WO1993002057A1 - Inhibiteurs de proteases retrovirales - Google Patents

Inhibiteurs de proteases retrovirales Download PDF

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Publication number
WO1993002057A1
WO1993002057A1 PCT/US1992/006047 US9206047W WO9302057A1 WO 1993002057 A1 WO1993002057 A1 WO 1993002057A1 US 9206047 W US9206047 W US 9206047W WO 9302057 A1 WO9302057 A1 WO 9302057A1
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amino
methyl
hydroxy
isopropyl
phenyl
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PCT/US1992/006047
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English (en)
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Thomas Joseph Carr
Peter Lawrence Demarsh
Goeffrey Bainbridge Dreyer
Ashley Edward Fenwick
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Smithkline Beecham Corporation
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Priority to EP92917238A priority Critical patent/EP0602069A4/fr
Priority to JP5503016A priority patent/JPH07500577A/ja
Publication of WO1993002057A1 publication Critical patent/WO1993002057A1/fr

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    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/12—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 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
    • C07D405/02—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
    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to retroviral protease inhibitor compounds, pharmaceutical compositions thereof, and a method of treating retroviral diseases therewith, including a method of treating disease states associated with human immunodeficiency virus (HIV-1, HIV-2).
  • HIV-1 human immunodeficiency virus
  • Retroviruses that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than
  • RNA-tumor viruses also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV), murine leukemia virus (MLV), mouse mammary tumor virus (MMTV), feline leukemia virus (FeLV), bovine leukemia virus (BLV), Mason-Pfizer monkey virus (MPMV), simian sarcoma virus (SSV), simian acquired immunodeficiency syndrome (SAIDS), human T- lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2), which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related
  • Such compounds are useful for inhibiting viral replication by inactivation of the protease.
  • the incorporation of heterocyclic elements in the P3' and P4' substrate positions of compounds containing a dipeptide isostere has been disclosed by deSolms et al . , J. Med. Chem. , 34, 2852 (1991).
  • these compounds can be less than desirable for obtaining optimal drug delivery in mammalian organisms, particularly in humans.
  • Some of these compounds can also have a less than desirable serum half-life, and therefore duration of action, because they contain amide bonds in relatively high proportion, and thus are prone to metabolic degradation, hepatic clearance, or other
  • the present invention provides compounds, hereinafter represented as formula (I), which bind to retroviral
  • proteases are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the present invention additionally provides a method for treating retroviral disease, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I).
  • R 1 and R 3 are each independently Q, Q-C 1-6 alkyl
  • Q is H, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, Ar or Het
  • R 2 is H or OH
  • R 4 is R 6 -NR 1 1 - or CONR 11 CHR 6 R 7 ;
  • R 5 is R 6 -NR 11- or R 10 -NR 1 1- ;
  • X is NR 11 , O or S
  • R 7 is Q, Q-C 1-6 alkyl or Q-C 2-6 alkenyl
  • R 8 and R 9 are each independently H, OH, halo, NO 2 , COR 12 , CF 3 , Ar, C 1-6 alkyl-R 15 , or R 17 (R 18 R 19 C) m , or together form a fused C 2-4 alkylene, aryl or heteroaryl moiety;
  • R 10 is A-(B) n -;
  • R 11 is H or C 1-4 alkyl
  • R 12 is R 7 , OR 7 , NR 7 R 11 or an amino acid or amino alcohol; B is an amino acid;
  • A is H, Ar, Het, R 17 (R 18 R 19 C) m , Ar-W, Het-W or
  • R 17 (R 18 R 19 C) m -W, or phthaloyl each optionally substituted by one to three groups chosen from R 15 or C 1-6 alkyl-R 15 ;
  • R 16 is H or C 1-6 alkyl
  • R 17 , R 18 and R 19 are independently: i) H, R 15 or
  • R 17 is as above and (R 18 R 19 C) are joined together to form a phenyl, naphthyl, C 3-6 cycloalkyl or Het ring, or iii) R 17 is as above and R 18 and R 19 together are
  • R 22 is H, C 1-6 alkyl, phenyl or phenyl-C 1-4 alkyl;
  • R 23 is - ⁇ '-(CH 2 ) q NR 24 R 25 , X"[((CH 2 ) r O) s ]R 26 ,
  • s is 1-6 and r is 1-3 within each repeating unit s;
  • X' is CH 2 , O, S or NH
  • X" is CH 2 , NR', O, S, SO or SO 2 ;
  • R 24 and R 25 are i) C 1-6 alkyl, optionally substituted by OH, C 1-3 alkoxy, or N(R') 2 , ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, O, S, SO, SO 2 , said heterocycle optionally substituted with C 1-4 alkyl, iii) aromatic heterocycle, optionally substituted with
  • R' is H or C 1-4 alkyl
  • U is NR' or O
  • R 27 is C 1-6 alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, C 1-3 alkoxy, CONR' 2 , NR' 2 , CO 2 R', SO 2 NR' 2 , CH 2 NR 2 , NR'COR', NR'SO 2 R', X" [ (CH 2 ) r O] s R' or CH 2 X"[ (CH 2 ) r O] s R';
  • R 28 is H, C 1-6 alkyl or together with R 27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
  • n 1-4;
  • n 0 or 1
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo .
  • nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule. Such compounds may occur as pure enantiomers or diastereomers or as a mixture of individual stereoisomers.
  • the definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • heterocyclic ring is an imidazole which can undergo
  • R 1 and R 3 are C 1-6 alkyl, Ar-Ci- ⁇ alkyl,
  • Ar-C 2-6 alkenyl, Ar-C 2-6 alkynyl, C 1-6 alkyl optionally
  • R 1 is benzyl and R 3 is benzyl, 4-hydroxybenzyl or phenylpropenyl.
  • R 2 is H.
  • X is S or N-R 11 .
  • X is NH.
  • R 4 is CONR 11 CHR 6 R 7 .
  • R 5 is R 10 -NR 11 .
  • R 5 is t- butyloxycarbonylamino or isopropyloxycarbonylamino.
  • R 7 is H, C 1-6 alkyl, C 3 -6cycloalkyl, phenyl or benzyl.
  • R 7 is C 1-6 alkyl. Isopropyl is most preferred.
  • R 8 is H, C 1-6 alkyl, COR 12 , NO 2 or Br .
  • R 8 is H .
  • R 9 is H, NO 2 , Br, COR 12 , CF 3 , Ar, C 1-6 alkyl or
  • R 12 is H, C 1-6 alkyl, Ar, OC 1-6 alkyl, NH 2 , and R 15 is OH .
  • R 9 is H or COR 12 .
  • B is Ala or Val .
  • m is 0 and B is absent.
  • A is Het, R 17 (R 18 R 19 C) m -W, Ar-W or Het-W.
  • R 17 , R 18 and R 19 are H, or C 1-4 alkyl, Het or Ar optionally substituted by one or two R 15 or C 1-6 alkyl-R 15 , or (R 18 R 19 C) are joind together to form a phenyl, C 3-6 cycloalkyl or Het ring.
  • R 17 (R 18 R 19 C) m - is Ar-CH 2 , Ar, Het, Het-CH 2 , C 1-6 alkyl or C 3 - 6 cycloalkyl optionally substituted by one to three groups selected from R 15 .
  • R 15 is OH.
  • R 17 or (R 18 R 19 C) are Het or Ar, Het is suitably quinolinyl, pyridyl, imidazolyl, thiazolyl, tetrahydrothiopyranyl or tetrahydropyranyl and Ar is phenyl.
  • R 23 is hydroxy-C 1-4 alkoxy, C ⁇ _ 4 alkoxy- C 1-4 alkoxy, or -O(CH 2 ) 2 NR 24 R 25 , wherein R 24 and R 25 are are a 5- or 6-membered heterocycle, such as morpholino.
  • Representative compounds of this invention are:
  • More preferred representative compounds are:
  • alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms.
  • C 1-4 alkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl; "C 1-6 alkyl” includes additionally pentyl, isopentyl,
  • Alkoxy refers to an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom.
  • Alkylthio refers to an alkyl group of the indicated number of carbon atoms attached through a bridging sulfur atom.
  • substituted alkyl as used herein is meant to include C 1-6 alkyl, Ar-C 1-6 alkyl, Het-C 1-6 alkyl, C 2-6 alkenyl, Ar-C 2-6 alkenyl, Het-C2-6 alkenyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkenyl-C 1-6 alkyl or C 1-6 alkyl substituted with acyl or hydroxyl.
  • Alkenyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms, which contains one or more carbon-carbon double bonds at any stable point along the chain, such as ethenyl, propenyl, butenyl,
  • Alkynyl refers to a straight or branched hydrocarbon chain of the indicated number of carbon atoms which contains a carbon-carbon triple bond at any stable point along the chain, such as ethynyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-methyl-3-propynyl, hexynyl and the like.
  • acyl means R 12 -CO, wherein R 12 is H ,
  • Cycloalkyl refers to a saturated ring group of the indicated number of carbon atoms.
  • C 3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
  • Cycloalkenyl refers to a saturated ring group of the indicated number of carbon atoms, having at least one endocyclic carbon-carbon double bond.
  • C 5-7 cycloalkenyl includes cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Aryl refers to phenyl or naphthyl, optionally substituted with one to three halo, OH, OR 10 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, CF 3 , amino, NO 2 , carboxy, C 1-4 alkylcarbonyl, aminocarbonyl,
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one to three halo, OH, alkyl, alkoxy, alkyl-Het, alkoxy-Het, alkyl-phenyl, alkoxy-phenyl.
  • heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
  • pyrazolidinyl imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, i ⁇ dolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.
  • Heteroaryl refers to a heterocycle which has aromatic character (eg., characterized by
  • Pyridine, imidazole, thiazole, furan and oxazole are examples of heteroaryl rings.
  • Amino acid means the D- or L- isomer of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,
  • amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem. , 158, 9 (1984) .
  • lipophilic amino acids are preferred for the moiety B, for instance, Val, Ala, Leu and lie.
  • a linkage B-O refers to an oxygen atom bonded to the carboxyl group of an amino acid
  • a B-N linkage indicates a nitrogen atom bonded to the carboxyl group of an amino acid, as in an amide bond.
  • Amino alcohol refers to an amino acid in which the carboxyl group has been reduced to a methylene hydroxy group.
  • Boc refers to the t-butoxycarbonyl radical.
  • Cbz refers to the carbobenzyloxy radical.
  • Bzl refers to the benyzl radical.
  • Ac refers to acetyl.
  • Ph refers to phenyl.
  • BOP refers to benzotriazol-1-yloxy- tris (dimethylamino)phosphonium hexafluorophosphate.
  • DCC refers to dicyclohexylcarbodiimide.
  • DMAP refers to dimethylamin-opyridine.
  • DMSO refers to dimethylsulfoxide.
  • HOBT refers to 1-hydroxybenzotriazole.
  • NMM is N- methylmorpholine.
  • DTT is dithiothreitol.
  • EDTA is
  • ethylenediamine tetraacetic acid DIEA is diisopropyl ethylamine.
  • DBU is 1.8 diazobicyclo[5.4.0]undec-7-ene.
  • DMSO is dimethylsulfoxide.
  • DMF is dimethyl formamide; Lawesson's reagent is 2,4-bis (4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide and THF is tetrahydrofuran.
  • HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
  • R 4 is CO-NR'CHR 6 R 7 , R 5 is R 10 R 11 N-, and R 1 , R 2 , R 3 and R 6 are as defined in formula (I), are prepared by:
  • R 1' , R 2' , R 3' , R 5' , R 6' and R 7' are as defined for formula (I) with any reactive groups protected, Pr 1 is H or a hydroxyl protecting group, and L' is OH or a leaving group; or
  • the coupling reactions may be accomplished by activating the substrate with a reactive functional group in situ or prior to the coupling reaction, such that it is reactive with an amino group.
  • acids may be converted to acid chlorides, bromides, activated esters or anhydrides, or by adding a coupling reagent.
  • Coupling agents are well known in the art for activating a functional group in situ,
  • Such agents are DCC and other carbodiimides, DMAPEC, BOP and PPA. These coupling agents may optionally be used with other reagents, such a HOBT, NMM and DMAP, which may facilitate the reaction.
  • Suitable leaving groups, L' are those which are
  • an amino group such as bromo, chloro, a substituted acyl (eg. trifluoroacetyl, bromobenzoyl,
  • A is a substituted alkyl group, such as
  • R 17 (R 18 R 19 C) m , L' may be a bromo, chloro, iodo or an alkyl or aryl sulonate.
  • A-L' may be a carboxylic acid halide, activated ester or anhydride, or a carboxylic acid in the presence of a coupling agent. Methods for preparing such compounds are well known.
  • A-L' may be a chloro- or bromo-formate, or an activated carbonate.
  • Haloformates may be prepared by reacting the appropriate alcohol with phosgene or
  • Activated carbonates may be prepared by reacting the appropriate alcohol with a suitable carbonate such as bis (4-nitrophenyl) carbonate.
  • A-L' may be a sulfonyl halide which may be prepared from the corresponding sulfonic acid.
  • A-L' may be a halothioformate, which may be prepared from a carbonyldihalide and an appropriate mercaptan.
  • A-L' may be a phosphonyl halide, which may be prepared from the corresponding phosphonic acid.
  • amino aldehydes are generally known or are prepared by methods well known in the art, for instance, by reduction of a suitable ⁇ -amino acid ester with diisobutylaluminum
  • acyl imidazoles may be prepared by coupling an ⁇ -amino acid to a substituted 4-amino-isoxazole, and
  • R 7' is C 1-6 alkyl and more preferably C 3-6 alkyl.
  • R 8 ' and R 9 ' are H, NO 2 , Br, COR 12 , CF 3 , Ar, C 1-6 alkyl or C 1-6 alkyl-R 15 , wherein R 12 is H, C 1-6 alkyl, Ar, OC 1-6 alkyl, NH 2 , and R 15 is OH or a protected hydroxyl group.
  • R 9 is H or COR 12 .
  • Thioamides are commonly prepared from carboxamides by reacting the corresponding carboxamides with a reagent such as Lawessons reagent, as disclosed, for instance, by Hamada et al . , Tet . Lett . , 931 (1991).
  • Suitable displaceable groups are those which are displaced by a sulfur nucleophile. such as chloride, bromide, iodide, mesylate, p-tolunesufonate groups, and the like.
  • the acid may be coupled to an appropriately organic compound
  • R 1' -R 4 ', R 7 ' and R 8 ' are as defined in formula (I) with any reactive groups protected, L' is a leaving group, such as halogen, and Pr 1 is a hydroxy-protecting group
  • R 4 is R 6 NR 11 - are prepared in an analogous manner from a compound of formula (IX):
  • acetyl, benzyl and silyl groups are useful for protecting the hydroxyl group.
  • the acetyl group is commonly removed by reacting the compound with a base, such as an alkali metal hydroxide, in a mixture of an alcohol and water.
  • the silyl group such as trimethyl silyl, dimethyl-t-butyl silyl, and t-butyl-diphenyl silyl may be removed by a fluoride reagent, such as a tetra-alkyl ammonium fluoride, or by acid
  • the benzyl group may be removed by catalytic hydrogenation.
  • Suitable protecting groups for the amino group are those disclosed by Greene et al. , as indicated previously.
  • the benzyloxycarbonyl and t-butoxycarbonyl groups are especially useful amino protecting groups.
  • the present invention includes pharmaceutically acceptable acid addition salts.
  • Acid addition salts of the present compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric,
  • cationic salts may be prepared.
  • the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation.
  • an alkaline reagent such as a hydroxide, carbonate or alkoxide, containing the appropriate cation.
  • Cations such as Na + , K + , Ca ++ and NH 4 + are examples of cations present in pharmaceutically acceptable salts.
  • Certain of the compounds form inner salts or zwitterions which may also be acceptable.
  • the compounds of the present invention selectively bind to retroviral proteases in the same manner as the virally coded natural substrates of the proteases and compete with these substrates for protease, thereby serving to inhibit viral replication by blocking the formation of crucial viral proteins from polyprotein precursors by the protease, and hence, to inhibit disease progression in vivo .
  • the present compounds achieve such beneficial therapeutic effect because they contain unique structural features which impart
  • sequences of the protease binding and peptide bond cleavage sites of various retroviruses appear to be highly conserved, an inhibitor is likely to be broadly active against more than one retrovirus.
  • DNA viruses which are dependant upon virally encoded proteases, such as the hepatitis virus, may also be susceptible to such treatment.
  • the compounds of formula (I) are used to inhibit retroviral replication, and are useful in treating mammals, particularly human patients, who are infected with
  • a human comprises internally administering (e.g. orally, parenterally, buccally, trans-dermally, rectally or by insufflation) to said mammal an effective amount of a compound of formula (I), preferably dispersed in a pharmaceutical carrier.
  • Dosage units of the active ingredient may be selected by procedures routine to one skilled in the art, and are generally in the range of 0.01-50 mg/kg. These dosage units may be administered one to ten times daily for acute or chronic infection. Preferably the compound is administered at a level of 1-10 mg/kg, two to four times daily. No unacceptable toxicological effects are indicated when compounds of this invention are administered in the above noted dosage range.
  • the present invention also provides a method of treating disease states associated with HIV infection or Acquired Immune Deficiency Syndrome (AIDS), comprising administering an effective amount of a compound of formula (I), preferably dispersed in a pharmaceutical carrier.
  • AIDS Acquired Immune Deficiency Syndrome
  • Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of the present invention.
  • anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen.
  • Nucleoside analogues which include 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyadenine (ddA) and 3'-azido-2',3'-dideoxythymide (AZT), are especially useful.
  • AZT is a preferred agent.
  • pharmaceutical compositions comprise an anti-viral agent, a protease
  • This invention is also a pharmaceutical formulation which comprises a compound of formula (I) and a
  • compositions of the compounds of the present invention, or derivatives thereof may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral
  • compositions may be added to enhance or stabilize the
  • Liquid carriers include syrup, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water.
  • Solubilizing agents such as dimethylsulfoxide, ethanol or formamide
  • Carriers such as oils, optionally with solubilizing excipients, are especially suitable.
  • Oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid, which is capable of dissolving lipophilic compounds. Natural oils, such as triglycerides are representative.
  • another aspect of this invention is a pharmaceutical composition comprising a compound of formula (I) and an oil.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when
  • the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • a suitable dosage form for oral administration has been prepared by dissolving the peptide of Example 1 (312.5 mg) in dimethyl sulfoxide (1 mL) and diluting to a concentration of 12.5 mg/mL with soybean oil.
  • a suitable dosage form for intravenous administration has been prepared by dissolving the compound of Example 1 (0.02 g) in dimethyl sulfoxide (1 mL) and diluting to 20 mL with a 70% propylene glycol/30% ethanol solution.
  • a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • the pharmacological activity of the compounds of this invention may be demonstrated by enzyme assays to determine the inhibitory activity of the retroviral protease, by in vitro cellular-based assays to determine the ability of the compounds to penetrate cells and inhibit viral replication, and by pharmacokinetic assays to determine oral
  • the ability of the compounds of this invention to inhibit the HIV-1 protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci . , U. S.A. , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000.
  • TheK i for the compounds of this invention are in the range of 1 nM to 5 ⁇ M.
  • Preferred compounds have K i 's of less than 100 nM.
  • the IC50 for the compounds of this invention are in the range of 0.1 to 10 ⁇ M.
  • T-lymphocytes trypan blue stained cells
  • tetrazolium salt XTT (2,3-bis[2-methoxy-4-nitro-5- sulfophenyl]-2H-tetrazolium-5-carboxanilide sodium salt), to its formazan dye.
  • the XTT assay allows determination of the 50% toxic concentration of compounds for the cell/virus system used.
  • Dual jugular cannulated Sprague Dawley rats weighing 200 to 250 g were utilized in all studies. All dosing and sample collection was done from conscious rats. Before dosing, a time 0 blood sample, 300 ⁇ L, was drawn using one of the catheters. Utilizing the second catheter the rats were dosed intravenously. At 1, 10, 30, 60, 90, 120, 150, 180 and 210 min after dosing, 300 ⁇ L blood samples were drawn. The rats dosed orally were administered the compound by utilizing a 22 gauge gastric gavage needle and samples were drawn at 30, 60, 90, 120, 240, 360, 480, 600, 720 and 1440 min.
  • the blood samples were placed in precooled tubes containing 30 mL of sodium citrate and centrifuged in a microfuge. The plasma was transferred then snap frozen on dry ice, and stored at -70°C until analyzed.
  • Standard stock solutions (1 mg/mL) of inhibitor was prepared in 100% DMSO.
  • a dilution series of the stock solutions were prepared in a total volume of 0.1 mL (pooled normal rat plasma/DMSO) to yield final concentrations of 0 and 0.5-120X the K i of the inhibitor. All dilutions were performed in triplicate. These spiked plasma solutions were extracted with 0.5 mL acetonitrile by vigorous vortexing, followed by centrifugation for 10 min.
  • v i /v 0 [AE t - I t - K i + (K i -AE t -I t ) 0.5 ]/(2AE t )
  • E t is the total enzyme concentration at time zero
  • K i is the apparent inhibition constant
  • A is the fraction of active enzyme.
  • the data was plotted as the natural log (In) of the plasma concentration versus time on semilogarithmic paper to generate the plasma concentration-vs-time curves.
  • the apparent terminal rate constant was determined form the linear regression analysis of the plasma
  • concentration-vs-time curve was determined by using the In/log trapezoidal rule.
  • C max represents the maximal plasma concentration and t max , the time following drug
  • Mass spectra were performed using fast atom bombardment (FAB) or electro-spray (ES) ionization. Melting points were taken on a Thomas-Hoover capillary melting point apparatus and are uncorrected.
  • J indicates the NMR coupling constant in
  • Celite® is filter aid composed of acid washed
  • Florisil® is an activated magnesium silicate chromatographic support and is a registered trademark of
  • Example 1(c) (0.140 g) was stirred in THF at room temperature under an argon atmosphere.
  • Tetrabutyl ammonium fluoride (0.38 mL, 6 eq) was added and the solution was stirred overnight. The mixture was diluted with water and extracted with dichloromethane (3X). The combined organic extracts were washed with water and
  • Boc-valineamide (0.5 g) was stirred in dry THF at room temperature under argon. Lawesson's reagent (1.56 g, 0.6 eq) was added and the mixture was stirred overnight. The solvent was evaporated and the residue chromatographed (silica, 2.5% methanol/dichloromethane) to give the title compound as a white solid (0.373 g, 70%). NMR(CDCl 3 ) ⁇ 8.59 (1H, br s),
  • Boc-valinethioamide (0.265 g) was stirred in dry acetone under argon at -10°C.
  • Ethylbromopyruvate (0.16 mL, 1.1 eq) was added and stirred for 1 h at -10°C.
  • the solution was poured into a well-stirred mixture of chloroform and water and then saturated with sodium bicarbonate.
  • the organic phase was separated and the aqueous layer extracted with chloroform.
  • the combined organic extracts were dried over MgSO 4 , filtered, and evaporated to an oil.
  • the oily residue was treated with trifluoroacetic anhydride (0.16 g) and pyridine (0.2 g) in dichloromethane for 1 h at -20°C.
  • Example 2 (c) The compound of Example 2 (c) (50 mg) was stirred in THF at 0°C. Excess 1.0N NaOH was added and the mixture was stirred for 12 h at 0°C. The mixture was diluted with 1.0N citric acid and extracted with dichloromethane (3X). The combined organic extracts were evaporated and dried in vacuo to give the title compound (0.045 g, 98%). NMR(CDCl 3 ) ⁇ 8.08
  • Example 2(e) The compound of Example 2(e) (52 mg) was stirred in neat trifluoroacetic acid for 10 min and evaporated. The residue was diluted with methanol and treated with 2 eq of cone. HCl. The solvents were evaporated and dried in vacuo to give a white solid. This solid (40 mg) was added to a solution of (2R,4S,5S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-5-(t- butoxycarbonyl) amino-6-phenyl-hexanoic acid (97 mg, 1.1 eq), DCC (38 mg, 1.1 eq), and HOBT (0.05 g, 2.2 eq) in DMF at room temperature under argon.
  • N-methylmorpholine (0.04 mL; 2.2 eq) was added and the mixture was stirred overnight.
  • the mixture was filtered through Celite®, evaporated, and diluted with ethyl acetate.
  • the solution was washed successively with 1.0N citric acid, 5% aqueous sodium bicarbonate, and sat. aqueous sodium chloride.
  • the organic layer was
  • Example 2(f) The compound of Example 2(f) (60 mg) was stirred in dry THF under argon and tetrabutylammonium fluoride (0.50 mL, 6 eq) was added. The solution was stirred at room temperature overnight. After diluting with water, the aqueous layer was extracted with dichloromethane (3X). The combined organic extracts were washed with water, evaporated, and triturated with diethyl ether and ethyl acetate to give a tan solid.
  • Example 2(c) The compound of Example 2(c) was stirred in neat quinoline. Cu powder (0.50 g) was added and the suspension was heated to 160°C for 2 h. After cooling to room
  • Example 2(f) -2(g) Following the procedure of Example 2(f) -2(g), except using the compound of Example 3(a) in place of (1'S)-1'-(t- butoxycarbonyl)amino-1'-isopropyl-1'-(4-aminocarbonylthiazo- 2-yl)methane, the title compound was prepared (88%).
  • Example 4(a) The compound of Example 4(a) (2.76 g) was stirred in methanol. 10% palladium on activated carbon (Pd/C) (250 mg) was added and hydrogen gas was bubbled through the solution for 1 h. The reaction was maintained under an hydrogen atmosphere overnight. The mixture was filtered through
  • Example 4 (c) The compound of Example 4 (c) was stirred in dry THF and tetrabutyl ammonium flouride (0.6 mL, 6 eq) was added. The mixture was stirred under argon overnight at room
  • Example 7(a) Following the procedure of Example 1(a) -1(d), except substituting the compound of Example 7(a) for (1'S)-1'- carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2-yl)methane, the title compound was prepared. NMR(CD 3 OD) ⁇ 7.15 (15H, m),
  • Example 9 (d) Using the procedure of Example 9 (d), except starting from (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-phenyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide (67 mg), the title compound was prepared (30 mg, 54%). NMR(CDCl 3 ) ⁇ 7.52-
  • Example 1 (a) The product of Example 1 (a) (273 mg, 1 mmol) was heated at 40°C for 2 h in methyl iodide (5 mL). The reaction mixture was evaporated, and the residue was suspended in aqueous Na 2 CO 3 . The mixture was extracted with
  • Example 9 (d) Following the procedure of Example 9 (d), except using (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-(3-phenylpropargyl) hexanamide, the title compound was prepared (161 mg, 79%).
  • Example 1(c) The product of Example 1(c) (0.20 g, 0.31 mmol) was dissolved in trifluoroacetic acid and stirred at room temperature
  • dichloromethane, 2 eq dichloromethane, 2 eq
  • 4-dimethylaminopyridine 0.75 g, 2 eq
  • dichloromethane 40 mL
  • the mixture was then partitioned between dichloromethane and saturated aqueous Na 2 CO 3 , and the organic extract was dried over Na 2 CO 3 .
  • the solvent was removed in vacuo, and the residue was
  • Example 14(a) To a solution of the compound of Example 14(a) (134.5 mg, 0.24 mmol) in dichloromethane (40 mL) under an argon atmosphere, benzyloxyethyl 4-nitrophenyl carbonate (160 mg, 2 eq) and 4-dimethylaminopyridine (60 mg, 2 eq) were added. The resulting mixture was allowed to stir at room temperature overnight, and was diluted with dichloromethane. The organic extract was washed successively with aqueous Na 2 CO 3 , H 2 O, aqueous Na 2 CO 3 and H 2 O, and dried over Na 2 CO 3 .
  • Example 1 8 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isooropyl-1'-(4-nitroimidazo1-2-yl)Imethyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S)-N-(1-(imidazol-2-yl)-2-methyl)propylacetamide
  • Example 1(b) -1(c) Following the procedure of Example 1(b) -1(c), except using the compound of Example 24(a) and (2R, 4S, 5S)-5-(t- butoxycarbonyl)amino-4-1-butyldimethylsiloxy-6-phenyl-2- phenylmethylhexanoic acid, the title compound was prepared.
  • Example 26(b) The compound of Example 26(b) (0.314 g, 1.0 eq) was stirred in anhydrous toluene at -78°C under an argon
  • Example 27(a) The compound of Example 27(a) (0.11 g, 1.0 eq) was stirred in anhydrous dichloromethane at room temperature under an inert argon atmosphere. Manganese dioxide (0.126 g, 4.0 eq) was added and the mixture was stirred at room temperature overnight. After 16 h and additional 2.0 eq of manganese dioxide was added. The reaction was complete by TLC after 2 h. The mixture was filtered through a pad of Celite® and the filter cake was washed with dichloromethane. The organic solvent was removed in vacuo to give the title compound as a white solid (0.075 g , 69%). NMR(CDCl 3 ) ⁇ 9.57
  • Example 27(b) The compound of Example 27(b) (0.1 g, 1.0 eq) was stirred in a 3:1 ether/THF mixture at 0°C under an argon atmosphere. Methyl magnesium bromide (0.47 mL, 3.0M in THF, 4.0 eq) was added and allowed to stir at 0°C for 1.5 h. The solution was diluted with 5% aqueous HCl and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate three times and the combined organic extracts were dried over sodium carbonate, filtered, and evaporated to a white solid (0.1 g, 95%). NMR(CDCl 3 ) ⁇ 7.19 (5H, s), 6.59
  • Example 27(c) The compound of Example 27(c) (0.1 g, 1.0 eq) was stirred in anhydrous methanol with 10% Pd on activated carbon (0.020 g). Hydrogen gas was bubbled through the solution via balloon for 1 h and the reaction was maintained under a hydrogen atmosphere for 3 h. The mixture was filtered through a pad of Celite® and the filter cake washed with methanol. The methanol was evaporated to give the title compound as a white solid (0.05 g, 87%). NMR(CDCl 3 ) ⁇ 6.63
  • Example 27(e) The compound of Example 27(e) (45 mg, 1.0 eq) was stirred in dry dichloromethane under an inert argon
  • Example 27(f) The compound of Example 27(f) (38 mg, 1.0 eq) was stirred in anhydrous THF under an argon atmosphere at room temperature. Tetrabutyl ammonium fluoride (0.33 mL, 1.0M in THF, 6.0 eq) was added and the solution stirred for 16 h. The solution was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with water and evaporated to a white solid. The solid was covered with diethyl ether, decanted twice, and dried to give the title compound as a white solid (25 mg, 79%).
  • Example 27 (f) Following the procedure of Example 27 (f), except using the compound of 31(c) (168 mg, 1.0 eq) and chromatographing the crude product (silica, 3% methanol/dichloromethane) the title compound was prepared as a white solid (132 mg, 79%).
  • Example 27 (e) Following the procedure of Example 27 (e), except using the compound of Example 29(b) (0.065 g, 1.1 eq), and
  • Example 27(f) Following the procedure Example 27(f), except using the compound of Example 29(c) (109 mg, 1.0 eq), the title compound was prepared as a white solid (80 mg, 74%).
  • Example 27 Following the procedure of Example 27 (g), except using the compound of Example 29(d) (80 mg, 1.0 eq), the title compound was prepared as a white solid (45 mg , 74%).
  • Example 1(d) The compound of Example 1(d) was dissolved in neat TFA. After 10 min the solution was concentrated to provide the amine salt, (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(l'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide trifluoroacetate. This amine salt (25 mg, 1 eq) was
  • hexamethylphosphoramide (0.57 mL, 2.0 eq) was added to the solution.
  • the solution was stirred for several min and l,l,l-trifluoro-4-iodobutane (0.78 g, 2.0 eq) was added.
  • Example 36(a) Following the procedure of Example 1(b) -1(d), except substituting the compound of Example 36(a) for (1'S)-1'- carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2-yl)methane, the title compound was prepared.
  • NMR(DMSO-d6) ⁇ 7.90 (lH,d), 7.29-7.02 (10H, m), 6.89 (2H,s), 6.50 (lH,d), 4.81 (lH,m), 4.55 (1H, dd)-, 3.56 (1H, m), 2.69 (5H,m), 1.80 (1H, m), 1.59
  • Example 40(b) The compound of Example 40(b) (68 mg, 0.44 mmol) was stirred as a solution in methanol (50 mL) with Pd(0) (10 mg) under 1 atm hydrogen for 12 h. The mixture was filtered, the solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (44 mg, 74%).
  • Example 46(b) The compound of Example 46(b) (58 mg, 0.073 mmol), methanol (3 mL), and 10% Pd on carbon (50 mg) were combined and stirred under 1 atm of H 2 for 24 h. Additional catalyst (50 mg) was added and stirring under H2 was continued for 8 h. The reaction was filtered through Celite®, concentrated and flash chromatographed (silica, step gradient, 0-8%
  • Example 48(a) The compound of Example 48(a) (0.13 gm.) was dissolved in anhydrous methanol with 10% Pd on activated carbon (0.02 g). Hydrogen gas was bubbled through the solution via balloon for 1 h and the solution was stirred overnight under a hydrogen atmosphere. The mixture was filtered through a pad of Celite® and evaporated to yield 1'-amino-1'-isopropyl- [4-(imidazol-2-yl)imidazol-2-yl]methane as a white solid (0.13 g, 100%).
  • Example 38(b) The compound of Example 38(b) (223 mg, 0.221 mmol) was dissolved in 10% aqueous methanol and combined with 1M HCl in ether (0.221 mL, 1 eq) at room temperature. After completion of the reaction the solvents were removed in vacuo. The residue was dissolved in dichloromethane and washed with aqueous saturated Na 2 CO 3 . The organic layer was concentrated and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to provide the title compound (138 mg, 94%). NMR (CDCI 3 ) 5 7.38-6.81 (12H, m), 4.93 + 4.65
  • Example 52(a) The compound of Example 52(a) (103 mg, 0.155 mmol) was stirred with acetic anhydride (30 mg, 0.309 mmol) and DMAP (40 mg, 0.309 mmol) in methylene chloride at room temperature under argon overnight. The solvent was removed in vacuo and the residue was flash chomatagraphed (silica, 4%
  • Example 52(a) The compound of Example 52(a) (100 mg, 0.151 mmol) was reacted with 2-chloro-1-methyl-pyridium iodide (92 mg, 0.36 mmol), DMAP (75 mg, 0.60 mmol) and Cbz-glycine (63 mg, 0.30 mmol) in methylene chloride (5 mL) under argon at reflux for 3 h. Solvents were removed in vacuo and the product was purified by flash chromatagraphy (silica, 4%
  • Example 53(a) The compound of Example 53(a) (58 mg, .0678mmol) was stirred in methanol with 10% Pd/C (50 mg) under 1 atm
  • Example 54(a) The compound of Example 54(a) (43.5 mg, 0.060 mmol) was stirred in methanol:water (9:1) with IM HCl in ether (0.12 mL, 2 eq) for 2 d. The solvents were removed in vacuo and the product was trituated with ether:methanol (20:1) to yield the title compound (40 mg, 98%).
  • Example 38 (b) -38 (c) Following the procedures of Example 38 (b) -38 (c), except substituting the compound of Example 55 (a) for
  • Example 56 Preparation of (2R,4S,5S,1'S)-5-((1S)-1-methyl-2- hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide using the procedure of Example 41, except substituting 2 (S)-t-butyldimethylsiloxy-1-methylethanol in 41(a) (prepared from 2 (S)-1,2-propanediol), the title compound was prepared.
  • NMR(CD30D) ⁇ 7.38-6.90 (10H, m), 6.83 (2H, s), 4.58 (2H, m),
  • the crude aldehyde was dissolved in water (50 mL), and ammonium chloride (6.51 g), potassium cyanide (7.16 g) and aqueous ammonium hydroxide (100 mL, 28% w/w).
  • the reaction mixture was stirred at room temperature overnight, extracted with ethyl acetate, and the combined organic extracts were dried over MgSO 4 . Filtration and evaporation of the solvent in vacuo yielded ⁇ -amino- ⁇ -cyclopropyl acetonitrile as an oil.
  • Example 61(c) The compound of Example 61(c) (15 mg) was dissolved in 1 mL of TFA and stirred at room temperature for 20 min.
  • Example 61(d) The compound of Example 61(d) was dissolved in DMF (2 mL) and NMM (26 mg, 0.25 mmol) was added and the solution was stirred at 0°C for 30 min. (2R,4S,5S)-2-phenylmethyl-4-(t- butyldimethyl)siloxy-5-(t-butoxycarbonyl)amino-6-phenyl hexanoic acid (38 mg, 0.07 mmol) and BOP reagent (30 mg, 0.07 mmol) were added and the reaction was stirred at room
  • Example 61 The compound of Example 61 (c) was dissolved in THF (2 mL) and tetrabutyl ammonium fluoride (200mL, IM in THF) was added. The reaction was stirred at room temperature
  • Example 64(b) (262 mg, 0.663 mmol) in dichloromethane (10 mL) was stirred for 48 h at 25°C. The organic solution was diluted with dichloromethane, washed with 5% sodium carbonate solution and the solvent removed at reduced pressure. The product was purified by flash chromatography (silica,
  • Example 65(a) The compound of Example 65(a) (1.0 g/ 3.88 mmol), MnO 2 , (1.69 g, 19.4 mmol), and CH 2 CI 2 (75 mL) were combined and stirred for 1 d. Additional Mn ⁇ 2 (1.69 g, 19.4 mmol) was added and stirring was continued for an additional 2 d.
  • Example 65(c) The compound of Example 65(c) (93 mg, 0.24 mmol) was dissolved in TFA (1 mL) and stirred for 20 m. The TFA was removed in vacuo to give the title compound (102 mg, 100%).
  • 1 H NMR(CDCl 3 , 400 MHz) 7.30 (m, 7H); 6.06 (d, 1 H, J 9 Hz),
  • Example 65(e) The compound of Example 65(e) (100 mg, 0.12 mmol) was desilylated by the procedure of 47(c) to cleanly afford the title compound (78 mg, 89%).
  • Example 13(a) The compound of Example 13(a) (0.13 g, 0.24 mmol) was dissolved in dichloromethane (3 mL) and t-butyl isocyanate (0.028 g, 0.29 mmol) was added. After stirring at 30°C for 18 h, the solvent was removed under reduced pressure and the residue was chromatographed (silica, 2:3 ethylacetate:hexane) to give the title compound as a white solid (0.12 g, 77%). NMR(CDCl 3 ), ⁇ 7.35-7.05 (12H, m), 6.85 (2H, s), 4.69 (1H, d,
  • Example 67(a) The compound of Example 67(a) (0.033 g, 0.05 mmol) was stirred in dry THF (0.25 mL) and tetrabutylammonium flouride (0.25 mL, 0.25 mmol) in THF was added. After 18 h at 50°C the reaction was cooled, diluted with ethyl acetate (25 mL), washed with water (5 mL), and dried (MgSO 4 ). The combined organic extracts were filtered and concentrated in vacuo. Chromatography (silica, 1:1 ethyl acetate:hexane) gave the title compound as a white solid (0.018 g, 66%). M.p 226°C (dec); NMR(CD 3 OD) ⁇ 7.37-6.90 (10H, m), 6.90 (2H, s), 4.58

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Abstract

L'invention concerne des composés et plus particulièrement des analogues de dipeptides qui se lient à des protéases rétrovirales. Ces composés sont des inhibiteurs de protéases rétrovirales et sont utiles pour le traitement de maladies dues à une infection par des rétrovirus.
PCT/US1992/006047 1991-07-17 1992-07-17 Inhibiteurs de proteases retrovirales WO1993002057A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92917238A EP0602069A4 (fr) 1991-07-17 1992-07-17 Inhibiteurs de proteases retrovirales.
JP5503016A JPH07500577A (ja) 1991-07-17 1992-07-17 レトロウイルス性プロテアーゼ・インヒビター

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US73156391A 1991-07-17 1991-07-17
US731,563 1991-07-17
US87097592A 1992-04-20 1992-04-20
US870,975 1992-04-20

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ES2068739A1 (es) * 1993-01-21 1995-04-16 Smithkline Beecham Corp Inhibidores retrovirables de proteasas.
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
WO1998038167A1 (fr) * 1997-02-26 1998-09-03 Pfizer Inc. Derives amines de l'acide heteroaryle-hexanoique, leur preparation, et leur utilisation comme inhibiteurs selectifs du mip-1 alpha par fixation a son recepteur ccr1
EP0633890B1 (fr) * 1992-04-03 1998-09-09 Zeneca Limited Support pour synthese d'oligonucleotides
US5932550A (en) * 1995-06-30 1999-08-03 Japan Energy Corporation Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6100234A (en) * 1997-05-07 2000-08-08 Tufts University Treatment of HIV
US6222043B1 (en) 1995-06-30 2001-04-24 Japan Energy Corporation Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6291432B1 (en) 1996-12-27 2001-09-18 Japan Energy Corporation Tripeptide compounds and anti-AIDS medicine
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
WO2002002512A2 (fr) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes utiles pour traiter la maladie d'alzheimer
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US6692753B2 (en) 1997-05-07 2004-02-17 Trustees Of Tufts College Potentiation of the immune response
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
WO2008077647A2 (fr) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Modulateurs de récepteurs de progestérone non-stéroïdiens
CN114605320A (zh) * 2022-04-06 2022-06-10 南京艾康生物科技有限公司 一种5-硝基-6-甲基烟酸乙酯的合成方法
US11572360B2 (en) 2018-08-16 2023-02-07 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds

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RU2126794C1 (ru) * 1992-03-11 1999-02-27 Нархекс Лимитед Аминопроизводные оксо- или гидроксизамещенных гидразинов, способ их получения и фармацевтические композиции для ингибирования ретровирусной протеазы
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
DE69333270T2 (de) 1992-03-11 2004-08-05 Narhex Ltd. Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons

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Cited By (35)

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Publication number Priority date Publication date Assignee Title
US7230074B2 (en) 1991-10-22 2007-06-12 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
EP0633890B1 (fr) * 1992-04-03 1998-09-09 Zeneca Limited Support pour synthese d'oligonucleotides
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
ES2068739A1 (es) * 1993-01-21 1995-04-16 Smithkline Beecham Corp Inhibidores retrovirables de proteasas.
US5932550A (en) * 1995-06-30 1999-08-03 Japan Energy Corporation Dipeptide compound or pharmaceutically acceptable salt thereof and medical use thereof
US5962640A (en) * 1995-06-30 1999-10-05 Japan Energy Corporation Methods for preparing novel dipeptide compounds or pharmacuetically acceptable salts thereof
US6222043B1 (en) 1995-06-30 2001-04-24 Japan Energy Corporation Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6875737B1 (en) 1996-06-28 2005-04-05 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6291432B1 (en) 1996-12-27 2001-09-18 Japan Energy Corporation Tripeptide compounds and anti-AIDS medicine
US6403587B1 (en) 1997-02-26 2002-06-11 Pfizer Inc. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-α binding to its CCR 1 receptor
AP1056A (en) * 1997-02-26 2002-04-05 Pfizer Novel hexanoic acid derivatives.
WO1998038167A1 (fr) * 1997-02-26 1998-09-03 Pfizer Inc. Derives amines de l'acide heteroaryle-hexanoique, leur preparation, et leur utilisation comme inhibiteurs selectifs du mip-1 alpha par fixation a son recepteur ccr1
AU745687B2 (en) * 1997-02-26 2002-03-28 Pfizer Inc. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-alpha binding to its CCR1 receptor
US6503882B2 (en) 1997-05-07 2003-01-07 Trustees Of Tufts College Treatment of HIV
US6692753B2 (en) 1997-05-07 2004-02-17 Trustees Of Tufts College Potentiation of the immune response
US6100234A (en) * 1997-05-07 2000-08-08 Tufts University Treatment of HIV
US6703238B2 (en) 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
US6770628B2 (en) 1998-05-04 2004-08-03 Point Therapeutics, Inc. Hematopoietic stimulation
US7067489B2 (en) 1998-05-04 2006-06-27 Point Therapeutics, Inc. Hematopoietic stimulation
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US6949514B2 (en) 1999-05-25 2005-09-27 Point Therapeutics, Inc. Anti-tumor agents
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
WO2002002512A2 (fr) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Composes utiles pour traiter la maladie d'alzheimer
WO2008077647A2 (fr) * 2006-12-21 2008-07-03 Bayer Schering Pharma Aktiengesellschaft Modulateurs de récepteurs de progestérone non-stéroïdiens
WO2008077647A3 (fr) * 2006-12-21 2008-10-16 Bayer Schering Pharma Ag Modulateurs de récepteurs de progestérone non-stéroïdiens
US11572360B2 (en) 2018-08-16 2023-02-07 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
US11827597B2 (en) 2018-08-16 2023-11-28 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds
CN114605320A (zh) * 2022-04-06 2022-06-10 南京艾康生物科技有限公司 一种5-硝基-6-甲基烟酸乙酯的合成方法
CN114605320B (zh) * 2022-04-06 2023-12-29 南京艾康生物科技有限公司 一种5-硝基-6-甲基烟酸乙酯的合成方法

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IL102534A0 (en) 1993-01-14
PT100704A (pt) 1993-10-29
AU2412992A (en) 1993-02-23
AP9200410A0 (en) 1992-07-31
MX9204233A (es) 1994-06-30
EP0602069A4 (fr) 1995-05-03
IE922316A1 (en) 1993-01-27
JPH07500577A (ja) 1995-01-19
EP0602069A1 (fr) 1994-06-22
CA2113644A1 (fr) 1993-02-04

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