WO1999033795A1 - Prodrugs of aspartyl protease inhibitors - Google Patents

Prodrugs of aspartyl protease inhibitors Download PDF

Info

Publication number
WO1999033795A1
WO1999033795A1 PCT/US1998/027510 US9827510W WO9933795A1 WO 1999033795 A1 WO1999033795 A1 WO 1999033795A1 US 9827510 W US9827510 W US 9827510W WO 9933795 A1 WO9933795 A1 WO 9933795A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
independently selected
formula
alkyl
alkenyl
Prior art date
Application number
PCT/US1998/027510
Other languages
French (fr)
Inventor
Michael R. Hale
Roger D. Tung
Christopher T. Baker
Andrew Spaltenstein
Eric Steven Furfine
Istvan Kaldor
Wieslaw Mieczyslaw Kazmierski
Original Assignee
Vertex Pharmaceuticals Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to AU20121/99A priority Critical patent/AU2012199A/en
Publication of WO1999033795A1 publication Critical patent/WO1999033795A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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.
  • WO 97/27180 describes another class of compounds that are inhibitors of aspartyl protease inhibitors. 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 ⁇ 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.
  • VX-478 A higher aqueous solubility would increase drug load per unit dosage of VX-478.
  • 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.
  • the present invention provides novel prodrugs of a class of 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 m 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 compounds is represented by formula I:
  • any Z may be optionally fused with R ⁇ ; each X and X' is independently selected from the group consisting of -C(O)-, -CJO) C (O) - , -S (0) - and -S(0 ) 2 ; each Y and Y' is independently selected from the group consisting of -(C(R 2 )2) p -, -NR 2 -, - (C (R 2 ) 2 ) p ⁇ M-,
  • each y is independently selected from the group consisting of hydrogen; R ⁇ ; CJ-Cg alkyl; C ⁇ -Cg alkenyl; C2-C5 alkynyl; C3-C5 cycloalkyl optionally fused with R ⁇ ; C5-C cycloalkenyl optionally fused with R 6 ; and where R 1 ' s are attached to adjacent atoms, the R 1 ' s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R 6 ; where any member of R 1 may be optionally substituted by one or more -0R Z , -C(W)-OR z , wherein W is 0, S or NH, -R 2 ; each R 2 is independently selected from hydrogen; R 3 ; CJ-C 6 alkyl; C2"Cg alkenyl;
  • each R ⁇ is independently selected from from the group consisting of OR 9 ; N(R 9 ) 2 ; X-R 9 ; C(0)N(R 9 ) 2 ; R 6 ;
  • R 6 where any member of R 4 may be optionally substituted by one or more groups independently selected from the group consisting of -OR z , -C(W)-R Z , wherein W is 0, S or NH, R 9 and R 3 ; each R 5 is independently selected from the group consisting of H, OH, 0, and R 1 ; each R z is independently selected from
  • each M" is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R 2 ) 4 , CJ-C ⁇ -alkyl , c 2 _c 12 ⁇ al ;en y 1 ' or ⁇ R6 '" wherein 1 to 4 -CH 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( ⁇ 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 0H, -CN, -C0 2 R 2 ,
  • M' is H, C ⁇ -C_2 ⁇ alkyl, C2-C ⁇ 2 ⁇ a l ken y 1 ' or -R 6 ; 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( ⁇ 2), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R ⁇ 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 ,
  • T is 0, S, N(R 2 )2, or, when M' ' is absent, H; K is P or S;
  • J is 0 or S; and s is 0 or 1;
  • each R 6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 / ⁇ R 9 " OR 9 , -CN, -C0 2 R 9 , -X-N(R 9 ) (R 9 ) , halogen, -N0 2 , and -CF 3 ; each R 7 is independently selected from the group consisting of hydrogen, OH and 0; each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocycly
  • An alternate object of this invention is a novel class of compounds represented by formula IV:
  • X and X' are independently -C(O)- or -S(0)2 ⁇
  • Y is - (C(R 2 ) 2 )-M-, -(C(R 2 ) 2 )p", -N(R 2 )- or -N(R 2 )-CH 2 -; and each R 1 , R 2 , R 7 , R 4 , p, R z and M is independently as defined for formula I.
  • Y is -(C(R 2 ) 2 )-M-, -(C(R 2 ) 2 )p-, -N(R 2 : or -N(R ⁇
  • Z is a structure of formula VI:
  • compositions comprising the compounds of formulas I, IV and V and methods for their use as inhibitors of aspartyl protease, and particularly, HIV aspartyl protease.
  • -SO2- 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 sulfmate ester.
  • alkyl alone or m combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-5 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoa yl, n-hexyl and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is as defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy and the like.
  • alkenyl alone or m combination with any other term, refers to a straight-chain or branched-cham mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms.
  • alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z, Z-hexadienyl and the like.
  • anti-viral agent or "anti- retroviral agent” refers to a compound or drug which possesses viral inhibitory activity. Such agents include reverse transcriptase inhibitors (including nucleoside and non-nucleoside analogs) and protease inhibitors.
  • the protease inhibitor is an HIV protease inhibitor.
  • nucleoside analog reverse transcriptase inhibitors include, but are not limited to, zidovudme (AZT) , dideoxycytidme (ddC) , ⁇ idanosme (ddl), stavudine (d4T) , 3TC, 935U83, 1592U89 and 524W91.
  • non-nucleoside analog reverse transcriptase inhibitor include, but are not limited to TIBO, delavirdme (U90) and nevirapme.
  • HIV protease inhibitors include, but are not limited to VX-478 (Vertex, also known as 141W94 (Glaxo-Wellcome) and .KVX-478 (Kissei)), saqumavir (Ro 31-8959, Roche), mdinavir (L- ⁇ 35,524, Merck)), ⁇ tonavir (ABT 538,
  • aryl refers to a carbocyclic aromatic radical (such as phenyl or naphthyl ) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
  • carbocycle and “carbocyclyl” radical, refers to a non-aromatic stable 3- to 8- membered carbon ring which may be saturated, mono- unsaturated or poly-unsaturated.
  • the carbocycle may be attached at any endocyclic carbon atom which results in a stable structure.
  • Preferred carbocycles have 5-6 carbons .
  • heterocycle and “heterocyclyl” radical, unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclic ring or 8- 11 membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic.
  • Each heterocycle consists of one or more 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.
  • any ring nitrogen may be optionally substituted with a substituent R 2 , as defined herein for compounds of formula I.
  • a heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 memebered bicyclic heterocycles.
  • Preferred heterocycles defined above include, for example, benzimidazolyl, lmidazolyl, lmidazolmoyl, lmidazolidmyl, qumolyl, isoquinolyl, mdolyl, mdazolyl, mdazolmolyl, perhydropy ⁇ dazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolmyl, pyrrolidmyl, pyrazolyl, pyrazmyl, qumoxolyl, pipe ⁇ dmyl, pyranyl, pyrazolmyl, piperaz yl, pyri idmyl, pyridaz yl,
  • 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.
  • inert solvent refers to a solvent reaction medium which allows the reagents to rqact together at a substantially increased rate relative to any reagent reacting with the designated solvent.
  • LG refers to groups readily displaceable by a nucleophile, such as an amme, alcohol, phosphorous or thiol nucleophile or their respective anions .
  • Sucn leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotr ⁇ azole, halogen (halides) , t ⁇ flates, tosylates, mesylates, alkoxy, thioalkoxy, phosphmates, phosphonates and the like.
  • Other potential nucleophiles include organometallic reagents known to those skilled the art.
  • protecting group refers to a suitable chemical group which may be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described T.W. Greene and P.G.M. Wuts, Protective Groups m Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) .
  • fused refers to a structure wherein two distinct ring systems are joined together such that both rings share at least two common atoms. This can be envisioned as the replacement of a carbon-hydrogen or nitrogen-hydrogen bond on a ring atom with a carbon- carbon (from a second ring) or nitrogen-carbon (from a second ring) bond.
  • a cyclohexyl ring fused to a second cyclohexyl ring results m a decahydronaphthalene
  • a cyclohexyl ring fused to a pipe ⁇ dme ring results m a decahydroqu olme or decahydroisoqu olme
  • a phenyl ring fused to a thiazole ring results m a benzothiazole .
  • substituents When more than one position m a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at every position (for example, the moiety -N(R 2 ) (R 2 )). Typically, when a structure may be optionally substituted, 0-3 substitutions are preferred, and 0-1 substitutions is more preferred. Most preferred substituents are those which enhance protease inhibitory activity or mtracellular antiviral activity permissive mammalian cells or immortalized mammalian cell lines, or which enhance deliverability by enhancing solubility characteristics or enhancing pharmacokmetic or pharmacodynamic profiles as compared to the unsubstituted compound.
  • substituents include those used m the compounds shown in Tables 1-5.
  • pharmaceutically effective amount refers to an amount effective m treating HIV infection m a patient either as monotherapy or m combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder m a patient or the improvement of an ascertamable measurement associated with a particular disorder. Specifically, with respect to HIV, effective treatment using the compounds and compositions of this invention would result m an improvement m an HIV associated ascertamable measurement.
  • the term “pharmaceutically effective amount” refers to an amount effective m treating HIV infection m a patient either as monotherapy or m combination with other agents.
  • treating refers to the alleviation of symptoms of a particular disorder m a patient or the improvement of an ascertamable measurement associated with a particular disorder. Specifically, with respect to HIV, effective treatment using the compounds and compositions of this invention would result m an improvement m an HIV associated ascertamable measurement.
  • prophylactically effective amount refers to an amount effective in preventing HIV infection m a patient.
  • patient refers to a mammal, including a human.
  • pharmaceutically acceptable carrier or adjuvant refers to a 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 and is nontoxic when administered m doses sufficient to deliver a therapeutic amount of the antiretroviral agent.
  • the compounds of this invention, including the compounds of formula I are defined to include pharmaceutically acceptable derivatives or prodrugs thereof.
  • a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an mhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfu ⁇ c, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succmic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphtha ene- 2-sulfon ⁇ c and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N- (C ⁇ _4 alkyl) 4 + salts.
  • thiocarba ates refers to compounds containing the functional group N-SO2-O.
  • the compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereome ⁇ c mixtures and individual diastereomers . All such lsomeric forms of these compounds are expressly included m the present invention.
  • Each stereogenic carbon may be of the R or S con uration.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use m affinity chromatography applications) .
  • such compounds are stable at a temperature of 40 °C or less, in tne absence of moisture or other chemically reactive conditions, for at least a week.
  • the compounds of the present invention may be used m the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, algmate, 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.
  • the compounds of this invention are those of formula I :
  • each X and X' is independently selected from the group consisting of -C(0)-, -C(0)C(0)-, -S (0) - and -S(0) 2 ; each Y and Y' is independently selected from the group consisting of -(C(R 2 ) 2 ) p -, -NR 2 -, - (C (R 2 ) 2 ) p -M-,
  • each R 1 is independently selected from the group consisting of hydrogen; R 6 ; C ⁇ -Cg alkyl; C2-C5 alkenyl; C2-C5 alkynyl; C3 ⁇ Cg cycloalkyl optionally fused with R 6 ; C5 ⁇ C cycloalkenyl optionally fused with R 6 ; and where R ⁇ ' s are attached to adjacent atoms, the R 1 ' s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R ⁇ ; where any member of R 1 may be optionally substituted by one or more -0R Z , -C(W)-0R z , wherein W is 0, S or NH, -R 2 ; each R 2 is independently selected from hydrogen; R 3 ; C ⁇ -Cg alkyl; C2 ⁇ C 6 alkenyl; C 2
  • R ⁇ where any member of R 4 may be optionally substituted by one or more groups independently selected from the group consisting of -OR z , -C(W)-R z , wherein W is 0, S or NH, R 9 and R 3 ; each y is independently selected from the group consisting of H, OH, 0, and R 1 ; each R z is independently selected from
  • each M" is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R 2 )4, C ⁇ -C ⁇ 2 -alkyl, C2-C 2 _ alkenyl, or -R 6 ; 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( ⁇ 2), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R ⁇ 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 ,
  • M' is H, C 1 -C 1 -alkyl, C2-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 0, S, S (0) , 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 ,
  • T is 0, S, N(R 2 )2 or, when M' ' is absent, H;
  • K is P or S; J is 0 or S; and s is 0 or 1;
  • each R ⁇ is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 ,
  • Preferred compounds of formula I are those wherein each Y and Y' is independently selected from the group consisting of -(C(R )2)p ⁇ / -NR 2 -, - (C (R 2 ) 2) p -M_ / and -N(R 2 )-CH 2 -; and each R 3 is independently selected from oxo, OR 9 , N(R 9 j 2 / N(R 9 )-X-R 9 , N(R 9 )-X-OR 9 , SR 9 , X-R 9 , 0-X-N(R 9 ) 2 , C(0)N(R 9 ) 2 , halogen, N0 2 , CN, COOR 9 and R 6 ; each R z is selected from:
  • each R 12 is independently selected from the group consisting of R 6 ; C ⁇ -Cg alkyl optionally substituted with R 6 ; C2 ⁇ C alkenyl; C2"Cg alkynyl; C3 ⁇ C cycloalkyl optionally fused with R ⁇ ; C5-C5 cycloalkenyl optionally fused with R ⁇ ; where any member of R ⁇ 2 may be optionally substituted by one or more R 2 .
  • Preferred compounds of formula I are those wherein n is equal to 1; those having the structure of formula II:
  • Y is - (C (R 2 ) 2) p -M-; those wherein X is -C(O)- or -S(0) 2 -and Y is (-C(R 2 ) 2 ") p ; those wherein X is -C(O)-, -C(0)C(0)- or -S(0)2 ⁇ ; and
  • Y is -N(R 2 )- or -N(R 2 )-CH 2 -.
  • An alternate object of this invention is a novel class of compounds represented by formula IV:
  • X and X' are independently -C(O)- or -S(0)2 _ ;
  • Y is - (C(R 2 ) 2 )-M-, -(C(R 2 ) 2 ) p -, -N(R 2 )- or -N(R 2 :
  • each R 1 , R 2 , R 7 , R 4 , p, R z and M is independently as defined for formula I.
  • Another object of this invention is a novel class of compounds represented by formula V:
  • X is -C (0)- or -S (0)2 ⁇
  • Y is - (C(R 2 ) 2 )-M-, -(C(R 2 ) 2 ) p -, -N(R 2 )- or -N(R 2 ;
  • R 10 is 0 or H 2 ;
  • R z is defined as in formula I.
  • Z is a structure of formula VI:
  • any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 substituents independently selected from R 2 and -R z (where in formula V, if R 10 is H2, a methylene is implied) ; and each R 1 , R 2 , R 7 , R 4 , R 8 , 0R Z , p, q, G, M, Q and X' is independently as defined for formula I.
  • G is S; and X' is -C(0)-; compounds having the structure of formula V, wherein
  • G is S; X' is -C(0)-; and y is t-butylammo; compounds having the structure of formula V, wherein
  • R 10 is 0;
  • X is -C(0)-
  • R 10 is H 2 .
  • Y is -(C(R 2 ) 2 )-; R 7 is H;
  • R 10 is H 2 ;
  • R 2 within the definition of Y is selected from hydrogen, R 3 or C ⁇ -Cg alkyl optionally substituted with
  • X and X' is -C(O)-;
  • Y is -(C(R 2 ) 2 )-;
  • R 7 is H
  • R 10 is H 2 ;
  • R 2 within the definition of Y is selected from hydrogen, -N(R ) or heterocyclyl, which may be optionally benzofused, and wherein said heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , -R 9 -
  • Y is -(C(R 2 ) 2 )-;
  • R 7 is H
  • R 10 is H 2 ;
  • R 2 within the definition of Y is selected from the group consisting of:
  • At least one R 2 withm the definition of Y is aryl optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , ⁇ R 9 ⁇
  • Y is - (C(R 2 ) 2 )-;
  • R 10 is H 2 ; ana at least one R ⁇ w ⁇ th the definition of Y is C ⁇
  • Y is -(C(R 2 ) 2 ) ⁇ ;
  • R 7 is H; at least one R 2 withm the definition of Y is C ⁇ Cg alkyl optionally substituted with R 3 ;
  • R 3 withm the definition of Y is aryl optionally substituted with 1-3 substituents selected from -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0 ⁇ X-N(R 9 ) 2 ,
  • R! is benzyl optionally substituted with 1-3 substituents selected from -OR 9 , -N(R 9 ) (R 9 ), SR 9 , -X-R 9 , -R 9 -OR 9 , -CN, halogen, -N0 2 , and -CF 3 ; those compounds according to any of the aforementioned preferred compounds of formula V wherein:
  • R 1 is benzyl optionally substituted with 1-3 substituents selected from -OR 9 , -N(R 9 ) (R 9 ), SR 9 , -X-R 9 , -R 9 -OR 9 , -CN, halogen, -N0 2 , and -CF 3 ; and wherein Z is
  • each R ⁇ is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , "R 9 ⁇ OR 9 , -CN, -C0 2 R 9 , -X-N(R 9 ) (R 9 ) , halogen, -N0 2 , -CF3, -0- (CH 2 ) q-R 6 , -0- (CH 2 ) q -OR 9 , 2 , 3-methylenedioxy and
  • each y is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , ⁇ R 9 ⁇ OR 9 , -CN, -C0 2 R 9 ,
  • R 2 within the definition of Y is selected from hydrogen, R 3 or C ⁇ -Cg alkyl optionally substituted with
  • each X, X', Y, Y', Z, R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R z , Q, M, n, r, p, q and G is independently as defined for formula I.
  • M is 0;
  • R 7 is H
  • R 10 is H 2 .
  • X is -C(0)- or -S(0)2 ⁇ ; and the compounds of formula IX wherein X is -C(0)-; Y i s - (C (R 2 ) 2 ) -M- ; and
  • R 7 is H; and those compounds of formula IX wherein X is -C(0)-;
  • Y is -N(R 2 )-; and R 7 is H; and those compounds of formula IX wherein X is -C(0)-; Y is -(C(R 2 ) 2 )-; and R 7 is H.
  • X and X' are independently -C(O)- or -S(0)2-/" those compounds of formula I having the structure of formula XII, wherein X and X' are independently -C(O)- or -S(0)2 _ ; and
  • R 4 is l-amino-2-hydroxyindanyl; and compounds of formula I having the structure of formula XII, wherein R 4 is 1 (S) -amino-2 (R) -hydroxyindanyl .
  • X and X' are independently -C (0) - or -S(0)2 _ compounds according formula I having the structure of formula XIII, wherein
  • X is -C (0) - or -S (0) 2 -;
  • R 7 is H; compounds of formula I having the structure of formula XIII, wherein
  • Y is -(C(R 2 ) 2 )-;
  • R 2 withm the definition of Y is selected from hydrogen, R 3 , or C -Cg alkyl optionally substituted those compounds according to formula XIII wherein: X is -C(O)-;
  • R 7 is H; ana
  • R 2 withm the definition of Y is selected from hydrogen, -N(R 9 )2 or heterocyclyl, which may be optionally benzofused, and wherein said heterocyclyl may be optionally substituted with 1-3 groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , ⁇ R 9 ⁇
  • Y is -(C(R 2 ) 2 )-; at least one R 2 within the definition of Y is selected from the group consisting of:
  • R 7 is H; and at least one R 2 within the definition of Y is aryl optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2/ -R 9 - OR 9 , -CN, -C0 2 R 9 , -X-N(R 9 ) (R 9 ) , halogen, -N0 2 , and -CF 3 ; those compounds according to formula XIII wherein: X is -C(0)-; X' is -C(0)-;
  • Y is -(C(R 2 ) 2 )-;
  • R 7 is H; and at least one R 2 within the definition of Y is C ⁇
  • Y is -(C(R 2 ) 2 )-;
  • R 7 is H; and at least one R 3 within the definition of Y is pyridyl, triazolyl, oxazolyl, isoxazolyl, pyrimidyl, pyrazolyl, pyridazinyl, thiazolyl, imidazolyl, thienyl thiadiazolyl, oxadiazolyl, triazinyl or pyrazinyl wherein said R 3 may be optionally substituted with 1-3 substituents selected from -OR 9 , -R 9 , -N(R 9 ) (R 9 ),
  • Y is -(C(R 2 ) 2 )-;
  • R 7 is H
  • R 3 within the definition of Y is aryl optionally substituted with 1-3 substituents selected from -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 ,
  • each R 1 is benzyl; and each R 9 not within the definition of Y is 2- hydroxyindanyl ; those compounds according to any of the aforementioned preferred compounds of formula XIII wherein: each R!
  • each R 9 not within the definition of Y is 2- hydroxyindanyl ; those compounds according to any of the aforementioned preferred compounds wherein: each Rl is independently selected from benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2; and those compounds according to any of the aforementioned preferred compounds wherein: each RI is independently selected from benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2 ; each R 9 not within the definition of Y is 2- hydroxyindanyl .
  • Another embodiment is compounds according to formula XIII, wherein:
  • each R D is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 / -R 9 ⁇ OR 9 , -CN, -C0 2 R 9 , -X-N(R 9 ) (R 9 ) , halogen, -N0 2 , -CF 3 , -0- (CH 2 ) q -R 6 , -0- (CH2) q-OR 9 , 2, 3-methylenedioxy and 3, -methylenedioxy; and each X, X', Y, Y', Z, R 1
  • Another embodiment is compounds according to formula XIII, wherein:
  • R 2 within the definition of Y is selected from hydrogen, R 3 or C ⁇ -Cg alkyl optionally substituted with
  • each R 6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR 9 , -R 9 , -N(R 9 ) (R 9 ), -N(R 9 )-X-R 9 , SR 9 , -X-R 9 , -0-X-N(R 9 ) 2 , ⁇ R 9 ⁇
  • X is -S ⁇ 2 ⁇ ;
  • X' is -C(0)-
  • X is -S ⁇ 2 ⁇
  • X' is -C(O)-; Y is -N(R 2 )-; and R 7 is H.
  • preferred compounds are those of formula V wherein R 10 is H 2 ; and Z is selected from the group consisting of:
  • R 2 is as defined in formula I; and those of formula V wherein Z is selected from the group consisting of
  • R 1 0 is H 2 .
  • R 7 is H
  • R 10 is H 2 ; and those compounds of formula V wherein X and X' is -C(0)-; Y is -N(R 2 )-; R 7 is H; R 10 is H 2 ; and those compounds of formula V, wherein X and X' is -C(O)-; Y is - (C(R 2 ) 2 )-M-;
  • M is 0;
  • R 7 is H
  • R 10 is H 2 ; and the aforementioned compounds of formula V wherein Z is selected from the group consisting of:
  • R 2 is as defined in claim 1. Also preferred are those compounds of formula
  • R 7 is H
  • R 10 is H 2 ; and those compounds of formula V wherein X and X' is -C(0) -; Y is -N(R 2 )-; R 7 is H;
  • R 10 is H 2 ; and those compounds of formula V, wherein X and X' is -C(0) -;
  • Y is - (C(R 2 ) 2 )-M-;
  • M is 0;
  • R 7 is H
  • R 10 is H 2 ; and the aforementioned compounds of formula V wherein Z is selected from the group consisting of:
  • Z is selected from the group consisting of -X'R 4 , -NtR 1 ) -X'-R 4 , -NfR 1 ) -NfR 1 ) -X'-R 4 , and formula VI;
  • any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 members independently selected from R 2 ; and each X, X', Y, Y' R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R z , Q, M, n, r, p, q and G is independently as defined in for formula I .
  • R 2 groups for formula I include:
  • Preferred compounds of this invention of formula I include the specific compounds contained in Tables 1-5. T.ABLE 1
  • R z is as defined in formula I and A and Z are as follows
  • R z is as defined in formula I and A, R-*- and Z are as defined below .
  • R z is as defined in formula I and A and Z are as defined below.
  • R z is as defined in formula I and A and Z are as defined below.
  • A is selected from:
  • R and R are as defined above for formula (I), p and R is optionally substituted with -OR .
  • Z in compound of formula (Z') is selected from:
  • the prodrugs of the present invention may be synthesized using conventional synthetic techniques.
  • Aspartyl protease inhibitors which are precursors of the prodrugs of the present application are disclosed m WO 97/27180, the disclosure of which is incorporated herein by reference.
  • Prodrugs of formula (I) of the present invention can be readily synthesized from the WO 97/27180 compounds using conventional techniques.
  • One of skill m the art would be well aware of conventional synthetic reagents to convert the -OH group of the WO 97/27180 compounds to a desired -OR z functionality of the present invention, wherein R z is as defined above.
  • the relative ease with which the compounds of this invention can be synthesized represents an enormous advantage m the large scale production of these compounds.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known m 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.
  • 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 z ) from one heteroatom withm the molecule to another heteroatom.
  • R z a functional 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 m 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 m vivo metabolism result m a greater bioavailability of the drug. As a result, the pill burden on a patient is signi icantly reduced.
  • the prodrugs of this invention may be employed m a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events m their life cycle. Sucn metho ⁇ s 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-mfected patient m a pharmaceutically acceptable manner and m 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 compounds of this invention may be administered with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated.
  • 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, dideoxycytidme, trisodium phosphonoformate, eflornithine, ⁇ bavi ⁇ n, acyclovir, alpha interferon and trimenotrexate .
  • non-nucleoside inhibitors of reverse transcriptase such as TIBO or nevirapme
  • Combination therapies according to this invention exert a synergistic effect 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.
  • 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 as single agents or 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.
  • co-admmistration of the compoun ⁇ s 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 mfectivity and its associated symptoms.
  • the prodrugs of this invention can also be administered m combination with lmmunomodulators e.g., bropirim e, anti-human alpha mterferon antioody, IL-2, GM-CSF, methionme enkephal , mterferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) ; and antibiotics (e.g., pentamidme lsethiorate) to prevent or combat infection ana disease associated with HIV infections, such as AIDS and ARC.
  • lmmunomodulators e.g., bropirim e, anti-human alpha mterferon antioody, IL-2, GM-CSF, methionme enkephal , mterferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO
  • antibiotics e.g., pen
  • the prodrugs of this invention are administered 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.
  • the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events m 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.
  • 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 m particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelm 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 m 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, glycme, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts cr electrolytes, such as protamme sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, z c salts, colloidal silica, magnesium trisilicate, polyvmyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vagmally 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, mtracutaneous, intravenous, intramuscular, mtra-articular, mtrasynovial, intrasternal, mtrathecal, tralesional and mtracranial injection or infusion techniques.
  • the pharmaceutical compositions may be the form of a sterile mjectable preparation, for example, as a sterile mjectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile mjectable preparation may also be a sterile mjectable solution or suspension m a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution m 1, 3-butaned ⁇ ol .
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and lsotomc 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 diglyce ⁇ des .
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful m the preparation of jectables, as are natural pnarmaceutically-acceptable oils, such as olive oil or castor oil, especially 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 m any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • 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.
  • 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.
  • compositions can be prepared by mixing a compound of this invention with a suitable non-irritatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components.
  • suitable non-irritatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components.
  • suitable non-irritatmg 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, polyoxy- ethylene 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 w ll 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Prodrugs of HIV aspartyl protease inhibitors of formula (I) wherein each Z is (a) or (b) or (c); each RZ is independently selected from (d) or (e); 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

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 IWEN ION
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. WO 97/27180 describes another class of compounds that are inhibitors of aspartyl protease inhibitors. 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 λ397 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 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 m 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 compounds that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of compounds is represented by formula I:
Figure imgf000006_0001
wherein
Figure imgf000006_0002
wnerem any Z may be optionally fused with R^; each X and X' is independently selected from the group consisting of -C(O)-, -CJO) C (O) - , -S (0) - and -S(0) 2; each Y and Y' is independently selected from the group consisting of -(C(R2)2)p-, -NR2-, - (C (R2 ) 2 ) p~M-,
>C=C(R2)2, and -N(R2) -CH2-; each y is independently selected from the group consisting of hydrogen; R^; CJ-Cg alkyl; C^-Cg alkenyl; C2-C5 alkynyl; C3-C5 cycloalkyl optionally fused with Rδ; C5-C cycloalkenyl optionally fused with R6; and where R1 ' s are attached to adjacent atoms, the R1 ' s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R6; where any member of R1 may be optionally substituted by one or more -0RZ, -C(W)-ORz, wherein W is 0, S or NH, -R2; each R2 is independently selected from hydrogen; R3; CJ-C6 alkyl; C2"Cg alkenyl; C2-C6 alkynyl; C3-C6 cycloalkyl optionally fused with R6; C5-C5 cycloalkenyl optionally fused with R6; and where two R2 ' s are attached to the same geminal atom, the R2 ' s together with their attached geminal atom may form a spirocarbocyclic or spiroheterocyclic ring system; where any member of R2 may be optionally substituted by one or more R3; each R3 is independently selected from oxo, OR9, N(R9)2, N(R9)-X-R9,N(R9)-X-OR9, N (R9) -X-N (R9) 2 , SR9, X- R9, 0-X-N(R9)2, C(0)N(R9)2, halogen, N02, CN, COOR9 and
R6; each R^ is independently selected from from the group consisting of OR9; N(R9)2; X-R9; C(0)N(R9)2; R6;
C -Cg alkyl; C2-C4 alkenyl; C3-C5 cycloalkyl optionally fused with R6; C5-C5 cycloalkenyl optionally fused with
R6; where any member of R4 may be optionally substituted by one or more groups independently selected from the group consisting of -ORz, -C(W)-RZ, wherein W is 0, S or NH, R9 and R3; each R5 is independently selected from the group consisting of H, OH, 0, and R1 ; each Rz is independently selected from
Figure imgf000008_0001
wherein each M" is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, CJ-C^-alkyl , c2_c12~al ;eny1' or ~R6'" wherein 1 to 4 -CH 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(θ2), 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, OCF3, -S(0)n-R6, N(R2)-S(0)2(R2), halo, -CF3, or -NO2;
M' is H, Cχ-C_2~alkyl, C2-Cχ2~alkeny1' 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(θ2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R^ 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, -OCF3, -S(0)n-R6,
-N(R2)-S (0)2 (R2) / halo, -CF3, or -N02 ;
T is 0, S, N(R2)2, or, when M' ' is absent, H; K is P or S;
J is 0 or S; and s is 0 or 1;
each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2/ ~R9" OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; each R7 is independently selected from the group consisting of hydrogen, OH and 0; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocyclyl; each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heterocyclyl, aralkyl, carbocyclylalkyl and heterocyclylalkyl wherein any aryl, carbocyclyl or heterocyclyl may be optionally fused with R8 and wherein any member of R8 may be optionally substituted by one or more groups independently selected from the group consisting of -OR8, -N(R8) , -CN, -N02, -X-R8, -X-N(R8)2, -C(0)0R8, -N(R8)-XNR8, and halogen; each Q is independently selected from CH and N; each M is independently selected from the group consisting of NH, -NR2-, -0-, -S-, -S (0) - and -S(0) -; each n is 1 or 2; each r is 0,1 or 2; each p is independently 1 or 2; each q is independently 1, 2 or 3; and each G is independently selected from the group consisting of -NH-, -NR2-, -0-, -S-, -S(O)-, S(0)2,
-C(0)-, and -C(R2) 2-. An alternate object of this invention is a novel class of compounds represented by formula IV:
Figure imgf000010_0001
wherein:
X and X' are independently -C(O)- or -S(0)2~
Y is - (C(R2)2)-M-, -(C(R2)2)p", -N(R2)- or -N(R2)-CH2-; and each R1, R2, R7, R4, p, Rz and M is independently as defined for formula I.
.Another object of this invention is a novel class of compounds represented by formula V:
Figure imgf000010_0002
wherein :
Figure imgf000010_0003
Y is -(C(R2)2)-M-, -(C(R2)2)p-, -N(R2: or -N(R^
CH2-;
Figure imgf000010_0004
Z is a structure of formula VI:
Figure imgf000010_0005
(VI) wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 substituents independently selected from R2; and each R1, R2, R7, R4 , R8, p, q, G, M, Q and X' is independently as defined for formula I.
It is also an object of this invention to provide pharmaceutical compositions comprising the compounds of formulas I, IV and V and methods for their use as inhibitors of aspartyl protease, and particularly, HIV aspartyl protease.
It is a further object of this invention to provide methods for treating viral diseases, and in particular HIV-related diseases, using the compounds and compositions of this invention.
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
Bn 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 dicyciohexylcarbodiimide DIC diisopropylcarbodiimide EDC 1- (3-dιmethylamιnopropyl) -3- ethylcarbodnmide hydrochloride
HOBt 1-hydroxybenzotrιazole
HOSu 1-hydroxysuccιnιmιde
TFA trifluoroacetic acid
DIEA dusopropylethylamme
DBU 1, 8-dιazabιcyclo (5.4.0) undec-7-ene
EtOAc ethyl acetate t-Bu tert-butyl lBu iso-butyl
DMF dimethylformamide
THP tertrahydropyran
THF tetrahydrofuran
DMSO dimethylsulfoxide
The following terms are employed herein: Unless expressly stated to the contrary, the terms "-SO2-" 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 sulfmate ester. The term "alkyl", alone or m combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1-10 and more preferably from 1-5 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoa yl, n-hexyl and the like.
The term "alkoxy" refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy and the like.
The term "alkenyl", alone or m combination with any other term, refers to a straight-chain or branched-cham mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2-10 carbon atoms and more preferably, from 2-6 carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z, Z-hexadienyl and the like. The term "anti-viral agent" or "anti- retroviral agent" refers to a compound or drug which possesses viral inhibitory activity. Such agents include reverse transcriptase inhibitors (including nucleoside and non-nucleoside analogs) and protease inhibitors. Preferably the protease inhibitor is an HIV protease inhibitor. Examples of nucleoside analog reverse transcriptase inhibitors include, but are not limited to, zidovudme (AZT) , dideoxycytidme (ddC) , αidanosme (ddl), stavudine (d4T) , 3TC, 935U83, 1592U89 and 524W91. Examples of non-nucleoside analog reverse transcriptase inhibitor include, but are not limited to TIBO, delavirdme (U90) and nevirapme. Examples of HIV protease inhibitors include, but are not limited to VX-478 (Vertex, also known as 141W94 (Glaxo-Wellcome) and .KVX-478 (Kissei)), saqumavir (Ro 31-8959, Roche), mdinavir (L-^35,524, Merck)), πtonavir (ABT 538,
Abbott) , nelfmavir (AG 1343, Agouron) , palmavir (Bila 2011 BS), U-.33017 (Upjohn), XM 412 (DuPont Merck), XM 450 (DuPont Merck), BMS 186318 (Bristol-Meyers Squibb), CPG 53,437 (CJoa Geigy) , CPG 61,755 (Ciba Geigy) , CPG 70,726 (Ciba Geigy), ABT 378 (Abbott), GS 3333 (Gilead Sciences), GS 3403 (Gilead Sciences), GS 4023 (Gilead Sciences), GS 4035 (Gilead Sciences), GS 4145 (Gilead Sciences), GS 4234 (Gilead Sciences), and GS 4263 (Gilead Sciences) .
The term "aryl", alone or in combination with any other term, refers to a carbocyclic aromatic radical (such as phenyl or naphthyl ) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms. Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term "carbocycle" and "carbocyclyl" radical, refers to a non-aromatic stable 3- to 8- membered carbon ring which may be saturated, mono- unsaturated or poly-unsaturated. The carbocycle may be attached at any endocyclic carbon atom which results in a stable structure. Preferred carbocycles have 5-6 carbons .
The term "heterocycle" and "heterocyclyl" radical, unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclic ring or 8- 11 membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more 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. In addition, any ring nitrogen may be optionally substituted with a substituent R2, as defined herein for compounds of formula I. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 memebered bicyclic heterocycles. Preferred heterocycles defined above include, for example, benzimidazolyl, lmidazolyl, lmidazolmoyl, lmidazolidmyl, qumolyl, isoquinolyl, mdolyl, mdazolyl, mdazolmolyl, perhydropyπdazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolmyl, pyrrolidmyl, pyrazolyl, pyrazmyl, qumoxolyl, pipeπdmyl, pyranyl, pyrazolmyl, piperaz yl, pyri idmyl, pyridaz yl, morpholmyl, thiamorpholmyl, furyl, thienyl, triazolyl, thiazolyl, β-carbolmyl, tetrazolyl, thiazo- lid yl, benzofuranoyl, thiamorpholmyl sulfone, oxazolyl, benzoxazolyl, oxopiperidmyl, oxopyrrold yl, oxoazepmyl, azepinyl, isoxazolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, diox yl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl and sulfolanyl, dioxanyl, dioxolanyl, tetrahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetrahydrofurofuranyl and tetrahydropyranofuranyl . The term "halogen" refers to a radical of fluorine, chlorine, bromine or iodine.
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 "inert solvent" refers to a solvent reaction medium which allows the reagents to rqact together at a substantially increased rate relative to any reagent reacting with the designated solvent.
The term "leaving group" or "LG" refers to groups readily displaceable by a nucleophile, such as an amme, alcohol, phosphorous or thiol nucleophile or their respective anions . Sucn leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotrιazole, halogen (halides) , tπflates, tosylates, mesylates, alkoxy, thioalkoxy, phosphmates, phosphonates and the like. Other potential nucleophiles include organometallic reagents known to those skilled the art.
The term "protecting group" refers to a suitable chemical group which may be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described T.W. Greene and P.G.M. Wuts, Protective Groups m Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) .
The term "fused" whether preceded by the term "optionally" or not, refers to a structure wherein two distinct ring systems are joined together such that both rings share at least two common atoms. This can be envisioned as the replacement of a carbon-hydrogen or nitrogen-hydrogen bond on a ring atom with a carbon- carbon (from a second ring) or nitrogen-carbon (from a second ring) bond. For example, a cyclohexyl ring fused to a second cyclohexyl ring results m a decahydronaphthalene, a cyclohexyl ring fused to a pipeπdme ring results m a decahydroqu olme or decahydroisoqu olme, or a phenyl ring fused to a thiazole ring results m a benzothiazole . The term "substituted", whether preceded by the term "optionally" or not, and substitutions contained in formulas of this invention, refer to the replacement of one or more hydrogen radicals a given structure with the radical of a specified substituent. When more than one position m a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at every position (for example, the moiety -N(R2) (R2)). Typically, when a structure may be optionally substituted, 0-3 substitutions are preferred, and 0-1 substitutions is more preferred. Most preferred substituents are those which enhance protease inhibitory activity or mtracellular antiviral activity permissive mammalian cells or immortalized mammalian cell lines, or which enhance deliverability by enhancing solubility characteristics or enhancing pharmacokmetic or pharmacodynamic profiles as compared to the unsubstituted compound. Other more preferred substituents include those used m the compounds shown in Tables 1-5. The term "pharmaceutically effective amount" refers to an amount effective m treating HIV infection m a patient either as monotherapy or m combination with other agents. The term "treating" as used herein refers to the alleviation of symptoms of a particular disorder m a patient or the improvement of an ascertamable measurement associated with a particular disorder. Specifically, with respect to HIV, effective treatment using the compounds and compositions of this invention would result m an improvement m an HIV associated ascertamable measurement. The term
"prophylactically effective amount" refers to an amount effective in preventing HIV infection m 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 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 and is nontoxic when administered m doses sufficient to deliver a therapeutic amount of the antiretroviral agent. As used herein, the compounds of this invention, including the compounds of formula I are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an mhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. 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, sulfuπc, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succmic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphtha ene- 2-sulfonιc and benzenesulfonic acids. Other acids, such as oxalic, while not m themselves pharmaceutically acceptable, may be employed m the preparation of salts useful as intermediates m 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- (Cχ_4 alkyl) 4+ salts.
The term "thiocarba ates" refers to compounds containing the functional group N-SO2-O.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeπc mixtures and individual diastereomers . All such lsomeric forms of these compounds are expressly included m the present invention. Each stereogenic carbon may be of the R or S con uration. Although the specific compounds exemplified m this application may be depicted m a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
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 which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use m affinity chromatography applications) . Typically, such compounds are stable at a temperature of 40 °C or less, in tne absence of moisture or other chemically reactive conditions, for at least a week.
The compounds of the present invention may be used m the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, algmate, 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 compounds of this invention are those of formula I :
Figure imgf000020_0001
(l) wherein each Z is
Figure imgf000021_0001
wherein any Z may be optionally fused with R , each X and X' is independently selected from the group consisting of -C(0)-, -C(0)C(0)-, -S (0) - and -S(0)2; each Y and Y' is independently selected from the group consisting of -(C(R2)2)p-, -NR2-, - (C (R2) 2 ) p-M-,
>C=C(R2)2, and -N(R2)-CH2-; each R1 is independently selected from the group consisting of hydrogen; R6; Cχ-Cg alkyl; C2-C5 alkenyl; C2-C5 alkynyl; C3~Cg cycloalkyl optionally fused with R6; C5~C cycloalkenyl optionally fused with R6; and where R^ ' s are attached to adjacent atoms, the R1 ' s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R^; where any member of R1 may be optionally substituted by one or more -0RZ, -C(W)-0Rz, wherein W is 0, S or NH, -R2; each R2 is independently selected from hydrogen; R3; Cχ-Cg alkyl; C2~C6 alkenyl; C2-Cg alkynyl; C3~C cycloalkyl optionally fused with R^; C5~C cycloalkenyl optionally fused with R6; and where two R2 ' s are attached to the same geminal atom, the R ' s together with their attached geminal atom may form a spirocarbocyclic or spiroheterocyclic ring system; where any member of R2 may be optionally substituted by one or more R3; each R3 is independently selected from oxo, OR9, N(R9)2, N(R9)-X-R9,N(R9)-X-OR9, N (R9) -X-N (R9) 2 , SR9, X- R9, 0-X-N(R9)2, C(0)N(R9)2, halogen, N02, CN, COOR9 and R6; each R4 is independently selected from from the group consisting of OR9; N(R )2; X-R9; C(0)N(R9)2; R6; C -Cg alkyl; C2-C4 alkenyl; C3~Cg cycloalkyl optionally fused with R6; C5~C cycloalkenyl optionally fused with
R^; where any member of R4 may be optionally substituted by one or more groups independently selected from the group consisting of -ORz, -C(W)-Rz, wherein W is 0, S or NH, R9 and R3; each y is independently selected from the group consisting of H, OH, 0, and R1; each Rz is independently selected from
Figure imgf000022_0001
wherein each M" is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, Cχ-Cι2-alkyl, C2-C 2_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(θ2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R^ 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, OCF3, -S(0)n-R6, N(R2)-S (0) 2 (R2) , halo, -CF3, or -N02;
M' is H, C1-C1 -alkyl, C2-Cχ2-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(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, -OCF3, -S(0)n-R6, -N(R2) -S (0)2 (R2) , halo, -CF3, or -N02 ;
T is 0, S, N(R2)2 or, when M' ' is absent, H;
K is P or S; J is 0 or S; and s is 0 or 1;
each R^ is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9,
-N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9~
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; each R7 is independently selected from the group consisting of hydrogen, OH and 0; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocyclyl; each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heterocyclyl, aralkyl, carbocyclylalkyl and heterocyclylalkyl wherein any aryl, carbocyclyl or heterocyclyl may be optionally fused with R8 and wherein any member of R8 may be optionally substituted by one or more groups independently selected from the group consisting of -OR8, -N(R8)2, -CN, -N02, -X-R8,
-X-N(R8)2, -C(0)0R8, -N(R8)-XNR8, and halogen; each Q is independently selected from CH and N; each M is independently selected from the group consisting of NH, -NR2-, -0-, -S-, -S(O)- and -S(0) -; each n is 1 or 2; each r is 0,1 or 2; each p is independently 1 or 2; each q is independently 1, 2 or 3; and each G is independently selected from the group consisting of -NH-, -NR2-, -0-, -S-, -S(O)-, S(0)2, -C(O) -, and -C(R2) 2~ •
Except where expressly noted to the contrary, the term "[variable] as defined for formula I" refers to the definitions shown directly above. In addition, where no reference is made to a particular definition for a given variable, the definition is to be taken as that defined for formula I shown directly above.
Preferred compounds of formula I are those wherein each Y and Y' is independently selected from the group consisting of -(C(R )2)p~/ -NR2-, - (C (R2) 2) p-M_/ and -N(R2)-CH2-; and each R3 is independently selected from oxo, OR9, N(R9j2/ N(R9)-X-R9, N(R9)-X-OR9, SR9, X-R9, 0-X-N(R9)2, C(0)N(R9)2, halogen, N02, CN, COOR9 and R6; each Rz is selected from:
Figure imgf000024_0001
- (L) -tyrosme, / -N —'IH ' -?y° ,
-P03(NH4)2, -CH2-OP03Na2,
Figure imgf000024_0002
- (L) -serme,
-S03Na2, ■ N- \, .Nπ.Mιvιe-j 2,. -S03Mg, -S03(NH4)2, Me H
N. .NH,
-CH2-OS03Na2, -CH2-OS03 (NH4)2, ^ O
Figure imgf000025_0001
, JY
Figure imgf000025_0002
(L)-valine, - (L) -glutamic acid, - (L) -aspartic acid,
ID -γ-t-butyl-aspart ic acid, Y oXλ
- (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, ^CF3
Figure imgf000025_0003
Pθ3K2, Pθ3Ca, Pθ3~spermine, PO3- (spermidine) 2 or PO3- (meglamine) 2 •
Alternate preferred compounds of formula I are those having the structure of formula IA:
Figure imgf000025_0004
wherein each R12 is independently selected from the group consisting of R6; Cχ-Cg alkyl optionally substituted with R6; C2~C alkenyl; C2"Cg alkynyl; C3~C cycloalkyl optionally fused with R^; C5-C5 cycloalkenyl optionally fused with R^; where any member of R^2 may be optionally substituted by one or more R2.
Preferred compounds of formula I are those wherein n is equal to 1; those having the structure of formula II:
Figure imgf000026_0001
and those having the structure of formula III:
Figure imgf000026_0002
(III)
Also preferred are compounds according to formula I wherein X is -C(O)- or -S(0)2_ and
Y is - (C (R2) 2)p-M-; those wherein X is -C(O)- or -S(0)2-and Y is (-C(R2)2")p; those wherein X is -C(O)-, -C(0)C(0)- or -S(0)2~; and
Y is -N(R2)- or -N(R2)-CH2-. An alternate object of this invention is a novel class of compounds represented by formula IV:
Figure imgf000027_0001
wherein :
X and X' are independently -C(O)- or -S(0)2_;
Y is - (C(R2)2)-M-, -(C(R2)2)p-, -N(R2)- or -N(R2:
CH2~; and each R1, R2, R7, R4, p, Rz and M is independently as defined for formula I.
Another object of this invention is a novel class of compounds represented by formula V:
Figure imgf000027_0002
wherein :
X is -C (0)- or -S (0)2~;
Y is - (C(R2)2)-M-, -(C(R2)2)p-, -N(R2)- or -N(R2;
CH2-;
R10 is 0 or H2;
Rz is defined as in formula I. Z is a structure of formula VI:
Figure imgf000027_0003
(VI) wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 substituents independently selected from R2 and -Rz (where in formula V, if R10 is H2, a methylene is implied) ; and each R1, R2, R7, R4 , R8, 0RZ, p, q, G, M, Q and X' is independently as defined for formula I.
Also preferred are those compounds having the structure of formula V, wherein
Figure imgf000028_0001
compounds having the structure of formula V, wherein
Figure imgf000028_0002
q is 1;
G is S; and X' is -C(0)-; compounds having the structure of formula V, wherein
Figure imgf000028_0003
G is S; X' is -C(0)-; and y is t-butylammo; compounds having the structure of formula V, wherein
R10 is 0;
X is -C(0)-;
Figure imgf000028_0004
compounds having the structure of formula V wherein X and X' is -C (0) -;
Figure imgf000028_0005
R10 is H2.
Also preferreα are those compounds of formula V wherein
Figure imgf000028_0006
Y is -(C(R2)2)-; R7 is H;
R10 is H2; and
R2 within the definition of Y is selected from hydrogen, R3 or Cχ-Cg alkyl optionally substituted with
R3;
Also preferred are those compounds of formula V wherein
X and X' is -C(O)-;
Y is -(C(R2)2)-;
R7 is H;
R10 is H2; and
R2 within the definition of Y is selected from hydrogen, -N(R ) or heterocyclyl, which may be optionally benzofused, and wherein said heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, -R9-
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3;
Also preferred are those compounds of formula V wherein X and X' is -C(O)-;
Y is -(C(R2)2)-;
R7 is H;
R10 is H2; and
R2 within the definition of Y is selected from the group consisting of:
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0002
Figure imgf000031_0001
Figure imgf000031_0003
Figure imgf000031_0004
those compounds according to formula V wherein:
Figure imgf000031_0005
at least one R2 withm the definition of Y is aryl optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9~
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; those compounds according to formula V wherein: X and X' is -C (0) - ;
Y is - (C(R2)2)-;
Figure imgf000031_0006
R10 is H2; ana at least one R^ w^th the definition of Y is C ~
Cg alkyl optionally substituted with R3 ; those compounds according to formula V wherein: X and X' is -C (0) - ; Y i s - ( C ( R2 ) 2 ) - ;
R7 i s H ; R1 0 i s H2 ; at least one R2 withm the definition of Y is C ~ Cg alkyl optionally substituted with R3; and at least one R3 withm the definition of Y is pyridyl, tπazolyl, oxazolyl, isoxazolyl, pyrimidyl, pyrazolyl, pyridazmyl, thiazolyl, imidazolyl, thienyl thiadiazolyl, oxadiazolyl, triazmyl or pyrazmyl wherein said R3 may be optionally substituted with 1-3 substituents selected from -OR9, -R9, -N(R9) (R9) , -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, -R9-OR9, -CN,
-CO2R9, -X-N(R9) (R9) , halogen, -N02, and -CF3. those compounds according to formula V wherein:
Figure imgf000032_0001
Y is -(C(R2)2)~;
R7 is H;
Figure imgf000032_0002
at least one R2 withm the definition of Y is C ~ Cg alkyl optionally substituted with R3; and
R3 withm the definition of Y is aryl optionally substituted with 1-3 substituents selected from -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0~X-N(R9)2,
-R9-OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3.
Also preferred are those compounds according to any of the aforementioned preferred compounds of formula V wherein: y is benzyl; and Z is
Figure imgf000033_0001
H
those compounds according to any of the aforementioned preferred compounds of formula V wherein:
R! is benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9) (R9), SR9, -X-R9, -R9-OR9, -CN, halogen, -N02, and -CF3; those compounds according to any of the aforementioned preferred compounds of formula V wherein:
R1 is benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9) (R9), SR9, -X-R9, -R9-OR9, -CN, halogen, -N02, and -CF3; and wherein Z is
Figure imgf000033_0002
those compounds according to any of the aforementioned preferred compounds of formula V wherein R^ is benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2 ; those compounds according to any of the aforementioned preferred compounds of formula V wherein R^ is benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2 and wherein Z is
Figure imgf000034_0001
An alternate embodiment of this invention is compounds according to formula V, wherein:
Figure imgf000034_0002
each R^ is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, "R9~ OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, -CF3, -0- (CH2) q-R6, -0- (CH2)q-OR9 , 2 , 3-methylenedioxy and
3, -methylenedioxy; and each X, X', Y, Y', Z, R1, R2, R3, R4, R5, R7 , R8, R9, Rz, Q, M, n, r, p, q and G is independently as defined for formula I; and those compounds according to formula V, wherein: each y is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9~ OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, -CF3, -0- (CH ) q-Rβ, -0- (CH ) g-OR9 , 2 , 3-methylenedioxy and
3, 4-methylenedioxy;
R2 within the definition of Y is selected from hydrogen, R3 or Cχ-Cg alkyl optionally substituted with
R3; and each X, X', Y, Y', Z, R1, R3, R4, R5, R7, R8, R9, Rz, Q, M, n, r, p, q and G is independently as defined for formula I. those compounds of formula V wherein X and X' is -C(0)-; Y is -N(R2)-; R7 is H; and R10 is H2; those compounds of formula V wherein X and X' is -C(0)-; Y is - (C(R2)2) -M-;
M is 0;
R7 is H; and
R10 is H2.
Also preferred is the compound of formula I having the structure of formula IX:
Figure imgf000035_0001
(IX) wherein
X is -C(0)- or -S(0)2~; and the compounds of formula IX wherein X is -C(0)-; Y i s - (C (R2 ) 2 ) -M- ; and
R7 is H; and those compounds of formula IX wherein X is -C(0)-;
Y is -N(R2)-; and R7 is H; and those compounds of formula IX wherein X is -C(0)-; Y is -(C(R2)2)-; and R7 is H.
Also preferred are those compounds of formula I having the structure of formula XII:
Figure imgf000036_0001
(xn) wherein
X and X' are independently -C(O)- or -S(0)2-/" those compounds of formula I having the structure of formula XII, wherein X and X' are independently -C(O)- or -S(0)2_; and
R4 is l-amino-2-hydroxyindanyl; and compounds of formula I having the structure of formula XII, wherein R4 is 1 (S) -amino-2 (R) -hydroxyindanyl .
Also preferred are the compounds according to formula I, having the structure of formula XIII:
Figure imgf000036_0002
wherein
X and X' are independently -C (0) - or -S(0)2_ compounds according formula I having the structure of formula XIII, wherein
X is -C (0) - or -S (0) 2-;
Figure imgf000037_0001
Y i s - ( C ( R2 ) 2 ) - or -N ( R2 ) - ; and
R7 is H; compounds of formula I having the structure of formula XIII, wherein
Figure imgf000037_0002
those compounds of formula XIII wherein
Figure imgf000037_0003
X' is -C(O)-;
Y is -(C(R2)2)-;
Figure imgf000037_0004
R2 withm the definition of Y is selected from hydrogen, R3, or C -Cg alkyl optionally substituted
Figure imgf000037_0005
those compounds according to formula XIII wherein: X is -C(O)-;
Figure imgf000037_0006
R7 is H; ana
R2 withm the definition of Y is selected from hydrogen, -N(R9)2 or heterocyclyl, which may be optionally benzofused, and wherein said heterocyclyl may be optionally substituted with 1-3 groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9~
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; those compounds according to formula XIII wherein:
Figure imgf000037_0007
Y is -(C(R2)2)-;
Figure imgf000037_0008
at least one R2 within the definition of Y is selected from the group consisting of:
Figure imgf000038_0001
Figure imgf000039_0001
those compounds according to formula XIII wherein: X is -C(0)-; X' is -C(0)-; Y is -(C(R2)2)-;
R7 is H; and at least one R2 within the definition of Y is aryl optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2/ -R9- OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; those compounds according to formula XIII wherein: X is -C(0)-; X' is -C(0)-;
Y is -(C(R2)2)-;
R7 is H; and at least one R2 within the definition of Y is C ~
Cg alkyl optionally substituted with R3; those compounds according to formula XIII wherein: X is -C(O)-; X' is -C(O)-;
Y is -(C(R2)2)-;
R7 is H; and at least one R3 within the definition of Y is pyridyl, triazolyl, oxazolyl, isoxazolyl, pyrimidyl, pyrazolyl, pyridazinyl, thiazolyl, imidazolyl, thienyl thiadiazolyl, oxadiazolyl, triazinyl or pyrazinyl wherein said R3 may be optionally substituted with 1-3 substituents selected from -OR9, -R9, -N(R9) (R9),
-N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, -R9-OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, or -CF3; those compounds according to formula XIII wherein: X is -C(O)-; X' is -C(O)-;
Y is -(C(R2)2)-;
R7 is H; and
R3 within the definition of Y is aryl optionally substituted with 1-3 substituents selected from -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2,
-R9-OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, or -CF3; those compounds according to any of the aforementioned preferred compounds of formula XIII wherein: each R1 is benzyl; and each R9 not within the definition of Y is 2- hydroxyindanyl ; those compounds according to any of the aforementioned preferred compounds of formula XIII wherein: each R! is independently selected from benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9) (R9'), SR9, -X-R9, -R9-OR9, -CN, halogen, -NO2, and -CF3; those compounds according to any of the aforementioned preferred compounds of formula XIII wherein: each R! is independently selected from benzyl optionally substituted with 1-3 substituents selected from -OR9, -N(R9) (R9), SR9, -X-R9, -R9-OR9, -CN, halogen, - O2, and -CF3; and each R9 not within the definition of Y is 2- hydroxyindanyl ; those compounds according to any of the aforementioned preferred compounds wherein: each Rl is independently selected from benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2; and those compounds according to any of the aforementioned preferred compounds wherein: each RI is independently selected from benzyl optionally substituted with 1-3 substituents selected from the group consisting of OCH3, OH and NH2 ; each R9 not within the definition of Y is 2- hydroxyindanyl .
Another embodiment is compounds according to formula XIII, wherein:
each RD is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2/ -R9~ OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, -CF3, -0- (CH2) q-R6, -0- (CH2) q-OR9 , 2, 3-methylenedioxy and 3, -methylenedioxy; and each X, X', Y, Y', Z, R1, R2, R3, R4, R5, R7, R8, R9, Rz, Q, M, n, r, p, q and G is independently as defined for formula XIII.
Another embodiment is compounds according to formula XIII, wherein:
Figure imgf000042_0001
(XIII)
wherein R2 within the definition of Y is selected from hydrogen, R3 or Cχ-Cg alkyl optionally substituted with
R3; each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9~
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, -CF3, -0- (CH2) q-R6, -0- (CH2 ) q-0R9 , 2, 3-methylenedioxy and
3, 4-methylenedioxy; and each X, X', Y, Y', Z, R1, R3, R4, R5, R7, R8, R9, Rz, Q, M, n, r, p, q and G is independently as defined for formula XIII . Another embodiment is compounds of formula I having the structure of formula XIII, wherein X is -C(0)-; X' is -C(0)-;
Y is -N(R2)-; and R7 is H; compounds of formula I having the structure of formula XIII, wherein
X is -Sθ2~;
X' is -C(0)-;
Y is - (C(R2)2)-; and R7 is H; and compounds of formula I having the structure of formula XIII, wherein
X is -Sθ2~;
X' is -C(O)-; Y is -N(R2)-; and R7 is H.
In an alternate embodiment, preferred compounds are those of formula V wherein R10 is H2; and Z is selected from the group consisting of:
Figure imgf000043_0001
and R2 is as defined in formula I; and those of formula V wherein Z is selected from the group consisting of
Figure imgf000043_0002
R1 0 is H2 .
Also preferred are those compounds of formula V wherein X and X' is -C(0)-; Y is - (C(R2)2)-;
R7 is H;
R10 is H2; and those compounds of formula V wherein X and X' is -C(0)-; Y is -N(R2)-; R7 is H; R10 is H2; and those compounds of formula V, wherein X and X' is -C(O)-; Y is - (C(R2)2)-M-;
M is 0;
R7 is H;
R10 is H2; and the aforementioned compounds of formula V wherein Z is selected from the group consisting of:
Figure imgf000044_0001
and R2 is as defined in claim 1. Also preferred are those compounds of formula
V wherein X and X' is -C(O)-; Y is -(C(R2)2)-;
R7 is H;
R10 is H2; and those compounds of formula V wherein X and X' is -C(0) -; Y is -N(R2)-; R7 is H;
R10 is H2; and those compounds of formula V, wherein X and X' is -C(0) -;
Y is - (C(R2)2)-M-;
M is 0;
R7 is H;
R10 is H2; and the aforementioned compounds of formula V wherein Z is selected from the group consisting of:
Figure imgf000045_0001
Also preferred are compounds of formula I wherein:
Figure imgf000045_0002
Z is selected from the group consisting of -X'R4, -NtR1) -X'-R4, -NfR1) -NfR1) -X'-R4, and formula VI;
Figure imgf000045_0003
(VI) wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 members independently selected from R2 ; and each X, X', Y, Y' R1, R2, R3, R4 , R5, R6, R7 , R8, R9, Rz , Q, M, n, r, p, q and G is independently as defined in for formula I .
In another embodiment, compounds of formula I with structures VII, VIII, IX, and X are preferred:
Figure imgf000046_0001
(VIII )
( X )
where all definitions of variables for formula I apply. Preferred R2 groups for formula I include:
C -Cg alkyl and alkenyl optionally substituted with R6; where two R2 taken together form a spriocyclic ring and C3~Cg cycloalkyl or cycloalkenyl optionally fused with
Preferred compounds of this invention of formula I include the specific compounds contained in Tables 1-5. T.ABLE 1
Figure imgf000047_0001
wherein Rz is as defined in formula I and A and Z are as follows
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
TABLE 2
Figure imgf000074_0001
wherein Rz is as defined in formula I and A, R-*- and Z are as defined below .
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
- 71
Figure imgf000080_0001
Figure imgf000081_0001
10 -
Figure imgf000082_0001
il -
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
14 -
Figure imgf000086_0001
15 -
Figure imgf000087_0001
Figure imgf000088_0001
17 -
Figure imgf000089_0001
T.ABLE 3
Figure imgf000090_0001
wherein Rz is as defined in formula I and A and Z are as defined below.
Figure imgf000090_0002
19 -
T.ABLE 4
Figure imgf000091_0001
wherein Rz is as defined in formula I and A and Z are as defined below.
Figure imgf000091_0002
Preferably, in compound of formula (Z' ) , A is selected from:
Figure imgf000092_0001
wherein R and R are as defined above for formula (I), p and R is optionally substituted with -OR .
Preferably, Z in compound of formula (Z') is selected from:
Figure imgf000092_0002
Figure imgf000092_0003
Figure imgf000092_0004
wherein Rz, W and R are as defined above for formula o 2
(I) and R is optionally substituted with -OR .
The prodrugs of the present invention may be synthesized using conventional synthetic techniques. Aspartyl protease inhibitors which are precursors of the prodrugs of the present application are disclosed m WO 97/27180, the disclosure of which is incorporated herein by reference. Prodrugs of formula (I) of the present invention can be readily synthesized from the WO 97/27180 compounds using conventional techniques. One of skill m the art would be well aware of conventional synthetic reagents to convert the -OH group of the WO 97/27180 compounds to a desired -ORz functionality of the present invention, wherein Rz is as defined above. The relative ease with which the compounds of this invention can be synthesized represents an enormous advantage m the large scale production of these compounds.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known m 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 m 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., Rz) from one heteroatom withm the molecule to another heteroatom. These protease inhibitors and their utility as inhibitors of aspartyl proteases are described m WO 97/27180, 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 m 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 m vivo metabolism result m a greater bioavailability of the drug. As a result, the pill burden on a patient is signi icantly reduced.
The prodrugs of this invention may be employed m a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events m their life cycle. Sucn methoαs of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For examo.e, a prodrug of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally-mfected patient m a pharmaceutically acceptable manner and m 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, dideoxycytidme, trisodium phosphonoformate, eflornithine, πbaviπn, acyclovir, alpha interferon and trimenotrexate . Additionally, non-nucleoside inhibitors of reverse transcriptase, such as TIBO or nevirapme, may be used to potentiate the effect of the compounds of this invention, as may viral uncoatmg inhibitors, inhibitors of trans- activat g proteins such as tat or rev, or inhibitors of the viral tegrase. Combination therapies according to this invention exert a synergistic effect 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 preventing the replication of HIV 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 combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors. We believe that the co-admmistration of the compounαs 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 mfectivity and its associated symptoms.
The prodrugs of this invention can also be administered m combination with lmmunomodulators e.g., bropirim e, anti-human alpha mterferon antioody, IL-2, GM-CSF, methionme enkephal , mterferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) ; and antibiotics (e.g., pentamidme lsethiorate) to prevent or combat infection ana disease associated with HIV infections, such as AIDS and ARC.
Wnen the prodrugs of this invention are administered 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 m 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 m particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelm 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 m 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, glycme, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts cr electrolytes, such as protamme sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, z c salts, colloidal silica, magnesium trisilicate, polyvmyl 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, vagmally 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, mtracutaneous, intravenous, intramuscular, mtra-articular, mtrasynovial, intrasternal, mtrathecal, tralesional and mtracranial injection or infusion techniques.
The pharmaceutical compositions may be the form of a sterile mjectable preparation, for example, as a sterile mjectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile mjectable preparation may also be a sterile mjectable solution or suspension m a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution m 1, 3-butanedιol . .Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and lsotomc 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 diglyceπdes . Fatty acids, such as oleic acid and its glyceride derivatives are useful m the preparation of jectables, as are natural pnarmaceutically-acceptable oils, such as olive oil or castor oil, especially 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 m 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 m 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-irritatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m 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, polyoxy- ethylene 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 w ll 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. 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 wnich 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:
1. A compound of formula (I) :
Figure imgf000104_0001
wherein : each Z is
Figure imgf000104_0002
wherein any Z may be optionally fused with R6; each X and X' is independently selected from the group consisting of -C(O)-, -C(0)C(0)-, -S(0)- and -S(0)2; each Y and Y' is independently selected from the group consisting of -(C(R2)2)p~, -NR2-, - (C (R2 ) 2 ) p- -, >C=C(R2)2, and -N (R2 ) -CH2-; each y is independently selected from the group consisting of hydrogen; R6; C -C6 alkyl; C2-C5 alkenyl; C2-C5 alkynyl; C3-C6 cycloalkyl optionally fused with R"; C5~Cg cycloalkenyl optionally fused with R^; and where R1 ' s are attached to adjacent atoms, the R^ ' s together with their attached adjacent atoms form a carbocyclic or heterocyclic ring system which may be optionally fused with R6; where any member of R1 may be optionally substituted by one or more -ORz, -C(W)-ORz, wherein W is 0, S or NH, -R2; each R2 is independently selected from hydrogen; R3; Cχ-Cg alkyl; C2-C6 alkenyl; C2~Cζ alkynyl; C3-C6 cycloalkyl optionally fused with R6; C5-C6 cycloalkenyl optionally fused with R^; and where two R2 ' s are attached to the same geminal atom, the R2 ' s together with their attached geminal atom may form a spirocarbocyclic or spiroheterocyclic ring system; where any member of R2 may be optionally substituted by one or more R3; each R3 is independently selected from oxo, OR9, N(R9)2, N(R9)-X-R9,N(R9)-X-OR9, N (R9) -X-N (R9) 2 , SR9, X-
R9, 0-X-N(R9)2, C(0)N(R9)2, halogen, N02, CN, COOR9 and R6; each R4 is independently selected from from the group consisting of OR9; N(R9)2; X-R9; C(0)N(R9)2; R6; Cχ-Cg alkyl; C2-C4 alkenyl; Cβ-Cg cycloalkyl optionally fused with R6; C5-C6 cycloalkenyl optionally fused with R6; where any member of R^ may be optionally substituted by one or more groups independently selected from the group consisting of -0Rz, -C(W)-RZ, wherein W is 0, S or NH, R9 and R3; each R^ is independently selected from the group consisting of H, OH, 0, and R1 ; each Rz is independently selected from
Figure imgf000105_0001
J wherein each M" is independently selected from H, Li, Na, K, Mg, Ca, Ba, -N(R2)4, Cχ-C12-alkyl, C2-Cχ2~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 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;
M' is H, Cχ-Cχ2-alkyl, C2-C -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(02), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R° 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, -OCF3, -S(0)n-R6, -N(R2)-S (0)2 (R2) , halo, -CF3, or -N02 ;
T is 0, S, N(R2)2, or, when M' ' is absent, H;
K is P or S; J is 0 or S; and s is 0 or 1;
each R6 is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl may be optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9, -N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, ~R9- OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, and -CF3; each R7 is independently selected from the group consisting of hydrogen, OH and 0; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, and heterocyclyl; each R9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heterocyclyl, aralkyl, carbocyclylalkyl and heterocyclylalkyl wherein any aryl, carbocyclyl or heterocyclyl may be optionally fused with R8 and wherein any member of R8 may be optionally substituted by one or more groups independently selected from the group consisting of -OR8, -N(R8)2, -CN, -N02, -X-R8,
-X-N(R8)2/ -C(0)0R8, -N(R8)-XNR8, and halogen; each Q is independently selected from CH and N; each M is independently selected from the group consisting of NH, -NR2-, -0-, -S-, -S (0) - and -S(0)2-; each n is 1 or 2; each r is 0,1 or 2; each p is independently 1 or 2; each q is independently 1, 2 or 3; and each G is independently selected from the group consisting of -NH-, -NR2-, -0-, -S-, -S(O)-, S(0)2,
-C(0) -, and -C(R2)2-.
2. The compound according to claim 1 wherein: each Y and Y' is independently selected from the group consisting of -(C(R )2)p-, -NR2-, -(C(R2)2)p- M-, and -N(R2)-CH2-; and each R3 is independently selected from oxo, OR9, N(R9)2, N(R9)-X-R9, N(R9)-X-OR9, SR9, X-R9, 0-X-N(R9)2,
C(0)N(R9)2, halogen, N02, CN, COOR9 and R6; each RZ is selected from:
Figure imgf000108_0001
O
.NH,
-P03 (NH ) 2 , -CH2-OP03Na2 , ' - (L) -serine,
Figure imgf000108_0002
- . ( / ,
Figure imgf000108_0003
NH2
(L)-valme, - (L) -glutamic acid, - (L) -aspartic acid,
- (L) -γ-t-butyl-aspartic ac id, A 3.
- (L) - (L) -3-pyridylalanine, - (L) -histidine, -CHO, -ΥF-,
Figure imgf000108_0004
0 0 0
I I I I I I pto- ^, NMe3 + -"Υ pro-
0. 0. yv\ 0.
P03κ2' Pθ3Ca, Pθ3-spermine, PO3- (spermidine) 2 or PO3- (meglamine) 2.
3. The compound according to claim 1 wherein: n is 2 ; and
R5 is R7.
4. The compound according to claim 1 wherein: n is 2 ; three of the R^ radicals are H; and the other R5 is R1.
5. The compound according to claim 1 wherein: n is 1 ; and the two R5 radicals are either H or are taken together to form a carbonyl .
6. The compound according to claim 5 wherein X and X' is -C(0)-.
7. The compound according to claim 5 wherein Y is -C(R )2-.
8. The compound according to claim 5 wherein Z is - 10!
Figure imgf000110_0001
H
A compound of formula (IV)
Figure imgf000110_0002
wherein:
X and X' are independently -C(O)- or -S(0) -;
Y is - (C(R2)2)-M-, -(C(R2)2)p-, -N(R2)- or -N(R2)-
CH -; and each R1, R2, R7, R4, p, RZ and M is independently as defined in claim 1.
10. A compound of formula (IX) :
Figure imgf000110_0003
(IX) wherein
X is -C(O)- or -S(0) -; and
R7 is H.
11. A compound of formula (XII) :
Figure imgf000111_0001
(xπ) wherein X and X' are independently -C (0) - or -S(0)2-.
12. The compound according to claim 11 wherein R7 is H.
13. The compound according to claim 11 wherein R4 is l-amino-2-hydroxyindanyl .
14. A compound of formula (XIII) : of formula XIII:
Figure imgf000111_0002
wherein
X and X' are independently -C(0)- or -S(0) -;
Y is -(C(R2)2)- or -N(R2)-; and R7 is H.
15. The compound according to claim 14 wherein :
R2 within the definition of Y is selected from hydrogen, R3 or Cχ-Cg alkyl optionally substituted with
R3; and each R^ is independently selected from the group consisting of aryl, carbocyclyl and heterocyclyl, wherein said aryl, carbocyclyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of oxo, -OR9, -R9,
-N(R9) (R9), -N(R9)-X-R9, SR9, -X-R9, -0-X-N(R9)2, -R9-
OR9, -CN, -C02R9, -X-N(R9) (R9) , halogen, -N02, -CF3, -0- (CH2)q-R6, -0- (CH2) q-OR9 , 2, 3-methylenedioxy and 3, 4-methylenedioxy .
16. The compound according to any of claims 1-7 and 9-15 wherein Z is selected from the group consisting of -X'R4, -N (R1 ) -X ' -R4, -N (R1 ) - (R1 ) -X ' -R4 , and formula VI;
Figure imgf000112_0001
wherein any structure of formula VI is optionally fused with an aryl, carbocyclic or heterocyclic ring and is optionally substituted with 1-3 members independently selected from R2 and wherein R2 is as defined in claim 1.
17. The compound according to any of claims 1-7 and 9-15 wherein Z is selected from the group consisting of:
Figure imgf000112_0002
- I l l -
Figure imgf000113_0001
wherein R2 is 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.
PCT/US1998/027510 1997-12-24 1998-12-24 Prodrugs of aspartyl protease inhibitors WO1999033795A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20121/99A AU2012199A (en) 1997-12-24 1998-12-24 Prodrugs of aspartyl protease inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7030997P 1997-12-24 1997-12-24
US60/070,309 1997-12-24

Publications (1)

Publication Number Publication Date
WO1999033795A1 true WO1999033795A1 (en) 1999-07-08

Family

ID=22094523

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/027510 WO1999033795A1 (en) 1997-12-24 1998-12-24 Prodrugs of aspartyl protease inhibitors

Country Status (2)

Country Link
AU (1) AU2012199A (en)
WO (1) WO1999033795A1 (en)

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038332A1 (en) * 1999-11-24 2001-05-31 Merck & Co., Inc. Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as hiv protease inhibitors
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
WO2006138265A3 (en) * 2005-06-14 2007-03-01 Schering Corp Heterocyclic aspartyl protease inhibitors, preparation and use 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
US7462636B2 (en) 2002-05-17 2008-12-09 Tibotec Pharmaceuticals Ltd Broadspectrum substituted benzisoxazole sulfonamide HIV protease inhibitors
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
US7659404B2 (en) 2001-02-14 2010-02-09 Tibotec Pharmaceuticals Ltd. Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors
CN101671307A (en) * 2003-12-15 2010-03-17 先灵公司 heterocyclic aspartyl protease inhibitors
US7723310B2 (en) 2004-10-18 2010-05-25 Three Rivers Pharmaceuticals, Llc Large dose ribavirin formulations
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
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
EP2460408A1 (en) 2004-12-17 2012-06-06 deVGen N.V. Nematicidal compositions
US8318731B2 (en) 2007-07-27 2012-11-27 Janssen Pharmaceutica Nv Pyrrolopyrimidines
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
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
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
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
WO2021170600A1 (en) 2020-02-24 2021-09-02 Katholieke Universiteit Leuven Pyrrolopyridine and imidazopyridine antiviral compounds
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4308096A1 (en) * 1993-03-13 1994-09-15 Hoechst Ag Prodrug derivatives of enzyme inhibitors with hydroxyl groups, process for their preparation and their use
WO1995014016A1 (en) * 1993-11-18 1995-05-26 Merck & Co., Inc. Prodrugs of an inhibitor of hiv protease
JPH08109180A (en) * 1994-10-11 1996-04-30 Hamari Yakuhin Kogyo Kk Acyl group intramolecular shifting (o to n)-type prodrug
US5585397A (en) * 1992-09-08 1996-12-17 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
WO1997027180A1 (en) * 1996-01-26 1997-07-31 Vertex Pharmaceuticals Incorporated Aspartyl protease inhibitors
US5686444A (en) * 1995-04-05 1997-11-11 Cephalon, Inc. Selected soluble esters of hydroxyl-containing indolocarbazoles

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5585397A (en) * 1992-09-08 1996-12-17 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
DE4308096A1 (en) * 1993-03-13 1994-09-15 Hoechst Ag Prodrug derivatives of enzyme inhibitors with hydroxyl groups, process for their preparation and their use
WO1995014016A1 (en) * 1993-11-18 1995-05-26 Merck & Co., Inc. Prodrugs of an inhibitor of hiv protease
JPH08109180A (en) * 1994-10-11 1996-04-30 Hamari Yakuhin Kogyo Kk Acyl group intramolecular shifting (o to n)-type prodrug
US5686444A (en) * 1995-04-05 1997-11-11 Cephalon, Inc. Selected soluble esters of hydroxyl-containing indolocarbazoles
WO1997027180A1 (en) * 1996-01-26 1997-07-31 Vertex Pharmaceuticals Incorporated Aspartyl protease inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 125, no. 9, 26 August 1996, Columbus, Ohio, US; abstract no. 115155, KIMURA,TOORU ET AL.: "Preparation of tripeptides with improved water solubility as prodrugs for HIV protease inhibitors." XP002099380 *

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6642237B1 (en) 1999-11-24 2003-11-04 Merck & Co., Inc. Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides and uses thereof
WO2001038332A1 (en) * 1999-11-24 2001-05-31 Merck & Co., Inc. Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as hiv protease inhibitors
US7659404B2 (en) 2001-02-14 2010-02-09 Tibotec Pharmaceuticals Ltd. Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors
US7244752B2 (en) 2001-04-09 2007-07-17 Tibotec Pharmaceuticals Ltd. Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide HIV protease inhibitors
US7595334B2 (en) 2001-04-09 2009-09-29 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
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
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
CN101671307A (en) * 2003-12-15 2010-03-17 先灵公司 heterocyclic aspartyl protease inhibitors
CN102627609A (en) * 2003-12-15 2012-08-08 先灵公司 Heterocyclic aspartyl protease inhibitors
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
WO2006024488A2 (en) 2004-08-30 2006-03-09 Interstitial Therapeutics Medical stent provided with inhibitors of atp synthesis
US7723310B2 (en) 2004-10-18 2010-05-25 Three Rivers Pharmaceuticals, Llc Large dose ribavirin formulations
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
US8722708B2 (en) 2005-06-14 2014-05-13 Merck Sharp & Dohme Inc. Substituted isoindolines as aspartyl protease inhibitors
US9382242B2 (en) 2005-06-14 2016-07-05 Merck Sharp & Dohme Corp. Preparation and use of compounds as protease inhibitors
WO2006138265A3 (en) * 2005-06-14 2007-03-01 Schering Corp Heterocyclic aspartyl protease inhibitors, preparation and use thereof
WO2007045496A1 (en) 2005-10-21 2007-04-26 Universiteit Antwerpen Novel urokinase inhibitors
US7803836B2 (en) 2005-11-28 2010-09-28 Tibotec Pharmaceuticals Ltd. Aminophenylsulfonamide derivatives as HIV protease inhibitor
US8084494B2 (en) 2005-11-28 2011-12-27 Tibotec Pharmaceuticals Ltd. Substituted aminophenylsulfonamide compounds as HIV protease inhibitor
US8492377B2 (en) 2006-07-13 2013-07-23 Janssen Pharmaceutica Nv MTKI quinazoline derivatives
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
EP2289564A2 (en) 2006-09-08 2011-03-02 Bayer Schering Pharma Aktiengesellschaft Derivatives of aniline as precursors for F18-labeling
EP2279759A2 (en) 2006-09-08 2011-02-02 Bayer Schering Pharma Aktiengesellschaft Compounds and methods for 18F labeled agents
US8318731B2 (en) 2007-07-27 2012-11-27 Janssen Pharmaceutica Nv Pyrrolopyrimidines
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
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
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
US8318929B2 (en) 2008-03-10 2012-11-27 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines
US8609836B2 (en) 2008-03-10 2013-12-17 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
WO2011061295A1 (en) 2009-11-19 2011-05-26 Blue Medical Devices Bv Narrow profile composition-releasing expandable medical balloon catheter
WO2011141515A1 (en) 2010-05-14 2011-11-17 Bayer Pharma Aktiengesellschaft Diagnostic agents for amyloid beta imaging
US8785648B1 (en) 2010-08-10 2014-07-22 The Regents Of The University Of California PKC-epsilon inhibitors
US9376423B2 (en) 2010-08-10 2016-06-28 The Regents Of The University Of California PKC-epsilon inhibitors
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
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
US11548881B2 (en) 2017-05-11 2023-01-10 Remynd N.V. Compounds for the treatment of epilepsy, neurodegenerative disorders and other CNS disorders
WO2018206760A1 (en) 2017-05-11 2018-11-15 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
WO2021170600A1 (en) 2020-02-24 2021-09-02 Katholieke Universiteit Leuven Pyrrolopyridine and imidazopyridine antiviral compounds
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

Also Published As

Publication number Publication date
AU2012199A (en) 1999-07-19

Similar Documents

Publication Publication Date Title
WO1999033795A1 (en) Prodrugs of aspartyl protease inhibitors
AP1172A (en) Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors.
EP0749421B1 (en) Sulphonamide derivatives as aspartyl protease inhibitors
AP862A (en) Oxygenated heterocycle containing sulfonamide inhibitors of aspartyl protease.
AU706732B2 (en) THF-containing sulfonamide inhibitors of aspartyl protease
US20020082249A1 (en) Prodrugs of aspartyle protease inhibitors
AU722850B2 (en) Treatment of the CNS effects of HIV with VX-478, alone or in combination with AZT or 3TC
WO1999033792A2 (en) Prodrugs os aspartyl protease inhibitors
AU674702B2 (en) N-(alkanoylamino-2-hydroxypropyl)-sulfonamides useful as retroviral protease inhibitors
JP2006528964A (en) Glyoxalase inhibitor
MXPA00006316A (en) Prodrugs of aspartyl protease inhibitors
MXPA00006315A (en) Sulphonamide derivatives as prodrugs of aspartyl protease inhibitors
MXPA97008055A (en) Consistent aspartile protease inhibitors ensulfonamide containing oxygen heterocicle
CZ20002364A3 (en) Sulfonamide derivatives and pharmaceutical preparation, in which they are comprised

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase