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WO1994026749A1 - Inhibiteurs de la protease de vih - Google Patents

Inhibiteurs de la protease de vih Download PDF

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Publication number
WO1994026749A1
WO1994026749A1 PCT/US1994/005128 US9405128W WO9426749A1 WO 1994026749 A1 WO1994026749 A1 WO 1994026749A1 US 9405128 W US9405128 W US 9405128W WO 9426749 A1 WO9426749 A1 WO 9426749A1
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WO
WIPO (PCT)
Prior art keywords
butyl
phenyl
hydroxy
tert
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1994/005128
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English (en)
Inventor
Arun K. Ghosh
Wayne J. Thompson
Sean P. Mckee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
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Merck and Co Inc
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Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU68288/94A priority Critical patent/AU6828894A/en
Publication of WO1994026749A1 publication Critical patent/WO1994026749A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the compounds, or pharmaceutically acceptable salts thereof, are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • the present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS & viral infection by HIV.
  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E., et. al., Proc. Natl. Acad. Sci.
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et ah, EMBO J. 4, 1267 (1985); Power, M.D. et ah, Science, 231, 1567 (1986); Pearl, L.H. et al., Nature 329, 351 (1987)]. Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.
  • EPO 389898, EPO 346847, and EPO 432695 each disclose HIV protease inhibitors but the compounds are very different because they have an amino acid (or analog thereof) attached to the amino-terminal end of the transition state analog.
  • EPO 432694 discloses synthetic intermediates which are different from the compounds of the present invention.
  • HBT (HOBT or HOBt) 1 -hydroxybenzotriazole hydrate
  • This invention is concerned with the compounds of
  • n 3 or 4;
  • R 1 is a 7- to 10-membered bicyclic heterocycle, either ring
  • heterocycle being unsubstituted or substituted with one or more of C 1 -4 alkyl, C 2-4 alkenyl, C 1 -3 alkoxy, halo- C 1 -3 alkyl, aryl-C 1 -3 alkyl, C 3-5 cycloalkyl, di-C 1 -3 - alkyl-amino-C 1 -4 alkyl, halo or aryl;
  • R 2 is a) C 1 -5 alkyl, unsubstituted or substituted with one or more of -OH or C 1 -3 alkoxy; or
  • R 3 is a) Phenyl unsubstituted or substituted with one or more of -OH or C 1 -3 alkoxy; or
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers or enantiomers, with all isomeric forms being included in the present invention.
  • variable e.g., C 1 -5 alkyl, R 1 or R 2 , etc.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic
  • hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Alkenyl is intended to include hydrocarbon claims of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, and the like.
  • Halo as used herein, means fluoro, chloro, bromo or iodo.
  • aryl is intended to mean phenyl (Ph) or naphthyl.
  • Carbocyclic is intended to mean any stable 5- to 7-membered carbon ring or 7- to 10-membered bicyclic carbon ring, any of which may be saturated or partially unsaturated.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur
  • heteroatoms may optionally be oxidized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements examples include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
  • pyrazolidinyl imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, enzothiopyranyl,
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of these compounds, which are formed, e.g., from inorganic or organic acids.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, bisulfate, citrate, digluconate, dodecylsulfate, fumarate, glycerophosphate, hemisulfate, hydrochloride, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, succinate and tartrate.
  • R 1 is a 7- to 10-membered bicyclic heterocycle, either ring of which is saturated or unsaturated, and which consists of carbon atoms and from one to three oxygen heteroatoms, said heterocycle being unsubstituted or substituted with one or more of C 1 -4 alkyl, C 2-4 alkenyl, C 1 -3 alkoxy, halo- C 1 -3 alkyl, aryl-C 1 -3 alkyl, C 3-5 cycloalkyl, di-C 1 -3 alkyl-amino-C 1-4 alkyl, halo or aryl;
  • R 2 is C 1 -5 alkyl, unsubstituted or substituted with one or more of -OH;
  • R 3 is phenyl unsubstituted or substituted with -OH or C 1 -3
  • R 1 is a bicyclic heterocycle of the structures:
  • R 2 is t-butyl or 2-methylpropyl
  • R 3 is phenyl
  • R 1 is:
  • R 2 is t-butyl or 2-methylpropyl
  • R 3 is phenyl
  • R 2 is t-butyl
  • R 3 is phenyl
  • Most preferred compounds of this invention include the following, in approximate order of decreasing potency: The compound [L-739,684], the most preferred:
  • the decahydro-isoquinoline intermediate 5 is synthesized by a first reaction of L-phenylalanine with formaldehyde and
  • Catalytic asymmetric or Sharpless epoxidation to produce 8 is performed by the methods of Gao, Y. et al., J- Am. Chem. Soc. 109, 5765 (1987).
  • Regio-selective azide opening of the 2,3-epoxy alcohol 8 to give 9 is facilitated by titanium according to Caron, M. et al., J. Org. Chem. 53, 5185 (1988).
  • Example 2 illustrates but does not limit Scheme II.
  • Condensation of the azide epoxide 10 with the decahydroisoquinoline intermediate 5 is performed by, for example, heating a mixture in refluxing isopropanol, to give the azido-alcohol 11 in good yield. Reduction over palladium on carbon yields the amine 12, which is then reacted with the appropriate N-substituted succinimide 13 in the presence of e.g. TEA to give compounds of Formula I or 14. Examples 3-6 illustrate but do not limit Scheme IB.
  • the compounds of the present invention are useful in the inhibition of HIV protease, the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (ADDS related complex), both symptomatic and asymtomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, accidental needle stick, or exposure to patient blood during surgery.
  • the compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition.
  • the compounds of this invention are commercial products to be sold for these purposes.
  • the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention, or a
  • compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.
  • compositions When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain macrocrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, flourocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • Dosage levels of the order of 0.02 to 5.0 or 10.0 grams-per-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher.
  • infection by HIV is effectively treated by the administration of from 10 to 50 milligrams of the compound per kilogram of body weight from one to three times per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS. See Table C. TABLE C
  • Ganciclovir (Palo Alto, CA) peripheral CMV
  • HIV Core Particle Rorer seropositive HIV Immunostimulant (Ft. Washington, PA)
  • Granulocyte Colony Amgen AIDS in combination Stimulating Factor (Thousand Oaks, CA) w/AZT rCD4 Recombinant Genentech AIDS, ARC
  • Tumor Necrosis Genentech ARC in combination Factor; TNF (S. San Francisco, w/gamma Interferon
  • Isethionate (IM & IV) (Rosemont, IL)
  • L-697,661 or '661' is 3-([4,7-dichloro-l ,3-benzoxazol-2-yl)methyl]amino)-5-ethyl-6-methyl-pyridin-2(1H)-one;
  • L-696,229 is 3-[2-(1 ,3-benzoxazol-2-yl)-ethyl]-5-ethyl-6-methyl-pyridin-2(1H)-one.
  • the synthesis of L-697,661 and L-696,229 is described in EPO 484071 , and EPO 462800, both herein incorporated by reference.
  • the synthesis of ddC, ddl and AZT are also described in EPO 484071.
  • Preferred combinations are simultaneous, intermittent, or alternating treatments of an inhibitor of HIV protease and a non-nucleoside inhibitor of HIV reverse transcriptase.
  • An optional third component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddl.
  • Preferred inhibitors of HIV protease are L-739,684 (Compound B) or L-739,594 (Compound C).
  • Preferred non-nucleoside inhibitors of HIV reverse transcriptase include L-697,661. These combinations may have synergistic effects on limiting the spread of HIV.
  • Preferred combinations include the following (1) L-739,684 or L-739,594, with L-697,661, and, optionally, AZT or ddl or ddC; (2) L-739,594 or L-739,684, and any of AZT or ddl or ddC.
  • Step 1 Preparation of cis-N-tert-butoxycarbonyl-2carboxydecahydro-isoquinoline
  • Step 2 Preparation of cis-N-tert-butyl-decahydro (4aS,8aS)- isoquinoline-3(S)-carboxamide
  • Step A Preparation of hexahydrofuro[2,3b]furan-3a-yl- succinimidyl carbonate
  • Step B Preparation of N-(2(R)-hydroxy-1 (S)-indany1)-5(S)- (hexahydrofuro[2,3b]-furanyl-3a-oxycarbonylamino)-4(S)- hydroxy-6-phenyl-2(R)-(4-(2-(4-morpholinyl)ethoxy)phenyl)methyl hexanamide
  • Step A (2R,3S,1'R) and (2R,3S,1'S) Methyl 2-(1'-tetrahydropyranyloxy)-3-allyl-succinate
  • Step C (2R,3R) 1,2-O-isopropylidene-3-allyl butane-1 ,4-diol
  • Step D (2R,3S,4R) and (2S,3S,4R) 2-methoxy-3-allyl-4- hydroxytetrahydrofuran
  • the aldehyde was taken up in 20 mL absolute ethanol, cooled to 0°C and 0.18 g of NaBH 4 was added in three portions with stirring over 10 min. After 15 min. the reaction was quenched with 3 mL 10% aqueous citric acid and concentrated. The residue was taken up in ethyl acetate and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Purification of the residue by chromatography over silica gel (75% ethyl acetate/hexanes) gave 430 mg of (2R,3S,4R) and (2S,3S,4R) 2-methoxy-3-(2'-hydroxyethyl)-4-hydroxy tetrahydrofuran as a clear, colorless oil.
  • Step A (2R, 3S, 4R) and (2S, 3S, 4R) 2-methoxy-3-(3'- hydroxypropyl)-4-hydroxytetrahydrofuran
  • Step B (3R, 3aS, 7aR) 3-hydroxyhexahydrofuro[2,3-b]pyran
  • Step A (1S, 3S, 4R,1'R,2"SR), (1S, 3S, 4R,1'S,2"SR), (IS, 3S,
  • tetrahydropyranyl ether as an oil.
  • a solution of the tetrahydropyranyl ether (300 mg) and 461 mg of mCPBA (60%, 1.6 mmole) in 25 mL of CH 2 CI 2 was stirred at 24°C for 12 h.
  • the solution was washed with 15 mL of sat'd NaHCO 3 , dried over Na 2 SO 4 and concentrated.
  • Step B (2R,3S,4R,2'SR, 2"SR) 2-methoxy-3-(2'-hydroxypropyl)- 4-(2"-tetrahydropyranyloxy)tetrahydrofuran
  • Step C (3R, 3aS, 5S, 6aR) and (3R, 3aS, 5R, 6aR) 3-hydroxy-5- methyl-hexahydrofuro[2,3-b]furan
  • Step A trans-2(2'-methyl-3'-propynyl-1'-oxy)-3-iodotetrahydropyran
  • Step B (2S, 3aR, 7aS), (2R, 3aS, 7aR), (2R, 3aR, 7aS) and (2S,
  • Step C (2S, 3S, 3aR, 7aS), (2R, 3R, 3aS, 7aR) and (2R, 3S, 3aR,
  • a stream of ozone was dispersed into a solution of (2S, 3aR, 7aS), (2R, 3aS, 7aR), (2R, 3aR, 7aS) and (2S, 3aS, 7aR) 3-methylene-2-methyl-4H-hexahydrofuro[2,3-b]pyran at -78 C in 150 mL of methanol and 150 mL of CH 2 CI 2 for 30 min. The resulting blue solution was purged with nitrogen until colorless, then quenched by addition of 20 mL of dimethyl sulfide. Concentration under reduced pressure gave 12 g of crude ketone.
  • Step A (1S, 2R) 1 -Methyl hydrogen cvclopentanedicarboxylate
  • Step B (1S, 2R) Methyl 2-formylcyclopentanecarboxylate
  • Step D (3S,4aS,7aS) Methyl 1-oxo-octahydro-1H-pyrindene-3- carboxylate
  • Step E (3S,4aS,7aS) Methyl octahydro-1H-pyrindene-3- carboxylate
  • Step G (3S,4aS,7aS,2'R,3'S) N-tert-Butyl 2(2'-hydroxy-4'-phenyl- 3'-azidobutyl)-octahydro-1H-pyrindene-3-carboxamide
  • a mixture of 3 g of (3S,4aS,7aS) N-tert-Butyl octahydro-1H-pyrindene-3-carboxamide and 4 g of 3(S)-azido-(1, 2R)-epoxy-4-phenylbutane in 50 mL of isopropanol was heated to 80°C overnight then concentrated to dryness under reduced pressure. Recrystalhzation from ethyl acetate-hexanes gave 2.16 g of product: mp 91-93oC;
  • Step H Preparation of (3S,4aS,7aS,2'R,3'S,3"S,3"aR,7”aS) N-tert- Butyl octahydro-2(2'-hydroxy-4'-phenyl-3'(3"-hexahydro- 4"H-furo[2,3-b]pyranyloxycarbonylamino)-butyl)-1H- pyrindene-3-carboxamide (Compound E)
  • Inhibition of the spread of HIV in cell culture was measured according to Nunberg, J. H. et al., J. Virol. 65, 4887 (1991).
  • MT-4 T-lymphoid cells were infected with HIV-1 by using a predetermined inoculum, and cultures were incubated for 24h. At this time, ⁇ 1 % of the cells were positive by indirect immunofluorescence. Cells were then extensively washed and distributed into 96-well culture dishes. Serial twofold dilutions of inhibitor were added to the wells, and cultures were continued for 3 additional days. At 4 days
  • MT cells are infected at Day 0 at a concentration of
  • a matrix of nanomolar range concentrations of the pairwise combinations (see Table S) is prepared.
  • Day 1 aliquots of 125 ⁇ l of inhibitors are added to equal volumes of HIV-infected MT-4 cells (50,000 per well) in a 96-well microtiter cell culture plate.
  • the settled cells are resuspended and 125 ⁇ l harvested into a separate microtiter plate.
  • the supernatant is assayed for HIV p24 antigen.
  • the concentration of HIV p24 antigen is measured by an enzyme immunoassay, described as follows. Aliquots of p24 antigen to be measured are added to microwells coated with a monoclonal antibody specific for HIV core antigen. The microwells are washed at this point, and at other appropriate steps that follow. Biotinylated HIV-specific antibody are then added, followed by conjugated strepavidinhorseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to the concentration of HIV p24 antigen.
  • Pairwise combinations of inhibitors are found to exhibit markedly enhanced inhibition of virus spread, in comparison to each inhibitor alone, or in comparison to merely additive inhibition of each inhibitor.
  • FIC fractional inhibitory concentration ratios

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Abstract

L'invention concerne des analogues d'oligopeptides. Ces composés présentent une efficacité dans l'inhibition de la protéase de VIH, dans la prévention ou dans le traitement de l'infection provoquée par VIH, ainsi que dans le traitement du sida, en tant que composés, sels pharmaceutiquement acceptables, ingrédients de composition pharmaceutiques combinés ou non à d'autres agents antiviraux, immunomodulateurs, antibiotiques ou vaccins. L'invention concerne également des procédés de traitement du sida, ainsi que des procédés de prévention ou de traitement d'infections provoquées par VIH.
PCT/US1994/005128 1993-05-14 1994-05-02 Inhibiteurs de la protease de vih Ceased WO1994026749A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68288/94A AU6828894A (en) 1993-05-14 1994-05-02 Hiv protease inhibitors

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US6189793A 1993-05-14 1993-05-14
US061,897 1993-05-14

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5932550A (en) * 1995-06-30 1999-08-03 Japan Energy Corporation Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof
US6222043B1 (en) 1995-06-30 2001-04-24 Japan Energy Corporation Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof
US6291432B1 (en) 1996-12-27 2001-09-18 Japan Energy Corporation Tripeptide compounds and anti-AIDS medicine
WO2003024974A3 (fr) * 2001-09-20 2004-07-29 Smithkline Beecham Corp Processus de preparation d'intermediaires d'inhibiteurs de protease
EP1485387A1 (fr) * 2002-03-12 2004-12-15 Board Of Trustees Of The University Of Illinois Carbamates inhibiteurs de protease du vih
JP2005502707A (ja) * 2001-09-10 2005-01-27 テイボテク・フアーマシユーチカルズ・リミテツド ヘキサヒドロ−フロ［２，３−ｂ］フラン−３−オールの製造法
WO2007126812A3 (fr) * 2006-03-29 2007-12-21 Gilead Sciences Inc Procédé de préparation d'inhibiteurs de la protéase du vih
USRE42889E1 (en) 1992-08-25 2011-11-01 G.D. Searle Llc α- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

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EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides
EP0434365A2 (fr) * 1989-12-18 1991-06-26 Merck & Co. Inc. Inhibiteurs de la HIV protéase utilisable dans le traitement du SIDA
EP0539192A1 (fr) * 1991-10-23 1993-04-28 Merck & Co. Inc. Inhibiteurs d'HIV-protéase

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EP0346847A2 (fr) * 1988-06-13 1989-12-20 F. Hoffmann-La Roche Ag Dérivés d'amminoacides
EP0434365A2 (fr) * 1989-12-18 1991-06-26 Merck & Co. Inc. Inhibiteurs de la HIV protéase utilisable dans le traitement du SIDA
EP0539192A1 (fr) * 1991-10-23 1993-04-28 Merck & Co. Inc. Inhibiteurs d'HIV-protéase

Non-Patent Citations (3)

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Title
A.K.GHOSH: "3-Tetrahydrofuran and pyran urethanes as high affinity P2 ligands for HIV protease inhibitors", J. MED. CHEM., vol. 36, 1993, pages 292 - 294 *
A.KROHN ET AL: "Novel binding mode of highly potent HIV-proteinase Inhibitors incorporating the (R)-Hydroxyethylamine Isostere", J. MED. CHEM, vol. 34, 1991, pages 3340 - 3342 *
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE43802E1 (en) 1992-08-25 2012-11-13 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE42889E1 (en) 1992-08-25 2011-11-01 G.D. Searle Llc α- and β- amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5962640A (en) * 1995-06-30 1999-10-05 Japan Energy Corporation Methods for preparing novel dipeptide compounds or pharmacuetically acceptable salts thereof
US6222043B1 (en) 1995-06-30 2001-04-24 Japan Energy Corporation Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof
US5932550A (en) * 1995-06-30 1999-08-03 Japan Energy Corporation Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof
US6291432B1 (en) 1996-12-27 2001-09-18 Japan Energy Corporation Tripeptide compounds and anti-AIDS medicine
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