ro-32-0445 (VI) as indicated.

SYN

Tritiated saquinavir: The cyclization of 4-bromoaniline (XVI) with crotonic aldehyde (II) by means of ZnCl2/HCl gives 6-bromo-4-methylquinoline (XVII), which is brominated as before giving tetrabromo derivative (XVIII). The hydrolysis of (XVIII) with sulfuric cid affords 6-bromoquinoline-2-carboxylic acid (XIX), which is condensed with Ro-32-0445 (VI) by means of HOBT and DCC as indicated giving the bromo derivative of saquinavir (XX). Finally, this compound is tritiated with T2 over Pd/C in ethanol.

SYN

5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII), which is reduced with Sn/HCl to the aniline (XXIII). The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV), which is brominated as before givig the tribromo derivative (XXV). The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI), which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.

Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3] It is taken by mouth.[3]

Common side effects include nausea, vomiting, diarrhea, and feeling tired.[3] More serious side effects include problems with QT prolongationheart blockhigh blood lipids, and liver problems.[3] It appears to be safe in pregnancy.[3] It is in the protease inhibitor class and works by blocking the HIV protease.[3]

Saquinavir was patented in 1988 and first sold in 1995.[4][5]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3]

Side effects

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhoeanausea, loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.[medical citation needed]

Bioavailability and drug interactions

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.[6]

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.[medical citation needed]

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.[medical citation needed]

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.[7]

Mechanism of action

Saquinavir is a protease inhibitorProteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.[8]

History

New HIV infections and deaths, before and after the FDA approval of “highly active antiretroviral therapy”,[9] of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors.Cully, Megan (28 November 2018). “Protease inhibitors give wings to combination therapy”nature. Open Publishing. Retrieved 28 October 2020. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.}}[9]

Saquinavir was developed by the pharmaceutical company Roche.[10] Saquinavir was the sixth antiretroviral and the first protease inhibitor approved by the US Food and Drug Administration (FDA), leading ritonavir and indinavir by a few months.[11] This new class of antiretrovirals played a critical role in the development of highly active antiretroviral therapy (HAART), which helped significantly lower the risk of death from AIDS-related causes, as seen by a reduction of the annual U.S. HIV-associated death rate, from over 50,000 to about 18,000 over a period of two years.[9][12]

Roche requested and received approval of Invirase via the FDA’s “Accelerated Approval” program—a process designed to speed drugs to market for the treatment of serious diseases—a decision that was controversial, as AIDS activists disagreed over the benefits of thorough testing versus early access to new drugs.[13][better source needed] It was approved again on November 7, 1997, as Fortovase,[14] a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, given reduced demand, Fortovase would cease being marketed early in 2006, in favor of Invirase boosted with ritonavir,[15] owing to the ability of the latter co-formulated drug to inhibit the enzyme that metabolizes the AIDS drugs.[citation needed]

Society and culture

Economics

As of 2015, it is not available as a generic medication.[16]

Formulations

Two formulations have been marketed:

  • a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
  • a soft-gel capsule formulation of saquinavir (microemulsion,[17] orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.[18]

References

  1. ^ “Saquinavir Use During Pregnancy”Drugs.com. 20 March 2018. Retrieved 28 January 2020.
  2. ^ “Invirase- saquinavir mesylate capsule INVIRASE- saquinavir mesylate tablet, film coated”DailyMed. 26 December 2019. Retrieved 28 January 2020.
  3. Jump up to:a b c d e f g h i “Saquinavir”. The American Society of Health-System Pharmacists. Archived from the original on 8 September 2015. Retrieved 5 September 2015.
  4. ^ Minor, Lisa K. (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN 9781420015706Archived from the original on 31 March 2016.
  5. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN 9783527607495.
  6. ^ “Fortovase”Drugs.com. 22 March 2019. Retrieved 28 January2020.
  7. ^ Winston A, Back D, Fletcher C, et al. (2006). “Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers”. AIDS20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8aPMID 16791014S2CID 44506039.
  8. ^ Raphael Dolin, Henry Masur, Michael S. Saag. “AIDS Therapy“, Churchill Livingstone, (1999), p. 129.
  9. Jump up to:a b c “HIV Surveillance—United States, 1981-2008”Archivedfrom the original on 9 November 2013. Retrieved 8 November 2013.
  10. ^ J. Hilts, Philip (8 December 1995). “MF.D.A. Backs A New Drug To Fight AIDS”New York Times. Retrieved 28 October 2020.
  11. ^ “Antiretroviral Drug Discovery and Development”NIH. 26 November 2018. Retrieved 29 October 2020.
  12. ^ The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to “highly active antiretroviral therapy”, without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
  13. ^ “Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications”. The Body. Archived from the original on 9 November 2013. Retrieved 20 February 2013.
  14. ^ “Drug Approval Package: Fortovase/Saquinavir NDA 20828”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 28 January 2020.
  15. ^ Withdrawal of Fortovase (PDF) Archived 2006-05-14 at the Wayback Machine
  16. ^ “Generic Invirase Availability”Drugs.com. Retrieved 9 July2020.
  17. ^ Gibaud S, Attivi D (August 2012). “Microemulsions for oral administration and their therapeutic applications” (PDF). Expert Opinion on Drug Delivery9 (8): 937–51. doi:10.1517/17425247.2012.694865PMID 22663249S2CID 28468973.
  18. ^ News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir) Archived 2015-02-22 at the Wayback Machine

External links

links

Clinical data
Trade namesInvirase, Fortovase
AHFS/Drugs.comMonograph
MedlinePlusa696001
License dataEU EMAby INNUS DailyMedSaquinavir
Pregnancy
category
AU: B1[1]
ATC codeJ05AE01 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Bioavailability~4% (without ritonavir boosting)[2]
Protein binding98%
MetabolismLiver, mainly by CYP3A4
Elimination half-life9–15 hours
Excretionfeces (81%) and urine (3%)
Identifiers
showIUPAC name
CAS Number127779-20-8 
PubChem CID441243
IUPHAR/BPS4813
DrugBankDB01232 
ChemSpider390016 
UNIIL3JE09KZ2F
KEGGD00429 
ChEMBLChEMBL114 
NIAID ChemDB000640
PDB ligandROC (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID6044012 
Chemical and physical data
FormulaC38H50N6O5
Molar mass670.855 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

///////////////saquinavir, Antiviral, Peptidomimetics, HIV Protease Inhibitor,  Ro-31-8959, EU 2021, APPROVALS 2021, Invirase, Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852

[H][C@@]12CCCC[C@]1([H])CN(C[C@@H](O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(N)=O)NC(=O)C1=NC3=C(C=CC=C3)C=C1)[C@@H](C2)C(=O)NC(C)(C)C

wdt-13

NEW DRUG APPROVALS

ONE TIME

$10.00

Fosamprenavir


Fosamprenavir.svg

 

Fosamprenavir

BASE

CAS 226700-79-4
[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)-2-(phosphonooxy)propyl]carbamic acidC-[(3S)-tetrahydro-3-furanyl] ester
Additional Names: (3S)-tetrahydro-3-furyl [(aS)-a-[(1R)-1-hydroxy-2-(N1-isobutylsulfanilamido)ethyl]phenethyl]carbamate dihydrogen phosphate (ester)
Manufacturers’ Codes: VX-175
Molecular Formula: C25H36N3O9PS
Molecular Weight: 585.61
Percent Composition: C 51.27%, H 6.20%, N 7.18%, O 24.59%, P 5.29%, S 5.48%
WO 9933815 PRODUCT PATENT

Fosamprenavir ball-and-stick.png

Fosamprenavir
Systematic (IUPAC) name
{[(2R,3S)-1-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-3-({[(3S)-oxolan-3-yloxy]carbonyl}amino)-4-phenylbutan-2-yl]oxy}phosphonic acid
Clinical data
Trade names Lexiva
AHFS/Drugs.com monograph
MedlinePlus a604012
  • C (United States)
Oral
Pharmacokinetic data
Bioavailability Unknown
Protein binding 90%
Metabolism Hydrolysed to amprenavirand phosphate in GI tractepithelium
Half-life 7.7 hours
Excretion Fecal (as metabolites of amprenavir)
Identifiers
226700-81-8 
J05AE07
PubChem CID 131536
DrugBank DB01319 Yes
ChemSpider 116245 Yes
UNII WOU1621EEG Yes
ChEMBL CHEMBL1664 Yes
NIAID ChemDB 082186
Chemical data
Formula C25H36N3O9PS
585.608 g/mol
623.700 g/mol (calciumsalt)
 Figure imgf000002_0001
Calcium salt
 CAS 226700-81-8
Manufacturers’ Codes: GW-433908G
Trademarks: Lexiva (GSK); Telzir (GSK)
Molecular Formula: C25H34CaN3O9PS
Molecular Weight: 623.67
Percent Composition: C 48.15%, H 5.49%, Ca 6.43%, N 6.74%, O 23.09%, P 4.97%, S 5.14%
Properties: White microcrystalline needles, mp 282-284°. Soly in water (25°): 0.31 mg/ml.
Melting point: mp 282-284°
Therap-Cat: Antiviral.

 

 

Fosamprenavir (marketed by ViiV Healthcare as the calcium salt), under the trade names Lexiva (U.S.) and Telzir (Europe) is apro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMEA approved it on July 12, 2004. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reducing the number of pills required versus standard amprenavir.

A head-to-head study with lopinavir[1] showed the two drugs to have comparable potency, but patients on fosamprenavir tended to have a higher serum cholesterol. Fosamprenavir’s main advantage over lopinavir is that it is cheaper.

PATENT

http://www.google.com/patents/WO2012032389A2

Fosamprenavir calcium has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses; it is chemically known as calcium (3S) tetrahydro-3-furanyl(l S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]- l-benzyl-2- (phosphonooxy)propyl carbamate and represented by formula la.

Figure imgf000002_0001

(la)

There are very few references available in the literature for preparation of fosamprenavir and its intermediates. Patent US 5 585 397 provides process for preparation of fosamprenavir intermediate (IV), as depicted in scheme 1 , wherein it is purified using silica gel chromatography, however it does not provide any purity data. Purification by column chromatography is not suitable on commercial scale, since it is time consuming, requires large volume of solvents and is very much laborious.

Figure imgf000003_0001

Scheme 1: Process for preparation of fosamprenavir intermediate (IV) as given in US 5

585 397 Another patent US 6 281 367, provides process for preparation of fosamprenavir intermediate (IV) as depicted in scheme 2, but it does not provide any method for purification of compound (IV).

Figure imgf000004_0001

P= amine protecting

group deprotection

Figure imgf000004_0002

Scheme 2: Process for preparation of fosamprenavir intermediate (VI) as given in US 6

281 367

The patent US 6 514 953 provides process for preparation of fosamprenvair calcium (la) utilizing compound (IV), as depicted in Scheme 3, however it does not provide purity of fosamprenavir calcium (la) or the intermediates thereof.

Figure imgf000005_0001

Aq. soln. of Ca(OAc)2

monohydrate

Figure imgf000005_0002

(la) crude (la)

Scheme 3: Process for preparation of fosamprenavir Calcium (la) as given in US 6 514

953 Another patent, US 6 436 989, which is product patent for fosamprenavir salts, provide process for preparation of fosamprenavir sodium salt (VII) from compound (IV) as depicted in Scheme 4:

Figure imgf000006_0001

(VIA)

(V)

3 eq. NaHC03

resin column,

lyophilize

Figure imgf000006_0002

Scheme 4: Process for preparation of fosamprenavir sodium (VII) as given in US 6 436989. US 6 436 989 provides compound (V) and (VIA) with an HPLC purity of 90% and 92% respectively, however purity of fosamprenavir sodium salt (VII) is not mentioned. This patent provides fosmaprenavir salt intermediates with very low HPLC purity. The prior art literature describes synthesis of fosamprenavir calcium and its intermediates and like any synthetic compound, fosmaprenavir calcium can contain number of impurities from various source like starting material, reaction by-products, degradation, isomeric impurities etc. The prior art documents for fosamprenavir calcium does not provide any information for the impurities that may have been formed from the various synthetic processes provided therein.

Fosamprenavir calcium i.e. calcium (3S) tetrahydro-3-furanyl(lS,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]- 1 -benzyl-2-(phosphonooxy)propyl carbamate (la), is a chiral substrate containing three asymmetrical carbon centre resulting into eight stereoisomers.

Different isomers of a chiral drug molecule bind differently to target receptors, one isomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects or sometimes even beneficial but entirely different effects, hence in the drug molecules the effective isomer is preferred in pure form, free of other undesired isomers, thus fosamprenavir calcium free of its other stereoisomer would always be preferred.

The methods described above for preparation of fosamprenavir does not describe suitable methods to minimize formation of R-isomer impurity (lb)

Figure imgf000007_0001

(lb)

One of the approach to minimize R-isomer impurity (lb) is to use highly pure intermediate (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (Ila), in the synthesis of fosamprenavir. US 5 585 397 provides process for preparation of N-succinimidlyl-(S)-3-tetrahydrofuryl carbonate (Ila), however it does not provide any method for purification neither does it provide any purity data for the same. The PCT application WO 94/18192 provides process for preparation (S)-3-tetrahydrofuranyl- N-succinimidyl carbonate (Ila) as depicted in scheme 5. The application discloses recrystallization of compound (Ila) from EtOAc/hexane. At our hands, crystallization of compound (Ila) from ethyl acetate/hexane provided compound (Ila) containing the intermediate R-isomer impurity compound (lib) upto 0.37% area percentage of HPLC, which is not suitable for its use in the synthesis of fosamprenavir substantially free of R-isomer impurity (lb).

Figure imgf000008_0001

(VIII) (IX) (II)

a= S-isomer a= S-isomer

b= R-isomer b= R-isomer

Scheme 5: process for preparation of (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate

Commercially available (S)-3-tetrahydrofuranol (Villa) contains upto 5% area percentage of HPLC of (R)-3-tetrahydrofuranyl (Vlllb), which on reaction with N,N-disuccinimidyl carbonate (IX) results in (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (Ila) containing upto 2.5% area percentage of HPLC of the R-isomer impurity, (R)-3-tetrahydrofuranyl-N- succinimidyl carbonate (lib). This impure (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (Ila) when converted to fosamprenavir calcium (la) by series of reaction, results into fosamprenavir calcium containing upto 2.0 % area percentage of HPLC of (3R) tetrahydro-3- furanyl(l S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]- 1 -benzy 1-2- (phosphonooxy)propyl carbamate (lb), which is undesired isomer of fosamprenavir calcium. Impurities of any form are undesirable in the active pharmaceutical product since it may have adverse effect on the patient to be treated.

The purity of API produced is clearly a necessary condition for commercialization. The impurities produced in the manufacturing process must be limited to very small amount and are preferred to be substantially absent. The ICH Q7A guidance for API manufacturers requires that process impurities must be maintained below set limits utilizing various parameters. In the United States the Food and Drug Administration guidelines, would mostly limit the amount of impurities present in the API, similarly in other countries the impurity levels would be defined in their respective pharmacopeias.

The process for preparation of fosamprenavir calcium (la) of present invention is as depicted in scheme 5.

Figure imgf000012_0001

crude fosamprenavir calcium (la)

Example 2: Preparation of pure fosamprenavir calcium (I).

Mixture of 100 g (0.23 mol) (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4- nitrobenzene sulphonamide (III), 65 g (0.28 mol) (S)-3-tetrahydrofuranyl-N-succinimidyl carbonate (Ila) (of Example 1) and 24 g (0.23) triethylamine in 800 ml dichloromethane was stirred at ambient temperature for 4 hours, extracted with 10% sodium bicarbonate solution. The organic layer was separated, washed with water and concentrated. To the concentrated mass was added 1000 ml methanol and heated to 60-65°, cooled to 25°C and solid was filtered, washed with methanol and dried. Mixture of 100 g (0.186 mol) (3S)-tetrahydro-3-furyl N-[(l S,2R)-l-benzyl-2-hydroxy-3-(N- isobutyl-4-nitrobenzene sulphonamido) propyl] carbamate (IV) and 200 ml pyridine was cooled to 0-10°C and 70.0 g (0.456 mol) of POCl3 was added and stirred at ambient temperature for 4 hours, 400 ml methyl isobutyl ketone was added, cooled and 1 : 1 cone. HC1- water was added. Mixture was heated to 50°C for 1 hour, cooled to 25-30°C. Organic layer was separated, washed with water and partially concentrated; 500 ml water and 31.5 g sodium bicarbonate was added and stirred. The organic layer was separated and 100 ml ethylacetate, 400 ml methanol and 5.0 g Pd/C was added. The reaction mass was stirred under hydrogen pressure for 4 hours at 30°C. The mixture was filtered, catalyst washed with methanol. The filtrate was heated to 50°C and 33.0 g (0.186 mol) calcium acetate monohydrate in 100 ml water was added and stirred for 30 minutes. Cooled to 30°C and stirred. Solid was filtered, washed with 1 : 1 mixture of methanol-water and dried to obtain crude fosamprenavir calcium. 65 g (0.104 mol) crude fosamprenavir calcium and 1 170 ml denatured ethanol was heated to 70-72°C, charcaolized. Water (138 ml) was added and mixture stirred for 30 minutes. Cooled to ambient temperature and stirred. Solid filtered, washed with 1 : 1 ethanol-water and dried. Methanol (315 ml) was added to the solid, stirred and filtered. The filtrate was concentrated under vacuum to obtain solid, which was dried to obtain 37.5 g pure fosamprenavir calcium. HPLC purity: fosamprenavir calcium (la): 99.85%; R-isomer impurity (lb): 0.05%; all other individual impurities less than 0.1%.

Fosamprenavir sodium, GW-433908A, 908, VX-175(free acid)

………………………………….

PAPER

Org. Biomol. Chem., 2004,2, 2061-2070

DOI: 10.1039/B404071F

http://pubs.rsc.org/en/content/articlelanding/2004/ob/b404071f#!divAbstract

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors(Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

 

Graphical abstract: New approaches to the industrial synthesis of HIV protease inhibitors

…………………

EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding the dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) (prepared by condensation of tetrahydrofuran-3(S)-ol (VIII) with phosgene and N-hydroxysuccinimide (IX)) and DIEA in acetonitrile to provide the corresponding carbamate (X). The deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide (XIII). Finally, the nitro group of (XIII) is reduced with H2 over Pd/C in ethyl acetate to afford the target

………………………….

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) — obtained by reaction of tetrahydrofuran-3(S)-ol (VIII) first with phosgene and then with N-hydroxysuccinimide (IX) — and DIEA in acetonitrile to provide the corresponding carbamate (X). Deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide intermediate (XIII).

……………………………

 

Esterification of the OH group of compound (XIII) with PO3H3 by means of DCC in hot pyridine gives the corresponding phosphite (XVII), which is oxidized with bis(trimethylsilyl)peroxide in bis(trimethylsilyl)azane to yield the expected phosphate (XVIII). Reduction of the nitro group of (XVIII) with H2 over Pd/C in ethyl acetate affords fosamprenavir (XIX). Finally, fosamprenavir (XIX) is treated with aqueous NaHCO3 or with calcium acetate in water to provide the corresponding salts. Alternatively, the phosphate (XIX) can be obtained directly by reaction of intermediate (XIII) with POCl3 in pyridine, followed by hydrolysis with 2N HCl.

………………………………………..

HIV protease inhibitor; water soluble prodrug of amprenavir, q.v. Prepn: R. D. Tung et al., WO 9933815;eidem, US 6559137 (1999, 2003 both to Vertex).

Prepn of crystalline calcium salt: I. G. Armitage et al., WO 0004033 (2000 to Glaxo); eidem, US 6514953 (2003 to SKB).

Clinical pharmacokinetics: C. Falcoz et al., J. Clin. Pharmacol. 42, 887 (2002).

Review of pharmacology and clinical experience in HIV: T. M. Chapman et al., Drugs 64, 2101-2124 (2004); C. Arvieux, O. Tribut,ibid. 65, 633-659 (2005).

References

  1.  Eron J Jr, Yeni P, Gathe J Jr et al. (2006). “The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial”. Lancet 368 (9534): 476–82.doi:10.1016/S0140-6736(06)69155-1. PMID 16890834.

 

WO1994005639A1 * Sep 7, 1993 Mar 17, 1994 Vertex Pharma Sulfonamide inhibitors of hiv-aspartyl protease
WO1994018192A1 Feb 7, 1994 Aug 18, 1994 Merck & Co Inc Piperazine derivatives as hiv protease inhibitors
INKO02772010A Title not available
US5585397 Sep 7, 1993 Dec 17, 1996 Vertex Pharmaceuticals, Incorporated Viricides
US6281367 Mar 18, 1999 Aug 28, 2001 Glaxo Wellcome Inc. Process for the synthesis of HIV protease inhibitors
US6436989 Dec 24, 1997 Aug 20, 2002 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6514953 Jul 15, 1999 Feb 4, 2003 Smithkline Beecham Corporation Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
Reference
1 * EKHATO I VICTOR ET AL: “Isotope labeled ‘HEA/HEE’ moiety in the synthesis of labeled HIV-protease inhibitors. Part II“, JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, JOHN WILEY, CHICHESTER, GB, vol. 48, no. 3, 1 January 2005 (2005-01-01), pages 179-193, XP009112607, ISSN: 0362-4803
2 * MOON KIM B ET AL: “SYNTHESIS OF A CHIRAL AZIRIDINE DERIVATIVE AS A VERSATILE INTERMEDIATE FOR HIV PROTEASE INHIBITORS“, ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 3, no. 15, 1 January 2001 (2001-01-01), pages 2349-2351, XP001179485, ISSN: 1523-7060, DOI: 10.1021/OL016147S
3 * SORBERA, L. A. ET AL.: “FOSAMPRENAVIR“, DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 26, no. 3, 1 March 2001 (2001-03-01), pages 224-231, XP009001334, ISSN: 0377-8282, DOI: 10.1358/DOF.2001.026.03.615590

 

Vertex Pharmaceuticals’ Boston Campus, United States of America

 

 

%d bloggers like this: