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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Prior art keywords
alkyl
optionally substituted
compound
compound according
independently selected
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PCT/US1998/004595
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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 AU65466/98A priority Critical patent/AU755087B2/en
Priority to MEP-820/08A priority patent/MEP82008A/en
Priority to PL342113A priority patent/PL202845B1/en
Priority to SK966-2000A priority patent/SK287123B6/en
Priority to EEP200000385A priority patent/EE04466B1/en
Priority to NZ505776A priority patent/NZ505776A/en
Priority to HU0101831A priority patent/HU229596B1/en
Priority to BR9814480-4A priority patent/BR9814480A/en
Priority to EA200000703A priority patent/EA003509B1/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to IL13694198A priority patent/IL136941A0/en
Priority to APAP/P/2000/001850A priority patent/AP1172A/en
Priority to YU39800A priority patent/RS52483B/en
Priority to UA2000074456A priority patent/UA72733C2/en
Publication of WO1999033815A1 publication Critical patent/WO1999033815A1/en
Priority to IL136941A priority patent/IL136941A/en
Priority to IS5546A priority patent/IS2817B/en
Priority to US09/602,494 priority patent/US6559137B1/en
Priority to NO20003304A priority patent/NO326265B1/en
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/en

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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 System
    • 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 System
    • 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

Abstract

The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, 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.

Description

SULPHONAMIDE DERIVATIVES AS PRODRUGS OF ASPARTYL PROTEASE INHIBITORS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, 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.
BACKGROUND OF THE INVENTION
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. For example, 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. While the oral bioavailability of this inhibitor in a "solution" formulation is excellent, the dosage of VX-478 in this form is severely limited by the amount of liquid present in the particular liquid dosage from, e.g., encapsulated into a soft gelatin capsule. A higher aqueous solubility would increase drug load per unit dosage of VX-478.
Currently, the solution formulation of 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.
Furthermore, 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.
Thus, there is a need to improve the drug load per unit dosage form for aspartyl protease inhibitors. Such an improved dosage form would reduce the pill burden and increase patient compliance. It would also provide for the possibility of increasing the amounts of the drug administered per day to a patient.
SUMMARY OF THE INVENTION
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.
These 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.
It is a principal object of this invention to provide a novel class of prodrugs of sulfonamide compounds that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of sulfonamides is represented by formula I :
Figure imgf000006_0001
w ere n:
A is selected from H; Ht ; -R1-Ht; -R1-Cι-C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cι-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N(R2)2 or -CO-N(R2)2; -R1-C2-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cι-C4 alkoxy, Ht , -O-Ht, -NR2-CO-N (R2) 2 or -CO-N(R2)2; or R7; each R1 is independently selected from -C(O)-, - S(0)2-, -C(0)-C(0)-, -O-C(O)-, -0-S(0)2, -NR2-S(0)2-, -NR2- C(O)- or -NR2-C(0) -C(O) - ; each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl ; C6-C10 aryl ; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), 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, -OR2, SR2, -R2, - N(R2) (R2) , -R2-OH, -CN, -C02R2, -C (0) -N (R2) 2 ,
-S(0)2-N(R2)2, -N(R2)-C(0)-R2, -C(0)-R2, -S(0)n-R2, -0CF3, - S(0)n-Q, methylenedioxy, -N(R2) -S (0) 2 (R2) , halo, -CF3, -N02, Q, -0Q, -OR7, -SR7, -R7, -N(R2) (R7) or -N(R7)2; each R2 is independently selected from H, or Cr C4 alkyl optionally substituted with Q; B, when present, is -N (R2) -C (R3) 2-C (O) - ; each x is independently 0 or 1; each R3 is independently selected from H, Ht , Cι-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl; wherein any member of said R3 , except H, is optionally substituted with one or more substituents selected from -OR2, -C(0)-NH-R2, -S (0) n-N (R2) (R2) , Ht , -CN, -SR2, -C02R2, NR2-C(0) -R2; each n is independently 1 or 2 ; G, when present, is selected from H, R7 or Cι-C alkyl, or, when G is Cχ-C alkyl, G and R7 are bound to one another either directly or through a Cι-C3 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 R7 group on -OR7;
D and D' are independently selected from Q; Ci- C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3, -O-Q or Q; C2-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, - OR2, -R3, -0-Q or Q; C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5-C6 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(R2) ; wherein Q is optionally substituted with one or more groups selected from oxo, -OR2, -R2, -N(R2)2, -N(R2) -C(0) -R2, -R-OH, -CN, -C02R2, - C (0 ) -N ( R2 ) 2 , halo or - CF3 ;
E is selected from Ht ; O-Ht; Ht-Ht; -O-R3; -N(R2) (R3) ; Ci-Cβ alkyl, which is optionally substituted with one or more groups selected from R4 or Ht ; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht ; C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht ; or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht ; each R4 is independently selected from -OR2, -SR2, -C(0)-NHR2, -S(0)2-NHR2, halo, -NR2-C (O) -R2, -N(R2)2 or -CN; each R7 is independently selected from
Figure imgf000008_0001
ted from H, Li, Na, K, Mg, Ca, Ba, -N(R )4, C1-C12- lkyl , C2- Cι2-alkenyl, or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group, other than the -CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S (0) , S(02), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, N(R2)2, N(R2)3, ROH, -CN, -C02R2, -C (O) -N (R2) 2 , S(0)2- N(R2)2, N(R2)-C(0)-R2, C(0)R2, -S(0)n-R2, 0CF3, -S(0)n-R6, N(R2) -S(0)2(R2) , halo, -CF3, or -N02;
M' is H, Cι-Ci2-alkyl, C2-CX2-alkenyl , or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from 0, S, S (O) , S (02) , or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, -N(R2)2, N(R2)3, -R2OH, -CN, -C02R2, -C(0)-N(R2)2, -S (0) 2-N (R2) 2 , -N(R2) -C(0) -R2, -C(0)R2, -S(0)n-R2, -0CF3, -S(0)n-R6, -N(R2) -S (0)2(R2) , halo, -CF3, or -N02;
Z is CH2, 0, S, N(R2)2, or, when M is absent, H;
Y is P or S;
X is 0 or S; and
R9 is C(R2)2, 0 or N(R2) ; and wherein when Y is S, Z is not S; and
R6 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(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, Cι-C alkyl, 0-C!-C4 alkyl or 0C(0)Cι-C4 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 .
DETAILED DESCRIPTION OF THE INVENTION In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
Designation Reagent or Fragment Ac acetyl
Me methyl Et ethyl Bzl benzyl
Trityl triphenylmethyl
Asn D- or L-asparagine lie D- or L-isoleucine Phe D- or L-phenylalanine
Val D- or L-valine
Boc tert-butoxycarbonyl
Cbz benzyloxycarbonyl (carbobenzyloxy)
Fmoc 9-fluorenylmethoxycarbonyl DCC dicyclohexylcarbodiimide
DIC diisopropylcarbodiimide
EDC 1- (3 -dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride
HOBt 1-hydroxybenzotriazole HOSu 1-hydroxysuccinimide
TFA trifluoroacetic acid
DIEA diisopropylethylamine
DBU 1 , 8-diazabicyclo (5.4.0) undec-7-ene
EtOAc ethyl acetate The following terms are employed herein:
Unless expressly stated to the contrary, the terms "-S02-" 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. For the compounds of formula I, and intermediates thereof, the stereochemistry of OR7 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) . If both OR7 and D reside on the same side of the plane defined by the extended backbone of the compound, the stereochemistry of OR7 will be referred to as "syn". If OR7 and D reside on opposite sides of that plane, the stereochemistry of OR7 will be referred to as "anti".
The term "aryl" , alone or in combination with any other term, refers to a carbocyclic aromatic radical containing the specified number of carbon atoms.
The term "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. As used herein, the terms "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, β- carbolinyl, tetrazolyl, thiazolidinyl , benzofuranoyl , thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl , oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl , tetrahydrofuranyl , thiadiazoyl, benzodioxolyl , thiophenyl, tetrahydrothiophenyl and sulfolanyl . The terms "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.
The term "pharmaceutically effective amount" refers to an amount effective in treating HIV infection in a patient. The term "prophylactically effective amount" refers to an amount effective in preventing HIV infection in a patient. As used herein, the term "patient" refers to a mammal, including a human. The term "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. Examples of suitable acids 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- (C1-4 alkyl)4+ salts. The term "thiocarbamates" refers to compounds containing the functional group N-S02-0.
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 .
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, 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, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
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.
The novel sulfonamides of this invention are those of formula I :
Figure imgf000014_0001
wherein:
A is selected from H; Ht; -R1-Ht; -R1-Cι-Ce alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cι-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N(R2)2 or -CO-N(R)2; -R1-C2-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cι-C alkoxy, Ht, -O-Ht, -NR2-CO-N(R2) 2 or -CO-N(R2)2; or
R' each R1 is independently selected from -C(O)-, - S(0)2-, -C(0)-C(0)-, -O-C(O)-, -0-S(0)2, -NR -S(0)2-, -NR2- C(0)- or -NR -C(0) -C(0) -; each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), 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, -OR2, SR2, -R2, - N(R2) (R2), -R2-OH, -CN, -C02R2, -C (0) -N (R2) 2 ,
-S(0)2-N(R2)2/ -N(R2)-C(0) -R2, -C(0)-R2, -S(0)n-R2, -OCF3, - S(0)n-Q, methylenedioxy, -N (R2) -S (0) 2 (R2) , halo, -CF3, -N02, Q, -0Q, -OR7, -SR7, -R7, -N(R2) (R7) or -N(R7)2; each R2 is independently selected from H, or Ci- C alkyl optionally substituted with Q;
B, when present, is -N (R2) -C (R3) 2-C (0) - ; each x is independently 0 or 1; each R3 is independently selected from H, Ht, d-Ce alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl; wherein any member of said R3 , except H, is optionally substituted with one or more substituents selected from -OR2, -C(0)-NH-R2, -S (0) n-N (R2) (R2) , Ht , -CN, -SR2, -C02R2, NR2-C (0) -R ; each n is independently 1 or 2 ;
G, when present, is selected from H, R7 or Cι-C4 alkyl, or, when G is Cι-C4 alkyl, G and R7 are bound to one another either directly or through a Cι-C3 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 R7 group in -OR7 with the concomitant displacement of one -ZM- group from R7;
D and D1 are independently selected from Q; Ci- C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, -OR2, -R3,
-0-Q or Q; C2-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, - OR2, -R3, -0-Q or Q; C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5-C6 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 0, N, S, S(0)n or N(R2) ; wherein Q is optionally substituted with one or more groups selected from oxo, -OR2, -R2, -N(R2)2, -N(R2) -C(O) -R2, -R2-OH, -CN, -C02R2, -C(0) -N(R2)2, halo or -CF3; E is selected from Ht ; O-Ht; Ht-Ht; -O-R3;
-N(R2) (R3) ; Cι-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht ; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C3 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; each R4 is independently selected from -OR2, -SR2, -C(0)-NHR2, -S(0)2-NHR2, halo, -NR2-C (O) -R2, -N(R2)2 or -CN; each R7 is independently selected from ZM
-ChL- Y- -Z(M) CHr-0 "(R9)χM'
Figure imgf000017_0001
wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, Cι-C12-alkyl , C2- Cι2-alkenyl, or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group, other than the -CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from 0, S, S(0), S(02), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or Rs is optionally replaced with a substituent selected from oxo, -OR2, -R2, N(R2)2, N(R2)3, R20H, -CN, -C02R2, -C (O) -N (R2) 2 , S(0)2- N(R2)2, N(R2)-C(0)-R2, C(0)R2, -S(0)n-R2, OCF3 , -S(0)n-R6, N(R2) -S(0)2(R2) , halo, -CF3, or -N02;
M' is H, Cχ-Cι2-alkyl, C2-Cι2-alkenyl , or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S (O) , S(02), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, -N(R2)2, N(R2)3, -ROH, -CN, -C02R2, -C(0)-N(R2)2, -S (O) 2-N (R2) 2, -N(R2) -C(0)-R2, -C(0)R2, -S(0)n-R2, -OCF3, -S(0)n-R6, -N(R2) -S(0)2(R2) , halo, -CF3, or -N02;
Z is CH2, 0, S, N(R2)2, or, when M is not present, H.
Y is P or S;
X is 0 or S; and
R9 is C(R2)2, 0 or N(R2 and wherein when Y is
S, Z is not S; and R R66 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(R2) ; and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C!-C4 alkyl, 0-Cx-C4 alkyl or 0-C(0)-Cι-C4 alkyl.
Preferably, at least one R7 is selected from:
Figure imgf000018_0001
O
.NMe
(L)-lysine, -P03Na2, o' 2 i
Figure imgf000018_0002
O
■NH,
-P03(NH4)2, -CH2-OP03Na2, ' - (L) -serine,
■S03Na 2/ NMe2/ _S03Mg, -S03(NH4)2,
Figure imgf000018_0003
-CH2-0S03Na2, •CH2-OS03(NH4)2,
Figure imgf000018_0004
Figure imgf000018_0005
Figure imgf000018_0006
- (L) -valine, (L) -glutamic acid, - (L) -aspartic acid,
(L) -γ-t-butyl-aspartic acid,
Figure imgf000018_0007
O
- (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, ^CF3
Figure imgf000019_0001
o o 0 O
I I /PΓO/^NH3 + 0^ ^NMe3 + /^^ o. 0. O. O.
P03K2, P03Ca, P03-spermine, P03- (spermidine) 2 or P03- (meglamine) 2.
It will be understood by those of skill in the art that 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 R9 depending upon the actual choice for M or M' . When M or M' is hydrogen, alkyl, alkenyl, or R6, M or M' is covalently bound to R9 or Z . If M is a mono- or bivalent metal or other charged species (i.e., NH4 +) , there is an ionic interaction between M and Z and the resulting compound is a salt.
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.
Except where expressly provided to the contrary, as used herein, the definitions of variables A, R^R4, R6-R9, Ht, B, x, n, D, D\ M, Q, X, Y, Z and E are to be taken as they are defined above for the compounds of formula I. According to a preferred embodiment, the compounds of this invention are those represented by formulas XXII, XXIII or XXXI:
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
wherein A, R3, R7, Ht , D, D', x, E are as defined above for compounds of formula I. For ease of reference, the two R3 moieties present in formula XXXI have been labeled R3 and R3 ' .
For compounds of formula XXII, more preferred compounds are those wherein:
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 C1-C4 alkyl which is optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, -OR2, -R3, -0-Q and Q;
E is Cs-Cio aryl optionally substituted with one or more substituents selected from oxo, -OR2, SR2, -R2, - N(R2)2, -R2-OH, -CN, -C02R2, -C (0) -N (R2) 2 , -S (0) 2-N (R2) 2 , -N(R2)-C(0)-R2, -C(0)-R2, -S(0)n-R2, -OCF3, -S(0)n-Q, methylenedioxy, "-N (R2) -S (0) 2 (R2) , halo, -CF3, -N02, Q, -0Q, -OR7, -SR7, -R7, -N(R2) (R7) or -N(R7)2; or 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 -CH3, R4, or Ht . Ht, insofar as it is defined as part of R3, 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(R7)2; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C1-C4 alkyl or -N(R2)4; and each M' is H or C!-C4 alkyl.
Another preferred embodiment for the formula XXII compounds are those wherein:
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 -CH3, R4, or Ht; and all other variables are as defined for formula I . Even more preferred are any of the formula XXI I compounds set forth above , wherein R7 in -OR7 is -PO (OM) 2 or C (0) CH2OCH2CH2OCH2CH2OCH3 and both R7 in -N (R7 ) 2 are H , wherein M is H , Li , Na , K or Cι - C4 alkyl ; or wherein R7 in -OR7 is C (0) CH2OCH2CH2OCH3 , one R7 in -N (R7) 2 is C (0) CH2OCH2CH2OCH3 and the other is H .
The most preferred compound of formula XXI I has the structure :
Figure imgf000022_0001
For compounds of formula XXIII, most preferred compounds are those wherein:
R3 is Cι-C6 alkyl, C2-C6 alkenyl, C5-C6 cycloalkyl, C5-
C6 cycloalkenyl or a 5-6 membered saturated or unsaturated heterocycle, wherein any member of said R3 may be optionally substituted with one or more substituents selected from the group consisting of -OR2, -C(0)-NH-R2, -
S(0)nN(R2) (R2) , Ht, -CN, -SR2, -C(0)2R2 and NR2-C (O) -R2 ; and D' is Cx-C3 alkyl or C3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, -OR2, -0-Q and Q (with all other variables being defined as above for compounds of formula I) .
Even more preferred are compounds of formula
XXIII described above, wherein R7 is -PO(OM)2 or -C(0)-M'. For compounds of formula XXXI, most preferred compounds are those wherein A is R1-Ht, each R3 is independently C!-C6 alkyl which may be optionally substituted with a substituent selected from the group consisting of -OR2, -C(0)-NH-R2, -S (0) nN (R2) (R2) , Ht , -CN, -SR2, -C02R2 or -NR2-C(0) -R2; and D' is Cι-C4 alkyl, which may be optionally substituted with a group selected from the group consisting of C3-C6 cycloalkyl, -OR2, -0-Q; and E is Ht, Ht-Ht and -NR2R3.
Even more preferred are those compounds of formula XXXI described above wherein R7 is -P0(0M)2 or -C(0) -M' .
TABLE I
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0002
TABLE II
Figure imgf000032_0001
Figure imgf000032_0003
Figure imgf000033_0002
TABLE II I
Figure imgf000033_0001
Figure imgf000033_0003
According to another embodiment, the invention provides compounds of the following formulae:
Figure imgf000034_0001
1001 1002
Figure imgf000034_0002
1003
Figure imgf000034_0003
1004 1005
Figure imgf000034_0004
Figure imgf000035_0001
1007 1008
Figure imgf000035_0002
1009 or
Figure imgf000035_0003
wherein, in compound 1005, when R7 is P03M, (G)x is not H; and wherein R10 is selected from isopropoyl or cyclopentyl; R11 is selected from NHR7 or OR7; and x, R7 and G are as defined above. The prodrugs of the present invention may be synthesized using conventional synthetic techniques.
United States patent 5,585,397 discloses the synthesis of compounds of formula:
Figure imgf000036_0001
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 λ 397 compounds to a desired -OR7 functionality of the present invention, wherein R7 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 .
For example, VX-478, a compound disclosed in the λ 397 patent, can be readily converted to the corresponding bis-phosphate ester derivative, as shown below:
Figure imgf000036_0002
Alternatively, if the monophosphate ester of VX-478 is desired, then the synthetic scheme can be readily adapted by beginning with the 4-nitrophenyl derivative of VX-478, as shown below:
Figure imgf000037_0001
H2, Pd/C EtOAc, 35 psi
Figure imgf000037_0002
Examples of specific compounds in addition to VX-478 which may be converted to the prodrugs of this invention by similar techniques (and the syntheses of those intermediates to the compounds of the present invention) are disclosed in WO 94/05639 and WO 96/33184, the disclosures of which are herein incorporated by reference.
Pharmaceutically acceptable salts of the compounds of the present invention may be readily prepared using known techniques. For example, the disodium salt of the mono-phosphate ester shown above can be prepared as shown below:
Figure imgf000037_0003
3) lyophilize 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
(e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. Without being bound by theory, we believe that two different mechanisms are involved in converting the prodrugs of this invention into the active drug, depending upon the structure of the prodrug. 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., R7) from one heteroatom within the molecule to another heteroatom. This transfer is demonstrated in the chemical reactions shown below:
Figure imgf000038_0001
and
Figure imgf000039_0001
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.
Figure imgf000039_0002
These protease inhibitors and their utility as inhibitors of aspartyl proteases are described in United States Patent 5,585,397, the disclosure of which is incorporated herein by reference. 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. For example, 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. Alternatively, 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. For example, 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. As such, 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. By administering the compounds of this invention with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated. For instance, 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. Additionally, 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. In particular, we have discovered that these 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.
Alternatively, 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 .
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. We believe that the co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms .
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.
When the prodrugs of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, 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. Although 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. In addition, 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.
Pharmaceutical 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 .
The pharmaceutical 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. The term 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 . Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, 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. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added .
The pharmaceutical 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. Such materials 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. For application topically to the skin, 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. Alternatively, 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.
The pharmaceutical 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. Typically, 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) . Preferably, such preparations contain from about 20% to about 80% active compound.
Upon improvement of a patient's condition, 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.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient's disposition to the infection and the judgment of the treating physician.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Example 1
General conditions :
(A) Analytical HPLC 0-100%B/30 min, 1.5 mL/min, A=0.1% TFA in water, B=0.1% TFA in acetonitrile .
Detection at 254 and 220 nm, C18 reverse phase Vydac, t0=2.4 min.
(B) 1/3 v/v EtOAc/hexane
(C) 1/2 v/v EtOAc/hexane (D) Analytical HPLC 0-100%B/l0 min, 1.5 mL/min, A=0.1% TFA in water, B=0.1% TFA in acetonitrile. Detection at 254 and 220 nm, C18 reverse phase Vydac, to=2.4 min.
Figure imgf000048_0001
197 198
A mixture of 2. Og (3.7 mMol) of 197 and 3. Og (16 mMol) of di-p-nitrophenyl carbonate in 10 ml of dimethylformamide was treated at 25° with 4 ml (4 mMol) of P4-phosphazene base (Fluka, 1M in hexane) . The mixture was stirred for 6h at 25° until all of the starting alcohol was consumed. The reaction mixture was partitioned between ethyl acetate and IN hydrochloric acid. The organic layer was washed with IN sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo . Titration with dichloromethane gave the desired mixed carbonate (1.2g cropl and 0.6g crop 2) as a fine powder. Combined yield: 69%. Rf=0.13 (1/3 EtOAc/hexane, conditions B) , Rf=0.40 (1/2 EtOAc/hexane, conditions C) , tHPLC=23.83 min (A), MS (ES+) 701 (M+l) . 1H-NMR (CDC13) : 0.82 (6H,dd), 1.9 (2H,m), 2.15 (lH,m), 2.8 (lH,m), 3.0 (4H,m) , 3.5 (2H,m), 3.6 (lH,m), 3.8 (4H,m), 4.3 (lH,bs), 4.8 (lH,m), 5.17 (2H,m), 7.7 (7H,m), 7.95 (2H,d) , 8.35 (4H,m) . 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.
Example 2
Figure imgf000049_0001
To 0.20g (0.286 mM) of 198 dissolved in 3 ml of THF was added 0.11 g (1.14 mM) of 1-Methyl-piperidine and the mixture was stirred overnight at room temperature ("rt") . All the solvents were then evaporated and the solid residue partitioned between EtOAc and water. The volatiles were removed and, where appropriate, the residue was treated with 1:1 TFA/DCM over 30 min at rt to remove the Boc protecting group. The product was dissolved in 0.25 ml TFA and 1.5 ml THF. Hydrogenolysis for 10 hours in presence of 30 mg of 10% Pd/C gave the desired compound. The final purification was on preparative reversed phase C18 using conditions Example 1, except that the flow rate was 18 ml/ in. C,H,N: calc: 49.27, 5.57, 8.25, found 49.15, 5.76, 8.29 C31H5N5O7S1 . 1.9CF3COOH
LC/MS (ES+) 632 (M+l) 1 peak at 4.71 min
Analytical HPLC (A) t=N/A min
1H:0.71 (3H,d), 0.74 (3H,d), 1.80 (2H,m), 2.03 (lH,m),
2.63 (2H,m), 2.74 (lH,m), 2.82 (3H,s), 2.92 (2H,m), 3.20 (4H,m), 3.42 (3H,m), 3.62 (2H,m), 3.75 (lH,m), 4.05 (3H,m), 4.97 (2H,m), 6.2 (lH,bs), 6.60 (2H,m), 7.22 (5H,m) , 7.40 (3H,m) ,
13C (DMSO) : 156.4, 154.0, 153.8, 138.8, 129.6, 129.5, 128.3, 126.5, 123.7, 112.7, 74.8, 72.9, 66.7, 58.2, 54.0, 53.1, 49.3, 42.3, 40.8, 36.0, 33.3, 25.8, 20.4, 20.3
Example 3
Figure imgf000051_0001
198 200
The synthesis of compound 200 from compound 198 was carried as described in Example 1, except that N,N- dimethyl-aminoethanol was used in place of di-p- nitrophenyl carbonate.
1HNMR (acetone-d6) : 0.82 (6H,dd), 1.83 (2H,m), 2.07
(lH,m), 2.64 (2H,m), 2.82 (6H,s), 2.90 (2H,m), 3.19 (lH,m), 3.38 (4H,m), 3.63 (2H,m), 3.76 (lH,m), 4.17
(2YH,m), 4.40 (lH,m), 4.56 (lH,m), 4.96 (lH,m), 5.06
(lH,m), 6.06 (lH,d), 6.68 (2H,d), 7.23 (5H,m), 7.47
(2H,d) .
13CNMR (acetone d6) : 20.2, 20.3, 27.5, 33.4, 35.6, 43.8, 50.1, 54.2, 56.4, 58.5, 63.1, 67.4, 73.6, 76.2, 79.9,
114.2, 118.3, 127.4, 129,2, 130.1, 130.3, 139.3, 153.4,
157.0.
LC/MS: 1 peak, 621 (MH+) .
Example 4
Figure imgf000051_0002
198 201 The synthesis of compound 201 from compound 198 was carried as described in Example 1, except that N- acetyl-ethylenediamine was used in place of di-p- nitrophenyl carbonate. C,H,N: calc: 49.66, 5.64, 8.83, found 49.76, 5.98, 8.93 C3oH43N508Sι . 1.4CF3COOH.
LC/MS (ES+) 634 (M+l) 1 peak at 5.08 min. Analytical HPLC (A) t=15.92 min. 1H: d-3 acetonitrile: 0.88 (6H,dd), 1.92 (3H,s), 1.94 (2H,m) , 2.17 (lH,m), 2.72 (2H,m), 2.96 (2H,m), 3.07 (3H,m), 3.29 (lH,m), 3.42 (3H,m), 3.69 (lH,m), 3.77 (lH,m), 3.82 (lH,m), 4.133 (lH,m), 4.40 (lH,bs), 5.05 (2H,m) , 5.80 (lH,m), 6.10 (lH,d), 6.78 (2H,d), 6.83 (lH,bs), 7.28 (5H,m), 7.58 (2H,d). 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.
Example 5
Figure imgf000052_0001
198 202
The synthesis of compound 202 from compound 198 was carried as described in Example 1, except that mono N-Boc-piperazine was used in place of di-p-nitrophenyl carbonate.
C,H,N: calc: 48.28, 5.68, 8.41, found 48.28, 5.36, 8.28
C3oH 3N507Sι x 2 CF3COOH
LC/MS (ES+) 618 (M+l) 1 peak at 4.36 min. Analytical HPLC (A) t=14.84 min.
1H: d6-DMSO: 0.72 (3H,d), 0.77 (3H,d), 1.78 (2H,m), 2.09 (lH,m), 2.64 (2H,m), 2.73 (lH,m), 2.80 (lH,m), 3.08 (4H,m), 3.32 (2H,m), 3.41 (lH,m) 3 , . 50 (4H, m) , 3 , . 54 (lH,m), 3.63 (lH,m), 3.70 (lH,m) 3 , . 98 ( lH, m) , 4 , . 89 (lH,m) , 4.97 (lH,m), 6.61 (2H,d) 7 , . 23 (5H, m) , 7 , . 42 (3H,m) , 8.88 (2H,bs) .
13C: (DMSO) : 155.7, 153.6, 153.0, 138.4, +129.1, +129.0, +128.1, +126.1, 123.2, +112.7, +75.2, +74.4, -72.5, -66.2, -56.9, +53.1, -48.8, -42.5, -40.8, -35.0, -32.2, +26.2, +20.0, +19.8.
Example 6
Figure imgf000053_0001
198 203 The synthesis of compound 203 from compound 198 was carried as described in Example 1, except that mono- N-Boc-ethylenediamine was used in place of di-p- nitrophenyl carbonate. C,H,N: calc: 46.89, 5.29, 8.54, found 46.50, 5.51, 8.54 C28H41N507S! x 2 CF3COOH .
LC/MS (ES+) 592 (M+l) 1 peak at 4.32 min.
Analytical HPLC (A) t=14.69 min. lH:d-6 DMSO: 0.77 (6H,d), 1.82 (2H,m), 2.06 (lH,m), 2.57
(2H,m), 2.82 (4H,m), 2.97 (lH,m), 3.30 (5H,m), 3.55 (lH,m), 3.65 (lH,m), 3.70 (lH,m), 3.95 (lH,m), 4.88
(lH,m), 4.95 (lH,m), 6.62 (2H,d), 7.20 (6H,m), 7.39
(3H,m) , 7.78 (3H,bs) . 13C (dmso): 155.9, 152.9, 138.5, 129.2, 128.9, 128.1, 126.1, 122.9, 112.7, 74.7, 74.5, 72.6, 66.2, 57.2, 53.2, 49.4, 38.8, 37.94, 35.1, 32.1, 26.3, 20.0, 19.8.
Figure imgf000054_0001
The synthesis of compound 204 from compound 198 was carried as described in Example 1, except that mono- 1 , 3-diamino-3-N-Boc-propane was used in place of di-p- nitrophenyl carbonate.
C,H,N: calc: 49.07, 5.64, 8.89, found 48.95, 6.00, 8.92 C29H3N5θ7S1 x 1.6 CF3COOH
LC/MS (ES+) 605 (M+l) 1 peak at 4.27 min. Analytical HPLC (A) t=14.72 min. lH:d-6 DMSO: 0.78 (6H,dd), 1.64 (2H,m), 1.83 (2H,m), 2.03 (lH,m) , 2.57 (lH,m), 2.78 (4H,m), 2.94 (lH,m), 3.03 (2H,m), 3.32 (2H,m), 3.58 (lH,m), 3.63 (lH,m), 3.73 (lH,m), 3.87 (lH,m), 4.84 (lH,m), 4.92 (lH,m), 6.61 (2H,d), 7.22 (6H.m), 7.36 (lH,d), 7.28 (2H,d), 7.76 (3H,ns) .
13C (dmso): 155.8, 155.7, 138.5, +129.1, +129.0, +128.0, +126.1, 122.9, +112.7, +74.6, +74.3, -72.7, -66.2, -57.2, +53.6, -49.5, -37.4, -36.7, -35.5, -32.1, -27.6, +26.2, +20.0, +19.8. Example 8
Figure imgf000055_0001
198 205
The synthesis of compound 205 from compound 198 was carried as described in Example 1, except that 1,4- diamino-4-N-Boc-butane was used in place of di-p- nitrophenyl carbonate.
C,H,N: calc: 48.17, 5.59, 8.26, found 48.02, 5.96, 8.24 C3θH45N507Sι . 2 CF3C00H LC/MS (ES+) 620 (M+l) 1 peak at 4.36 min. Analytical HPLC (A) t=14.93 min.
1H: d-6 DMSO: 0.77 (6H,dd), 1.43 (4H,m), 1.82 (2H,m), 2.03 (lH,m), 2.77 (4H,m), 2.95 (3H,m), 3.31 (2H,m), 3.56 (lH,m), 3.63 (lH,m), 3.70 (lH,bq), 3.82 (lH,m), 4.85 (lH,m), 4.92 (lH,m), 6.62 (2H,d), 7.2 (7H,m), 7.38 (2H,d) , 7.72 (3H,bs) .
13C: 155.7, 152.9, +138.6, +129.1, +129.0, +128.0, +126.1, +123.0, +112.7, +74.4, +74.3, -72.7, -66.2, - 57.2, +53.7, -49.7, -38.6, -38.5, -35.4, -32.1, -26.3, +26.2, -24.4, +20.1, +19.9.
Example 9
Figure imgf000055_0002
198 206 The synthesis of compound 206 from compound 198 was carried as described in Example 1, except that (3R) - (+) -3-Boc-aminopyrrolidine was used in place of di-p- nitrophenyl carbonate. C,H,N: calc: 48.28, 5.36, 8.28, found 47.89, 5.53, 8.57
Figure imgf000056_0001
LC/MS (ES+) 618 (M+l) 1 peak at 4.32 min. Analytical HPLC (A) t=14.31 min.
IH and 13C NMR: complex and overlapping mixtures of rotomers.
Example 10
Figure imgf000056_0002
198 207
The synthesis of compound 207 from compound 198 was carried as described in Example 1, except that (3S) - ( -) -3-Boc-aminopyrrolidine was used in place of di-p- nitrophenyl carbonate.
LC/MS (ES+) 618 (M+l) 1 peak at 4.19 min. Analytical HPLC (A) t=14.75 min. IH and 13C NMR: complex and overlapping mixtures of rotomers .
- -
Figure imgf000057_0001
198 308
The synthesis of compound 308 from compound 198 was carried as described in Example 1, except that N- triphenylmethyl-N,N' -dimethylethanediamine was used in place of di-p-nitrophenyl carbonate.
1H-NMR: 0.76 (6H,dd), 1.65 (2H,m), 1.95 (lH,m), 2.07 (lH,m), 2.7 (2H,m), 2.75 (3H,s), 2.95 (3H,m), 3.45 (2H,m), 3.7 (4H,m), 4.2 (2H,bm), 5.05 (2H,bd), 6.62 (2H,d), 7.2 (5H,m), 7.5 (2H,d). LC/MS: 1 peak, 620 (MH+) .
Example 12
General Procedures Acylation:
Figure imgf000057_0002
To 200mg (.37mM) of 197 dissolved in 5ml CH2C12 was added N-CBz-L-Benzyl tyrosine 183mg (.41mM) followed by 231 mg (1.12mM) DCC, followed by 29mg (.23mM) DMAP. The reaction is stirred at rt for 24hr. The precipitates present were removed by filtration. The filtrate was then concentrated in vacuo . The final compound was purified on preparative reversed phase C18 using purification by HPLC C18 Waters Delta Prep 3000 Column: YMC-Pack ODS AA 12S05-2520WT 250X20 mm I.D. S-5mm, 120A, 0-100% B over l/2h, flow=18 ml/min, monitored at 220 nm, B=0.1% trifluoroacetic acid in acetonitrile, A=0.1% trifluoroacetic acid in water. Analytical Column: YMC- Pack ODS AA1 2S05-2520WT 250X4.6 mml.D. S-5mm, 120A, 0- 100% B at 1.5 ml/min. over 1/2 h, monitored at 220 nm, B=0.1% trifluoroacetic acid in acetonitrile, A=0.1% trifluoroacetic acid in water.
The aqueous phase was lyophilized to give 59 mg, (16.3%) GW431896X, (U11484-72-10) tHPLC=11.71 min., MW=966.04, LC/MS=MH+967.
Reduction of the Nitro Functionality:
Figure imgf000058_0001
209 210
A slurry of 209 (170 mg) and 10 mg of 10% Pd.C in 95% EtOH was flushed with hydrogen in a scintillation vial equipped with septum and a stir bar. Continuous overnight hydrogenolysis under hydrogen balloon resulted in a complete conversion. The crude preparation was then filtered off the catalyst, and purified on RP C18 HPLC (Prep Nova-Pack C186 urn, 60 A, gradient 0-100% B over 30 min. The desired product was collected and lyophilized affording a white fluffy solid (50 mg, 30.8%). Example 13
Figure imgf000059_0001
197 211
Compound 211 was obtained following the acylation and reduction procedures of Example 12. ES+ 669.2 (M+l), tHPLC=8.06 min (D) , 13C NMR (DMSO) 168.9, 156.9, 155.7, 153.1, 138.1, 130.5, 129.2, 129.1, 128.1, 126.2, 124.7, 122.5, 112.8, 76.2, 74.5, 72.5, 66.1, 58.0, 53.6, 52.6, 49.2, 33.6, 32.1, 26.6, 25.3, 20.0. tHPLC=11.71 min (D) , ES+ 967 (M+l).
Example 14
Figure imgf000059_0002
197 212 212 was obtained following the procedures of
Example 12. tHPLC= 9.45 min (D) , ES+ 592.2 (M+l).
13C NMR (DMSO) 171.5, 155.8, 148.9, 137.8, 129.5, 129.3, 128.5, 126.7, 115.2, 75.2, 73.8, 73.1, 68.3, 67.0, 58.7, 57.1, 53.3, 49.2, 35.4, 32.4, 26.7, 20.1, 19.8.
1H(CDC13, 399.42 KHz): 8.33 (2H, d, J=8.8), 7.95 (2H, d, J=8.8), 7.23 (5H, m) 5.22 (m, 2H) , 5.08 (m, IH) , 4.08 (m, IH) , 3.80-3.45 (7H, m) , 3.41 (3H, s) , 2.98 (m, 3H) , 2.66 - o -
(m, IH) , 2.57 (m, 2H) , 2.10 (s, IH) , 1.93 (2H, m) , 0.82 (3H, d) , 0.78 (3H, d) . ES+ 622 (M+l) , 644 (M+Na) tHPLC =10.29 min (D) .
13C NMR (CDC13) : 171.3, 155.5, 149.9, 145.6, 136.9, 129.2, 128.6, 128.5, 126.8, 124.4, 76.7, 75.3, 73.2, 72.9, 68.2, 66.9, 58.7, 55.9, 53.1, 48.3, 35.3, 32.7, 26.3, 19.9, 19.8.
Example 15
Figure imgf000060_0001
197 213
Compound 213 was obtained following the procedure of Example 12. tHPLC = 9.21 min (D) ; ES+ 622 (M+l) .
13C NMR (CDC13) : 170.54, 156.2, 148.6, 136.8, 129.4, 129.2, 128.6, 126.6, 115.7, 76.7, 74.6, 73.2, 71.8, 70.6, 68.2, 66.9, 58.9, 57.3, 53.8, 49.4, 36.2, 33.1, 26.8, 19.8, 19.5. Intermediate: t HPLC = 10.05 min (D) ; ES+= 652 (M+H) 674 (M+Na) .
Example 1
Figure imgf000061_0001
197 214
214 was obtained following the procedure of Example 12.
ES+ 634.4 (M+l); t HPLC = 7.17 min (D) .
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 17
Figure imgf000061_0002
197 215 215 was obtained following the procedure of
Example 12. t HPLC = 9.12 min (D)
IH (DMSO) all signals broad: 7.38 (3H, br m) , 7.20 (5H, br m) , 6.62 (2H, br m) , 5.15 (IH, br m) , 4.92 (IH, br m) , 4.00 (3H, m) , 3.7-3.0 (16H, m) , 2.78 (2H, m) , 2.57 (3H, m) , 2.04 (m, IH) , 1.78 (m, 2H) , 0.77 (6H, m) 13C (DMSO) 170.6, 156.3, 153.7, 139.1, 129.8, 128.4, 126.7, 123.7, 113.3, 79.8, 79.2, 77.3, 76.1, 75.4, 75.2, 73.0, 71.9, 52.3, 51.8, 48.2, 46.7, 39.9, 38.7, 25.8, 22.6.
Intermediate : t HPLC = 10.18 min (D) ; ES+ 696.3 (M+l).
Example 18
Figure imgf000062_0001
216 was obtained following the procedure of Example 12.
1H-NMR: 0.97 (6H,t), 1.95 (2H,m), 2.20 (lH,m), 2.9 (2H,m), 2.96 (6H,s), 3.00 (3H,s), 3.38 (lH,m), 3.42 (3H,m), 3.36 (lH,m), 3.6 (2H,m), 3.7 (6H,m), 3.98 (2H,m), 4.2 (2H,dd), 5.1 (lH,bs), 5.4 (lH,m), 6.8 (2H,d), 7.4 (5H,m) , 7.6 (2H,d) .
LC-MS: 1 peak, 692 (MH+) .
Example 19
Figure imgf000062_0002
197 217
217 was obtained following the procedure of
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 20 General Procedure for N-acylated Compounds
Figure imgf000063_0001
A mixture of 0.5g (1 mMol) of (3S) -Tetrahydro- 3-furfuryl-N- ( (1S,2R) -l-benzyl-2-hydroxy-3- (N-isobutyl-4- aminobenzenesulfonamido)propyl) carbamate, 0.4g (1.5 mMol) of Boc- (S) -3-pyridyl alanine, 0.29g (1.5 mMol) EDCI and 0. Ig 4 -dimethylamino pyridine in 10 ml of N,N- dimethylformamide was stirred at 25° for 12 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and IN hydrochloric acid. The organic layer was washed with IN sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a 2 inch plug of silica gel (1:1 ethyl acetate: hexane) to give the desired N-acylated material. Deprotection by treatment with 50 ml of trifluoroacetic acid, followed by co-evaporation of residual acid with methanol gave the desired prodrug as a white foam (0.2g, 26%) .
HI -NMR (acetonitrile-D3) : 0.95 (6H,dd), 2.0 (2H,m), 2.25 (lh,m) , 2.8-3.1 (5H,m), 3.6-4.0 (7H,m), 4.25 (lH,m), 4.75 (lH,m), 5.18 (lH,m), 5.45 (lH,m), 7.0 (2H,d), 7.4 (5H,m), 7.75 (2H,d), 8.2 (lH,m), 8.8 (lH,d), 8.85 (lH,d), 9.15 (lH,s) . LC/MS: 1 peak, 654 (MH+) .
Example 21
Figure imgf000064_0001
218 220
220 was obtained using the general procedure in Example 20. IH-NMR (acetone-d6/ methanol -d4 ) : 0.95 (6H,t), 2.0 (2H,m), 2.2 (lH,m), 2.90 (lH,dd), 2.95 (2H,d), 3.12 (lH,dd), 3.4 (2H,m), 6 (lH,d), 3.8 (5H,m), 4.4 (2H,bm), 6.82 (2H,d), 7.20 (lH,s), 7.4 (5H,m), 7.65 (2H,d), 8.0 (lH,s) . LC/MS: 1 peak, 643 (MH+) .
Example 22
Figure imgf000065_0001
218 221
221 was obtained using the general procedure in
Example 20.
IH-NMR (DMSO d-6) : 0.76 (6H,t), 1.80 (2H,m), 2.10 (lH,m), 3.7 (4H,m) , 3.75 (3H,s), 3.2 (5H,m), 3.58 (2H,s), 3.7 (4H,m), 4.97 (lH,bm), 5.18 (lH,bs), 6.7 (2H,d), 7.22 (5H,m) , 7,45 (2H,d) .
LC/MS: 1 peak, 646 (MH+) .
Example 23
Figure imgf000065_0002
23JL 222
222 was obtained using the general procedure in
Example 20.
IHNMR (acetonitrile d-3): 1.0 (6H,t), 2.0 (2H,m), 2.2
(lH,m), 3.00 (6H,s), 3.02 (3H,s), 3.1 (4H,m), 3.5 (3H,m), 3.8 (8H,m), 4.4 (2H,s), 5.15 (lH,bs), 7.4 (5H,m), 7.97
(2H, d) , 8.04 (2H,d) . LC/MS: 1 peak, 692 (MH+) .
Example 24
Figure imgf000066_0001
218 223
223 was obtained using the general procedure in
Example 20. t HPLC = 9.22 min (D) ; ES+ 622 (M+l).
IH NMR d6- DMSO: 0.76 (6H,dd) , 1.0-1.8 (15H,m) , 2.03 (lH,m) , 2.58 (2H,m) , 2.79 (2H,m) , 3.11 (lH,m) , 3.28
(3H,s) , 3.3-3.5 (12H,m) , 3.94 (lH,m) , 4.08 (lH,m) , 4.94
(lH,m) , 5.14 (lH,m) , 6.61 (2H,d) , 7.22 (5H,m) , 7.40
(3H,m) .
13C (DMSO) 169.7, 165.9, 152.9, 138.4, 129.2, 129.1, 128.1, 126.2, 123.1, 112.8, 74.4, 74.1, 72.5, 71.2, 69.8,
66.1, 58.1, 57.1, 52.9, 47.5, 33.4, 33.2, 26.3, 24.5,
18.9, 18.8.
Example 25
Figure imgf000066_0002
224 was obtained using the general procedure in Example 20.
Example 26 0, 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 .
Figure imgf000067_0001
218 225 t HPLC 9.26 min (D) ; ES+ 738 (M+l) 760 (M+Na). 13C (DMSO): 170.2, 169.8, 156.4, 143.4, 138.8, 129.5, 128.8, 128.5, 126.8, 119.7, 74.9, 74.2, 73.7, 71.6, 70.7, 70.3, 68.0, 67.2, 59.3, 57.6, 53.8, 49.6, 35.7, 33.8, 27.1, 20.4.
IH (DMSO): 10.1 (IH, s) , 7.84 (d, 2H, J=8.5), 7.76 (d, J=8.7, 2H) , 7.40 (IH, d, J=9.2), 7.22 (m, 5H) , 5.14 (IH, m) , 4.95 (IH, m) , 4.1 (m, 8H) , 3.7-3.3 (m, 13H) , 3.28 (s, 3H) , 3.26 (s, 3H) , 2.86 (m, 2H) , 2.73 (m, IH) , 2.59 (m, IH) , 2.04 (m, IH) , 1.83 (m, 2H) , 0.78 (m, 6H) .
Example 27
Figure imgf000068_0001
197 226
To a mixture of 197 (2.93 g, 5.47 mmol) and phosphorous acid (Aldrich, 2.2 equiv. , 12.03 mmol, 987 mg) in 20 ml pyridine was added 1,3- dicyclohexylcarbodiimide (Aldrich, 2.1 equiv., 11.49 mmol, 2.37 g) and the reaction heated to 60 °C under nitrogen for 3h. Solvent was removed in vacuo, the residue treated with 200 ml 0. IN aqueous sodium bicarbonate and stirred lh at ambient temperature. The mixture was filtered, the filtrate acidified to pH 1.5 by addition of cone. HCl and extracted with ethyl acetate (3 x 100 ml) . The combined orgnic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 3.15g (96%) of desired product 226 which was used directly in the next reaction. HPLC: Rt = 8.91 min (96%), MS (AP+) 600.5 (M+l).
Example 28
Figure imgf000068_0002
226 227 A suspension of 226 (-5.47 mmol) in 18 ml hexamethyldisilazane was stirred at 120°C until homogeneous followed by addition of bis (trimethylsilyl) peroxide (Gelest, Inc., 2.3 equiv., 12.58 mmol, 2.24 g, 2.71 ml) . After lh the mixture was cooled to ambient temperature, solvent removed in vacuo, the residue stirred with 100 ml methanol, solvent removed in vacuo, the residue stirred with 100 ml 0. IN aqueous sodium bicarbonate, acidified to pH 1.5 by addition of cone. HCl, saturated with brine and extracted with ethyl acetate (3 x 100 ml) . The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.98 g (88%) of desired product 227 , which was used directly in the next reaction. HPLC: Rt = 9.28 min (90%), MS (AP+) 616.5 (M+l).
Alternatively, 227 can be synthesized directly from 197. In this method, 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 N2 to 5°C, and treated with POCl3 (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) . 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) .
Example 29
Figure imgf000070_0001
227 228
A solution of 227 (2.98 g, 4.84 mmol) in 50 ml ethyl acetate was treated with 10% palladium on carbon (Aldrich, 300 mg) and put under 35 psi of hydrogen on a Parr shaker for 15h. Catalyst was removed by filtration and solvent removed in vacuo to give 2.66 g (94%) of desired product 228. HPLC: Rt = 7.23 min (92%), MS (ES+) 586.3 (M+l) .
Example 30
Figure imgf000070_0002
228 229 Solid 228 (2.66 g, 4.54 mmol) was treated with
10 ml aqueous sodium bicarbonate (Baker, 3.0 equiv., 13.63 mmol, 1.14 g) and loaded onto a resin column (Mitsubishi Kasei Corp., MCI-gel, CHP-20). Distilled water was run through until the eluent was neutral followed by product elution with 1% acetonitrile in water. Pure fractions were pooled and lyophilized to give 918 mg of pure bis-sodium salt 229.
Alternatively, 7 g of 228 was dissolved in 100 ml of EtOAc with warming and the solution was extracted with 100 ml of aqueous 250 mM triethylammonium bicarbonate (TEABC) (2X) . The aqueous extracts were combined and diluted to 1500 ml with water. This solution was applied to a 300 ml DEAE-52 column (Whatman) which was equilibrated with 50 mM TEABC. The column was washed with 8 L of 50 mM TEABC and the TEA salt was eluted with 2 L of 250 mM TEABC. 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
200 ml) . The ethyl acetate solution was dried with MgS04 then evaporated en vacuo to yield 4 g of the free acid. Two grams of the free acid was dissolved in 50 ml of acetonitrile and a solution of 573 mg NaHC03 in 200 ml water was added. The mixture was lyophilized yielding 2.1 g of the bis sodium salt (compound 229) .
Example 31
Figure imgf000071_0001
231
0 . 53 g (3 . 0 mmol ) 2 - [2 - (2 -Methoxyethoxy) ethoxy] acetic acid was added to a stirred solution of 1 . 2 g (3.15 mmol) HATU 0.2 g (1.47 mmol) HOAt 0.4 g (4.0 mmol) NMM in 10 ml anhydrous N, N-dimethylformamide . The mixture was stirred at room temperature for 30 minutes, then 0.5 g (1 mmol) of (3S) -Tetrahydro-3-furfuryl-N- ( (1S,2R) -1-benzyl -2hydroxy-3- (N-isobutyl-4- aminobenzenesulfonamido) -propyl) carbamate was added to the solution in one portion. The mixture was stirred at 20°C for an hour then at 50°C for an additional 12 hours. It was then cooled to 20°C, 50 ml of ether was added, and the solution was washed with water three times. The aqueous phase was washed with ether, and then the combined organic phases were dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain the desired Mono- (N) acylated (102 mg, 15 %) and Bis-(0,N) acylated (262 mg, 32%) compounds.
Mono- (N) -acylated: IH-NMR (CDC13) : 0.85 (dd, 6H) , 1.85 (m, 2H) , 2.08 (m,lH), 2.8-3.1 ( , 7H) , 3.33 (s, 3H) , 3.55 (m, 3H) , 3.70-3.90 (m, 8H) , 4.1 (s, 2H) , 5.0 (d, IH) , 5.08 (s(br), IH) , 7.2 (m, 5H) , 7.70 (d, 2H) , 7.80 (d, 2H) , 9.09 (s, IH) . MS(FAB+) : 666 (M+l) . Bis- (0,N) -acylated: IH-NMR (CDC13) : 0.77 (m, 6H) , 1.81 (m, IH) , 1.95 (m, IH) , 2.05 (m, IH) , 2.6-3.0 (m, 6H) , 3.2
(m, IH) , 3.332 (s, 3H) , 3.338 (s, 3H) , 3.5-3.8 (m, 18H) , 4.1 (s, 2H) , 4.14 (s, 2H) , 4.17 (m, IH) , 5.05 (m, 2H) , 5.25 (s(br), IH) , 7.2 (m, 5H) , 7.69 (d, 2H) , 7.78 (d 2H) , 9.06 (s, IH) . MS(FAB+): 826 (M+l), 848 (M+Na) . Example 32
Figure imgf000073_0001
We dissolved 0.521g (1 M) of 1273W94 in 5 ml THF, then cooled to -78°C under nitrogen, and added 1.56 ml (2.5 mM) of a 1.6 M solution of nBuLi in hexane . After 20 min at -78°C, we added 105 μh (1.1 mM) of ethyl chlorocarbamate and warmed up the reaction to room temperature, followed by addition of another 105 μL of ethyl chlorocarbamate.
After stirring for additional 4 hrs, the reaction was quenched with water and the organic solvent evaporated. Part of the crude product was purified on a silica gel (Rf=0.69 (1:2 ethyl acetate : hexane) ) , yielding 0.131g of the product.
C,H,N: calc: 46.06, 4.97, 5.88, found 45.90, 4.97, 5.88
Figure imgf000073_0002
LC/MS (ES+) 594 (M+l) 1 peak at 6.96 min. Analytical HPLC (A) t=24.57 min. 13C (CDC13) : 155.8, 154.4, 149.9, 145.7, 136.8, +129.2,
+128.7, +126.8, +124.2, 80.1, +76.9, -64.3, -56.2, -52.5, -48.7, -36.2, +28.1, +26.4, +20.0, +19.8, +14.3. Example 33
Figure imgf000074_0001
233 We dissolved 0.131g of the above ethyl carbonate in 4 ml DCM, followed by 4 ml of TFA. Solvents were then removed after 45 min at room temperature, resulting in the title compound.
IH (DMSO): 8.37 (2H, d, J=7.2), 8.15 (2H, m) , 8.00 (2H, d, J=7.0), 7.37 (5H, m) , 5.04 (IH, d, J=6.9), 4.06 (2H, q, J=7.0), 3.82 ((IH, m) , 3.35 (2H, m) , 2.95 (4H, m) , 1.82 (IH, m) , 1.20 (3H, t, J=7.0), 0.72 (overlapping doublets, 6H, J=6.2). LC/MS 1 peak at 4.76 min. ES+ 497.3 (M+l) .
Example 34
O , N-Ac loxy Rearrangement
Figure imgf000074_0002
LC/MS (ES+) 594 (M+l) 1 peak at 6.96 min. Analytical HPLC (A) t=24.57 min.
IH (DMSO): 8.34 (2H, d, J=8.7), 8.02 (2H, d, J=8.0), 7.19 (5H, m) , 6.98 (IH, d, J=7.2), 5.00 (IH, m) , 3.83 (2H, q) , 3.50 (2H, m) , 3.06 (m, 2H) , 2.96 (2H, m) , 2.43 (IH, m) , 1.97 (IH, m) , 1.02 (3H, t), 0.84 (3H, d) , 0.82 (3H, d) . 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.
Example 35
Figure imgf000075_0001
235 Synthesis of 235 was accomplished analogous to that set forth in Example 1.
Yield 15.2%; tHPLC=25.2 min (A). Rf=0.54 (B) ; ES+ 687.3 (M+l).
IH (CDC13) : 8.34 (overlapping d+d, 4H) , 7.97 (d, 2H, J=8.9), 7.35 (7H, m) , 5.09 (IH, m) , 4.56 (IH, d, J=8.4), 4.20 (IH, m) , 3.54 (IH, m) , 3.00 (3H, m) , 2.82 (IH, m) , 1,84 (IH, m) , 1.37 (9H, s) , 0.84 (3H, d) , 0.82 (3H, d) . Example 36
Figure imgf000076_0001
236
We dissolved 150 mg of 235 in 3 ml of anhydrous dioxane, added 0.35 ml of S (+) -3-OH-THF and 0.14 ml triethyl amine. The mixture was refluxed gently under nitrogen for 2 days. Conversion to 236 was quantitative. Solvents were removed and the compound purified on silica (B) . tHPLC=22.98 min (A); ES+ 636.2 (M+l).
IH MR (CDC13) : 8.29 (2H, d) , 7.91 (2H, d) , 7.22 (5H, m) , 5.13 (IH, m) , 4.96 (IH, m) , 4.52 (IH, d) , 4.02 (IH, m) , 3.84 (2H, m) , 3.44 (IH, m) , 3.36 (IH, m) , 3.10 (3H, m, overlap), 2.88 (2H, m) , 2.64 (IH, m) , 2.14 (IH, m) , 2.05 (IH, m) , 1.84 (IH, m) , 1.27 (9H, s) , 0.78 (6H, two overl . d) .
Example 37 Carbohydrate-Based Prodrugs
197 237
Figure imgf000077_0001
A mixture of 0.54g (1 mMol) of (3S) -Tetrahydro- 3-furfuryl-N- ( (1S,2R) -1-benzyl-2 -hydroxy-3- (N- isobutyl -4- aminobenzenesulfonamido)propyl) carbamate, 0.46g (2 mMol) of 5-dimethyl -tert-butyosilyloxypentanoic acid, 0.346g (1.8mMol) of EDCI and 0.556mL (4 mMol) of triethylamine in 10 ml of dimethyl formamide was stirred at rt for 24h. Another 3 mMol each of acid, EDCI and triethylamine were added and stirring was continued for an additional 96h. A third batch of acid and EDCI was added (3 mMol each) and the mixture was stirred 72h to complete the reaction.
The reaction mixture was then diluted with ethyl acetate and extracted with IN hydrochloric acid, saturated sodium bicarbonate and water. Evaporation of the solvent and purification on silica gel (30% ethyl acetate-hexane) gave the desired product (500mg) as a waxy solid. LCMS: 1 peak, 772.5 (M+Na)
IH NMR (CDCL3) : 0.01 (6H,s), 0.78 (6H,dd), 0.95 (9H,s), 1.4-1.8 (6H,m), 1.9 (2H,m), 2.05 (lH,m), 2.3 (2H,m), 2.65 (lH,m), 2.95 (2H,m), 3.22 (lH,m), 3.4 (lH,m), 3.6 (2H,m), 3.75 (3H,m) , 4.8 (lH,d), 5.1 (lH,bs), 5.2 (lH,bs), 7.2 (5H,m), 7.95 (2H,d), 8.36 (2H,d).
450mg of the 238 was dissolved in 30 ml of tetrahydrofuran and treated with 20 ml of water and 50 ml of acetic acid. The mixture was stirred at rt for 2h and evaporated. Titration with hexane gave the desired alcohol (290mg) as a white solid.
A mixture of 0.15g (0.24 mMol) of the alcohol produced above from the previous reaction, 0.205g (0.5 mMol) of tetraacetylglucosylbromide and 0.191g (0.7 mMol) of silver carbonate in 3 ml of dichloromethane was stirred at rt for 6h. 150mg of additional glucosyl bromide and 150 mg of silver carbonate were added and the mixture was stirred at rt overnight. The mixture was loaded onto a pad of silica gel and eluted with 30% ethylacetate-hexane to afford the desired protected carbohydrate pro-drug as a white foam (200mg) . LCMS: 1 peak, 966 (M+H) .
IH-NMR (CDC13) : 0.78 (6H,dd), 1.9 (2H,m), 2.00 (3H,s)_, 2.02 (3H,s), 2.05 (3H,s), 2.06 (3H,s), 2.1 (2H,m), 2.3 (2H,m), 2.7 (lH,m), 2.94 (3H,bd), 3.35 (2H,m), 3.45 (2H.m), 3.8 (5H,m) , 4.1 (3H,m), 4.5 (lH,d), 4.9 (lH,bs), 4.95 (lH,t,), 5.08 (4H,m), 2H,d), 8.35 (2H,d). Example 38
Figure imgf000079_0001
197 239
1.5 g (9.4 mmol) S03.py complex was added to a stirred solution of 1 g (1.87 mmol) of 197 in 25 mL anhydrous tetrahydrofurane . The mixture was stirred at 20°C for 12 hours, then filtered. The filtrate was concentrated at reduced pressure, and the residue was transferred to a silica gel column and eluted with EtOAc (neat), followed by EtOAc:EtOH (4:1) to obtain 471 mg (47 %) 239 as a colorless foam.
IH-NMR (CDC13) : 0.80 ( , 6H) , 1.8-2.1 (m, 3H) , 4.15 (s(br), IH) , 4.8 (t, IH) , 5.04 (s (br) , IH) . MS(ES-) : 614 (M-l) .
Figure imgf000079_0002
100 mg (0.162 mmol) 239 dissolved in 15 ml anhydrous tetrahydrofuran and 200 mg Pd/BaS04 (5%) was added to the solution. The mixture was stirred under atmospheric pressure of hydrogen for 8 hours, and then the catalyst was filtered. The filtrate was concentrated under reduced pressure then dried under vacuum (-1 Hg mm, 48 hrs.) to produce 80 mg (81 %) 240 as a colorless foam. IH-NMR (DMSO-d6) : 0.85 (dd, 6H) , 0.90 (m, IH) , 2.05 (m, 2H) , 2.58 (m, 3H) , 2.84 (dd, IH) , 3.05 ( , 2H) , 3.55-3.80 (m, 6H) , 4.20 (t, IH) , 4.42 (m, IH) , 4.93 (s(br), IH) , 6.09 (s, 2H) , 6.70 (d, 2H) , 6.80 (d, IH) , 7.15-7.40 (m, 4H) , 7.51 (d, 2H) .
MS(ES-) : 584 (M-l)
Example 39
Figure imgf000080_0001
197 241
780 mg (3 mmol) 2-Chloro-l , 3 , 2-dioxaphospholane was added to a stirred solution of 1.07 g (2 mmol) 197 and 0.7 ml (4 mmol) N,N-Diisopropylethylamine in 25 ml dichloromethane at 0°CT The mixture was allowed to warm up to room temperature and it was stirred for 2 hours. The mixture was then cooled to 0°C and 1.5 g (9.3 mmol) bromine was added in 5 ml dichloromethane. The mixture was stirred for 1 hour at 20°C, followed by evaporation under reduced pressure. An aqueous solution (50%) of 15 ml trimethylamine was added to the residue, and the mixture was stirred at 20 °C for 12 hours.
Solvents were removed under reduced pressure and 50 ml EtOAc : EtOH (9:1) was added to the residue. The solid was filtered, washed with EtOAc: EtOH (9:1) then the filtrate was concentrated under reduced pressure. The residue was chromatographed on a 3 inch plug of silica gel using ethyl acetate (neat) , then methanol (neat) , as eluents to obtain 1.15 g (82 %) 241 as an off-white solid.
IH-NMR (CDC13 ) : 0.60 (dd, 6H) , 1.70 (m, IH) , 1.95 (m, IH) , 2.10 (m, IH) , 2.8-3.2 ( , 6H) , 3.4 (s (br) , 9H) , 5.09 (s(br), IH) , 7.25 (m, 5H) , 7.83 (d, 2H) , 8.28 (d, 2H) . - -
MS(ES+): 701 (M+l), 184 (phosphatidyl choline+) .
Example 40
Figure imgf000081_0001
241 242
250 mg Pd/C (10 %) was added to a solution of 250 mg (0.35 mmol) 241 in 10 ml methanol, and the mixture was stirred under atmospheric pressure of hydrogen for 4 hours at 20°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was then dissolved in 10 ml water and lyophilized to obtain 174 mg (74 %) 242 as white solid. IH-NMR (DMSO-d6) : 0.82 (dd, 6H) , 1.80-2.00 (m, 2H) , 2.10 (m, IH) , 2.80 (m, 3H) , 3.00 (m, 2H) , 3.2 (s (br) , 9H) , 4.0-4.3 (m, 4H) , 4.91 (s(br), IH) , 6.08 (s (br) , 2H) ,
6.67(d, 2H) , 7.30 (m, 5H) , 7.48 (d, 2H) , 8.12 (d, IH) . MS(ES+): 671 (M+l), 184 (phosphatidyl choline+) .
Example 41
Figure imgf000081_0002
243 - -
0.175 ml (2 mmol) phosphorus trichloride was added to a stirred solution of 1.07 g (2 mmol) 197 and 0.35 ml (2 mmol) N,N-Diisopropylethylamine in 25 ml dichloromethane at 20°C. The mixture was stirred for 4 hours at 20°C, then 1 ml water was added and stirred for an additional 12 hours at 20°C. 3 g anhydrous magnesium sulfate was added to the mixture and it was stirred for 30 minutes, then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using EtOAc: Hexane (4:1), then EtOAc: EtOH (1:1), to obtain 402 mg (48%) 226 and 427 mg (36%) 243. 226:
IH-NMR (DMSO-d6) : 0.82 (dd, 6H) , 1.84 (m, IH) , 1.98 (m, IH) , 2.10 (m, IH) , 2.68 (dd, IH) , 2.9-3.2 (m, 4H) , 3.6- 3.8 (m, 3H) , 3.94 (t, IH) , 4.30, (s (br) , IH) , 4.97
(s(br), IH) , 7.30 (m, 5H) , 8.14 (d, 2H) , 8.43 (d, 2H) . MS(ES-) : 598 (M-l) . 243 : (1:1 mix of diastereomers) : IH-NMR (CDC13) : 0.80 (m, 6H) , 1.8-2.1 (m, 4H) , 2.8-3.2 (m, 6H) , 3.7-3.9 (m, 4H) , 4.15 (m, IH) , 4.8-5.15 (m, 2H) ,
5.57, 5.72 ((d,d), IH) , 7.25 (m, 5H) , 7.95 (dd, 2H) , 8.35 (m, 2H) . MS(ES-): 580 (M-l), 598 ((M+H20)-l).
Example 42
Figure imgf000082_0001
243 244
The reduction was carried out as described in Example 40; (Yield: 79%) . IH-NMR (DMSO-d6) : 0.81 (dd, 6H) , 1.82 (m, IH) , 1.95 (m, IH) , 2.08 (m, IH) , 2.6-3.15 (m, 6H) , 3.6-3.75 ( , 3H) , 4.03 (t, IH) , 4.28, (m, IH) , 4.96 (s (br) , IH) , 6.07 (s, 2H) , 6.65 (d, 2H) , 7.25 (m, 5H) , 7.42 (d, 2H) . MS(ES-) : 568 (M-l) .
Example 43
Figure imgf000083_0001
226 245 The reduction was carried out as described in
Example 40; (Yield: 98 %) .
(1:1 mix of diastereomers) :
IH-NMR (DMSO-d6) : 0.82 (m, 6H) , 1.75-2.0 (m, 2H) , 2.05 (m,
IH) , 2.6-3.2 (m, 6H) , 3.55-3.8 (m, 4H) , 4.02, 4.22 (m, t, IH) , 4.75 (m, IH) , 4.90, 5.01 ((d,d), IH) , 6.12 (s, IH) ,
6.68 (d, 2H) , 7.30 (m, 5H) , 7.49 (d, 2H) .
MS(ES-): 550 (M-l), 568 ( (M+H20) -1) .
Example 44 Pharmacokinetics In Sprague-Dawley Rats
Following Single Oral Dose
In order to study the pharmacokinetics of the prodrugs of this invention, we administered single oral doses of a series of prodrugs of this invention, as well as VX-478, to male and female Sprague-Dawley rats. Administration of molar equivalents of a series of prodrugs of this invention in a variety of pharmaceutical vehicles was tested. Separate groups of male and female Sprague- Dawley rats (3/sex/group) received oral doses of compound 229 by oral gavage, in different vehicles at the same dose equivalent (40 mg/kg molar equivalent of VX-478) . The different vehicles for compound 229 were: 1) water; 2) 5/4/1; 3) PEG 400; 4) TPGS/PEG 400; and 5) PEG. The vehicles for VX-478 were: 1) 33% TPGS/PEG400/PEG; and 2) 12.5 % TPGS/PEG 400/PEG.
Blood samples were collected following administration at various time intervals and analyzed for the presence of both compound 229 and its metabolite, VX- 478, by HPLC and MS methods. The results of this study are tabulated below (Table IV) .
TABLE IV
Compound 229 , 229 229 ' 229 VX-478 VX-478
•
: vehicle H20 H20:PG:EtOH ■ PEG 400 TPGS/PEG ; 33% TPGS/ 12.5% TPGS/ ■ 5:4:1 400/PG ; PEG 400/ PG ■ PEG 400/PG j i number of rats 1 3 3 , 3 i 3 ! 6 ! D3 ;
Molar equiv. ι 40 PO 40 PO 40 PO 40 PO 41 PO 50 PO dose/ 478 Dose j (mg/Kg) !
AUC 11.7± 4.8 10.6 ± 7.4 7.4 i 1.8 8.2 ± 1.6 29.6 i 5.8 16.2 ± 1.8 (ug*hr/ml)
Cmax (μM) 7.1± 1.7 ! 3.3 ± 0.6 3.1 ± 0.3 i 3.0 ± 0.7 ■ 14.0 ± 2.2 : 6.0 ± 1.0
: half life (hr) 1.7 3.4 2.8 2.8" 2.5 ± 0.9 2.2 ± 1.0
Relative Avail, of j 395! 35.8t β1.8tt ; 25.θt , 27jt reference reference X-478 '> 90.2tt 57.ltt 63.3tt
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 ).
Represents the harmonic mean t Relative availability of VX-478 when compared to a prototype clinical formulation tt Relative availability of VX-478 when compared to a prototype toxicology formulation We performed a similar study on dogs using both a solid capsule formulation of compound 229 and an ethanolic/methyl cellulose solution formulation, as compared to a TPGS-containing solution formulation of VX- 478. The results from this study are presented below in Table V.
TABLE V
Compound 229 229 VX-478 vehicle solid capsule methyl 22% cellulose in 5% TPGS/PEG EtOH/water 400/PG
. number of dogs 2 , 2 >2
1 Molar equiv. dose/ 478 Dose (mg/Kg) 17 PO 17 PO 17 PO
| AUC 16.7 ± 2.7 . 14.2 ± 3.2 23.5 ± 7.4 (ug*hr/ml)
' Cmax (μg/ml) 6.1± 1.7 6.3 ± 0.3 6.8 ± 1.1 j Tmax (hr) 2.3 ± 0.6 0.5 ± 0.5 1.0 ± 0.8 i Relative Avail, of VX-478 (%) 71.1 . 60.4 reference
The results demonstrate that oral administration of compound 229 as an aqueous solution resulted in improved bioavailability in comparison to the other vehicles studied. Also, following administration of compound 229, none of that compound was detected in the first time point blood sample (or later samples) , suggesting first pass metabolism to VX-478. Comparison of the aqueous dose of compound 229 with the two non- aqueous formulations used for VX-478 indicated equivalence in delivery as illustrated by the range found for the bioavailability. Example 45
Figure imgf000086_0001
197 400
We added 0.28 ml (3.0 mmol) POCl3 to a stirred solution of 1.07 g (2.0 mmol) of compound 197 in 10 ml anhydrous pyridine at 5°C. The mixture was allowed to warm up to room temperature and stirred at 20°C for 3 hours. The mixture was cooled to 0°C, and quenched with 10 ml water. The solvents were removed under reduced pressure, the residue was dissolved in 100 ml ethyl acetate and washed with 20 ml 1M sodium bicarbonate solution. The organic phase was dried with anhydrous magnesium sulfate, filtered then concentrated. Chromatographic purification (Si02, EtOAc) produce 280 mg of compound 400 (Yield = 23%) .
IH-NMR (DMSO-d6) : 0.86 (dd, 6H) , 2.05 (m, 2H) , 2.84 (d, 2H) , 2.95 (dd, 1H) ,3.06 (m, IH) , 3.25 (dd, IH) , 3.50-3.70 (m, 4H) , 4.20 (m, IH) , 4.35 (m, lH) ,7.2-7.4 (m, 5H) , 7.9- 8.1 (m, 2H) , 8.40 (m, 2H) . MS(ES-) : 596 (M-l) .
Figure imgf000086_0002
Compound 400 was converted to compound 401 using the standard hydrogenation method described above employing H2/PdC(10%), atmospheric pressure, 4 hours at room temperature, solvent: MeOH-H20 (5 : 1) . Yeld of 401 = 68%.
IH-NMR (DMSO-d6) : 0.85 (dd, 6H) , 2.0 (m, 2H) , 2.6-3.1 (m, 4H) , 4.15 (m, 1H),4.40 ( , IH) , 6.1 (s (br) , IH) , 6.61 m (2H) , 7.2-7.5 (m, 7H) .
MS (ES - ) : 566 (M- l ) . Example 46
Figure imgf000087_0001
350C n = 2 , R = -C(=NH)NHCbz
218
We added 1.0 g (2.8) mmol Na-t-Boc-nd-Cbz-L- Ornithine was added to stirred solution of 1.2 g (3.15 mmol) HATU, 0.2 g (1.47 mmol) HOAt, 0.4 g (4.0 mmol) NMM inlO ml DMF. The mixture was stirred at room temperature for 2 hrs. then 0.5 g(1.0 mmol) of compound 218 was added and the solution was stirred at 50°C for 12 hours. The mixture was cooled to room temperature, 100 ml ether was added and extracted with 5x 50 ml water. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hexane-EtOAc (1:1) then EtOAc (neat)) to yield 410 mg (48%) of compound 350. Compound 350 A
IH-NMR (CDC13 ) : 0.85 (dd, 6H) , 1.41 (s, 3H) , 1.45 (s, 6H) , 1.60 (m, 4H) , 1.90 (m, 2H) , 2.1 (m, IH) , 2.75-3.25 (m, 6H) , 3.60-3.90 ( , 6H) , 5.15 (dd, 2H), 7.2-7.4 (m, 10H) , 7.68 (dd, 4H) .
MS (ES-) : 852 (M-l) . MS (ES+) : 854 (M+l) .
Compound 350 B IH-NMR (CDC13 ) : 0.81 (dd, 6H) , 1.39 (s, 9H) , 1.40-2.10 (m,
9H) , 2.70-3.20 (m, 8H) , 3.60-3.90 (m, 6H) , 4.10 (m, IH) ,
4.80 (d, IH) , 5.04 (s(br), 2H) , 7.1-7.3 (m, 10H) , 7.61
(s, 4H) .
MS (ES-) : 866 (M-l) . MS (ES+) : 868 (M+l) .
Compound 350 C
IH-NMR (CDC13 ) : 0.86 (dd, 6H) , 1.40 (s, 3H) , 1.46 (s, 6H) , 1.60-2.10 (m, 7H) , 2.70-3.15 (m, 6H) , 3.60 (d, IH) , 3.70- 4.10 (m, 6H) , 4.81 (d, IH) , 5.05-5.30(m, 7H) , 7.18-7.4 (m, 17H) , 7.55 (d, 2H) . MS (FAB+) : 1030 (M+l) , 1052 (M+Na) .
Figure imgf000088_0001
Compounds 350A, 350B and 350C were converted to
Compounds 402 , 403 , and 404 , respectively, using the standard hydrogenation method set forth above: H2/PdC(10%), atmospheric pressure, 4 hours, room temperature, solvent: EtOH, Yield: 81 %.
Compound 402 IH-NMR (CDC13 ) : 0.80 (dd, 6H) , 1.38 (s, 9H) , 1.8 (m, 6H) , 2.10 ( , 2H) , 2.75-3.30 (m, 8H) , 3.50-4.00 (m, 7H) , 4.55 (s(br), IH) , 7.2 (m, 5H) , 7.60 (d, 2H) , 7.81 (d, 2H) . MS (ES+) : 720 (M+l) .
Compound 403
IH-NMR (CDC13) : 0.87 (dd, 6H) , 1.45 (s, 9H) , 1.50-2.00 (m, 8H) , 2.08 (m, IH) , 2.75-3.15 (m, 8H) , 3.60 (d, IH) , 3.75- 3.90 ( , 5H) , 4.28 (s(br), IH) , 4.92 (d, IH) , 5.11 (m, IH) , 5.27 (s(br), IH) , 7.28-7.35 (m, 5H) , 7.70 (s, 4H) . MS (ES+) : 734 (M+l) .
Compound 404
IH-NMR (CDC13 ) : 0.80 (dd, 6H) , 1.32 (s, 9H) , 1.50-2.10 (m, 7H) , 2.60-3.20 (m, 8H) , 3.40-3.80 (m, 5H) , 5.0(s(br) , IH) , 7.05-7.2 (m, 5H) , 7.50-7.80 (m,4H) . MS (ES+) : 762 (M+l) .
Example 47
Figure imgf000089_0001
We added 5 ml TFA to a stirred solution of 260 mg (0.3 mmol) Compound 350A, 350B, or 350C in 20 ml chloroform. The mixture was stirred for 5 hours at room temperature, and then the solvents were removed under reduced pressure. The residue was dissolved in 20 ml dichloromethane, 2 ml (11 mmol) N, N-diisopropylethylamine and 1 ml (10 mmol) acetic anhydride was added to the reaction mixture. The solution was stirred for 1 hour, then the solvents were removed. The residue was purified by silica gel chromatography (eluant: EtOAc-EtOH (9 : 1) ) to obtain 170 mg (71 %) of compound 351A, 351B or 351C, respectively .
Compound 351A
IH-NMR (CDC13 ) : 0.85 (dd, 6H) , 1.60 (m, 3H) , 1.80-2.00 (m, 3H) , 2.06 (2, 3H) , 2.75 (dd, IH) , 2.80-3.20 (m, 5H) , 3.60-3.90 (m, 7H) , 4.85 (d, 2H) , 5.10 (m, 3H) , 6.46 (d, IH) , 7.25 (m, 10H) , 7.67 (s, 4H) , 9.30 (s, IH) . MS (ES+) : 796 (M+l) , 818 (M+Na) .
Compound 351B
IH-NMR (CDC13 ) : 0.80 (dd, 6H) , 1.38 (m, 2H) , 1.50 (m, 2H) ,
1.70 (m, 2H) , 1.85 (m, 2H) , 2.00 (s, 3H) , 2.70 (dd, IH) , 2.75-3.20 (m, 7H) , 3.55 (d, IH) , 3.75 (m, 6H) , 4.45 (q,
IH) , 4.83 (d, IH) , 4.95 (t, IH) , 5.03 (s(br), 3H) , 6.46
(d, IH) , 7.20 (m, 10H) , 7.61 (s, 4H) , 9.29 (s, IH) .
MS (ES+) : 810 (M+l) , 832 (M+Na) .
Compound 351C
IH-NMR (CDC13 ) : 0.85 (dd, 6H) , 1.70-2.00 (m, 6H) , 2.07 (s, 3H) , 2.70 (dd, IH) , 2.80-3.00 (m, 3H) , 3.10 (dd, IH) , 3.60 (d, IH) , 3.65-4.00 (m, 6H) , 4.1(m, IH) , 4.62 (q, IH) , 4.82 (d, IH) , 5.00-5.30 (m, 5H) , 7.10-7.40 (m, 15H),7.55 (d, 2H) , 7.65 (m, 3H) 9.18 (s(br), IH) , 9.45 (s(br), IH) , 9.56(s(br) ,1H) . MS (FAB+) : 972 (M+l) , 994 (M+Na) .
Figure imgf000091_0001
The conversion of compounds 351A, 351C, and 351C to 405 , 406 , and 407 , respectively was achieved by standard hydrogenation using H2/PdC(10%), atmospheric pressure, 4 hours at room temperature, solvent: EtOH, Yield = 46%.
Compound 405
IH-NMR (DMSO-d6) : 0.85 (dd, 6H) , 1.62 (m, 3H) , 1.81 (m, 2H) , 1.94 (s, 3H) , 2.00-2.2 (m, 2H) , 2.75-3.00 (m, 5H) ,
3.10 (m, 2H) , 3.50-3.80 (m, 5H) , 4.54 (m, 1H),5.00 (m,
IH) , 5.11 (d, IH) , 7.2-7.4 (m, 5H) , 7.80-8.00 (m, 5H) ,
10,72 (s, IH) .
MS (ES+) : 662 (M+l) .
Compound 406
IH-NMR (DMSO-d6) : 0.80 (dd, 6H) , 1.30-1.80 (m, 7H) , 1.85
(s, 3H) , 1.95-2.10 (m, 2H) , 2.70 (m, 4H) , 2.99 (m, 2H) ,
3.30 (m, 5H) , 3.40-3.80 (m, 4H) , 4.35 (m, IH) , 4.90 (s, IH) , 5.00 (d, IH) , 7.08-7.25 (m, 5H) , 7.50 (s(br), IH) ,
7.71 (d, 2H) , 7.79 (d, 2H) , 10.54 (s, IH) .
MS (ES+) : 676 (M+l) .
Compound 407 IH-NMR (DMSO-d6) : 0.80 (dd, 6H) , 1.40-1.60 (m, 4H) , 1.75
(m, 2H) , 1.86 (s, 3H) , 2.00 (m, 2H) , 2.75 (dt, 2H) , 3.00
(m, 2H) , 3.10 (q, 2H) , 3.40-3.70 (m, 5H) , 4.39 (q, IH) , 4.92 (s (br) , IH) , 5.01 (d, IH) , 7.20 (m, 5H) , 7.70 (d+m, 3H) , 7.81 (d, 2H) , 8.30 (d, IH) , 10.60 (s, IH) . MS (ES+) : 704 (M+l) .
Example 48
Figure imgf000092_0001
We added 1.0 g (7.5 mmol) methanephosphonyl dichloride to a stirred solution of 2.14 g (4.00 mmol) of compound 197 in 20 ml toluene, containing 10% pyridine. The mixture was stirred at 100°C for 5 hours, then cooled to 40°C, 2 g (18.5 mmol) benzyl alcohol was added to the reaction, and the mixture was stirred at 20°C for 12 hours. The solid was filtered, washed with 2 x 10 ml toluene and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel chromatography (eluants: Hexane-EtOAc (1:1), then EtOAc (neat)) to yield 550 mg (20 %) of compound 352.
IH-NMR (CDC13 ) : 0.67 (dd, 6H) , 1.53 (d, 3H) , 1.70 (m, IH) , 1.90-2.10 (m, 2H) , 2.65-3.20 (m, 6H) , 3.55 (d, IH) , 3.80 ( , 3H) , 4.10 (m, IH) , 4.70 (q, IH) , 4.90-5.20 (m, 4H) , 6.37 (d, IH) , 7.2-7.4 (m, 10H) , 7.90 (d, 2H) , 8,30 (d, 2H) . MS (ES+) : 704 (M+l) , 726 (M+Na) .
Figure imgf000093_0001
352 408
Compound 352 was converted to compound 408 using standard hydrogenation method: H2/PdC(10%), atmospheric pressure, 2 hours, room temperature, solvent: MeOH; Yield: 78%.
IH-NMR (DMSO-d6) : 0.84 (dd, 6H) , 1.44 (d, 3H) , 1.82 (m, IH) , 1.90-2.10 (m, 2H) , 2.62 (m, 2H) , 2.95 (m, 2H) , 3.10 (d, IH) , 3.39 (d, IH) , 3.45-3.80 (m, 4H) , 4.14 (t, IH) , 4.53 (m, IH) , 5.00 (s (br) , IH) , 6.68 (d, 2H) , 7.2-7.4 (m, 5H) , 7.50 (d, 2H) . MS (ES-) : 582 (M-l) . While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments which have been presented by way of example.

Claims

We claim:
A compound of formula I :
Figure imgf000094_0001
wherein:
A is selected from H; Ht ; -R1-Ht; -R1- (Cι-C6) - alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cχ-C4 alkoxy, Ht, -O-Ht, -NR2-CO-N(R2)2 or -CO-N(R2)2; -R1- (C2-C3) - alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, Cx-C4 alkoxy, Ht, -O-Ht, -N(R2) -C(0) -N(R2)2 or -CO-N(R2)2; or R7; each R1 is independently selected from -C(0)-, -S(0)2-, -C(0)-C(0)-, -0-C(0)-, -0-S(0)2, -N(R2) -S(0)2-, -N(R2)-(0)- or -N(R2) -C(0) -C(0) -; each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2) , 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, -OR2, SR2, -R2, -N(R2)2, -R2-OH, -CN, -C(0)0-R2, -C (0) -N (R2) 2 , -S(0)2-N(R2)2, -N(R2)-C(0)-R2, -C(0)-R2, -S(0)n-R2, -0CF3, -S(0)n-Q, methylenedioxy, -N (R2) -S (0) 2-R2, halo, -CF3, -N02, Q, -0Q, -OR7, -SR7, -R7, -N(R2) (R7) or -N(R7)2; each R2 is independently selected from H, or (C1-C4) -alkyl optionally substituted with Q;
B, when present, is -N (R2) -C (R3) 2-C (0) - ; each x is independently 0 or 1 ; each R3 is independently selected from H, Ht , (Cx-Cg) -alkyl, (C2-C6) -alkenyl , (C3-C6) -cycloalkyl or (C5- C6) -cycloalkenyl ; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from -OR2, -C(0)-NH-R2, -S (0) n-N (R2) 2, Ht , -CN, -SR2, -C02R2, N(R2) -C(0) -R2; each n is independently 1 or 2 ;
G, when present, is selected from H, R7 or (Ci- C4) -alkyl, or, when G is (C!-C ) -alkyl , G and R7 are bound to one another either directly or through a Cχ-C3 linker to form a heterocyclic ring; or when G is absent, the atom to which G is attached is bound directly to the R7 group in -OR7 with the concomitant displacement of one -ZM group from R7;
D and D' are independently selected from Q; (Ci- C6) -alkyl, which is optionally substituted with one or more groups selected from (C3-Ce) -cycloalkyl, -OR2, -R3, -0-Q or Q; (C2-C4) -alkenyl , which is optionally substituted with one or more groups selected from (C3-C6) - cycloalkyl, -OR2, -R3, -0-Q or Q; (C3-C6) -cycloalkyl , which is optionally substituted with or fused to Q; or (C5-C6) - 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 0, N, S, S(0)n or N(R2) ; wherein any ring in Q is optionally substituted with one or more groups selected from oxo, -OR2, -R2, -N(R2)2, -N(R2) -C(0) -R2, -R2-OH, -CN, -C(0)OR2, -C(0) -N(R2)2, halo or -CF3;
E is selected from Ht ; O-Ht; Ht-Ht; -0-R3; -N(R2)(R3); (C╬╣-C6) -alkyl, which is optionally substituted with one or more groups selected from R4 or Ht ; (C2-C6) - alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht ; (C3-C6) -saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht ; or (C5-C6) -unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht ; each R4 is independently selected from -OR2, -SR2, -C(0)-NHR2, -S(0)2-NHR2, halo, -N (R2) -C (0) -R2, -N(R2)2 or -CN; each R7 is independently selected from
ZM
-CH„- -Z(M) CH—0 -(R9)χM'
Figure imgf000096_0001
x wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, (C╬╣-C╬╣2) -alkyl , (C2-C12) -alkenyl, or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group, other than the -CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from 0, S, S (0) , S(0)2, or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, N(R2)2, N(R2)3, R20H, -CN, -C(0)0R2, -C (0) -N (R2) 2, S(0)2-N(R2)2, N(R2)-C(0)-R2, C(0)R2, -S(0)n-R2, 0CF3 , -S(0)n- R6, N(R2) -S(0)2-R2, halo, -CF3, or -N02; M' is H, (Ci-C╬╣2) -alkyl, (C2-C12) -alkenyl , or -R6; wherein 1 to 4 -CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from 0, S, S (0) , S(0)2, or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, -OR2, -R2, -N(R2)2, N(R2)3, -R20H, -CN, -C02R2, -C(0)-N(R2)2, -S (0) 2-N (R2) 2 , -N(R2) -C(0)-R2, -C(0)R2, -S(0)n-R2, -0CF3, -S(0)n-R6, -N(R2) -S(0)2-R2, halo, -CF3, or -N02;
Z is CH3, 0, S, N(R2)2, or, when M is not present, H.
Y is P or S;
X is 0 or S; and
R9 is C(R2)2, 0 or N(R2) ; and wherein when Y is S, Z is not S; and
R6 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(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C╬╣-C alkyl, 0- (C╬╣-C4) -alkyl or 0-C (0) - (C╬╣-C ) -alkyl .
2. The compound according to claim 1, wherein at least one R7 is selected from:
Figure imgf000098_0001
O O
.NHAc
(L) -tyrosine, ύ NH ■P03Mg,
O
.NH,
-P03(NH4)2, -CH2-OP03Na2, ' - (L) -serine,
O
-S03Na2, N ΓÇóNMe2, -S03Mg, -S03(NH4)2, e
O
H
N. .NH,
-CH2-OS03Na2, -CH2-OS03(NH4) 2/ ΓûáQ o NH,
O
Figure imgf000098_0002
, _ (L) _valine /
Figure imgf000098_0003
- (L) -glutamic acid, - (L) -aspartic acid,
- (L) -╬│-t-butyl-aspartic acid,
Figure imgf000098_0004
O
- (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, ^CF3
Figure imgf000098_0005
P03K2, P03Ca, P03-spermine, P03- (spermidine) 2 or P03- (meglamine) 2. ΓÇö ΓÇö
3. The compound according to claim 2 , wherein said compound has formula XXII:
Figure imgf000099_0001
wherein A, D' , R7 and E are as defined in claim 1.
4. The compound according to claim 3 , wherein
A is selected from 3-tetrahydrofuryl-O-C (0) - , 3- (1, 5-dioxane) -0-C(0) - , or 3-hydroxy-hexahydrofura [2 , 3-b] - furanyl-O-C(O) -;
D' is (C╬╣-C4) -alkyl which is optionally substituted with one or more groups selected from the group consisting of (C3-C6) -cycloalkyl, -OR2, -R3, -0-Q and Q;
E is (C6-C╬╣o) -aryl optionally substituted with one or more substituents selected from oxo, -OR2, SR2, -R2, - N(R2)2, -R2-OH, -CN, -C(0)0-R2, -C (0) -N (R2) 2 , -S (0) 2-N (R2) 2 , -N(R2) -C(0) -R2, -C(0)-R2, -S(0)n-R2, -0CF3, -S(0)n-Q, ethylenedioxy, -N (R2) -S (0) 2-R2, halo, -CF3, -N02, Q, -0Q, -OR7, -SR7, -R7, -N(R2) (R7) or -N(R7)2; or 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 -CH3, R4, or Ht ; and
Ht, insofar as it is defined as part of R3, is defined as in claim 1 except for the exclusion of heterocycles. ΓÇö o -
5. The compound according to claim 4, wherein:
A is 3-tetrahydrofuryl-0-C(0) -; G is hydrogen; D' is isobutyl;
E is phenyl substituted with N(R7)2; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C╬╣-C4 alkyl or -N(R2)4; and each M' is H or C╬╣-C alkyl.
6. The compound according to claim 3 , wherein:
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 -CH3, R4, or Ht.
7. The compound according to claim 3, wherein:
E is Ht substituted with N(R7)2;
R7 in the -OR7 group shown in formula XXII is -PO(OM)2 or C(0)CH2OCH2CH2OCH2CH2OCH3 and both R7 in the -N(R7)2 substituent of Ht are H; or R7 in -OR7 group shown in formula XXII is C (0) CH2OCH2CH2OCH3, one R7 in the -N(R7)2 substituent of Ht is C (0) CH2OCH2CH2OCH3 and the other R7 in the -N(R7)2 substituent of Ht is H; and wherein M is H, Li, Na, K or C╬╣-C4 alkyl.
8. The compound according to claim 3, having the structure:
Figure imgf000101_0001
wherein each M is Na or K.
9. The compound according to claim 8, wherein each M is Na .
10. The compound according to claim 2, wherein said compound has formula XXIII:
Figure imgf000101_0002
11. The compound according to claim 10, wherein:
R3 is (d-Cs) -alkyl, (C2-C6) -alkenyl , (C5-C6) - cycloalkyl, (C5-C6) -cycloalkenyl , or a 5-6 membered saturated or unsaturated heterocycle; wherein any member of R3 is optionally substituted with one or more substituents selected from the group consisting of -OR2, C(0)-NH-R2, -S(0)nN(R)2, -Ht, -CN, -SR2, -C(0)0-R2 and N(R2) -C(O) -R2; and D' is (C1-C3) -alkyl or C3 alkenyl; wherein D' is optionally substituted with one or more groups selected from (C3-C6) -cycloalkyl, -OR2, -0-Q or Q.
12. The compound according to claim 11, wherein R7 in the -OR7 group depicted in formula XXIII is -P0(0M)2 or -C(O) -M' .
13. The compound according to claim 2, wherein said compound has formula XXXI:
Figure imgf000102_0001
14. The compound according to claim 13, wherein:
A is R^Ht; each R3 is independently (C╬╣-C6) -alkyl which is optionally substituted with -OR2, -C(0)-NH-R2, -S(0)nN(R2)2, -Ht, -CN, -SR2, -C02R2 or -N (R2) -C (0) -R2; and
D' is (C1-C4) -alkyl, which is optionally substituted with (C3-C6) -cycloalkyl, -OR2, -O-Q; and E is Ht, Ht-Ht and -N(R2) (R3) .
15. The compound according to claim 14, wherein R7 in the -OR7 group depicted in formula XXXI is -PO(OM)2 or -C(O) -M' .
16. The compound according to claim 1, wherein said compound is selected from any one of compound numbers 198 to 231, 237 to 242, 245 to 267, or 308, depicted in Table 1; any one of compound numbers 232 to 236 depicted in Table II; or any one of compound numbers 243 to 244 depicted in Table III.
17. A compound selected from:
Figure imgf000103_0001
1001 1002
Figure imgf000103_0002
Figure imgf000104_0001
1006
Figure imgf000104_0002
1007 1008
Figure imgf000104_0003
1009
Figure imgf000105_0001
1010 wherein:
R10 is selected from isopropoyl or cyclopentyl;
R11 is selected from NHR7 or OR7; in compound 1005, when R7 is P03M, (G)x is not H; and x, R7 and G are as defined in claim 1.
18. A pharmaceutical composition, comprising a compound according to any one of claims 1 to 17 in an amount effective to treat infection by a virus that is characterized by an aspartyl protease; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
19. The pharmaceutical composition according to claim 18, wherein said virus is HIV.
20. The pharmaceutical composition according to claim 18, wherein said pharmaceutical composition is formulated for oral administration.
21. The pharmaceutical composition according to claim 18, further comprising one or more agents selected from an anti-viral agent, an HIV protease inhibitor other than a compound according to claim 1, and an immunostimulator .
22. The pharmaceutical composition according to claim 21, further comprising one or more agents selected from zidovudine (AZT) , zalcitabine (ddC) , didanosine (ddl), stavudine (d4T) , 3TC, 935U83, 1592U89, 524W91, saquinavir (Ro 31-8959), L-735,524, SC-52151, ABT 538 (A80538) , AG 1341, XM 412, XM 450, CPG 53,437, or tuscarasol .
23. A method for inhibiting aspartyl protease activity in a mammal, comprising the step of contacting administering to said mammal a pharmaceutical composition according to claim 18.
24. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutical composition according to any one of claim 18.
25. The method according to claim 24, wherein said mammal is additionally administered one or more additional agents selected from an anti-viral agent, an HIV protease inhibitor other than a compound according to claim 1, and an immunostimulator either as a part of a single dosage form with said pharmaceutical composition or as a separate dosage form.
26. The method according to claim 25, wherein said additional agent is selected from zidovudine (AZT) , zalcitabine (ddC) , didanosine (ddl) , stavudine (d4T) , 3TC, 935U83, 1592U89, 524W91, saquinavir (Ro 31-8959), L- -
735,524, SC-52151, ABT 538 (A80538), AG 1341, XM 412, XM 450, CPG 53,437, or tuscarasol.
27. The method according to claim 24, wherein said step of administering comprises oral administration.
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Cited By (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004033A1 (en) * 1998-07-18 2000-01-27 Glaxo Group Limited Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate
WO2001000635A2 (en) * 1999-06-24 2001-01-04 Glaxo Group Limited Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
WO2003048120A2 (en) 2001-11-30 2003-06-12 Osi Pharmaceuticals, Inc. 2-aryl pyrrologpyrimidines for a1 and a3 receptors
WO2003049746A2 (en) * 2001-12-12 2003-06-19 Tibotec Pharmaceuticals Ltd. Combination of cytochome p450 dependent protease inhibitors
US6664252B2 (en) 1999-12-02 2003-12-16 Osi Pharmaceuticals, Inc. 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
US6673802B2 (en) 2000-12-01 2004-01-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US6680324B2 (en) 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6800633B2 (en) 1998-06-02 2004-10-05 Osi Pharmaceuticals, Inc. Pyrrolo[2,3d]pyrimidine compositions and their use
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
WO2005061450A2 (en) * 2003-12-11 2005-07-07 Abbott Laboratories Hiv protease inhibiting sulfonamides
WO2006024488A2 (en) 2004-08-30 2006-03-09 Interstitial Therapeutics Medical stent provided with inhibitors of atp synthesis
WO2006058905A1 (en) 2004-12-01 2006-06-08 Devgen Nv 5-CARBOXAMIDO SUBSTITUTED THIAZOLE DERIVATIVES THAT INTERACT WITH ION CHANNELS, IN PARTICULAR WITH ION CHANNELS FROM THE Kv FAMILY
US7160890B2 (en) 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US7199148B2 (en) 2002-08-14 2007-04-03 Tibotec Pharmaceuticals Ltd Broadspectrum substituted oxindole sulfonamide HIV protease inhibitors
WO2007045496A1 (en) 2005-10-21 2007-04-26 Universiteit Antwerpen Novel urokinase inhibitors
US7244752B2 (en) 2001-04-09 2007-07-17 Tibotec Pharmaceuticals Ltd. Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7417055B2 (en) 2003-04-25 2008-08-26 Gilead Sciences, Inc. Kinase inhibitory phosphonate analogs
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7432272B2 (en) 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7462636B2 (en) 2002-05-17 2008-12-09 Tibotec Pharmaceuticals Ltd Broadspectrum substituted benzisoxazole sulfonamide HIV protease inhibitors
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US7501407B2 (en) 2001-12-20 2009-03-10 Osi Pharmaceuticals, Inc. Pyrimidine A2B selective antagonist compounds, their synthesis and use
WO2009052970A2 (en) 2007-10-26 2009-04-30 Bayer Schering Pharma Aktiengesellschaft Compounds for use in imaging, diagnosing, and/or treatment of diseases of the central nervous system or of tumors
EP2100900A1 (en) 2008-03-07 2009-09-16 Universitätsspital Basel Bombesin analog peptide antagonist conjugates
WO2009112439A1 (en) 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
EP2116236A1 (en) 2008-04-21 2009-11-11 Université de Mons-Hainaut Bisbenzamidine derivatives for use as antioxidant
US7622490B2 (en) 2001-05-11 2009-11-24 Tibotec Pharmaceuticals, Ltd. Broadspecturm 2-amino-benzoxazole sulfonamide HIV protease inhibitors
US7645754B2 (en) 2001-12-20 2010-01-12 Osi Pharmaceuticals, Inc. Pyrrolopyrimidine A2B selective antagonist compounds, their synthesis and use
US7645747B2 (en) 2003-04-25 2010-01-12 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7649015B2 (en) 2002-04-26 2010-01-19 Gilead Sciences, Inc. Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds
US7659404B2 (en) 2001-02-14 2010-02-09 Tibotec Pharmaceuticals Ltd. Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors
EP2165709A3 (en) * 2004-08-02 2010-06-23 Ambrilia Biopharma Inc. Lysine based compounds
US7763641B2 (en) 2001-12-21 2010-07-27 Tibotec Pharmaceuticals Ltd. Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors
US7803836B2 (en) 2005-11-28 2010-09-28 Tibotec Pharmaceuticals Ltd. Aminophenylsulfonamide derivatives as HIV protease inhibitor
EP2279759A2 (en) 2006-09-08 2011-02-02 Bayer Schering Pharma Aktiengesellschaft Compounds and methods for 18F labeled agents
WO2011061295A1 (en) 2009-11-19 2011-05-26 Blue Medical Devices Bv Narrow profile composition-releasing expandable medical balloon catheter
WO2011061590A1 (en) 2009-11-17 2011-05-26 Hetero Research Foundation Novel carboxamide derivatives as hiv inhibitors
US8008297B2 (en) 2004-08-02 2011-08-30 Ambrilia Biopharma Inc. Lysine based compounds
WO2011114212A1 (en) * 2010-03-19 2011-09-22 Lupin Limited Ammonium, calcium and tris salts of fosamprenavir
WO2011141515A1 (en) 2010-05-14 2011-11-17 Bayer Pharma Aktiengesellschaft Diagnostic agents for amyloid beta imaging
US8084494B2 (en) 2005-11-28 2011-12-27 Tibotec Pharmaceuticals Ltd. Substituted aminophenylsulfonamide compounds as HIV protease inhibitor
US8143421B2 (en) 2002-03-12 2012-03-27 Tibotec Pharmaceuticals Ltd. Broadspectrum substituted benzimidazole sulfonamide HIV protease inhibitors
WO2012062847A1 (en) 2010-11-10 2012-05-18 Protea Biopharma N.V. Use of 2',5'-oligoadenylate derivative compounds
US8193227B2 (en) 2003-12-11 2012-06-05 Abbott Laboratories HIV protease inhibiting compounds
EP2460408A1 (en) 2004-12-17 2012-06-06 deVGen N.V. Nematicidal compositions
US8227450B2 (en) 2005-11-30 2012-07-24 Ambrilia Biopharma Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US8318731B2 (en) 2007-07-27 2012-11-27 Janssen Pharmaceutica Nv Pyrrolopyrimidines
US8410300B2 (en) 2006-09-21 2013-04-02 Taimed Biologics, Inc. Protease inhibitors
US8492377B2 (en) 2006-07-13 2013-07-23 Janssen Pharmaceutica Nv MTKI quinazoline derivatives
US8557854B2 (en) 2005-04-15 2013-10-15 Janssen R&D Ireland Use of a sulfonamide compound for improving the pharmacokinetics of a drug
EP2700396A2 (en) 2012-06-20 2014-02-26 Sylphar Nv Strip for the delivery of oral care compositions
US8691224B2 (en) 2005-11-30 2014-04-08 Abbvie Inc. Anti-Aβ globulomer 5F7 antibodies
US8772272B2 (en) 2003-12-18 2014-07-08 Janssen Pharmaceutica Nv Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents
US8785648B1 (en) 2010-08-10 2014-07-22 The Regents Of The University Of California PKC-epsilon inhibitors
US8877190B2 (en) 2006-11-30 2014-11-04 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US8895004B2 (en) 2007-02-27 2014-11-25 AbbVie Deutschland GmbH & Co. KG Method for the treatment of amyloidoses
US8951986B2 (en) 2008-07-08 2015-02-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US8987419B2 (en) 2010-04-15 2015-03-24 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9107956B2 (en) 2007-03-12 2015-08-18 Nektar Therapeutics Oligomer-protease inhibitor conjugates
US9176150B2 (en) 2003-01-31 2015-11-03 AbbVie Deutschland GmbH & Co. KG Amyloid beta(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US9227990B2 (en) 2012-10-29 2016-01-05 Cipla Limited Antiviral phosphonate analogues and process for preparation thereof
WO2016003450A1 (en) 2014-07-01 2016-01-07 The Regents Of The University Of California Pkc-epsilon inhibitors
WO2016083490A1 (en) 2014-11-27 2016-06-02 Remynd Nv Compounds for the treatment of amyloid-associated diseases
US9457035B2 (en) 2004-07-27 2016-10-04 Gilead Sciences, Inc. Antiviral compounds
WO2016176437A1 (en) 2015-04-28 2016-11-03 Newsouth Innovations Pty Limited Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity
US9688691B2 (en) 2004-12-08 2017-06-27 Janssen Pharmaceutica Nv Macrocyclic quinazole derivatives and their use as MTKI
US9877981B2 (en) 2012-10-09 2018-01-30 President And Fellows Of Harvard College NAD biosynthesis and precursors for the treatment and prevention of cancer and proliferation
WO2018206760A1 (en) 2017-05-11 2018-11-15 Remynd N.V. Compounds for the treatment of epilepsy, neurodegenerative disorders and other cns disorders
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
WO2021170600A1 (en) 2020-02-24 2021-09-02 Katholieke Universiteit Leuven Pyrrolopyridine and imidazopyridine antiviral compounds
WO2021209563A1 (en) 2020-04-16 2021-10-21 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
WO2022136486A1 (en) 2020-12-22 2022-06-30 Luxembourg Institute Of Health (Lih) Conolidine analogues as selective ackr3 modulators for the treatment of cancer and cardiovascular diseases
WO2022184898A1 (en) 2021-03-04 2022-09-09 Universiteit Antwerpen Quinazolin-4-one and thieno[2,3-d]pyrimidin-4-one inhibitors of erbb4 (her4) for use in the treatment of cancer
WO2022253785A2 (en) 2021-05-31 2022-12-08 Universität Heidelberg Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof
WO2023021132A1 (en) 2021-08-18 2023-02-23 Katholieke Universiteit Leuven 6-substituted- and 6,7-disubstituted-7-deazapurine ribonucleoside analogues
WO2023046900A1 (en) 2021-09-23 2023-03-30 Katholieke Universiteit Leuven Ribonucleoside analogues against -sars-cov-2
WO2023241799A1 (en) 2022-06-15 2023-12-21 Université Libre de Bruxelles Flavanols for use in the treatment of retroviral infections
WO2024062043A1 (en) 2022-09-21 2024-03-28 Universiteit Antwerpen Substituted phenothiazines as ferroptosis inhibitors

Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040122000A1 (en) * 1981-01-07 2004-06-24 Vertex Pharmaceuticals Incorporated. Inhibitors of aspartyl protease
UA59384C2 (en) * 1996-12-20 2003-09-15 Пфайзер, Інк. Preventing bone mass loss and recovery thereof by means of prostaglandin agonists
US6436989B1 (en) * 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
AU6329599A (en) * 1998-09-28 2000-04-17 Glaxo Group Limited Antiviral combinations comprising (s)-2-ethyl -7-fluoro -3-oxo-3, 4-dihydro -2h-quinoxaline -1-carboxylic acid isopropyl ester
US7576084B2 (en) * 2001-10-12 2009-08-18 Choongwae Pharma Corporation Reverse-turn mimetics and method relating thereto
US7157489B2 (en) * 2002-03-12 2007-01-02 The Board Of Trustees Of The University Of Illinois HIV protease inhibitors
CA2425031A1 (en) * 2003-04-01 2004-10-01 Smithkline Beecham Corporation Pharmaceutical compositions
US20050137174A1 (en) * 2003-07-09 2005-06-23 Paratek Pharmaceuticals, Inc. Prodrugs of 9-aminomethyl tetracycline compounds
US20050143352A1 (en) 2003-07-09 2005-06-30 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US20050119163A1 (en) 2003-09-18 2005-06-02 The Government Of The United States Of America, As Represented By The Secretary, SH2 domain binding inhibitors
US7834043B2 (en) * 2003-12-11 2010-11-16 Abbott Laboratories HIV protease inhibiting compounds
AU2004299040A1 (en) * 2003-12-15 2005-06-30 Pharmacopeia, Inc. Heterocyclic aspartyl protease inhibitors
JP5142714B2 (en) 2004-07-06 2013-02-13 アボット・ラボラトリーズ Prodrugs of HIV protease inhibitors
EP2161275A1 (en) * 2005-01-19 2010-03-10 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
JP2008533017A (en) * 2005-03-11 2008-08-21 スミスクライン ビーチャム コーポレーション HIV protease inhibitor
US20060287316A1 (en) * 2005-04-27 2006-12-21 Ambrilia Biopharma Inc. Method for improving pharmacokinetics of protease inhibitors and protease inhibitor precursors
ES2533007T3 (en) * 2005-12-27 2015-04-06 Otsuka Pharmaceutical Co., Ltd. Water soluble benzoacepin compound and its pharmaceutical composition
EP2262538B1 (en) * 2008-03-12 2014-12-10 Nektar Therapeutics Oligomer-amino acid conjugate
NZ612380A (en) 2008-12-09 2015-01-30 Gilead Sciences Inc Modulators of toll-like receptors
WO2010134045A1 (en) * 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Amorphous fosamprenavir calcium
EP2440249A2 (en) 2009-06-12 2012-04-18 Nektar Therapeutics Covalent conjugates comprising a protease inhibitor, a water-soluble, non-peptidic oligomer and a lipophilic moiety
EP2477996A1 (en) 2009-09-16 2012-07-25 Ranbaxy Laboratories Limited Process for the preparation of fosamprenavir calcium
EP2507250A1 (en) 2010-01-07 2012-10-10 Pliva Hrvastka D.O.O. Solid state forms of fosamprenavir calcium salt and process for preparation thereof
EA202190473A3 (en) 2010-01-27 2021-12-31 Вайв Хелткер Компани ANTIVIRAL THERAPY
US20110223131A1 (en) 2010-02-24 2011-09-15 Gilead Sciences, Inc. Antiviral compounds
US20110224443A1 (en) * 2010-03-15 2011-09-15 Venkata Naga Brahmeshwara Rao Mandava Preparation of fosamprenavir calcium
WO2011158259A1 (en) 2010-06-18 2011-12-22 Matrix Laboratories Ltd Novel process for the preparation of (3s)-tetrahydrofuran-3-yl (is, 2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-(phosphonooxy) propylcarbamate and its pharmaceutically acceptable salts thereof
WO2012032389A2 (en) 2010-09-10 2012-03-15 Lupin Limited Process for preparation of substantially pure fosamprenavir calcium and its intermediates
WO2012085625A1 (en) 2010-12-21 2012-06-28 Lupin Limited Process for the preparation of fosamprenavir calcium and intermediate used in its preparation
WO2012107937A2 (en) * 2011-02-10 2012-08-16 Mylan Laboratories Ltd Crystalline fosamprenavir calcium and process for the preparation thereof"
SG10201800715PA (en) 2011-06-21 2018-02-27 Alnylam Pharmaceuticals Inc Angiopoietin-like 3 (angptl3) irna compostions and methods of use thereof
US20140235693A1 (en) 2011-06-23 2014-08-21 Alnylam Pharmaceuticals, Inc. Serpina1 sirnas: compositions of matter and methods of treatment
US9309213B2 (en) 2011-07-11 2016-04-12 Purdue Research Foundation C-3 substituted bicyclooctane based HIV protease inhibitors
WO2013011485A1 (en) 2011-07-20 2013-01-24 Ranbaxy Laboratories Limited Process for the preparation of sulfonamides useful as retroviral protease inhibitors
IN2012DE00082A (en) 2012-01-10 2015-05-01 Council Scient Ind Res
US9127274B2 (en) 2012-04-26 2015-09-08 Alnylam Pharmaceuticals, Inc. Serpinc1 iRNA compositions and methods of use thereof
JP6574383B2 (en) 2012-12-05 2019-09-11 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． PCSK9 iRNA composition and method of use thereof
KR20230162998A (en) 2013-03-14 2023-11-29 알닐람 파마슈티칼스 인코포레이티드 Complement component c5 irna compositions and methods of use thereof
KR102365809B1 (en) 2013-05-22 2022-02-23 알닐람 파마슈티칼스 인코포레이티드 Tmprss6 compositions and methods of use thereof
HUE038146T2 (en) 2013-05-22 2018-09-28 Alnylam Pharmaceuticals Inc Serpina1 irna compositions and methods of use thereof
AU2014362262B2 (en) 2013-12-12 2021-05-13 Alnylam Pharmaceuticals, Inc. Complement component iRNA compositions and methods of use thereof
CA2938857A1 (en) 2014-02-11 2015-08-20 Alnylam Pharmaceuticals, Inc. Ketohexokinase (khk) irna compositions and methods of use thereof
WO2015175510A1 (en) 2014-05-12 2015-11-19 Alnylam Pharmaceuticals, Inc. Methods and compositions for treating a serpinc1-associated disorder
JP6811094B2 (en) 2014-05-22 2021-01-13 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Angiotensinogen (AGT) iRNA composition and its use
WO2016001907A1 (en) 2014-07-02 2016-01-07 Prendergast Patrick T Mogroside iv and mogroside v as agonist/stimulator/un-blocking agent for toll-like receptor 4 and adjuvant for use in human/animal vaccine and to stimulate immunity against disease agents.
KR102019572B1 (en) 2014-07-11 2019-09-06 길리애드 사이언시즈, 인코포레이티드 Modulators of toll-like receptors for the treatment of hiv
WO2016040589A1 (en) 2014-09-12 2016-03-17 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting complement component c5 and methods of use thereof
WO2016061487A1 (en) 2014-10-17 2016-04-21 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting aminolevulinic acid synthase-1 (alas1) and uses thereof
US9738664B2 (en) 2014-10-29 2017-08-22 Wisconsin Alumni Research Foundation Boronic acid inhibitors of HIV protease
WO2016069694A2 (en) 2014-10-30 2016-05-06 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof
CN113846101A (en) 2014-11-17 2021-12-28 阿尔尼拉姆医药品有限公司 Apolipoprotein C3(APOC3) iRNA compositions and methods of use thereof
WO2016130806A2 (en) 2015-02-13 2016-08-18 Alnylam Pharmaceuticals, Inc. Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof
MX2017013102A (en) 2015-04-13 2018-02-23 Alnylam Pharmaceuticals Inc Angiopoietin-like 3 (angptl3) irna compositions and methods of use thereof.
WO2016179342A2 (en) 2015-05-06 2016-11-10 Alnylam Pharmaceuticals, Inc. Factor xii (hageman factor) (f12), kallikrein b, plasma (fletcher factor) 1 (klkb1), and kininogen 1 (kng1) irna compositions and methods of use thereof
WO2016205323A1 (en) 2015-06-18 2016-12-22 Alnylam Pharmaceuticals, Inc. Polynucleotde agents targeting hydroxyacid oxidase (glycolate oxidase, hao1) and methods of use thereof
EP3350328A1 (en) 2015-09-14 2018-07-25 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting patatin-like phospholipase domain containing 3 (pnpla3) and methods of use thereof
US20170071944A1 (en) 2015-09-15 2017-03-16 Gilead Sciences, Inc. Modulators of toll-like receptors for the treatment of hiv
BR112018011450A2 (en) 2015-12-07 2018-11-27 Genzyme Corp methods and compositions for treating a serpinc1-associated disorder
WO2017100542A1 (en) 2015-12-10 2017-06-15 Alnylam Pharmaceuticals, Inc. Sterol regulatory element binding protein (srebp) chaperone (scap) irna compositions and methods of use thereof
JP2019518028A (en) 2016-06-10 2019-06-27 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Complement component C5i RNA composition and its use for treating paroxysmal nocturnal hemoglobinuria (PNH)
TW202313978A (en) 2016-11-23 2023-04-01 美商阿尼拉製藥公司 Serpina1 irna compositions and methods of use thereof
EP3555292A1 (en) 2016-12-16 2019-10-23 Alnylam Pharmaceuticals, Inc. Methods for treating or preventing ttr-associated diseases using transthyretin (ttr) irna compositions
WO2019016732A1 (en) 2017-07-21 2019-01-24 Viiv Healthcare Company Regimens for treating hib infections and aids
US11866701B2 (en) 2017-11-01 2024-01-09 Alnylam Pharmaceuticals, Inc. Complement component C3 iRNA compositions and methods of use thereof
AR114551A1 (en) 2018-08-13 2020-09-16 Alnylam Pharmaceuticals Inc COMPOSITIONS OF hdRNA AGENTS AGAINST HEPATITIS B VIRUS (HBV) AND METHODS FOR THEIR USE
CN113557023A (en) 2019-01-16 2021-10-26 建新公司 Serpinc1 iRNA compositions and methods of use thereof
WO2021154941A1 (en) 2020-01-31 2021-08-05 Alnylam Pharmaceuticals, Inc. Complement component c5 irna compositions for use in the treatment of amyotrophic lateral sclerosis (als)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005639A1 (en) * 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3743722A (en) 1971-07-14 1973-07-03 Abbott Lab Anti-coagulant isolation
FR2459235A1 (en) 1979-06-14 1981-01-09 Sanofi Sa NOVEL SULFONYL-ANILINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
JPS5946252A (en) 1982-09-09 1984-03-15 Dainippon Ink & Chem Inc Fluorine-containing aminocarboxylate and its preparation
JPS5948449A (en) 1982-09-13 1984-03-19 Dainippon Ink & Chem Inc Straight-chain fluorine-containing anionic compound and its preparation
JPS6171830A (en) 1984-09-17 1986-04-12 Dainippon Ink & Chem Inc Cationic surfactant
US4616088A (en) 1984-10-29 1986-10-07 E. R. Squibb & Sons, Inc. Amino acid ester and amide renin inhibitor
US4629724A (en) 1984-12-03 1986-12-16 E. R. Squibb & Sons, Inc. Amino acid ester and amide renin inhibitors
DE3635907A1 (en) 1986-10-22 1988-04-28 Merck Patent Gmbh HYDROXY AMINO ACID DERIVATIVES
CH676988A5 (en) 1987-01-21 1991-03-28 Sandoz Ag
CA1340588C (en) 1988-06-13 1999-06-08 Balraj Krishan Handa Amino acid derivatives
IL91780A (en) 1988-10-04 1995-08-31 Abbott Lab Renin inhibiting hexanoic acid amide derivatives, process for their preparation and pharmaceutical compositions containing them
WO1990007329A1 (en) 1989-01-06 1990-07-12 The Regents Of The University Of California Selection method for pharmacologically active compounds
US5151438A (en) 1989-05-23 1992-09-29 Abbott Laboratories Retroviral protease inhibiting compounds
US5354866A (en) * 1989-05-23 1994-10-11 Abbott Laboratories Retroviral protease inhibiting compounds
IE902295A1 (en) 1989-07-07 1991-01-16 Abbott Lab Amino acid analog cck antagonists
GB8927913D0 (en) * 1989-12-11 1990-02-14 Hoffmann La Roche Amino acid derivatives
HUT64738A (en) 1990-06-01 1994-02-28 Du Pont Merck Pharma Process for preparing 1,4-diamino-2,3-dihydroxi-butane compounds and pharmaceutical compositions contianing them
TW225540B (en) 1990-06-28 1994-06-21 Shionogi & Co
ES2059289T3 (en) 1990-11-19 1997-10-16 Monsanto Co RETROVIRAL PROTEASE INHIBITORS.
EP0558673B1 (en) 1990-11-19 1996-04-17 Monsanto Company Retroviral protease inhibitors
ES2059294T3 (en) 1990-11-19 1997-04-01 Monsanto Co RETROVIRIC PROTEASES INHIBITORS.
JPH06505963A (en) 1990-11-19 1994-07-07 モンサント　カンパニー Retroviral protease inhibitors
IE913840A1 (en) 1990-11-20 1992-05-20 Abbott Lab Retroviral protease inhibiting compounds
CA2195027C (en) 1991-11-08 2000-01-11 Joseph P. Vacca Hiv protease inhibitors useful for the treatment of aids
AU676479B2 (en) 1992-05-20 1997-03-13 G.D. Searle & Co. Method for making intermediates useful in synthesis of retroviral protease inhibitors
CA2136312A1 (en) 1992-05-21 1993-11-25 Michael Clare Retroviral protease inhibitors
WO1994004491A1 (en) 1992-08-25 1994-03-03 G.D. Searle & Co. N-(alkanoylamino-2-hydroxypropyl)-sulfonamides useful as retroviral protease inhibitors
ATE218541T1 (en) 1992-08-25 2002-06-15 Searle & Co HYDROXYETHYLAMINOSULFONAMIDES USABLE AS INHIBITORS OF RETROVIRAL PROTEASES
ATE161828T1 (en) 1992-08-25 1998-01-15 Searle & Co SULFONYLALKANOYLAMINOHYDROXYETHYLAMINOSULFONAMI E USABLE AS RETROVIRAL PROTEASE INHIBITORS
ES2137998T3 (en) * 1992-09-03 2000-01-01 Boehringer Ingelheim Pharma NEW AMINO ACID DERIVATIVES, PROCEDURE FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINED IN THESE COMPOUNDS.
US5783701A (en) 1992-09-08 1998-07-21 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US5723490A (en) * 1992-09-08 1998-03-03 Vertex Pharmaceuticals Incorporated THF-containing sulfonamide inhibitors of aspartyl protease
TW372972B (en) 1992-10-23 1999-11-01 Novartis Ag Antiretroviral acyl compounds
EP0885881B1 (en) 1992-10-30 2003-03-12 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfamic acids useful as retroviral protease inhibitors
ES2170305T3 (en) 1992-10-30 2002-08-01 Searle & Co HYDROXYETHYLAMINOSULPHAMIC ACID DERIVATIVES N-SUBSTITUTES USEFUL AS INHIBITORS OF RETROVIRIC PROTEASES.
US5484926A (en) 1993-10-07 1996-01-16 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
WO1994018192A1 (en) 1993-02-12 1994-08-18 Merck & Co., Inc. Piperazine derivatives as hiv protease inhibitors
JP3419539B2 (en) 1993-02-17 2003-06-23 中外製薬株式会社 Indoline-2-one derivatives
DE69415326T2 (en) 1993-08-24 1999-06-02 Searle & Co HYDROXYAMINOSULPHONAMIDES USED AS INHIBITORS OF RETROVIRAL PROTEASES
IL110898A0 (en) 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
IL111584A0 (en) 1993-11-18 1995-01-24 Merck & Co Inc Prodrugs of an inhibitor of hiv protease and pharmaceutical compositions containing them
US5527829A (en) 1994-05-23 1996-06-18 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
DE19506742A1 (en) 1995-02-27 1996-08-29 Bayer Ag Use of quinoxalines in combination with protease inhibitors as medicaments for the treatment of AIDS and / or HIV infections
US5691372A (en) 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
US5750493A (en) 1995-08-30 1998-05-12 Raymond F. Schinazi Method to improve the biological and antiviral activity of protease inhibitors
US5646180A (en) 1995-12-05 1997-07-08 Vertex Pharmaceuticals Incorporated Treatment of the CNS effects of HIV
US6180634B1 (en) 1997-11-13 2001-01-30 Merck & Co., Inc. Combination therapy for the treatment of AIDS
CN1110492C (en) * 1997-12-24 2003-06-04 沃泰克斯药物股份有限公司 Prodrugs of aspartyl protease inhibitors
US6436989B1 (en) * 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
CO5261510A1 (en) * 1999-02-12 2003-03-31 Vertex Pharma ASPARTIL PROTEASA INHIBITORS

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005639A1 (en) * 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease

Cited By (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US7429574B2 (en) 1998-06-02 2008-09-30 Osi Pharmaceuticals, Inc. 4-heterocyclo-pyrrolo[2,3d] pyrimidine compositions and their use
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
US6800633B2 (en) 1998-06-02 2004-10-05 Osi Pharmaceuticals, Inc. Pyrrolo[2,3d]pyrimidine compositions and their use
EP1240903A2 (en) * 1998-07-18 2002-09-18 Glaxo Group Limited Combination of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate with ritonavir
EP1240903A3 (en) * 1998-07-18 2003-02-12 Glaxo Group Limited Combination of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3- [[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate with ritonavir
WO2000004033A1 (en) * 1998-07-18 2000-01-27 Glaxo Group Limited Calcium (3s) tetrahydro-3-furanyl(1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcarbamate
WO2001000635A2 (en) * 1999-06-24 2001-01-04 Glaxo Group Limited Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
WO2001000635A3 (en) * 1999-06-24 2003-04-17 Glaxo Group Ltd Derivatives of (3s) tetrahydro-3-furanyl (1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
US7160890B2 (en) 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6664252B2 (en) 1999-12-02 2003-12-16 Osi Pharmaceuticals, Inc. 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US7598252B2 (en) 2000-12-01 2009-10-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A, receptors and uses thereof
US6680324B2 (en) 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US6673802B2 (en) 2000-12-01 2004-01-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US7659404B2 (en) 2001-02-14 2010-02-09 Tibotec Pharmaceuticals Ltd. Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors
US7595334B2 (en) 2001-04-09 2009-09-29 Tibotec Pharmaceuticals Ltd. Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors
US7244752B2 (en) 2001-04-09 2007-07-17 Tibotec Pharmaceuticals Ltd. Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors
US7622490B2 (en) 2001-05-11 2009-11-24 Tibotec Pharmaceuticals, Ltd. Broadspecturm 2-amino-benzoxazole sulfonamide HIV protease inhibitors
US7863306B2 (en) 2001-05-11 2011-01-04 Tibotec Pharmaceuticals Ltd Broadspectrum 2-amino-benzoxazole sulfonamide HIV protease inhibitors
WO2003048120A2 (en) 2001-11-30 2003-06-12 Osi Pharmaceuticals, Inc. 2-aryl pyrrologpyrimidines for a1 and a3 receptors
EP2050751A1 (en) 2001-11-30 2009-04-22 OSI Pharmaceuticals, Inc. Compounds specific to adenosine A1 and A3 receptors and uses thereof
US7504407B2 (en) 2001-11-30 2009-03-17 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 and A3 receptors and uses thereof
WO2003049746A3 (en) * 2001-12-12 2003-12-31 Tibotec Pharm Ltd Combination of cytochome p450 dependent protease inhibitors
WO2003049746A2 (en) * 2001-12-12 2003-06-19 Tibotec Pharmaceuticals Ltd. Combination of cytochome p450 dependent protease inhibitors
US7501407B2 (en) 2001-12-20 2009-03-10 Osi Pharmaceuticals, Inc. Pyrimidine A2B selective antagonist compounds, their synthesis and use
US7645754B2 (en) 2001-12-20 2010-01-12 Osi Pharmaceuticals, Inc. Pyrrolopyrimidine A2B selective antagonist compounds, their synthesis and use
US7763641B2 (en) 2001-12-21 2010-07-27 Tibotec Pharmaceuticals Ltd. Broadspectrum heterocyclic substituted phenyl containing sulfonamide HIV protease inhibitors
US8143421B2 (en) 2002-03-12 2012-03-27 Tibotec Pharmaceuticals Ltd. Broadspectrum substituted benzimidazole sulfonamide HIV protease inhibitors
US7649015B2 (en) 2002-04-26 2010-01-19 Gilead Sciences, Inc. Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds
US7462636B2 (en) 2002-05-17 2008-12-09 Tibotec Pharmaceuticals Ltd Broadspectrum substituted benzisoxazole sulfonamide HIV protease inhibitors
US7199148B2 (en) 2002-08-14 2007-04-03 Tibotec Pharmaceuticals Ltd Broadspectrum substituted oxindole sulfonamide HIV protease inhibitors
US9176150B2 (en) 2003-01-31 2015-11-03 AbbVie Deutschland GmbH & Co. KG Amyloid beta(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US8022083B2 (en) 2003-04-25 2011-09-20 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7645747B2 (en) 2003-04-25 2010-01-12 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7417055B2 (en) 2003-04-25 2008-08-26 Gilead Sciences, Inc. Kinase inhibitory phosphonate analogs
US7452901B2 (en) 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US9139604B2 (en) 2003-04-25 2015-09-22 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US8871785B2 (en) 2003-04-25 2014-10-28 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
EP2216334A1 (en) * 2003-12-11 2010-08-11 Abbott Laboratories Hiv protease inhibiting sulfonamides
EP2264032A3 (en) * 2003-12-11 2011-03-23 Abbott Laboratories Hiv protease inhibiting sulfonamides
WO2005061450A2 (en) * 2003-12-11 2005-07-07 Abbott Laboratories Hiv protease inhibiting sulfonamides
WO2005061450A3 (en) * 2003-12-11 2005-10-20 Abbott Lab Hiv protease inhibiting sulfonamides
US8193227B2 (en) 2003-12-11 2012-06-05 Abbott Laboratories HIV protease inhibiting compounds
US8653141B2 (en) 2003-12-11 2014-02-18 Abbvie Inc. HIV protease inhibiting compounds
US8772272B2 (en) 2003-12-18 2014-07-08 Janssen Pharmaceutica Nv Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents
US8933067B2 (en) 2003-12-18 2015-01-13 Janssen Pharmaceutica Nv Pyrido and pyrimidopyrimidine derivatives as anti-profilerative agents
US7432272B2 (en) 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
US9457035B2 (en) 2004-07-27 2016-10-04 Gilead Sciences, Inc. Antiviral compounds
US9579332B2 (en) 2004-07-27 2017-02-28 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
US8008297B2 (en) 2004-08-02 2011-08-30 Ambrilia Biopharma Inc. Lysine based compounds
EP2165709A3 (en) * 2004-08-02 2010-06-23 Ambrilia Biopharma Inc. Lysine based compounds
WO2006024488A2 (en) 2004-08-30 2006-03-09 Interstitial Therapeutics Medical stent provided with inhibitors of atp synthesis
WO2006058905A1 (en) 2004-12-01 2006-06-08 Devgen Nv 5-CARBOXAMIDO SUBSTITUTED THIAZOLE DERIVATIVES THAT INTERACT WITH ION CHANNELS, IN PARTICULAR WITH ION CHANNELS FROM THE Kv FAMILY
US10208062B2 (en) 2004-12-08 2019-02-19 Janssen Pharmaceutica Nv Macrocyclic quinazole derivatives and their use as MTKI
US9688691B2 (en) 2004-12-08 2017-06-27 Janssen Pharmaceutica Nv Macrocyclic quinazole derivatives and their use as MTKI
EP2460408A1 (en) 2004-12-17 2012-06-06 deVGen N.V. Nematicidal compositions
US8557854B2 (en) 2005-04-15 2013-10-15 Janssen R&D Ireland Use of a sulfonamide compound for improving the pharmacokinetics of a drug
WO2007045496A1 (en) 2005-10-21 2007-04-26 Universiteit Antwerpen Novel urokinase inhibitors
US8084494B2 (en) 2005-11-28 2011-12-27 Tibotec Pharmaceuticals Ltd. Substituted aminophenylsulfonamide compounds as HIV protease inhibitor
US7803836B2 (en) 2005-11-28 2010-09-28 Tibotec Pharmaceuticals Ltd. Aminophenylsulfonamide derivatives as HIV protease inhibitor
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US8691224B2 (en) 2005-11-30 2014-04-08 Abbvie Inc. Anti-Aβ globulomer 5F7 antibodies
US8227450B2 (en) 2005-11-30 2012-07-24 Ambrilia Biopharma Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies
US9540432B2 (en) 2005-11-30 2017-01-10 AbbVie Deutschland GmbH & Co. KG Anti-Aβ globulomer 7C6 antibodies
US8580995B2 (en) 2005-11-30 2013-11-12 Taimed Biologics, Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
US10323084B2 (en) 2005-11-30 2019-06-18 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US8492377B2 (en) 2006-07-13 2013-07-23 Janssen Pharmaceutica Nv MTKI quinazoline derivatives
EP2289564A2 (en) 2006-09-08 2011-03-02 Bayer Schering Pharma Aktiengesellschaft Derivatives of aniline as precursors for F18-labeling
EP2455105A2 (en) 2006-09-08 2012-05-23 Bayer Pharma Aktiengesellschaft Bombesin analogues
EP3056509A1 (en) 2006-09-08 2016-08-17 Piramal Imaging SA Bombesin analogues for use in diagnosis
EP2279759A2 (en) 2006-09-08 2011-02-02 Bayer Schering Pharma Aktiengesellschaft Compounds and methods for 18F labeled agents
US8742158B2 (en) 2006-09-21 2014-06-03 TaiMed Biologies, Inc. Protease inhibitors
US8410300B2 (en) 2006-09-21 2013-04-02 Taimed Biologics, Inc. Protease inhibitors
US9394360B2 (en) 2006-11-30 2016-07-19 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US9359430B2 (en) 2006-11-30 2016-06-07 Abbvie Inc. Abeta conformer selective anti-Abeta globulomer monoclonal antibodies
US9951125B2 (en) 2006-11-30 2018-04-24 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US8877190B2 (en) 2006-11-30 2014-11-04 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US8895004B2 (en) 2007-02-27 2014-11-25 AbbVie Deutschland GmbH & Co. KG Method for the treatment of amyloidoses
US9107956B2 (en) 2007-03-12 2015-08-18 Nektar Therapeutics Oligomer-protease inhibitor conjugates
US8318731B2 (en) 2007-07-27 2012-11-27 Janssen Pharmaceutica Nv Pyrrolopyrimidines
EP2374779A1 (en) 2007-10-26 2011-10-12 Bayer Pharma Aktiengesellschaft Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
EP2388245A1 (en) 2007-10-26 2011-11-23 Bayer Pharma AG Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors
WO2009052970A2 (en) 2007-10-26 2009-04-30 Bayer Schering Pharma Aktiengesellschaft Compounds for use in imaging, diagnosing, and/or treatment of diseases of the central nervous system or of tumors
EP2100900A1 (en) 2008-03-07 2009-09-16 Universitätsspital Basel Bombesin analog peptide antagonist conjugates
WO2009112439A1 (en) 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
US8609836B2 (en) 2008-03-10 2013-12-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines
US8318929B2 (en) 2008-03-10 2012-11-27 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines
EP2116236A1 (en) 2008-04-21 2009-11-11 Université de Mons-Hainaut Bisbenzamidine derivatives for use as antioxidant
US8951986B2 (en) 2008-07-08 2015-02-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9381206B2 (en) 2008-07-08 2016-07-05 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9783568B2 (en) 2008-07-08 2017-10-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
WO2011061590A1 (en) 2009-11-17 2011-05-26 Hetero Research Foundation Novel carboxamide derivatives as hiv inhibitors
WO2011061295A1 (en) 2009-11-19 2011-05-26 Blue Medical Devices Bv Narrow profile composition-releasing expandable medical balloon catheter
WO2011114212A1 (en) * 2010-03-19 2011-09-22 Lupin Limited Ammonium, calcium and tris salts of fosamprenavir
US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US8987419B2 (en) 2010-04-15 2015-03-24 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
WO2011141515A1 (en) 2010-05-14 2011-11-17 Bayer Pharma Aktiengesellschaft Diagnostic agents for amyloid beta imaging
US9376423B2 (en) 2010-08-10 2016-06-28 The Regents Of The University Of California PKC-epsilon inhibitors
US8785648B1 (en) 2010-08-10 2014-07-22 The Regents Of The University Of California PKC-epsilon inhibitors
US10047121B2 (en) 2010-08-14 2018-08-14 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
WO2012062847A1 (en) 2010-11-10 2012-05-18 Protea Biopharma N.V. Use of 2',5'-oligoadenylate derivative compounds
EP2700396A2 (en) 2012-06-20 2014-02-26 Sylphar Nv Strip for the delivery of oral care compositions
US9877981B2 (en) 2012-10-09 2018-01-30 President And Fellows Of Harvard College NAD biosynthesis and precursors for the treatment and prevention of cancer and proliferation
US9227990B2 (en) 2012-10-29 2016-01-05 Cipla Limited Antiviral phosphonate analogues and process for preparation thereof
WO2016003450A1 (en) 2014-07-01 2016-01-07 The Regents Of The University Of California Pkc-epsilon inhibitors
WO2016083490A1 (en) 2014-11-27 2016-06-02 Remynd Nv Compounds for the treatment of amyloid-associated diseases
WO2016176437A1 (en) 2015-04-28 2016-11-03 Newsouth Innovations Pty Limited Targeting nad+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity
WO2018206760A1 (en) 2017-05-11 2018-11-15 Remynd N.V. Compounds for the treatment of epilepsy, neurodegenerative disorders and other cns disorders
US11548881B2 (en) 2017-05-11 2023-01-10 Remynd N.V. Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders
US11939324B2 (en) 2017-05-11 2024-03-26 Remynd N.V. Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
WO2021170600A1 (en) 2020-02-24 2021-09-02 Katholieke Universiteit Leuven Pyrrolopyridine and imidazopyridine antiviral compounds
WO2021209563A1 (en) 2020-04-16 2021-10-21 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
WO2022136486A1 (en) 2020-12-22 2022-06-30 Luxembourg Institute Of Health (Lih) Conolidine analogues as selective ackr3 modulators for the treatment of cancer and cardiovascular diseases
WO2022184898A1 (en) 2021-03-04 2022-09-09 Universiteit Antwerpen Quinazolin-4-one and thieno[2,3-d]pyrimidin-4-one inhibitors of erbb4 (her4) for use in the treatment of cancer
WO2022253785A2 (en) 2021-05-31 2022-12-08 Universität Heidelberg Improved prostate-specific membrane antigen targeting radiopharmaceuticals and uses thereof
WO2023021132A1 (en) 2021-08-18 2023-02-23 Katholieke Universiteit Leuven 6-substituted- and 6,7-disubstituted-7-deazapurine ribonucleoside analogues
WO2023046900A1 (en) 2021-09-23 2023-03-30 Katholieke Universiteit Leuven Ribonucleoside analogues against -sars-cov-2
WO2023241799A1 (en) 2022-06-15 2023-12-21 Université Libre de Bruxelles Flavanols for use in the treatment of retroviral infections
WO2024062043A1 (en) 2022-09-21 2024-03-28 Universiteit Antwerpen Substituted phenothiazines as ferroptosis inhibitors

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