WO1999033815A1 - Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors - Google Patents

Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors Download PDF

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Publication number
WO1999033815A1
WO1999033815A1 PCT/US1998/004595 US9804595W WO9933815A1 WO 1999033815 A1 WO1999033815 A1 WO 1999033815A1 US 9804595 W US9804595 W US 9804595W WO 9933815 A1 WO9933815 A1 WO 9933815A1
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alkyl
optionally substituted
compound
compound according
independently selected
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PCT/US1998/004595
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English (en)
French (fr)
Inventor
Roger D. Tung
Michael R. Hale
Christopher T. Baker
Eric Steven Furfine
Wieslaw Mieczyslaw Kazmierski
Istvan Kaldor
Andrew Spaltenstein
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Vertex Pharmaceuticals Incorporated
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Priority to EA200000703A priority Critical patent/EA003509B1/ru
Priority to BR9814480-4A priority patent/BR9814480A/pt
Priority to EEP200000385A priority patent/EE04466B1/xx
Priority to MEP-820/08A priority patent/MEP82008A/xx
Priority to AU65466/98A priority patent/AU755087B2/en
Priority to SK966-2000A priority patent/SK287123B6/sk
Priority to PL342113A priority patent/PL202845B1/pl
Priority to YU39800A priority patent/RS52483B/en
Priority to NZ505776A priority patent/NZ505776A/xx
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to IL13694198A priority patent/IL136941A0/xx
Priority to APAP/P/2000/001850A priority patent/AP1172A/en
Priority to HU0101831A priority patent/HU229596B1/hu
Priority to UA2000074456A priority patent/UA72733C2/uk
Publication of WO1999033815A1 publication Critical patent/WO1999033815A1/en
Priority to IL136941A priority patent/IL136941A/en
Priority to IS5546A priority patent/IS2817B/is
Priority to US09/602,494 priority patent/US6559137B1/en
Priority to NO20003304A priority patent/NO326265B1/no
Priority to US10/370,171 priority patent/US6838474B2/en
Priority to US10/958,223 priority patent/US7592368B2/en
Priority to NO2009008C priority patent/NO2009008I2/no
Priority to US12/504,243 priority patent/US20100124543A1/en
Priority to HUS1400042C priority patent/HUS1400042I1/hu

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors.
  • this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient.
  • This invention also relates to pharmaceutical compositions comprising these prodrugs.
  • the prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.
  • Aspartyl protease inhibitors are considered the most effective current drug in the fight against HIV infection. These inhibitors, however, require certain physicochemical properties in order to achieve good potency against the enzyme. One of these properties is high hydrophobicity. Unfortunately, this property results in poor aqueous solubility and low oral bioavailability.
  • United States Patent 5,585,397 describes a class of sulfonamide compounds that are inhibitors of the aspartyl protease enzyme. These compounds illustrate the drawbacks concomitant to pharmaceutical compositions comprising hydrophobic aspartyl protease inhibitors.
  • VX-478 (4-amino-N- ( (2-syn, 3S) -2-hydroxy-4- phenyl-2 ( (S) -tetrahydrofuran-3-yl-oxycarbonylamino) - butyl -N-isobutyl-benzenesulfonamide) is an aspartyl protease inhibitor disclosed in the v 397 patent. It has a relatively low aqueous solubility.
  • VX-478 produces an upper limit of 150 mg of VX-478 in each capsule. Given a therapeutic dose of 2400 mg/day of VX- 478, this formulation would require a patient to consume 16 capsules per day. Such a high pill burden would likely result in poor patient compliance, thus producing sub-optimal therapeutic benefit of the drug. The high pill burden is also a deterrent to increasing the amount of the drug administered per day to a patient. Another drawback of the pill burden and the concomitant patient compliance problem is in the treatment of children infected with HIV.
  • these "solution" formulations such as the mesylate formulation, are at a saturation solubility of VX-478. This creates the real potential of having the drug crystallize out of solution under various storage and/or shipping conditions. This, in turn, would likely result in a loss of some of the oral bioavailability achieved with VX-478.
  • One way of overcoming these problems is to develop a standard solid dosage form, such as a tablet or a capsule or a suspension form. Unfortunately, such solid dosage forms have much lower oral bioavailability of the drug.
  • the present invention provides novel prodrugs of a class of sulfonamide compounds that are inhibitors of aspartyl protease, in particular, HIV aspartyl protease. These prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo .
  • the present invention also provides pharmaceutical compositions comprising these prodrugs and methods of treating HIV infection in mammals using these prodrugs and the pharmaceutical compositions thereof.
  • prodrugs can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
  • This novel class of sulfonamides is represented by formula I :
  • A is selected from H; Ht ; -R 1 -Ht; -R 1 -C ⁇ -C 6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R 2 ) 2 ; -R 1 -C 2 -C 6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht , -O-Ht, -NR 2 -CO-N (R 2 ) 2 or -CO-N(R 2 ) 2 ; or R 7 ; each R 1 is independently selected from -C(O)-, - S(0) 2 -, -C(0)-C(0)-, -O-C(O)-, -0-S(0) 2 , -NR 2 -S(0) 2 -, -NR 2
  • each R 2 is independently selected from H, or C r C 4 alkyl optionally substituted with Q;
  • B when present, is -N (R 2 ) -C (R 3 ) 2 -C (O) - ;
  • each x is independently 0 or 1;
  • each R 3 is independently selected from H, Ht , C ⁇ -C 6 alkyl, C
  • D and D' are independently selected from Q; Ci- C 6 alkyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, -OR 2 , -R 3 , -O-Q or Q; C 2 -C 4 alkenyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, - OR 2 , -R 3 , -0-Q or Q; C 3 -C 6 cycloalkyl, which is optionally substituted with or fused to Q; or C 5 -C 6 cycloalkenyl, which is optionally substituted with or fused to Q; each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(0) n or N(R 2 ) ; where
  • E is selected from Ht ; O-Ht; Ht-Ht; -O-R 3 ; -N(R 2 ) (R 3 ) ; Ci-C ⁇ alkyl, which is optionally substituted with one or more groups selected from R 4 or Ht ; C 2 -C 6 alkenyl, which is optionally substituted with one or more groups selected from R 4 or Ht ; C 3 -C 6 saturated carbocycle, which is optionally substituted with one or more groups selected from R 4 or Ht ; or C 5 -C 6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R 4 or Ht ; each R 4 is independently selected from -OR 2 , -SR 2 , -C(0)-NHR 2 , -S(0) 2 -NHR 2 , halo, -NR 2 -C (O) -R 2 , -N(R 2 ) 2 or -CN; each R 7 is independently selected from
  • M' is H, C ⁇ -Ci 2 -alkyl, C 2 -C X2 -alkenyl , or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from 0, S, S (O) , S (0 2 ) , or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6 is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , N(R 2 ) 3 , -R 2 OH, -CN, -C0 2 R 2 , -C(0)-N(R 2 ) 2 , -S (0) 2 -N (R 2 ) 2 , -N(R 2 ) -C(0) -R 2 , -C(0)R 2 , -S(0) n -R 2 , -
  • Z is CH 2 , 0, S, N(R 2 ) 2 , or, when M is absent, H;
  • Y is P or S
  • X is 0 or S
  • R 9 is C(R 2 ) 2 , 0 or N(R 2 ) ; and wherein when Y is S, Z is not S; and
  • R 6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C ⁇ -C alkyl, 0-C ! -C 4 alkyl or 0C(0)C ⁇ -C 4 alkyl. It is a also an object of this invention to provide pharmaceutical compositions comprising the sulfonamide prodrugs of formula I and methods for their use as prodrugs of HIV aspartyl protease inhibitors .
  • the terms "-S0 2 -" and “-S(0) 2 -” as used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S) , and not a sulfinate ester.
  • the stereochemistry of OR 7 is defined relative to D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compounds of formula XI, XV, XXII, XXIII and XXXI) .
  • aryl refers to a carbocyclic aromatic radical containing the specified number of carbon atoms.
  • heterocyclic refers to a stable 5-7 membered monocycle or 8-11 membered bicyclic heterocycle which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic.
  • Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • nitrogen and sulfur heteroatoms include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • the heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable structure.
  • Preferred heterocycles defined above include, for example, benzimidazolyl, imidazolyl, imidazolinoyl , imidazolidinyl , quinolyl , isoquinolyl, indolyl , pyridyl, pyrrolyl , pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, ⁇ - carbolinyl, tetrazolyl, thiazolidinyl , benzofuranoyl , thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl , oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl ,
  • HIV protease and “HIV aspartyl protease” are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
  • pharmaceutically effective amount refers to an amount effective in treating HIV infection in a patient.
  • prophylactically effective amount refers to an amount effective in preventing HIV infection in a patient.
  • patient refers to a mammal, including a human.
  • pharmaceutically acceptable carrier or adjuvant refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acids examples include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N- (C 1 - 4 alkyl) 4+ salts.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium
  • N- (C 1 - 4 alkyl) 4+ salts thiocarbamates
  • the compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers . All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be of the R or S configuration.
  • the explicitly shown hydroxyl is also preferred to be syn to D, in the extended zigzag conformation between the nitrogens shown in compounds of formula I .
  • stable refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • the compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrox- yethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, pers
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.
  • the basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • novel sulfonamides of this invention are those of formula I :
  • A is selected from H; Ht; -R 1 -Ht; -R 1 -C ⁇ -C e alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C 4 alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R) 2 ; -R 1 -C 2 -C 6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C ⁇ -C alkoxy, Ht, -O-Ht, -NR 2 -CO-N(R 2 ) 2 or -CO-N(R 2 ) 2 ; or
  • each R 1 is independently selected from -C(O)-, - S(0) 2 -, -C(0)-C(0)-, -O-C(O)-, -0-S(0) 2 , -NR -S(0) 2 -, -NR 2 - C(0)- or -NR -C(0) -C(0) -; each Ht is independently selected from C 3 -C 7 cycloalkyl; C 5 -C 7 cycloalkenyl; C 6 -C 10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R 2 ), 0, S and S(0) n ; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, -OR 2 , SR 2 , -R 2 , - N(R 2 ) (R 2 ), -R 2
  • each R 2 is independently selected from H, or Ci- C alkyl optionally substituted with Q;
  • G when present, is selected from H, R 7 or C ⁇ -C 4 alkyl, or, when G is C ⁇ -C 4 alkyl, G and R 7 are bound to one another either directly or through a C ⁇ -C 3 linker to form a heterocyclic ring; or when G is not present (i.e., when x in (G) x is 0) , then the nitrogen to which G is attached is bound directly to the R 7 group in -OR 7 with the concomitant displacement of one -ZM- group from R 7 ;
  • D and D 1 are independently selected from Q; Ci- C 6 alkyl, which is optionally substituted with one or more groups selected from C 3 -C 6 cycloalkyl, -OR 2 , -R 3 ,
  • each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ) ; wherein Q is optionally substituted with one or more groups selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , -N(R 2 ) -C(O) -R
  • each R 4 is independently selected from -OR 2 , -SR 2 , -C(0)-NHR 2 , -S(0) 2 -NHR 2 , halo, -NR 2 -C (O) -R 2 , -N(R 2 ) 2 or -CN; each R 7 is independently selected from ZM
  • each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R 2 ) 4 , C ⁇ -C 12 -alkyl , C 2 - C ⁇ 2 -alkenyl, or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group, other than the -CH 2 that is bound to Z, is optionally replaced by a heteroatom group selected from 0, S, S(0), S(0 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R s is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , N(R 2 ) 2 , N(R 2 ) 3 , R 2 0H, -CN, -C0 2 R 2 , -C (O) -N (R 2 ) 2 , S(0) 2 - N(R 2 ) 2 , N(R 2 )
  • M' is H, C ⁇ -C ⁇ 2 -alkyl, C 2 -C ⁇ 2 -alkenyl , or -R 6 ; wherein 1 to 4 -CH 2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S (O) , S(0 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6 is optionally replaced with a substituent selected from oxo, -OR 2 , -R 2 , -N(R 2 ) 2 , N(R 2 ) 3 , -ROH, -CN, -C0 2 R 2 , -C(0)-N(R 2 ) 2 , -S (O) 2 -N (R 2 ) 2 , -N(R 2 ) -C(0)-R 2 , -C(0)R 2 , -S(0) n -R 2 , -OCF 3
  • Z is CH 2 , 0, S, N(R 2 ) 2 , or, when M is not present, H.
  • Y is P or S
  • X is 0 or S
  • R 9 is C(R 2 ) 2 , 0 or N(R 2 and wherein when Y is
  • R R 66 iiss aa 55-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from 0, N, S, S(0) n or N(R 2 ) ; and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C ! -C 4 alkyl, 0-C x -C 4 alkyl or 0-C(0)-C ⁇ -C 4 alkyl.
  • At least one R 7 is selected from:
  • component M or M' in the formulae set forth herein will have either a covalent, a covalent/ zwitterionic, or an ionic association with either Z or R 9 depending upon the actual choice for M or M' .
  • M or M' is hydrogen, alkyl, alkenyl, or R 6
  • M or M' is covalently bound to R 9 or Z .
  • M is a mono- or bivalent metal or other charged species (i.e., NH 4 + )
  • Z When x is 0 in (M) x , Z may be a charged species. When that occurs, the other M may be oppositely charged to produce a 0 net charge on the molecule. Alternatively, the counter ion may located elsewhere in the molecule.
  • the compounds of this invention are those represented by formulas XXII, XXIII or XXXI:
  • A is selected from 3-tetrahydrofuryl-O-C (0) - , 3- (1, 5-dioxane) -0-C (0) - , or 3-hydroxy-hexahydrofura [2 , 3-b] - furanyl-0-C (0) - ;
  • D' is C 1 -C 4 alkyl which is optionally substituted with one or more groups selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -R 3 , -0-Q and Q;
  • E is Cs-Cio aryl optionally substituted with one or more substituents selected from oxo, -OR 2 , SR 2 , -R 2 , - N(R 2 ) 2 , -R 2 -OH, -CN, -C0 2 R 2 , -C (0) -N (R 2 ) 2 , -S (0) 2 -N (R 2 ) 2 , -N(R 2 )-C(0)-R 2 , -C(0)-R 2 , -S(0) n -R 2 , -OCF 3 , -S(0) n -Q, methylenedioxy, " -N (R 2 ) -S (0) 2 (R 2 ) , halo, -CF 3 , -N0 2 , Q, -0Q, -OR 7 , -SR 7 , -R 7 , -N(R 2 ) (R 7 ) or -N(R
  • Ht insofar as it is defined as part of R 3 , is defined as above except for the exclusion of heterocycles ; and all other variables are as defined for formula I .
  • Even more preferred are compounds of formula XXII, wherein A is 3-tetrahydrofuryl-O-C (0) - ; G is hydrogen; D' is isobutyl; E is phenyl substituted with N(R 7 ) 2 ; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C 1 -C 4 alkyl or -N(R 2 ) 4 ; and each M' is H or C ! -C 4 alkyl.
  • E is a 5 -membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from -CH 3 , R 4 , or Ht; and all other variables are as defined for formula I .
  • R 7 in -OR 7 is -PO (OM) 2 or C (0) CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 and both R 7 in -N (R 7 ) 2 are H , wherein M is H , Li , Na , K or C ⁇ - C 4 alkyl ; or wherein R 7 in -OR 7 is C (0) CH 2 OCH 2 CH 2 OCH 3 , one R 7 in -N (R 7 ) 2 is C (0) CH 2 OCH 2 CH 2 OCH 3 and the other is H .
  • R 3 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 5 -C 6 cycloalkyl, C 5 -
  • D' is C x -C 3 alkyl or C 3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -0-Q and Q (with all other variables being defined as above for compounds of formula I) .
  • R 7 is -PO(OM) 2 or -C(0)-M'.
  • R 3 is independently C ! -C 6 alkyl which may be optionally substituted with a substituent selected from the group consisting of -OR 2 , -C(0)-NH-R 2 , -S (0) n N (R 2 ) (R 2 ) , Ht , -CN, -SR 2 , -C0 2 R 2 or -NR 2 -C(0) -R 2 ; and D' is C ⁇ -C 4 alkyl, which may be optionally substituted with a group selected from the group consisting of C 3 -C 6 cycloalkyl, -OR 2 , -0-Q; and E is Ht, Ht-Ht and -NR 2 R 3 .
  • the invention provides compounds of the following formulae:
  • United States patent 5,585,397 discloses the synthesis of compounds of formula: wherein A, B, n, D, D' , and E are as defined above.
  • Prodrugs of formula (I) of the present invention can be readily synthesized from the '397 compounds using conventional techniques.
  • One of skill in the art would be well aware of conventional synthetic reagents to convert the -OH group of the ⁇ 397 compounds to a desired -OR 7 functionality of the present invention, wherein R 7 is as defined above.
  • the relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds .
  • VX-478 a compound disclosed in the ⁇ 397 patent, can be readily converted to the corresponding bis-phosphate ester derivative, as shown below:
  • compositions of the present invention may be readily prepared using known techniques.
  • disodium salt of the mono-phosphate ester shown above can be prepared as shown below:
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system
  • the prodrugs of this invention increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the first mechanism involves the enzymatic or chemical transformation of the prodrug species into the active form.
  • the second mechanism involves the enzymatic or chemical cleavage of a functionality on the prodrug to produce the active compound.
  • the chemical or enzymatic transformation can involve to transfer of a functional group (i.e., R 7 ) from one heteroatom within the molecule to another heteroatom. This transfer is demonstrated in the chemical reactions shown below:
  • the cleavage mechanism is demonstrated by the reaction below where a phosphate ester-containing prodrug is converted into the active form of the drug by removal of the phosphate group.
  • the prodrugs of the present invention are characterized by unexpectedly high aqueous solubility. This solubility facilitates administration of higher doses of the prodrug, resulting in a greater drug load per unit dosage.
  • the prodrugs of the present invention are also characterized by facile hydrolytic cleavage to release the active aspartyl protease inhibitor in vivo .
  • the high aqueous solubility and the facile in vivo metabolism result in a greater bioavailability of the drug. As a result, the pill burden on a patient is significantly reduced.
  • the prodrugs of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
  • a prodrug of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally- infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
  • the prodrugs of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time.
  • the prodrugs may be employed in such vaccines either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of protease inhibitors in vaccines.
  • a prodrug of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against HIV infection.
  • the novel protease inhibitors of this invention can be administered as agents for treating or preventing HIV infection in a mammal.
  • the prodrugs of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV.
  • the co- administered anti -viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA.
  • Anti-HIV agents targeting such early life cycle events include, didanosine (ddl) , alcitabine (ddC) , d4T, zidovudine (AZT) , polysulfated polysaccharides, sT4 (soluble CD4) , ganiclovir, dideoxycytidine, trisodium phosphonoformate, eflor- nithine, ribavirin, acyclovir, alpha interferon and tri- menotrexate.
  • non-nucleoside inhibitors of reverse transcriptase such as TIBO or nevirapine may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase .
  • Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication.
  • the use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
  • These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents.
  • These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
  • These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
  • prodrugs act synergistically in preventing the replication of HIV in human T cells.
  • Preferred combination therapies include the administration of a prodrug of this invention with AZT, ddl, ddC or d4T.
  • the prodrugs of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species .
  • HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species .
  • prodrugs of this invention we prefer administering the prodrugs of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
  • retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
  • retroviral reverse transcriptase inhibitors such as derivatives of AZT, or other HIV aspartyl protease inhibitors.
  • the prodrugs of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) ; and antibiotics (e.g., pentamidine isethiorate) to prevent or combat infection and disease associated with HIV infections, such as AIDS and ARC.
  • immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO
  • antibiotics e.g., pentamidine isethiorate
  • prodrugs of this invention When the prodrugs of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient.
  • pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of a prodrug of this invention and another therapeutic or prophylactic agent.
  • this invention focuses on the use of the prodrugs disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, as well as other AIDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, but are not limited to, HTLV-I and HTLV-II.
  • the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors.
  • compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat .
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial , intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
  • the pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added .
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such 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, fluorocarbons , and/or other solubilizing or dispersing agents known in the art.
  • Dosage levels of between about .01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w) .
  • such preparations contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • 13C (CDC13) : 155.2 152.2, 149.9, 145.6, 135.9, +129.0, +128.8, +128.5, +127.2, +125.4, +124.4, +121.8, +78.1, +75.8, -73.1, -66.9, -56.5, +52.7, -48.2, -35.9, -35.9, 32.6, -+26.4, +19.9, +19.8.
  • 13C (d3-acetonitrile) : 157.1, 157.0, 153.2, 139.6 , +130.3 , +130.2, +129.2, +127.2, 126.2, +114.2, +76.0, +75.4, - 73.6, -67.4, -58.2, +54.9, -50.2, -41.6, -39.8, -35.9, - 33.4, +27.3, +23.1, +20.4, +20.2.
  • 13C (DMSO): 169.3, 155.8, 153.1, 138.0, 129.1, 129.0, 128.1, 126.3, 122.6, 112.8, 94.3, 75.6, 74.6, 72.4, 66.1, 57.8, 52.7, 52.0, 49.3, 38.4, 34.7, 32.2, 29.1, 26.6, 21.4, 20.1, 20.0.
  • Example 12 1H-NMR (CDC13) : 0.78 (6H,dd), 1.9 (2H,m), 2.1 (lH,m), 2.3 (3H,s), 2.9 (8H,m), 2.9 (2H,m), 3.15 (lH,m), 3.35 (lH,m), 3.5 (lH,m) , 3.75 (4H,m), 4.06 (2H,s), 4.15 (2H,m), 4.9 (lH,dd), 5.05 (lH,bs), 5.2 (lH,bs), 6.63 (2H,d), 7.2 (5H,m), 7.55 (2H,d), 8.0 (2H,m). ESMSP: 676 (MH+) .
  • Example 26 N-diacylated Prodrugs
  • the general procedure for N, O-diacylated compounds followed the protocol outlined in Example 20, above, except that a five fold excess of reagents was used relative to the starting material .
  • 227 can be synthesized directly from 197.
  • 197 was dissolved in pyridine (300mL) .
  • the resulting solution was concentrated in vacuo to about 150 ml at 50-55°C.
  • the solution was then cooled under N 2 to 5°C, and treated with POCl 3 (6.5 ml, 1.24 equiv.) over 2 minutes.
  • the cooling bath was removed and the reaction stirred at ambient temperature for 2.5 hrs .
  • the solution was then cooled to 5°C and water (300 ml) was added over 30 minutes.
  • the resulting mixture was extracted with 4- methylpentan-2-one (MIBK, 2 x 150 ml) .
  • MIBK 4- methylpentan-2-one
  • the combined extracts were washed with 2N HCl (2 x 250 ml) .
  • the acid washes were back extracted with MIBK (60 ml) , then the combined MIBK solutions were treated with 2N HCl (150 ml) .
  • the two phase mixture was stirred rapidly and heated to 50°C for 2 hours.
  • the reaction mixture was cooled to 20°C, the phases were separated and the MIBK solution was washed with brine (150 ml) .
  • the product, 227 was isolated by drying the solution with magnesium sulfate, filtering of the drying agent and concentrating in vacuo at 40°C to give the product as a pale yellow foam (31 g, 90% yield) .
  • the solution was evaporated en vacuo to 100 ml then lyophilized to yield the TEA salt (1.5 TEA equivalents) .
  • the TEA salt was (5.8 g) was dissolved in 200 ml water, 300 ml of 1 N HCl was added and the mixture was extracted with EtOAc (3 x
  • 13C (DMSO): 156.2, 150.1, 145.7, 140.0, +129.7, +129.2, +128.5, +126.3, +125.0, +71.8, -60.0, +56.2, -56.0, -51.8, -36.0, +26.3, +20.3, +20.1, +14.6.
  • a dose of 50 mg / Kg of compound 229 is equal to 40 mg/ Kg of VX-478. no compound 229 was detected in plasma at 15 min. ( first data point ).
  • Compound 229 229 VX-478 vehicle solid capsule methyl 22% cellulose in 5% TPGS/PEG EtOH/water 400/PG

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PCT/US1998/004595 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors WO1999033815A1 (en)

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IL13694198A IL136941A0 (en) 1997-12-24 1998-03-09 Sulphonamide derivatives and pharmaceutical compositions containing the same
HU0101831A HU229596B1 (en) 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
EEP200000385A EE04466B1 (et) 1997-12-24 1998-03-09 Sulfoonamiidi derivaadid kui aspartüülproteaasi inhibiitorid
MEP-820/08A MEP82008A (en) 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
AU65466/98A AU755087B2 (en) 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
SK966-2000A SK287123B6 (sk) 1997-12-24 1998-03-09 Deriváty sulfónamidov a farmaceutický prostriedok, ktorý ich obsahuje
PL342113A PL202845B1 (pl) 1997-12-24 1998-03-09 Pochodne sulfonamidowe, zawierające je kompozycje farmaceutyczne i zastosowanie pochodnych sulfonamidowych
YU39800A RS52483B (en) 1997-12-24 1998-03-09 SULFONAMIDE DERIVATIVES AS ASPARTYL PROTEASE INHIBITOR PRO-DRUGS
NZ505776A NZ505776A (en) 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
BR9814480-4A BR9814480A (pt) 1997-12-24 1998-03-09 Derivados de sulfonamida como pró-drogas de inibidores de aspartil protease
APAP/P/2000/001850A AP1172A (en) 1997-12-24 1998-03-09 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors.
EA200000703A EA003509B1 (ru) 1997-12-24 1998-03-09 Сульфонамидные производные в качестве пролекарств, ингибиторов аспартилпротеаз
UA2000074456A UA72733C2 (en) 1997-12-24 1998-09-03 Sulfonamide derivatives as precursors of aspartyl protease inhibitors
IL136941A IL136941A (en) 1997-12-24 2000-06-22 History of sulfonamides and pharmaceutical preparations containing them
IS5546A IS2817B (is) 1997-12-24 2000-06-22 Súlfonamíðafleiður sem forlyf fyrir tálma við aspartýlprótínkljúfum
NO20003304A NO326265B1 (no) 1997-12-24 2000-06-23 Sulfonamid-derivater som medisinforloper av aspartylproteaseinhibitorer
US09/602,494 US6559137B1 (en) 1997-12-24 2000-06-23 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
US10/370,171 US6838474B2 (en) 1997-12-24 2003-02-19 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
US10/958,223 US7592368B2 (en) 1997-12-24 2004-10-04 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
NO2009008C NO2009008I2 (US06559137-20030506-C00106.png) 1997-12-24 2009-04-22
US12/504,243 US20100124543A1 (en) 1997-12-24 2009-07-16 Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
HUS1400042C HUS1400042I1 (hu) 1997-12-24 2014-07-18 Szulfonamid-származékok mint aszpartil-proteáz inhibitorok prodrugjai

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US6559137B1 (en) 2003-05-06
HUS1400042I1 (hu) 2017-06-28
NL300339I1 (nl) 2008-06-02
TR200002615T2 (tr) 2001-01-22
NO20003304L (no) 2000-08-21
HU229596B1 (en) 2014-02-28
SK287123B6 (sk) 2009-12-07
NO326265B1 (no) 2008-10-27
NO20003304D0 (no) 2000-06-23
KR100520737B1 (ko) 2005-10-12
EP0933372A1 (en) 1999-08-04
FR08C0015I2 (fr) 2009-10-30
EP0933372B1 (en) 2007-12-26
EP1944300A2 (en) 2008-07-16
NO2009008I2 (US06559137-20030506-C00106.png) 2010-09-27
AR017965A1 (es) 2001-10-24
EA200000703A1 (ru) 2000-12-25
NL300339I2 (nl) 2009-11-02
LU91426I2 (fr) 2008-06-02
US20100124543A1 (en) 2010-05-20
CN101565412A (zh) 2009-10-28
JP2005350478A (ja) 2005-12-22
PT933372E (pt) 2008-03-31
US7592368B2 (en) 2009-09-22
DE69838903T2 (de) 2008-09-18
JPH11209337A (ja) 1999-08-03
CO4990992A1 (es) 2000-12-26
US20050148548A1 (en) 2005-07-07
OA11468A (en) 2004-05-05
BG104631A (en) 2001-02-28
US6436989B1 (en) 2002-08-20
ME00561B (me) 2011-10-10
EA003509B1 (ru) 2003-06-26
DE69838903D1 (de) 2008-02-07
JP4282639B2 (ja) 2009-06-24
EE200000385A (et) 2001-12-17
IL136941A0 (en) 2001-06-14
AU6546698A (en) 1999-07-19
SK9662000A3 (en) 2001-02-12
DE122008000021I2 (de) 2010-02-04
RS52483B (en) 2013-02-28
EE04466B1 (et) 2005-04-15
MEP82008A (en) 2011-12-20
DE122008000021I1 (de) 2008-08-14
JP2009102400A (ja) 2009-05-14
JP3736964B2 (ja) 2006-01-18
MY131525A (en) 2007-08-30
IS2817B (is) 2012-11-15
PE20000048A1 (es) 2000-02-08
CN100503589C (zh) 2009-06-24
NO2009008I1 (US06559137-20030506-C00106.png) 2009-05-04
CZ20002363A3 (cs) 2000-11-15
PL342113A1 (en) 2001-05-21
AU755087B2 (en) 2002-12-05
CZ301653B6 (cs) 2010-05-12
AP2000001850A0 (en) 2000-06-30
CA2231700A1 (en) 1999-06-24
ES2299193T3 (es) 2008-05-16
KR20010033600A (ko) 2001-04-25
US6838474B2 (en) 2005-01-04
FR08C0015I1 (US06559137-20030506-C00106.png) 2008-05-30
CA2231700C (en) 2005-08-09
EP1944300A3 (en) 2008-11-05
SI0933372T1 (sl) 2008-06-30
LU91426I9 (US06559137-20030506-C00106.png) 2018-12-28
TW486474B (en) 2002-05-11
AP1172A (en) 2003-06-30
BR9814480A (pt) 2001-09-25
ID24962A (id) 2000-08-31
ATE382042T1 (de) 2008-01-15
HK1021737A1 (en) 2000-06-30
IS5546A (is) 2000-06-22

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