WO1993002057A1 - Retroviral protease inhibitors - Google Patents

Retroviral protease inhibitors 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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WIPO (PCT)
Prior art keywords
amino
methyl
hydroxy
isopropyl
phenyl
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PCT/US1992/006047
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French (fr)
Inventor
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 JP5503016A priority Critical patent/JPH07500577A/en
Priority to EP92917238A priority patent/EP0602069A4/en
Publication of WO1993002057A1 publication Critical patent/WO1993002057A1/en

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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

Abstract

The present invention provides compounds, more particularly dipeptide analogs, which bind to retroviral proteases. These compounds are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.

Description

RETROVIRAL PROTEASE INHIBITORS
Background of the Invention
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).
Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than
deoxyribonucleic acid. 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
complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed.
Retroviral replication occurs only in host cells.
Critical to this replication is the production of functional viral proteins. Protein synthesis is accomplished by translation of the appropriate open reading frames into polyprotein constructs, which are processed, at least in part, by a viral protease into the functional proteins. The proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. In fact, it has been demonstrated that retroviruses which lack the protease or contain a mutated form of it, lack
infectivity. See Katoh et al . , Virology, 145, 280-92(1985), Crawford, et al . , J. Virol . , 53, 899-907(1985) and Debouk, et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987).
Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease.
The use of isosteric replacements has been disclosed as a strategy for the development of protease inhibitors for HIV-1. European Patent Applications EP-A 337 714, EP-A 357 332, EP-A 346 847, EP-A 342 541, EP-A 352 000, EP-A 393 445 and EP-A 434 365 are representative, and are incorporated herein by reference. These references disclose dipeptide analogs of the natural polyprotein substrates of retroviral proteases. As discussed therein, these dipeptide analogs bind selectively and competitively to retroviral proteases; however, the protease is unable to cleave the carbon-carbon bond presented to it instead of the scissile amide bond of the natural substrate. Thus, 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). However, 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
elimination mechanisms.
There exists a need for novel compounds which inhibit retroviral protease activity, and a need for compounds which possess desirable pharmacokinetic properties for good drug delivery and metabolic stability for good serum half-life and duration of action. Such pharmaceutical uses provide
therapies for retroviral diseases in mammals, especially in humans, which have been heretofore difficult to treat. SUMMARY OF THE INVENTION
The present invention provides compounds, hereinafter represented as formula (I), which bind to retroviral
proteases. These compounds are inhibitors of retroviral proteases and are useful for treating diseases related to infection by retroviruses.
The present invention also provides 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). DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are illustrated by formula (I): - A -
Figure imgf000006_0002
wherein :
R1 and R3 are each independently Q, Q-C1-6alkyl,
Q-C2-6alkenyl, Q-C2-6alkynyl or C1-6alkenyl substituted by one to five fluorine atoms, each optionally substituted by R23;
Q is H, C3-6cycloalkyl, C5-6cycloalkenyl, Ar or Het
R2 is H or OH;
R4 is R6-NR1 1- or CONR11CHR6R7 ;
R5 is R6-NR11- or R10-NR1 1-;
R6 is
Figure imgf000006_0001
X is NR11, O or S;
R7 is Q, Q-C1-6alkyl or Q-C2-6alkenyl;
R8 and R9 are each independently H, OH, halo, NO2, COR12, CF3, Ar, C1-6alkyl-R15, or R17 (R18R19C)m, or together form a fused C2-4alkylene, aryl or heteroaryl moiety;
R10 is A-(B)n-;
R11 is H or C1-4alkyl;
R12 is R7, OR7, NR7R11 or an amino acid or amino alcohol; B is an amino acid;
A is H, Ar, Het, R17 (R18R19C)m, Ar-W, Het-W or
R17 (R18R19C)m-W, or phthaloyl each optionally substituted by one to three groups chosen from R15 or C1-6alkyl-R15;
W is C=O, OC(=O), NR11C(=O), SC(=O), NR11C(=S), SO2, NR11SO2 or P (=O) (OR22);
R15 is H, nitro, C1-6alkoxy, C1-6alkylthio, O(C=O)R16, C=OR22, CO2R22, CON(R16)2, N(R22)2, NHC (=N) NH-A, I, Br, Cl, F, OR10, or OH, provided that when R15 is a substituent of the carbon adjacent to W, R15 is not halogen or OH when W is OC(=O) or NHCO;
R16 is H or C1-6alkyl;
R17, R18 and R19 are independently: i) H, R15 or
C1-4alkyl, C2-6alkenyl, phenyl, naphthyl, C3-6cycloalkyl or Het, each optionally substituted by one to three R15 or R15-C1-6aallkkyenlyglroups, or ii) R17 is as above and (R18R19C) are joined together to form a phenyl, naphthyl, C3-6cycloalkyl or Het ring, or iii) R17 is as above and R18 and R19 together are
=O;
R22 is H, C1-6alkyl, phenyl or phenyl-C1-4alkyl;
R23 is -χ'-(CH2)qNR24R25, X"[((CH2)rO)s]R26,
CH2X" [ ( (CH2)rO)s]R26, or benzofuryl, indolyl, azacycloalkyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl, optionally substituted with C1-4alkyl;
q is 2-5;
s is 1-6 and r is 1-3 within each repeating unit s;
X' is CH2, O, S or NH;
X" is CH2, NR', O, S, SO or SO2;
R24 and R25 are i) C1-6alkyl, optionally substituted by OH, C1-3alkoxy, 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, SO2, said heterocycle optionally substituted with C1-4alkyl, iii) aromatic heterocycle, optionally substituted with
C1-4alkyl or N(R')2,
R' is H or C1-4alkyl;
R26 is H, C1-4alkyl, C(=O)R27, C(=O)U[ (CH2)mO]nR',
P(=O) (OM)2, CO2R27, C(=O)NR27R28, where M is a mono or
divalent metal ion, and U is NR' or O;
R27 is C1-6alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, C1-3alkoxy, CONR'2, NR'2, CO2R', SO2NR'2, CH2NR2, NR'COR', NR'SO2R', X" [ (CH2)rO]sR' or CH2X"[ (CH2)rO]sR';
R28 is H, C1-6alkyl or together with R27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
m is 1-4; and
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo .
Formula (I) is intended to encompass all unique
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.
Compounds of this invention which include acyclic double bonds may be present in either the cis (Z) or trans (E) geometrical configuration with respect to any two
substituents.
When X is NH, it will be appreciated that the
heterocyclic ring is an imidazole which can undergo
tautomerization. All tautomeric forms of the imidazole are within the scope of this invention.
Suitably R1 and R3 are C1-6alkyl, Ar-Ci-εalkyl,
Ar-C2-6alkenyl, Ar-C2-6alkynyl, C1-6alkyl optionally
substituted by one to five fluorine atoms or benzyl
substituted in the 4-position by R23. Preferably R1 is benzyl and R3 is benzyl, 4-hydroxybenzyl or phenylpropenyl.
Suitably R2 is H.
Suitably X is S or N-R11. Preferably X is NH.
Preferably R4 is CONR11CHR6R7.
Suitably R5 is R10-NR11. Preferably R5 is t- butyloxycarbonylamino or isopropyloxycarbonylamino.
Suitably R7 is H, C1-6alkyl, C3-6cycloalkyl, phenyl or benzyl. Preferably R7 is C1-6alkyl. Isopropyl is most preferred.
Suitably R8 is H, C1-6alkyl, COR12, NO2 or Br . Preferably R8 is H .
Suitably R9 is H, NO2 , Br, COR12, CF3, Ar, C1-6alkyl or
C1-6alkyl-R15, wherein R12 is H, C1-6alkyl, Ar, OC1-6alkyl, NH2, and R15 is OH . Preferably R9 is H or COR12 . Suitably B is Ala or Val . Preferably m is 0 and B is absent.
Suitably A is Het, R17 (R18R19C)m-W, Ar-W or Het-W.
Suitably R17, R18 and R19 are H, or C1-4alkyl, Het or Ar optionally substituted by one or two R15 or C1-6alkyl-R15, or (R18R19C) are joind together to form a phenyl, C3-6cycloalkyl or Het ring.
Suitably W is C=O, OC(=O), NHC(=O), NHC(=S), or SC (C=O). Suitably R17 (R18R19C)m- is Ar-CH2, Ar, Het, Het-CH2, C1-6alkyl or C3-6cycloalkyl optionally substituted by one to three groups selected from R15. Suitably R15 is OH. When R17 or (R18R19C) are Het or Ar, Het is suitably quinolinyl, pyridyl, imidazolyl, thiazolyl, tetrahydrothiopyranyl or tetrahydropyranyl and Ar is phenyl.
Suitably R23 is hydroxy-C1-4alkoxy, Cχ_4alkoxy- C1-4alkoxy, or -O(CH2)2NR24R25, wherein R24 and R25 are are a 5- or 6-membered heterocycle, such as morpholino.
In one preferred embodiment W is C=O.
In another preferred embodiment W is OC(=O).
In a third preferred embodiment R10 is C1-6alkylOC (=O) or C5-6cycloalkyl0C (=O) substituted by one or two OH or CH2OH groups.
Representative compounds of this invention are:
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-isopropyl-1'-(4-aminocarbonyl-thiazo-2- yl)]methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-isopropyl-1'-(thiazo-2-yl)]methyl- hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-(1'-imidazo-2-yl) methyl-hexanamide
hydrochloride;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methyl- hexanamide hydrochloride;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-benzyl-1'-(imidazo-2-yl)]methyl- hexanamide hydrochloride; (2R,4S,5S,1'S)-5-(carbobenzyloxy)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(N'-methyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3- phenylpropargyl) hexanamide;
(2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl) amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2- propenyl) hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-nitroimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- ethyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- propyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl-6-ρhenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-(4-methylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-(4-trifluoromethylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-methyl- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-carbomethoxyimidazol-2-yl)]methyl-6-ρhenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl- 2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-(4-phenylcarbonyl-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-(4-formylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-(hydroxymethyl)-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-((tetrahydrothiσpyran-4-yl)oxycarbonyl)- amino-4-hydroxy-N-(l'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(4,4,4- trifluorobut-1-yl) hexanamide ;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-((1RS)-1-hydroxyethyl)-imidazol-2-yl)]methyl- 6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-(1- methyl)propyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(propylaminocarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(4-hydroxybutanoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(benzyloxy- carbonyl)valylamino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2- yl)methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(N-acetylvalyl)- amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2-yl)methyl- hexanamide;
(2R,4S,5S,1'S)-5-[(imidazol-2-yl)methyloxycarbonyl]amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S,1"RS)-5-((1"-(imidazol-2-yl)-2"-methyl)- propyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-(imidazol-2-yl)imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(1-oxo-thian-4-yl)oxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide;
(2R,4S,5S,1'S)-5-((tetrahydrosulfonylpyran-4- yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)-5-((1,1-dimethyl-2-(benzyloxycarbonyl- glycyloxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide hydrochloride salt;
(2R,4S,5S,1'S)-5-((1,1-dimethyl-2-glycyloxy)ethoxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamidedihydrochloridesalt;
(2R,4S,5S,1'S)-5-((1-acetyl)amino-4-hydroxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- benzyloxyphenylmethyl) hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- hydroxyphenylmethyl) hexanamide;
(2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2- phenylmethyl-6-phenyl-N-[1'-cyclopropyl-1'-imidazol-2- yl3methyl-hexanamide;
(2R,4S,5S,1'S)-5-((isopropylthiol)carbonyl)-amino-4-hydroxy- 2-phenylmethyl-6-phenyl-N-[1-isopropyl-1'-imidazol-2- yl]methyl-hexanamide;
(2R,4S,5S,1'S)-5-[3-(lH-imidazol-2-yl)-3-hydroxy-4- methylpentylamido]-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-[(4-methoxyphenoxy)carbonyl]amino-4-hydroxy- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide;
2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(methylaminocarbonyl)-;
amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-phenylaminocarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
(2R,4S,5S,1'S)-5-N-(propylaminocarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl- hexamide;
(2R,4S,5S,1'S)-5-(n-propylaminothiono)amino-4-hydroxy-N-
(1'isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; 2R,4S,5S,1'S)-5-(isopropylaminocarbonyl)-amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethylhexamide;
(2R,4S,5S,1'S)-5-(aminocarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; (2R,4S,5S,1'S)-5-(6-quinolinylmethyloxy-carbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(benzoyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(2-furylcarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(4-methoxybenzoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-benzylcarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; (2R,4S,5S,1'S)-5- (4-hydroxybenzoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(cinnamoyl)amino-4-hydroxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(2-hydroxybenzoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(imidazoyl-4-yl-acetyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-carbomethoxyethylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-carboxamidoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1-oxopropyl)-2- thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1-oxopropyl)-2- thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide; (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5- (5-propyl-2- thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide; and
(2R,4S,5S,1'S)-5-(nicotinyl)amino-4-hydroxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide.
Another group of preferred representative compounds are:
(2R,4S,5S,1'S)-5-[di(hydroxymethyl)-methoxycarbonyl]amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- pheny lmethy 1-hexanamide;
(2R,4S,5S,1'S)-5-( 1, 1-diιrtethyl-2-acetoxyethoxycarbonyl) amino-
4-hydroxy-N- (1 ' -isopropyl-1 ' -imidazol-2-yl) methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-((1,1-dimethyl-2-hydroxy)ethoxy- carbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-(4- isopropylcarbonyl-imidazol-2-yl))methyl-6-phenyl-2- phenylmethyl-hexanamide dihydrochloride salt;
(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;
(2R,4S,5S,1'S)-5-((IR)-1-methyl-2-hydroxyethoxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)5-(1-hydroxymethyl-cyclopentyloxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- ρhenyl-2-phenylmethyl-hexamide;
(2R,4S,5S,1'S)-5-(1,1-dimethyl-2-hydroxyethoxycarbonyl)amino-
4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide hydrochloride;
(2R,4S,5S,1'S)-5-(hydroxyethoxycarbonyl)amino-4-hydroxy-N- (1'-isoproρyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide; and
(2R,4S,5S,1'S)-5-(2-hydroxy-1-methylethoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide.
More preferred representative compounds are:
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl- hexanamide hydrochloride; (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-isopropylcarbonyl-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(1,1-dimethyl-2-hydroxyethoxycarbonyl)amino- 4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide hydrochloride;
(2R,4S,5S,1'S)-5-(hydroxyethoxycarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide; and
(2R,4S,5S,1'S)-5-(2-hydroxy-1-methylethoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide.
The term "alkyl" refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms.
"C1-4alkyl" as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl; "C1-6alkyl" includes additionally pentyl, isopentyl,
2-methylbutyl, 1-methylbutyl, 2-ethylpropyl, neopentyl, n- hexyl 2,2-dimethylbutyl, 2-methylpentyl, and the like.
"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.
The term "substituted alkyl" as used herein is meant to include C1-6alkyl, Ar-C1-6alkyl, Het-C1-6alkyl, C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6 alkenyl, C3-6cycloalkyl-C1-6alkyl, C3-6cycloalkenyl-C1-6alkyl or C1-6alkyl 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,
pentenyl, 2-methylpropenyl, hexenyl, and the like.
"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.
The term "acyl" means R12-CO, wherein R12 is H,
C1-6alkyl, Ar-C1-6alkyl, Het-C1-6alkyl, C2-6alkenyl,
Ar-C2-6alkenyl, Het-C2-6alkenyl, C3-6cycloalkyl- C1-6alkyl, C5-6cycloalkenyl-C1-6alkyl, OH, NHR13, wherein R13 is H, C1-6alkyl, Ar-C1-6alkyl, Het-C1-6alkyl, C2-6alkenyl,
Ar-C2-6alkenyl, Het-C2-6alkenyl, C3-6cycloakyl-C1-6alkyl, or C3-6cycloalkyl, or C5-6cycloalkenyl-C1-6alkyl; or an α-amino acid or an α-amino alcohol bonded at the nitrogen.
"Cycloalkyl" refers to a saturated ring group of the indicated number of carbon atoms. "C3-7cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl. "Cycloalkenyl" refers to a saturated ring group of the indicated number of carbon atoms, having at least one endocyclic carbon-carbon double bond. "C5-7cycloalkenyl" includes cyclopentenyl, cyclohexenyl and cycloheptenyl.
"Aryl", abbreviated as Ar, refers to phenyl or naphthyl, optionally substituted with one to three halo, OH, OR10, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, CF3, amino, NO2, carboxy, C1-4alkylcarbonyl, aminocarbonyl,
Ci-εalkyl-Het, C1-6alkoxy-Het, C1-6alkyl-phenyl, Cι-6alkoxy- phenyl, C1-6alkyl-, C1-6alkoxy-, HetC1-6alkyl-, HetC1-6alkoxy-, phenylC1-6alkyl-, phenylC1-6alkoxy- or phenyloxy.
As used herein except where noted, the term
"heterocycle", abbreviated as "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.. Examples of such 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, iήdolyl, 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
delocalized electron resonance and the ability to sustain a ring current). 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,
threonine, tryptophan, tyrosine, valine or trifluoroalanine. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem. , 158, 9 (1984) . Usually lipophilic amino acids are preferred for the moiety B, for instance, Val, Ala, Leu and lie. It will be understood that a linkage B-O refers to an oxygen atom bonded to the carboxyl group of an amino acid, and that 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.
Certain chemical names are abbreviated herein for the sake of convenience. 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.
The compounds of formula (I):
Figure imgf000019_0001
wherein R4 is CO-NR'CHR6R7, R5 is R10R11N-, and R1, R2, R3 and R6 are as defined in formula (I), are prepared by:
1) (a) coupling a compound of the formula (II):
Figure imgf000019_0003
with a compound of formula (III):
HR'N-CHR6'R7'
(III)
where R1', R2', R3', R5', R6' and R7' are as defined for formula (I) with any reactive groups protected, Pr1 is H or a hydroxyl protecting group, and L' is OH or a leaving group; or
(b) coupling a compound of the formula (IV):
Figure imgf000019_0002
with a compound of the formula (V): A' - (B ' ) n-L '
(V)
wherein A* and B' are as defined in formula (I) with any reactive groups protected; or
(c) coupling a compound of the formula (VI) :
Figure imgf000020_0001
with a compound of the formula (VII):
A'-L'
(VII)
and,
2) if appropriate, a coupling agent; and
3) removing any protecting groups and
4) forming a pharmaceutically acceptable salt thereof.
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. For instance, 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,
Exemplary of 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
displaceable by an amino group, such as bromo, chloro, a substituted acyl (eg. trifluoroacetyl, bromobenzoyl,
nitrobenzoyl) or a substituted phenol (eg. 4-nitrophenol) and the like. If L' is OH, so that A-OH is an acid, it will be appropriate to use a coupling agent as hereinbefore
described.
For instance: When A is a substituted alkyl group, such as
R17 (R18R19C)m, L' may be a bromo, chloro, iodo or an alkyl or aryl sulonate.
When A is R17 (R18R19C)m-W, Ar-W or Het-W, and W is C=O, 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.
When W is OC=O, 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
carbonyldibromide. Activated carbonates may be prepared by reacting the appropriate alcohol with a suitable carbonate such as bis (4-nitrophenyl) carbonate.
When W is SO2, A-L' may be a sulfonyl halide which may be prepared from the corresponding sulfonic acid.
When W is SC=O, A-L' may be a halothioformate, which may be prepared from a carbonyldihalide and an appropriate mercaptan.
When W is PO(OR22), A-L' may be a phosphonyl halide, which may be prepared from the corresponding phosphonic acid.
Compounds wherein A is R17 (R18R19C)m-W, Ar-W or Het-W, and W is NR'C=O are ureas, and may be prepared by reacting a compound of formula (VII) with an isocyanate of the formula R17(R18R19C)m-NCO, Ar-NCO or Het-NCO, in a suitable solvent such as methylene chloride, optionally with heating.
Compounds of formula (III), wherein X is nitrogen, are imidazoles and may be prepared according to Scheme 1, wherein Pr2 is a removeable amino protecting group, and R7', R8' and R9' correspond to R7, R8 and R9 as defined for formula (I), or a group which may be converted into R7, R8 or R9, with any reactive groups protected.
Scheme 1
Figure imgf000021_0001
The amino aldehydes are generally known or are prepared by methods well known in the art, for instance, by reduction of a suitable α-amino acid ester with diisobutylaluminum hydride. Further reaction of the aldehyde with a gem
dialdehyde, or diketone, and ammonia yields the desired imidazole. Alkylation and further modification of the substituent groups of the imidazole are within the skill of the art. Such a method and other methods for preparing imidazoles are disclosed, for instance, by Baldwin et al . , J. Med. Chem. , 29, 1065 (1986), Angew. Chem. Int . , 22, 560
(1983), and Hughey et al . , Synthesis, 489 (1980).
Alternately, acyl imidazoles may be prepared by coupling an α-amino acid to a substituted 4-amino-isoxazole, and
subsequent reduction and base catalyzed rearrangement as disclosed generally by Reiter, L.A., J. Org. Chem. , 52, 2714 (1987). Intermediate compounds of formula (VIII) are a part of this invention. Preferably, R7' is C1-6alkyl and more preferably C3-6alkyl. Suitably, R8' and R9' are H, NO2, Br, COR12, CF3, Ar, C1-6alkyl or C1-6alkyl-R15, wherein R12 is H, C1-6alkyl, Ar, OC1-6alkyl, NH2, and R15 is OH or a protected hydroxyl group. Preferably R9 is H or COR12.
Compounds of formula (III), wherein X is sulfur, are thiazoles and may be prepared according to Scheme 2, wherein L" is a suitable displaceable group.
Scheme 2
Figure imgf000022_0001
Accordingly, a thioamide is reacted with a ketone or
aldehyde. 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.
Compounds of formula (III), wherein X is oxygen, are oxazoles and may be prepared according to Scheme 3 from common amino acids.
Scheme 3
Figure imgf000023_0001
Typically the acid may be coupled to an appropriately
substituted amino alcohol by common techniques, as described above, and cyclized by treatment with thionyl chloride to yield an oxazoline, as described by Meyers et al . , J. Org. Chem., 43, 1372 (1978). Oxidation of the oxazoline, such as described by Evans et al . , J. Org. Chem., 44, 497 (1979), yields an oxazole.
The compounds of formula (II), (IV) and (VI), wherein R2 is H, are prepared, for instance, according to Scheme 4.
Scheme 4
Figure imgf000024_0001
Other methods for preparing protected 5-amino-4-hydroxy- 2,5-disubstituted-pentanoate esters and acids, and the corresponding γ-lactones, are well known and are disclosed, for instance, in Szelke et al . , U.S. Patent 4,713,455, Boger et al . , U.S. Patent 4,661,473, EP-A 0 352 000, Evans et al . , J. Org. Chem., 50, 4615 (1985), Kempf, J. Org. Chem., 51, 3921 (1986), Fray et al . , J. Org. Chem., 51, 4828 (1986), Halladay et al . , Tett. Lett., 24, 4401 (1983), Wuts et al . , J. Org. Chem., 53, 4503 (1988), DeCamp et al . , Tett. Lett., 32,1867 (1991), and Szelke et al . , WO 84/03044, all of which are incorporated herein by reference.
The compounds of formula (II), (IV) and (VI), wherein R2 is OH, are also prepared by methods common in the art such as those disclosed in U.S. Patent 4,864,017. and Thaisrivongs et al . , J. Med. Chem. , 30, 976 (1987).
Compounds of formula (I), wherein R5 is R6-NR11, are prepared according to Scheme 5, Scheme 6 or Scheme 7: Scheme 5
Figure imgf000025_0001
wherein R1'-R4', R7' and R8' are as defined in formula (I) with any reactive groups protected, L' is a leaving group, such as halogen, and Pr1 is a hydroxy-protecting group Compounds wherein R4 is R6NR11- are prepared in an analogous manner from a compound of formula (IX):
Figure imgf000026_0001
Suitable protecting groups for the amino, hydroxyl, carboxylic acid, mercaptan group, and reagents for
deprotecting these functional groups are disclosed in Greene et al . , PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second
Edition, John Wiley and Sons, New York, 1991. Deprotection indicates the removal of the protecting group and replacement with an hydrogen atom. In particular, suitably substituted 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
hydrolysis. 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,
phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final
compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na+, K+, Ca++ and NH4 + 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
desirable pharmacokinetic properties to the compounds. One such property is long duration of action. We have found that substitution of a heterocycle, especially imidazole, in the putative P2' position of the present compounds affords compounds which retain good enzyme binding affinity, good antiviral activity, a favorable duration of action and water solubility for good drug delivery.
When a compound of the present invention is administered to an animal infected or potentially infected with a
retrovirus, viral replication is inhibited and hence disease progression is retarded. Inasmuch as the amino acid
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. Also, 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
susceptible retroviruses and require such treatment. The method of treating a retroviral disease in a mammal,
particularly 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.
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. Examples of 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. Suitably, pharmaceutical compositions comprise an anti-viral agent, a protease
inhibiting compound of the present invention, and a
pharmaceutically acceptable carrier.
This invention is also a pharmaceutical formulation which comprises a compound of formula (I) and a
pharmaceutically acceptable carrier. Pharmaceutical
acceptable carrier are well known in the art and are
disclosed, for instance, in SPROWL'S AMERICAN PHARMACY,
Dittert, L. (ed.), J.B. Lippincott Co., Philadelphia, 1974, and REMINGTON'S PHARMACEUTICAL SCIENCES, Gennaro, A. (ed.), Mack Publishing Co., Easton, Pennsylvania, 1985.
Pharmaceutical 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. Examples of 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.
Alternately, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral
administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the
composition, or to facilitate preparation of the composition. Liquid carriers include syrup, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water.
Solubilizing agents, such as dimethylsulfoxide, ethanol or formamide, may also be added. 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. In fact, 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
necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such 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.
For rectal administration, 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. 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
bioavailability, drug half-life and clearance. These assays are well known in the art.
ENZYME ACTIVITY
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. TheKi for the compounds of this invention are in the range of 1 nM to 5 μM. Preferred compounds have Ki's of less than 100 nM.
INFECTIVITY
The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al . ,
Nature, 343, 90 (1990), and Petteway et al . , Trends
Pharmacol . Sci, 12, 28 (1991). The IC50 for the compounds of this invention are in the range of 0.1 to 10 μM.
CYTOTOXICITY
Cytoitoxicity is assessed by both direct microscopic examination of trypan blue stained cells (T-lymphocytes) and by the treated culture's ability to metabolize the
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.
PHARMACOKINETICS
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 μL, 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 μL 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 Ki 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. An aliquot (0.4 mL) of the supernatant was removed and dried in Eppendorf tubes using a Speed-vac. The resulting residue was redissolved in DMSO. The inhibition of the HIV-1 protease activity was assayed as follows. An aliquot of the extracted sample was added to a 50 μL mixture containing IX MENDT buffer, 1 mM substrate and incubated at 37°C < 10 min. The reaction was then initiated by the addition of HIV-1 protease and
continued at 37°C for an additional 15 min, then quenched by the addition of TFA (0.5% final concentration). Initial rates were determined for each standard curve as the fraction of remaining enzymatic activity (vi/v0) at each inhibitor concentration, in which vo is the velocity of the I
(inhibitor concentration)=0 sample. Assuming that all of the original inhibitor in the spiked samples was extracted, the values of vi/v0 were plotted versus inhibitor concentration of the original extracted sample and fitted to the equation: vi/v0=[AEt - It - Ki + (Ki-AEt-It)0.5]/(2AEt)
in which Et is the total enzyme concentration at time zero, Ki is the apparent inhibition constant and A is the fraction of active enzyme.
Ex vivo animal plasma samples containing unknown levels of protease inhibitor were prepared and analyzed as described for the standard curve described above. The concentration of inhibitor in these samples was then determined using the Ki and A parameters from the fitted standard curve according to the following equation: It=AEt [1-(vi//v0)] + Ki (v0/vi).
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. Using the IV data, the apparent terminal rate constant was determined form the linear regression analysis of the plasma
concentration-vs-time curve. The elimination half-life (t1/2) was derived by dividing In 0.5 (=0.693) by the
terminal rate constant. The area under the plasma
concentration-vs-time curve (AUC) was determined by using the In/log trapezoidal rule. Cmax represents the maximal plasma concentration and tmax, the time following drug
administration at which Cmax was observed. Both values were estimated by inspection of the plasma concentration-vs-time curve. Total plasma clearance (CL) was calculated by dividing the dose by the AUC. The fraction of the oral dose available to the systemic circulation (the bioavailable fraction, F) was determined by the equation: F =
[AUCpo/DOSEpo] X [DOSEiv/AUCiv].
The Examples which follow serve to illustrate this invention. The Examples are not intended to limit the scope of this invention, but are provided to show how to make and use the compounds of this invention.
In the Examples, all temperatures are in degrees
Centigrade. 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.
NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer, unless otherwise indicated. Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane.
Multiplicities for NMR spectra are indicated as : s=singlet , d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets etc. and br indicates a broad signal. J indicates the NMR coupling constant in
Hertz.
Celite® is filter aid composed of acid washed
diatomaceous silica manufactured by Mansville Corp., Denver, Colorado. Florisil® is an activated magnesium silicate chromatographic support and is a registered trademark of
Floridon Co., Pittsburgh, Pennsylvania. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
Example 1
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- hutoxycarhonyl)amino-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide hydrochloride a) (1'S)-1'-carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2- yl)methane
Cbz-valinal (4.6 g, 1 eq) and glyoxal trimeric dihydrate (1.33 g, leq) were stirred in MeOH at -10°C. Ammonia was bubbled through the solution for several min and the mixture was allowed to stir for 4 h at -10°C. The mixture was allowed to warm to room temperature over 14 h, then was poured into 250 mL water. The suspension was filtered and the filter cake washed twice with water to give the title compound as a white solid (1.9 g, 36%). NMR(CD3OD) δ 7.28 (5H, m), 6.89 (2H, s), 5.04 (2H, dd), 4.46 (1H, d), 2.10 (1H, m), 0.91 (3H, d), 0.70 (3H, d); MS(CI/CH4) m/e 274.2 [M+H]+,
230.1, 166.1, 123.1, 91.1. b) (1'S)-1'-amino-1'-isopropyl-1'-(imidazo-2-yl) methane
(1'S)-1'-carbobenzyloxyamino-1'-isopropyl-1'-(imidazolyl) methane (1.9 g) was stirred in methanol over 10% Pd/C (200 mg). Hydrogen was bubbled through the solution for 1 h and the solution was maintained under a positive hydrogen
atmosphere overnight. The mixture was filtered through
Celite® and was evaporated to a tacky solid (720 mg, 75%). NMR(CDCl3) δ 6.87 (2H, s), 3.88 (1H, d), 2.04 (1H, m), 0.81 (6H, dd); MS(DCI/NH3) m/e 190.2 [M+H]+. c) (2R,4S,5S,1'S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-5- (t-butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-(imidazo-
2-yl)]methyl-hexanamide
To a solution of (2R,4S,5S)-2-phenylmethyl-4-(t- butylmethyl) siloxy-5-(t-butoxycarbonyl)amino-6-phenyl- hexanoic acid (200 mg, 0.38 mmol) in dichloromethane, (1'S)- 1'-amino-1'-isopropyl-1'-(imidazo-2-yl)methane (48 mg, 0.35 mmol), BOP reagent (168 mg, 0.38 mmol), and triethylamine (0.053 mL, 0.38 mmol) were added. The mixture was stirred under argon overnight, and washed successively with water, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The solution was dried over MgSO4, filtered, and evaporated to a white solid. The solid was chromatographed (silica, 4% methanol/dichloromethane) to afford the title compound as a white solid (0.154 g, 68%). NMR(CDCl3) δ 7.18
(10H, m), 6.91 (2H, d), 6.32 (1H, d), 4.69 (1H, d), 4.40 (1H, t), 3.92 (1H, q), 3.63 (1H, m), 2.84 - 2.31 (6H, m), 1.67
(4H, m), 1.24 ( 9H, s), 0 .89 ( 9H, s), 0 .74 ( 6H, dd), 0 .05 ( 6H, d) ; MS (DCI/NH3) m/e 649. 6 [M+H] + . d) (2R, 4S, 5S, 1 ' S) -2-phenylmethyl-4-hydroxy-5- (t- butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-(imidazo-2- yl) ]methyl-hexanamide hydrochloride
The compound 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
evaporated. The residue was treated with 1 eq of methanolic HCl, concentrated, and triturated with diethyl ether and ethyl acetate to give the title compound as a white solid (95 mg, 83%). NMR(DMSO-d6) δ 7.78 (1H, d), 7.16 (10H, m), 6.71
(2H, s), 6.39 (1H, d), 4.68 (1H, m), 4.52 (1H, d), 2.71 (3H, m), 2.48 (3H, m), 1.97 (1H, m), 1.61 (1H, m), 1.30 (9H, s), 0.78 (3H, d), 0.61 (3H, d); MS(DCI/NH3) m/e 535.4 [M+H]+ .
Example 2 Preparation of (2R,4S,5S.1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N- [1'-isopropyl-1'-(4- aminocarbonyl-thiazo-2-yl)]methyl-hexanamide a) Boc-valineamide
To a solution of di-t-butyl-dicarbonate (7.15 g, 1 eq) in dry dichloromethane was added valinamide hydrochloride (5.0 g, 1 eq) and triethylamine (9.14 mL, 2 eq). The mixture was heated to reflux for 4 h, and cooled to room temperature. The organic layer was washed twice with water and evaporated to give the title compound (6.03 g, 85%). NMR(CDCl3) δ 6.00
(1H, br), 5.54 (1H, br), 5.01 (1H, br), 3.93 (1H, dd), 2.12 (1H, m), 1.44 (9H, s), 0.92 (6H, dd). b) Boc-valinethioamide
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(CDCl3) δ 8.59 (1H, br s),
8.09 (1H, br s), 5.41 (1H, d (br)), 4.20 (1H, dd), 1.99 (1H, m), 1.39 (9H, s), 0.90 (6H, m). c) (1'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl-1'-(4- carboethoxythiazo-2-yl) methane
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 MgSO4, 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. Excess solvent was removed in vacuo and the residue dissolved in dichloromethane. The solution was washed with sat. aqueous sodium bicarbonate and 1. ON KHSO4 until pH 7. The solution was dried over sodium sulfate, filtered, and evaporated to an oil which was chromatographed (silica, 4% methanol/
dichloromethane) to give the title compound as a tan solid. NMR(CDCl3) δ 8.04 (1H, s), 5.26 (1H, br d), 4.85 (1H, m), 4.37 (2H, q), 2.40 (1H, m), 1.41 (9H, s), 1.34 (3H, t), 0.93 (3H, d), 0.84 (3H, d). d) (1'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl-1'-(4- carboxythiazo-2-yl) methane
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(CDCl3) δ 8.08
(1H, s), 5.19 (1H, m), 4.80 (1H, m), 2.31 (1H, m), 1.38 (9H, s), 0.86 (6H, dd). e) (1'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl-1'- (4-aminocarbonylthiazo-2-yl)methane
(1'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl-1'-(4- carboxythiazo-2-yl) methane (0.078 g, 0.26 mmol) was stirred under argon in dry THF at -40°C. NMM (0.06 mL; 0.55 mM) and isobutyl chloroformate (0.034 mL; 0.26 mmol) were added.
After stirring 15 min, ammonia was bubbled through the mixture for several min. The solution was warmed to room termperature and the THF evaporated. The residue was diluted with ethyl acetate and washed successively with 1.0N citric acid, 5% aqueous sodium bicarbonate, and sat. aqueous sodium chloride. The organic layer was dried over MgSO4, filtered, and evaporated to a solid which was chromatographed (silica,
3% methanol/dichloromethane) to give the title compound as a white solid (0.052 g, 67%). NMR(CDCl3) δ 8.02 (1H, s), 7.14
(1H, s (br), 6.28 (1H, s (br)), 5.24 (1H, d(br)), 4.82 (1H, m), 2.30 (1H, m), 1.39 (9H, s), 0.92 (6H, dd). f) (2R,4S,5S,1'S)-2-phenylmethyl-4-(t-butyldimethylsiloxy)-5- (t-butoxy carbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-(4- aminocarbonyl-thiazo-2-yl)]methyl-hexanamide
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
chromatographed (silica, 2.5% methanol/dichloromethane) to yield the title compound (60 mg, 55%). NMR(CDCl3) δ 7.89 (1H, s), 7.60 (1H, d), 7.24 (10H, m), 6.82 (1H, m), 5.12 (1H, m), 4.89 (1H, m), 3.92 (1H, q), 3.81 (1H, dd), 2.73 (4H, m), 2.21 (1H, m), 1.73 (2H, m), 1.40 (9H, s), 1.23 (1H, m), 0.93 (9H, s), 0.84 (6H, dd), 0.11 (6H, d). g) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-(4- aminocarbonyl(thiazo-2-yl)]methyl-hexanamide
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.
The solid was chromatographed (silica gel, 4%
methanol/dichloromethane) to give the title compound as a white solid (0.022 g). NMR(CDCl3) δ 7.90 (1H, s), 7.15 (10H, m), 6.39 (1H, d), 5.93 (1H, br s), 5.06 (1H, dd), 4.91 (1H, d), 3.90 (1H, d), 3.67 (2H, m), 2.91 (4H, m), 2.64 (1H, d), 2.13 (1H, m), 1.87 (3H, m), 1.36 (9H, s), 0.83 (6H, dd);
MS (DCI/NH3) m/e 612 [M+NH4] +, 595 [M+H] +, 495, 413 . 1, 391,
374 , 356, 239 . 1, 202, 185 . Example 3
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-l'-(thiazo-2- yl)lmethyl-hexanamide a) (1'S)-1'-(t-butoxycarbonyl)amino-1'-isopropyl-1'-(thiazo- 2-yl)methane
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
temperature, the solution was diluted with ethyl acetate and washed with 2.0N citric acid (4X). The organic layers were combined and dried over MgSO4, filtered, and evaporated to a dark oil. The oil was chromatographed (silica, 4%
methanol/dichloromethane) to give the title compound as an orange oil. NMR(CDCl3) δ 7.68 (1H, d), 7.19 (1H, d), 5.26
(1H, d), 4.88 (1H, m), 2.31 (1H, m), 1.43 (9H, s), 0.92 (3H, d), 0.84 (3H, d). b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-ρhenyl-N-[1'-isopropyl-1'-(thiazo-2- yl)]methyl-hexanamide
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%).
NMR(DMSO-d6) δ 8.31 (1H, d), 7.62 (1H, d), 7.49 (1H, d), 7.16
(10H, m), 2.61 (6H, m), 1.28 (9H, s), 0.89 (3H, dd);
MS(DCI/NH3) m/e 552.3 [M+H]+, 413.2, 331.1, 183.1, 157.1,
142.0, 120.1.
Example 4 Preparation of (2R,4S,5S,1' S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-benzimidazo- 2-yl)] methy1-hexanamide a) (1'S)-1'-carbobenzyloxyamino-1'-isopropyl-1'-(benzimidazo- 2-yl)methane
Cbz-valine (2.0 g, 1 eq) was stirred at -10°C in dry THF under argon. Triethylamine (1.11 mL, 1.0 eq) was added, followed by isobutyl chloroformate (1.03 mL, 1 eq). The reaction mixture was stirred for 10 min. Phenylene diamine (0.944 g, 1.1 eq) was added slowly in 10 mL dry THF. The mixture was warmed to room temperature and stirred for 1 h. The solvents were evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 5% aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered, and evaporated.
The residue was dissolved in glacial acetic acid and heated to 65°C for 16 h. The solvents were evaporated and the residue diluted with water. After neutralizing with
saturated aqueous sodium bicarbonate, the solid was filtered and the filter cake was washed with hexane. The solid was recrystallized from ethyl acetate and hexane. NMR(CD3OD) δ
7.48-7.11 (9H, m), 5.06 (2H, q), 4.62 (1H, m), 2.27 (1H, m), 1.23 (1H, m), 1.02 (3H, d), 0.84 (3H, d). b) (1'S)-1'-amino-1'-isopropyl-1'-(benzimidazo-2-yl) methane
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
Celite® and the solvents evaporated to give the title compound as a white solid (1.58 g, 98%). NMR(CDCl3) δ 7.48- 7.10 (4H, m), 4.02 (1H, d), 2.24 (1H, m), 0.96 (3H, d),
0.83 (3H, d); MS(DCI/NH3) m/e 190.2 [M+H]+. c) (2R,4S,5S,1'S)-2-phenylmethyl-4-(t-butyldimethyl)siloxy-5- (t-butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'- benzimidazo-2-yl]methyl-hexanamide
To a solution of (2R,4S,5S)-2-phenylmethyl-4-(t- butyldimethyl) siloxy-5-(t-butoxycarbonyl)amino-6-phenylhexanoic acid (75 mg, 1.1 eq) in dimethyl formamide under argon, the compound of Example 4(b) (25 mg, 1.0 eq), DCC (30 mg, 1.1 eq) and HOBT (44 mg, 2.2 eq) were added. The mixture was stirred overnight, then filtered through Celite®. The solvents were evaporated and the residue was
chromatographed (silica gel, 4% methanol/dichloromethane) to give the title compound (0.070 g, 78%). NMR(CDCl3) δ 7.88
(1H, d), 7.30 (14H, m), 6.80. (1H, d), 4.93 (2H, m), 4 .26 (1H, q), 4.00 (1H, m), 2.92 (7H, m), 2.01 (2H, m), 1.53 (9H, s), 1.20 (9H, s), 1.14 (6H, d), 0.41 (6H, d); MS(DCI/NH3) m/e 699.6 [M+H]+. d) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-[1'-isopropyl-1'-benzimidazo-
2-yl]methyl-hexanamide
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
temperature. The solution was diluted with water and
extracted with dichloromethane (3X). The combined organic layers were washed with water and evaporated to a residue which was chromatographed (silica, 2% methanol/CH2CL2) to give the title compound (0.029 g, 50%). NMR(CDCl3) δ 7.54
(1H, m), 7.11 (11H, m), 6.69 (4H, s), 4.98 (1H, d), 4.69 (2H, m), 3.66 (2H, m), 2.74 (5H, m), 2.31 (1H, m), 1.73 (2H, m), 1.32 (9H, s), 0.70 (6H, d); MS(DCI/NH3) m/e 585.4 [M+H]+,
413.3, 364.3, 296.2, 190.2, 173.1, 120.1.
Example 5 Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- hutoxycarbonyl) amino-6-phenyl-N-(1'-imidazo-2-yl)methyl- hexanamide hydrochloride a) 2-(carbobenzyloxyamino)methyl-imidazole
Following the procedure of Example 1(a), except
substituting Cbz-glycinal for Cbz-valinal, the title compound was prepared. NMR(CDCl3) δ .33 (5H, s), 6.95 (2H, s), 5.95 (1H, s(br)), 5.12 (2H, s), 4.42 (2H, d); MS(DCI/NH3) m/e 232.2 [M+H]+, 188, 171. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-(1'-imidazo-2-yl) methyl- hexanamide hydrochloride
Following the procedure of Example 1(b)-1(d), except substituting the compound of Example 5(a) for (1'S)-1'- carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2-yl)methane, the title compound was prepared. NMR(CD3OD) δ 7.20 (10H,m),
6.94 (2H,s), 6.11 (1H,d), 4.24 (2H,dd), 3.61 (1H,m), 3.52 (1H,m), 2.69 (4H,m), 1.66 (2H,m), 1.28 (9H,s); MS (DCI/NH3) m/e 493.7 [M+H]+, 475.7, 120.2, 98.2, 83.1, 69.1. Example 6
Preparation of (2R, 4S, 5S, 1 'S) -2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl) amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methyl-hexanamide hydrochloride a) (1'S)-1'-carbobenzyloxyamino-1'-methyl-1'-(imidazo-2- yl)methane
Following the procedure of Example 1 (a), except
substituting Cbz-alanal for Cbz-valinal, the title compound was prepared. NMR(CDCl3) δ .35 (5H,s), 6.92 (2H,s),
5.52 (1H,d), 5.12 (2H,q), 4.90 (1H, q); MS(DCI/NH3) m/e 246
[M+H]+, 202, 185. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methyl-hexanamide hydrochloride
Following the procedure of Example 1(b)-1(d), except substituting the compound of Example 6(a) for (1'S)-1'- carbobenzyloxyamino-1'-isopropyl-1'-(imidazo-2-yl)methane, the title compound was prepared. NMR(CD3OD) δ 7.11 (10H, m),
6.86 (2H, s), 4.69 (1H, d), 3.62 (1H, d), 3.51 (1H, m) , 2.68 (6H, m), 1.59 (2H, m), 1.30 (9H, s), 1.14 (3H, d);
MS(DCI/NH3) m/e 507.5 [M+H]+, 489.4, 112.1. Example 7
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl) amino-6-phenyl-N-[ 1'-benzyl-1'-(imi dazo-2- yl)]methyl-hexanamide hydrochloride a) (1'S)-1'-carbobenzyloxyamino-1'-benzyl-1'-(imidazo-2- yl)methane
Following the procedure of Example 1(a), except
substituting Cbz-phenylalaninal for Cbz-valinal, the title compound was prepared. NMR(CDCl3) δ 7.37-7.05 (10H,m), 6.95
(2H, s br), 5.52 (1H, d), 5.05 (2M, s), 4.95 (1H, q), 3.32 (2H, d); MS(DCI/NH3) m/e 322, 261, 171. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-(1'-benzyl-1'-(imidazo-2-yl)) methyl-hexanamide hydrochloride
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(CD3OD) δ 7.15 (15H, m),
6.79 (2H, s), 5.78 (1H, d), 5.04 (1H, d), 3.58 (1H, m), 3.47 (1H, m), 2.68 (8H, m), 1.59 (2H, m), 1.31 (9H, s).
Example 8
Preparation of (2R,4S,5S,1'S)-5-(carbobenzyloxy)amino-4- hydroxy-N-(1'-isooropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmpthyl-hexanamide
A solution of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino- 4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide (0.086 g) in trifluoroacetic acid was stirred for 10 min, then was evaporated in vacuo . To the residue were added dimethylformamide, benzylchloroformate (1 eq) and triethylamine (5 eq), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into H2O and extracted with dichloromethane. The combined organic extracts were evaporated, and the residue was triturated with diethyl ether to afford the title compound as a white solid. NMR(CD3OD) δ 7.36-6.94 (15H, m), 6.84 (2H, s), 4.99 (2H, s), 4.54 (2H, d), 3.76 (1H, m), 3.52 (1H, dd), 2.77 (5H, m), 2.04 (1H, m), 1.76 (1H, m), 1.58 (1H, m), 0.82 (3H, d), 0.66 (3H, .d).
Example 9
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4,5-dimethyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4 ,5- dimethylimidazol-2-yl) methane
Cbz-Valinal (4.14 g) was stirred in methanol with 2,3- butanedione (1.54 mL, 1.0 eq). Ammonia was bubbled through the solution at -25°C for 5 min. The cooling bath was removed and the mixture allowed to warm to 20°C. The
solution was stirred for 16 h under Ar. The solvents were removed by rotary evaporation, and the residue was diluted with dichloromethane and extracted with dilute aqueous HCl. The organic layer was concentrated to afford unreacted Cbz- valinal (4.02 g). The acidic aqueous layer was basified with IN NaOH and extracted with dichloromethane, the organic extract was concentrated and the residue purified by flash chromatography (4% methanol in dichloromethane) to provide the title compound as a white solid (50 mg). NMR(CD3OD) δ 7.29 (5H, m), 5.04 (2H, dd), 4.38 (1H, d), 2.06 (6H, s), 2.01 (1H, m), 0.93 (3H, d), 0.77 (3H, d). b) (1S)-1-(4,5-dimethylimidazol-2-yl)-2-methylpropylamine
The benzyloxycarbonyl group was cleaved by
hydrogenolysis using the same procedure as described
previously in Example 1 (b) , except using the product of 1 (a) (50 mg), to afford the title compound as a white solid (24 mg, 87%) . NMR (CDCl3) δ 4 .11 (2H, s (br) ), 3 .71 (1H, d), 2 .06 (6H, s), 2 .00 (1H, m), 0 .71 (6H, dd) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-(4,5-dimethyl) imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl-hexanamide
Using the procedure of Example 1 (c), except substituting (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy- 6-phenyl-2-phenylmethylhexanoic acid and (1S)-1-(4,5- dimethylimidazol-2-yl)-2-methylpropylamine (24 mg), the title compound was prepared (55 mg, 57%). NMR(CDCl3) δ 7.26-6.80
(10H, m), 4.65 (1H, d), 4.24 (1H, dd), 3.87 (1H, q), 3.61 (1H, m), 2.77-2.39 (5H, m), 2.22 (1H, m), 1.98 (6H, s), 1.79 (1H, m), 1.58 (1H, m), 1.24 (9H, s), 0.85 (9H, s), 0.69 (6H, d), 0.06 (6H, d). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
By following the deprotection procedure described in Example 1(d), except using (2R,4S,5S,1'S)-5-(t- butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl- 1'-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide (55 mg) and omitting the final treatment with methanolic HCl, the title compound was prepared (25 mg, 62%). NMR(CDCl3) δ 7.29-6.88 (10H, m), 4.98
(1H, br d), 4.47 (1H, m), 4.29 (1H, m), 3.58 (2H, m), 2.84- 2.51 (5H, m), 2.20 (1H, m), 2.04 (6H, s), 1.71 (2H, m), 1.38 (9H, s), 0.69 (6H, dd).
Example 10
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4 ,5-dimethyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S) -1-carbobenzyloxyamino-1-isopropyl-1- (4- phenylimidazol-2-yl) methane Using the procedure of Example 1 (a), except using Cbz- (L)-valine (2.19 g) and α-ketophenylacetaldehyde instead of glyoxal, the title compound was prepared (1.54 g, 48%).
NMR(CDCl3) δ 7.62 (1H, (br)), 7.24 (10H, m), 5.79 (1H, d), 5.04 (2H, dd), 4.32 (1H, dd), 2.31 (1H, m), 0.96 (3H, d), 0.79 (3H, d); MS m/e 350.4 [M+H]+, 199.0. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amiho-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-phenyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide
Using the procedure of Example 1 (b)-1 (c), except using the compound of 10(a) (72 mg), the title compound was prepared (67 mg, 44%). NMR(CDCl3) δ 7.70 (1H, d), 7.40-6.71
(16H, m), 4.73 (1H, d), 4.54 (1H, dd), 3.96 (1H, q), 3.69 (1H, m), 2.88-2.36 (5H, m), 1.73 (2H, m), 1.33 (9H, s), 0.91 (9H, s), 0.84 (6H, dd), 0.11 (6H, d); MS m/e 725.4 [M+H]+. c) (2R, 4S, 5S, 1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [1'-isoproρyl-1'-(4-phenyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
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(CDCl3) δ 7.52-
6.67 (16H, m), 5.48 (1H, d), 3.60 (1H, q), 3.44 (1H, d), 2.60 (4H, m), 1.96 (1H, m), 1.62 (2H, m), 1.23 (9H, s), 0.73 (3H, d), 0.62 (3H, d); MS m/e 611.4 [M+H]+, 242.2, 195.0, 150.2. Example 11
Preparation of ( 2R , 4S , 5S , 1 ' S ) -5-(t-butoxycarhonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(N'-methyl)imidazol-2-yl]methyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S)-carbobenzyloxyamino-1-isoproρyl-1-(N'-methylimidazol- 2-yl)methane
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 Na2CO3. The mixture was extracted with
dichloromethane, dried (Na2CO3) and concentrated. The crude product was purified by flash chromatography (silica, 2% methanol/dichloromethane) to yield the title compound (200 mg, 70%). NMR(CDCl3) δ 7.29 (5H, s), 6.92 (1H, s), 6.69 (1H, s), 5.94 (1H, d), 5.03 (2H, q), 4.55 (1H, dd), 3.64 (3H, s), 2.20 (1H, m), 1.01 (3H, d), 0.82 (3H, d). b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'-methyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1(b)-1(c), except using the compound of 11(a) (90 mg), the title compound was prepared (104 mg, 50%). NMR(CDCl3) δ 7.32-6.89 (10H, m), 6.81 (1H, s), 6.59 (1H, s), 6.08 (1H, d), 4.71 (2H, m), 3.94
(1H, q), 3.70 (1H, m), 3.25 (3H, s), 2.80-2.36 (5H, m), 2.21
(1H, m), 1.73 (2H, m), 1.31 (9H, s), 0.94 (9H, s), 0.85 (6H, dd), 0.11 (6H, s). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(N'-methyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 9 (d), except using (2R,4S 5S,1'S)-5-(t-butoxycr bonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'-methyl)imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide (100 mg), the title compound was prepared (74 mg, 89%). NMR(CDCl3) δ 7.21-
6.74 (11H, m), 6.70 (1H, s), 6.59 (1H, s), 4.95 (1H, d), 4.61 (1H, dd), 3.60 (3H, m), 3.48 (3H, s), 2.71 (5H, m), 2.06 (1H, m), 1.64 (2H, m), 1.32 (9H, s), 0.82 (3H, d), 0.63 (3H, d); MS m/e 549.3 [M+H]+. Example 12
Preparation of (2R,4S,5S,1'S,-5-(t-butoxycarbonyl)amino-4- hydroxv-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- (3-phenylpropargyl)hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3- (3-phenyIpropargyl)-tetrahydrofuran-2-one
To a solution of lithium diisopropylamide (3.61 mL, 2.0 M in THF, 2.2 eq) in THF at -78°C under an argon
atmosphere, (5S,1'S)-(1'-t-butoxycarbonylamino-2'- phenyl) ethyl-tetrahydrofuran-2-one (1.0 g, 1.0 eq) was added. After stirring at -78°C for 15 min, hexamethylphosphoramide (1.14 mL, 2 eq) was added, and stirring was continued an additional 10 min. PhenyIpropargyl bromide (1.28 g, 2.0 eq), was added and the resulting mixture was stirred at -78°C for 2 h, then poured into dilute aqueous HCl and extracted with dichloromethane. The combined organic extracts were
evaporated under reduced pressure to an oil, which was chromatographed (silica, 20% ethyl acetate/hexanes) to afford the title compound as a white solid (0.455 g, 33%).
NMR(CDCl3) δ 7.18 (10H, m), 4.50 (2H, m), 3.93 (1H, q), 2.79
(5H, m), 2.23 (2H, m), 1.24 (9H, s). b) (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-4-t-butyldimethy1- siloxy-6-phenyl-2- (3-pheny Ipropargyl) hexanoic acid
The title compound (496 mg, 84%) was prepared by the procedure of Evans et al . , J. Org. Chem. 50, 4615 (1985) from the product of 12 (a) (450 mg) . NMR (CDCl3) δ 7.49-7.10 (10H, m), 4.71 (1H, d), 3.94 (3H, m), 2.69 (4H, m), 1.90 (2H, m), 1.31 (9H, s), 0.89 (9H, s), 0.11 (6H, d) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-(3-phenyIpropargyl)hexanamide
Following the procedure of Example 1 (c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy- 6-phenyl-2-(3-phenyIpropargyl) hexanoic acid (240 mg) and (1S)-1-imidazol-2-yl-2-methylpropylamine, the title compound was prepared (244 mg, 84%). NMR(CDCl3) δ 7.14 (12H, m), 6.72
(1H, d), 4.58 (1H, d), 4.49 (1H, dd), 3.92 (1H, q), 3.80 (1H, m), 2.54 (5H, m), 1.65 (2H, m), 1.20 (9H, s), 0.81 (9H, s), 0.80 (6H, dd), 0.05 (6H, d). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3- phenyIpropargyl)hexanamide
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%). NMR(CDCl3) δ 7.24-6.98 (10H, m), 6.68 (2H, s), 5.20 (1H, m), 4.52 (1H, d), 3.49 (2H, m), 3.06 (1H, m), 2.56 (5H, m), 2.04 (1H, m), 1.61 (2H, m), 1.26 (9H, s), 0.68 (6H, dd); MS m/e 581.2 (M+Na)+, 559.2 [M+H]+, 541.4, 503.2, 485.2, 459.2, 441.2. Example 13
Preparation of (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide a) (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide
The product of Example 1(c) (0.20 g, 0.31 mmol) was dissolved in trifluoroacetic acid and stirred at room
temperature for 5 min, and partitioned between
dichloromethane and saturated aqueous Na2CO3. The organic extract was dried over Na2CO3, filtered and evaporated to afford the title compound (0.17 g, 100%) which was used without further purification. b) (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'- isopropoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
A mixture containing the compound of 13(a) (0.17 g, 0.31 mmol), isopropyl chloroformate (0.62 mL, 1M in
dichloromethane, 2 eq) and 4-dimethylaminopyridine (0.75 g, 2 eq) in dichloromethane (40 mL) was allowed to stir at room temperature overnight under an argon atmosphere. The mixture was then partitioned between dichloromethane and saturated aqueous Na2CO3, and the organic extract was dried over Na2CO3. The solvent was removed in vacuo, and the residue was
purified by flash chromatography (silica, 4%
methanol/dichloromethane) to afford the title compound (0.214 g, 96%). NMR(CDCl3) δ 7.35-6.78 (12H, m), 6.57 (1H, d), 5.61
(1H, dd), 5.19 (1H, m), 4.86 (1H, m), 4.77 (1H, d), 3.97 (1H, q), 3.63 (1H, t), 2.88 (1H, dd), 2.70-2.48 (4H, m), 2.06 (1H, m), 2.00-1.85 (1H, m), 1.79-1.64 (1H, m), 1.45 (6H, dd), 0.94 (9H, s), 0.85 (6H, d), 0.12 (6H, d). c) (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
To a solution of the compound of 13(b) (0.214 g) in methanol, excess aqueous HCl (~ 5 eq) was added. The
resulting solution was allowed to stir at room temperature overnight, and was concentrated under reduced pressure. The residue was diluted with H2O, and basified with aqueous
Na2CO3. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (0.150 g, 97%). NMR(CDCl3) δ 7.32-
6.96 (13H, m), 5.48 (1H, d), 5.08 (1H, m), 5.00 (1H, s (br) ), 4.87 (1H, m), 3.78 (1H, m), 3.62 (1H, m), 3.25 (1H, m), 2.96- 2.67 (4H, m), 2.29 (1H, m), 1.95-1.65 (2H, m), 1.25-1.12 (6H, dd), 0.80-0.60 (6H, dd); MS m/e 521 [M+H]+, 519 (M-H)-. d) (2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide hydrochloride
The product of 13(c) (100 mg, 0.192 mmol) was dissolved in methanol (10 mL) and a IM solution of HCl in ether (0.192 mL) was added. The solution was concentrated by rotary evaporation without heating/ and the residue was trituated with ether and dried under vacuum to afford the title compound (104 mg, 98%). NMR(CD3OD) δ 7.30 (2H, s), 7.21- 6.88 (10H, m), 4.61 (2H, m), 3.65 (1H, m), 3.48 (1H, d), 2.99 (1H, m), 2.87 (1H, m), 2.74-2.56 (2H, m), 2.12 (1H, m), 1.75- 1.50 (2H, m), 1.17-1.00 (6H, dd), 0.90 (3H, d), 0.64 (3H, d).
Example 14
Preparation of (2R,4S,5S,1'S)-5-(benzyloxyethoxycarhonyl) amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide a) benzyloxyethyl-(4-nitro)phenylcarbonate
To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis (4-nitrophenyl) carbonate (5.0 g, 1 eq) in
dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed successively with H2O and saturated aqueous NaCl and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m), 7.34 (7H, m), 4 . 62 (2H, s),
4.49 (2H, t), 3.70 (2H, t). b) (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'-benzyloxyethoxy- carbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
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 Na2CO3, H2O, aqueous Na2CO3 and H2O, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (180 mg, 82%). NMR(CDCl3) δ 7.45- 6.80 (22H, m), 6.62 (1H, d), 5.60 (1H, t), 5.06 (1H, d), 4.60 (2H, s), 4.52 (2H, s), 4.50 (2H, m), 4.31 (1H, m), 4.07 (2H, m), 3.80 (2H, t), 3.68 (1H, q), 3.57 (1H, q), 2.85 (1H, m),
2.77-2.41 (4H, m), 2.09 (1H, m), 1.90 (1H, m), 1.73 (1H, m),
0.95 (9H, s), 0.81 (6H, dd), 0.11 (6H, d). c) (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl)amino-4-hydroxy-
N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 13 (c) , except using the compound of Example 14 (b) (160 mg), the title compound was prepared (100 mg, 81%). NMR(CDCl3, CD3OD) δ 7.40-6.79
(17H, m), 4.55 (2H, s), 4.45 (1H, d), 4.20 (2H, m), 3.80-3.45 (5H, m), 2.95-2.66 (4H, m), 2.59 (1H, dd), 2.07 (1H, m), 1.71 (2H, m), 0.80 (3H, d), 0.68 (3H, d).
Example 15
Preparation of (2R,4S,5,S,1'S)-5-(methoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide a) (2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'- methoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13 (b), except using (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide, the title compound was prepared (89%).
NMR(CDCl3) δ 7.40-6.79 (12H, m), 6.52 (1H, d), 5.58 (1H, dd),
4.91 (1H, d), 3.96 (3H, s), 3.95 (1H, d), 3.66 (1H, t), 3.60
(3H, s), 2.85 (1H, m), 2.73-2.40 (4H, m), 2.08 (1H, m), 1.90 (1H, m), 1.69 (1H, m), 0.95 (9H, s), 0.85 (6H, dd), 0.14 (6H, d). b) (2R,4S,5S,1'S)-5-(methoxycarbonyl)amiho-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13(c), except using the compound of Example 15 (a), the title compound was prepared (70%). NMR(CDCl3, CD3OD) δ 7.23-6.60 (12H, m), 4.38
(1H, d), 3.65 (1H, t), 3.54 (3H, s), 3.33 (1H, m), 2.95 (1H, m), 2.82-2.40 (4H, m), 1.95 (1H, m), 1.64 (2H, m), 0.69 (6H, dd).
Example 16 Preparation of (2R, 4S, 5S, 1'S)-5-(ethoxycarbonyl)amino-4- hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide a) (2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'- ethoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13 (b), except using (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide and ethylchloroformate, the title compound was prepared (90%). NMR(CDCl3) δ 7.35-6.77 (12H, m), 6.55 (1H, d), 5.60 (1H, dd), 4.86 (1H, d), 4.41 (2H, m), 4.15-3.90 (3H, m), 3.66 (1H, t), 2.87 (1H, m), 2.75-2.45 (4H, m), 2.08 (1H, m), 1.92 (1H, m), 1.70 (1H, m), 1.45 (3H, t), 1.18 (3H, t), 0.98 (9H, s), 0.85 (6H, dd), 0.13 (6H, d). b) (2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13 (c), except using the compound of Example 16(a), the title compound was prepared (95%). NMR(CDCl3, CD3OD) δ 7.25-6.75 (12H, m), 4.43
(1H, d), 3.95 (2H, q), 3.61 (1H, q), 3.40 (1H, m), 2.85 (1H, m), 2.80-2.40 (4H, m), 2.05 (1H, m), 1.61 (2H, t), 1.11 (3H, t), 0.72 (3H, d), 0.55 (3H, t).
Example 1,7
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- (1'-isopropyl-1'-imiriazol-2-yl)methyl-6-phenyl-2- (3-phenyl-2-propenyl)hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3- (3-phenylprop-2-enyl)-tetrahydrofuran-2-one
Following the procedure of Example 12 (a), except using cinnamyl bromide (0.485 mL) as the alkylating agent, the title compound was prepared (0.51 g, 75%). NMR(CDCl3) δ
7.35-7.10 (10H, m), 6.43 (1H, d), 6.09 (1H, m), 4.60 (1H, m), 4.48 (1H, q), 4.00 (1H, t (br)), 2.96-2.55 (4H, m), 2.53-2.21 (2H, m), 2.05 (1H, m), 1.35 (9H, s). b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl- siloxy-6-phenyl-2-(3-ρhenyl-2-propenyl) hexanoic acid
Following the procedure of Example 12 (b), except using the compound of Example 17 (a), the title compound was prepared (77%). NMR(CDCl3) δ 7.40-7.05 (10H, m), 6.48-6.00
(4H, m), 4.78 (1H, d), 3.94 (1H, q), 3.80 (1H, m), 2.89 (1H, m), 2.83-2.26 (4H, m), 1.90 (1H, m), 1.59 (1H, m), 1.28 (9H, s), 0.90 (9H, s), 0.08 (6H, d). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-(3-phenyl-2-propenyl)hexanamide
Following the procedure of Example 1(c), except using the compound of 17 (b), the title compound was prepared (82%). NMR(CDCl3) δ 7.35-7.15 (10H, m), 7.14-6.85 (2H, m), 6.73 (1H, s), 6.20 (1H, d), 6.10-5.88 (1H, m), 4.78 (1H, d), 4.65 (1H, t), 3.97 (1H, q), 3.76 (1H, m), 2.77 (2H, d), 2.50-2.25 (2H, m), 2.12 (1H, m), 1.70 (1H, m), 1.63 (1H, m), 1.36 (9H, s), 0.92 (9H, s), 0.81 (6H, d), 0.09 (6H, d). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2- propenyl)hexanamide
Following the procedure of Example 9 (d), except using the compound of 17(c), the title compound was prepared (90%). NMR(CDCl3, CD3OD) δ 7.30-7.00 (10H, m), 6.71 (2H, s), 6.26
(1H, d), 6.41 (1H, m), 3.66 (1H, d), 3.50 (1H, d), 2.88-2.45
(4H, m), 2.36 (1H, m), 2.23 (1H, m), 2.06 (1H, m), 1.70 (2H, m), 1.34 (9H, s), 0.88 (3H, d), 0.74 (3H, d).
MS m/e 561 [M+H] +.
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
To a solution of the compound of Example 1(b) (175 mg) in dichloromethane (10 mL) at 0°C was added diisopropylethylamine (355 mg, 2.75 mmol) followed by acetyl chloride (215 mg, 2.75 mmol). The resulting mixture was stirred overnight, washed with saturated aqueous Na2CO3, and
concentrated. The residue was treated with methanol, stirred overnight and concentrated under reduced pressure to afford the title compound (181 mg, 78%) as a white solid.
NMR(CD3OD) δ 6.95 (2H, s), 4.72 (1H, d, J=6 Hz), 2.35-2.10 ( 1H, m), 1 . 98 (3H, s), 0 . 98 (3H, d, J=5 , 3 Hz), 0 . 82 (3H, d, J=5 Hz) . b) (1S)-N-(1-(4-nitroimidazol-2-yl)-2-methyl)propylacetamide The compound of Example 18(a) (290 mg, 1.60 mmol) was dissolved in cold concentrated H2SO4 (2 mL), and after stirring for 15 min, 90% HNO3 (0.4 mL) was added dropwise. The resulting mixture was slowly warmed to 40°C and stirred for 2 h. The mixture was then poured onto ice, and the pH was adjusted to 4 by the addition of solid NaHCO3. The mixture was extracted with ethyl acetate (6x), and the combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure to afford the title compound (153 mg, 42%). NMR(CD3OD) δ 7.98 (1H, s), 4.70 (1H, d, J=6 Hz), 2.35-2.15 (1H, m), 1.98 (3H, s), 0.95 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz); MS m/e 475.2 (2M+Na)+, 249.2 (M+Na)+, 227.2 [M+H]+, 185.2, 168.0. c) (1S)-1-(4-nitroimidazol-2-yl)-2-methylpropylamine, dihydrochloride salt
A mixture of the compound of Example 18(b) (153 mg, 0.68 mmol) in 6N HCl (2 mL) was heated at 90°C for 12 h, cooled and concentrated under reduced pressure. The title compound was obtained (138 mg, 80%) and used without further
purification. NMR(CD3OD) δ 8.12 (1H, s), 4.30 (1H, d, J=4
Hz), 2.45-2.30 (1H, m), 1.12 (3H, d, J=4 Hz), 0.90 (3H, d, J=4 Hz). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-nitroimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy- 6-phenyl-2-phenylmethylhexanoic acid and (1S)-1-(4- nitroimidazol-2-yl)-2-methylpropylamine, the title compound was prepared. NMR(CDCl3) δ 7.30-6.90 (10 H, m), 6.60 (1H, d,
J=4 Hz), 4.70 (1H, d, J=5 Hz), 4.40 (1H, t, J=4 Hz), 3.90 (1H, q, J=4 Hz), 3.75 (1H, dd, J=8, 3 Hz), 2.75-2.30 (6H, m), 1 .80-1 .50 (2H, m), 1 .25 (9H, s), 0 . 85 (9H, s), 0.70 (6H, m), 0 .05 ( 6H, d, J=4 Hz) . e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-nitroimidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the deprotection procedure of Example 1 (d), except using the compound of Example 18 (d), the title
compound was prepared. NMR(CD3θD) δ 7.90 (1H, s), 7.40-6.90 (10H, m), 4.53 (1H, d, J=6 Hz), 3.70 (1H, m), 3.50 (1H, m),
2.90-2.60 (5H, m), 2.00 (1H, m), 1.90-1.55 (2H, m), 1.49 (9H, s), 0.85 (3H, d, J=4 Hz), 0.70 (d, 3H, J=4 Hz); MS m/e 602.4
(M+Na)+, 580.4 [M+H]+, 524.4, 480.4. Example 19
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-(1'-ethyl-1'-imidazol-2-yl)methyl-6-pheny1-2- phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-ethyl-1-(imidazol-2- yl)methane
Following the procedure of Example 1 (a), except using Cbz-(L)-α-ethylglycinal in place of valinal, the title compound was prepared. NMR(CDCl3) δ 7.45-7.10 (5H, m), 6.90 (2H, s), 5.65 (1H, d, J=6 Hz), 5.10-4.95 (2H, m), 4.40 (1H, q, J=5 Hz), 2.00-1.70 (2H, m), 1.00-0.80 (3H, m). b) (1S)-(1-imidazol-2-yl)propylamine
Following the procedure of Example 1 (b), except using the compound of Example 19(a), the title compound was prepared. NMR(CDCl3) δ 6.90 (2H, s), 5.00-4.50 (2H, br s),
4.00 (1H, t, J=5 Hz), 2.00-1.70 (2H, m), 1.00-0.80 (3H, m). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-ethyl-1'-imidazol-2-yl]methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy- 6-phenyl-2-phenylmethylhexanoic acid and the compound of Example 19(c), the title compound was prepared. NMR(CDCl3) δ
7.35-6.90 (10H, m), 6.78 (2H, s), 6.20 (d, J=5 Hz), 4.80-4.65 (2H, m), 4.05 (1H, q, J=5 Hz), 3.72 (1H, dd, J=10, 3 Hz), 2.90-2.50 (5H, m), 2.10-2.05 (1H, m), 1.90-1.65 (3H, m), 1.40 (9H, s), 0.95 (9H, s), 0.90-0.85 (3H, m), 0.50 (6H, s). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- ethyl-1'-imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 9(d), except using the compound of Example 19(c), the title compound was
prepared. NMR(CD3OD) δ 7.40-7.00 (10H, m), 6.85 (2H, s),
3.60-3.50 (2H, m), 2.95-2.60 (5H, m), 1.95-1.52 (4H, m), 1.48-1.26 (9H, m), 0.8-0.9 (3H, m).
MS m/e 521.2 [M+H]+; 503.4, 447.4.
Example 20 Preparation of (2R,4S,5S,1'S)-5-(t-bntoxycarbonyl)amino-4- hydroxy-N-(1'-propyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 19 (a)-19(d), except substituting Cbz-(L)-α-propylglycinal for Cbz-(L)-α- ethylglycinal, the title compound was prepared. Data for the intermediates of this synthesis were: a) (1S)-1-carbobenzyloxyamino-1-propyl-1-(imidazol-2- yl)methane. NMR(CDCl3) δ 7.40-7.10 (10H, m), 6.65 (2H, s),
5.55 (1H, d, J=6 Hz), 5.10-4.90 (2H, m), 4.65 (1H, q, J=5 Hz), 2.05-1.93 (1H, m), 1.90-1.75 (1H, m), 1.45-1.20 (4H, m), 0.95-0.85 (3H, m) . b) (1S)-1-(imidazol-2-yl)butylamine. NMR(CDCl3) δ 6.90 (2H, s), 5.10-4.40 (2H, s(br)), 4.05 (1H, t, J=5 Hz), 1.90-1.55 (2H, m), 1.45-1.20 (4H, m), 0.95-0.80 (3H, m) . c) (2R, 4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-propyl-1'-imidazol-2-yl]methyl-6- phenyl-2-phenylmethyl-hexanamide. NMR(CDCl3) δ 7.35-7.00
(10H, m), 6.78 (2H, s), 6.22 (1H, d, J=5 Hz), 4.85-4.68 (2H, m), 4.00 (1H, q, J=3 Hz), 3.75 (1H, dd, J=10, 3 Hz), 2.80-
2.50 (5H, m), 2.12-1.95 (1H, m), 1.90-1.60 (3H, m), 1.40-1.20 (13H, m), 0.90 (9H, s), 0.87-0.80 (3H, m), 0.07 (6H, s). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- propyl-1'-imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide. NMR(CD3OD) δ 7.40-7.00 (10H, m), 6.90 (2H, s),
3.78-3.50 (2H, m), 2.90-2.60 (5H, m), 1.90-1.55 (4H, m), 1.45-1.20 (13H, m); MS m/e 535.4 [M+H]+. Example 21
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4-hromoimiriazol-2-yl) ] methyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S)-N-1-(4-bromoimidazol-2-yl)-2-methyIpropylacetamide and
(1S)-N-1-(4,5-dibromoimidazol-2-yl)-2-methyIpropylacetamide To a solution of (1S)-N-1-imidazol-2-yl-2- methyIpropylacetamide (1.58 g, 8.73 mmol) in 95% ethanol (30 mL), 2, 4, 4, 6-tetrabromocyclohexadienone (3.93 g, 9.60 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the title compound (650 mg, 29%). NMR(CDCl3) δ 7.70 (1H, d, J=7 Hz), 6.85 (1H, s), 4.67 (1H, t, J=7 Hz), 2.35-2.25 (1H, m), 1.95 (3H, s), 1.05 (3H, d, J=5 Hz), 0.80 (3H, d, J=5 Hz).
Also isolated was (1S)-N-1-(4,5-dibromoimidazol-2-yl)-2- methylpropylacetamide (50 mg, 8%) : NMR(CDCl3) δ 4.68 (1H, t, J=7 Hz), 2.38-2.25 (1H, m), 2.05 (3H, s), 1.05 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz); MS m/e 340.0 [M+H]+, 280.8. b) (1S)-1-(4-bromoimidazol-2-yl)-2-methylpropylamine, dihydrochloride
Following the procedure of Example 18 (c), except using (1S)-N-1-(4-bromoimidazol-2-yl)-2-methyIpropylacetamide, the title compound was prepared. NMR(CD3OD) δ 7.60 (1H, s), 4.35
(1H, d, J=7 Hz), 2.50-2.38 (1H, m), 1.10 (3H, d, J=5 Hz), 0.82 (3H, d, J=5 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-bromoimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy- 6-phenyl-2-phenylmethylhexanoic acid and (1S) -1-(4- bromoimidazol-2-yl)-2-methylpropylamine dihydrochloride, the title compound was prepared. NMR(CDCl3) δ 7.40-7.00 (10H, m), 6.70 (1H, s), 6.45 (1H, d, J=5 Hz), 4.80 (1H, d, J=6 Hz), 4.40 (1H, t, J=5 Hz), 4.02 (1H, q, J=4 Hz), 3.78 (1H, dd,
J=7, 2 Hz), 2.90-2.30 (9H, m), 1.85-1.60 (2H, m), 1.45 (9H, s), 1.00 (9H, s), 0.85 (6H, t, J=4 Hz), 0.10 (6H, d, J=6 Hz). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 9 (d), except using (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl- siloxy-N-[1'-isopropyl-1'-(4-bromoimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide, the title compound was prepared. NMR(CDCl3) δ 7.40-7.00 (10H, m), 6.70 (1H, s),
6.55 (1H, m), 4.90 (1H, d, J=5 Hz), 4.50 (1H, t, J=5 Hz), 3.75-3.55 (2H, m), 2.95-2.65 (5H, m), 2.40-2.25 (1H, m), 1.90-1.60 (2H, m), 1.48 (9H, s), 0.80 (6H, t, J=6 Hz).
MS m/e 613.2 [M+H]+; 535.2.
Example 22
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl- 6-phenyl-2-phenylmethyl-hexanamide Following the procedures of Examples 18(c) -18(d) and 9(d), except substituting (1S)-N-1-(4,5-dibromoimidazol-2- yl)-2-methyIpropylacetamide for (1S)-N-(1-4-nitroimidazol-2- yl)-2methyl)propylacetamide, the title compound was prepared. Analytical data for the intermediates of this synthesis were: a) (1S)-1-(4,5-dibromoimidazol-2-yl)-2-methylpropylamine, dihydrochloride. NMR(CD3OD) δ 4.10-3.90 (1H, br s), 2.30-
2.10 (1H, s(br)), 1.10 (3H, d, J=5 Hz), 0.85 (3H, d, J=5 Hz). b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyl- dimethylsiloxy-N-[1'-isopropyl-1'-(4,5-dibromoimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide. NMR(CDCl3) δ
7.40-6.90 (10H, m), 6.38 (1H, d, J=5 Hz), 4.80-4.50 (3H, m), 4.00 (1H, q, J=5 Hz), 3.72 (1H, dd, J=7, 2 Hz), 2.85-2.50 (5H, m), 2.30 (1H, br s), 2.20-2.05 (1H, m), 1.85-1.65 (2H, m), 1.38 (9H, s), 0.90 (9H, s), 0.80-0.60 (6H, m), 0.10 (6H, d, J=3 Hz) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide. NMR(CDCl3) δ 7.35-6.85 (10H, m),
6.65 (1H, br s), 4.92 (1H, d, J=4 Hz), 4.50 (1H, m), 3.72- 3.50 (2H, m), 2.98-2.63 (5H, m), 2.15-2.02 (1H, m), 1.90-1.70 (2H, m), 1.40 (9H, s); MS m/e 693.0 [M+H] +; 637, 619, 593, 575, 291.
Example 23
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4-methylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- methylimidazol-2-yl) methane.
Cbz-(L)-valinal (1.0 g, 3.9 mmol) and pyruvaldehyde (4.3 mmol, 40% in H2O) were dissolved in methanol (10 mL) and chilled in an ice bath. Concentrated aqueous ammonia (2 mL) was added and the reaction mixture was stirred at 20°C overnight. The solvent was removed in vacuo and the residue dissolved in 5% HCl (50 mL) and extracted with ethyl acetate (3x20 mL). The aqueous layer was basified to pH 10 with solid Na2CO3. A tan solid (463 mg) precipitated. The solid was purified by flash chromatography (silica, 2%-3%
methanol/dichloromethane) to yield the title compound as a white solid (180 mg, 16%). mp 163-164°C; NMR(CDCl3) δ 7.45-
7.35 (5H, m), 6.60 (1H, s), 6.00 (1H, d, J=4 Hz), 5.05 (2H, q, J=4 Hz), 4.40 (1H, t, J=4 Hz), 2.45-2.30 (1H, m), 2.20
(3H, s), 0.95 (3H, d, J=4 Hz), 0.80 (3H, d, J=4 Hz); MS m/e 575.4 (2M+H)+, 288.0 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-methylimidazol-2- yl)]methyl-6-ρhenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1(b)-1(c), except using (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-6-phenyl-2-phenylmethylhexanoic acid and the compound of Example 23 (a), the title compound was
prepared. NMR(CDCl3) δ 7.37-6.90 (10H, m), 6.45 (1H, s),
6.38 (1H, d, J=3 Hz), 4.75 (1H, d, J=5 Hz), 4.40 (1H, t, J=5 Hz), 3.95 (1H, q, J=4 Hz), 3.72-3.68 (1H, m), 2.90-2.70 (4H, m), 2 . 60-2.48 (1H, m), 2 .45-2 .30 (1H, m), 2 . 17 (3H, s), 1 . 90- 1 .80 (1H, m), 1 .75-1 . 62 (1H, m), 1 . 40 ( 9H, s), 0 . 95 ( 9H, s), 0 .75 ( 6H, t, J=3 Hz), 0 . 10 ( 6H, d, J=2 Hz ) . c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-methylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 9(d), except using the compound of Example 23 (b), the title compound was
prepared. NMR(CDCl3) δ 7.38-7.00 (10H, m), 6.52 (1H, s),
4.92 (1H, d, J=5 Hz), 4.42 (1H, t, J=4 Hz), 3.72-3.55 (2H, m), 2.95-2.65 (5H, m), 2.35-2.20 (1H, m), 2.18 (3H, s), 1.75 (2H, br s), 1.42 (9H, s), 0.75 (6H, d, J=3 Hz); MS m/e 549.2 [M+H]+.
Example 24
Preparation of (2R,4S,5S,1'S)-5-(t-hutoxycarhonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4-trifluoromethylimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- trifluoromethylimidazol-2-yl)methane.
Sodium acetate trihydrate (5.35 g, 2.2 eq) was dissolved in water (16 mL) and 1,1 dibromotrifluoroacetone (5.31 g, 1.1 eq) was added. The solution was stirred for 30 min at 90°C. The solution was cooled to 0°C and poured into a 0°C solution of Cbz-Valinal (4.22 g, 1.0 eq) in anhydrous methanol (80 mL). Concentrated ammonium hydroxide (22 mL) was added and the mixture stirred overnight at room temperature. The solvents were evaporated to give a white precipitate which was covered with 150 mL of water. The suspension was filtered and the solid washed twice with water. The white solid was dissolved in ethyl acetate, dried over sodium sulfate, filtered, and evaporated to a white solid (5.24 g, 86%).
1HNMR(CD3OD) δ 7.45 (1H, s), 7.40-7.20 (5H, m), 5.05 (2H, q,
J=4 Hz), 4.50 (1H, d, J=4 Hz), 2.38-2.10 (1H, m), 1.00 (3H, d, J=4 Hz), 0.80 (3H, d, J=4 Hz), 13CNMR (CD3OD, 1H-decoupled) δ 18.9, 19.4, 67, 117 (q, J=3 Hz), 123.2 (q, J=266 Hz), 128.7, 129.3, 133 (q, J=39 Hz), 138.0, 151.7; MS m/e 342.0 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyl- dimethylsiloxy-N-[1'-isopropyl-1'-(4-trifluoromethylimidazol- 2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
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. NMR(CDCl3) δ 7.35-6.95 (11 H, m), 6.50 (1H, d, J=4 Hz), 4.75
(1H, d, J=6 Hz), 4.25 (1H, t, J=4 Hz), 3.95 (1H, q, J=4 Hz), 3.80-3.68 (1H, m), 2.90-2.40 (5H, m), 1.80-1.60 (2H, m), 1.35 (9H, s), 0.90 (9H, s), 0.80 (3H, d, J=3 Hz), 0.70 (3H, d, J=3 Hz), 0.05 (6H, d, J=2 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-trifluoromethylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 9(d), except using the compound of Example 24 (b), the title compound was
prepared. NMR(CDCl3) δ 7.35 (1H, s), 7.25-6.90 (10H, m),
4.53 (1H, d, J=5 Hz), 3.68 (1H, t, J=4 Hz), 3.52 (1H, d, J=6 Hz), 2.90-2.55 (5H, m), 2.10-1.95 (1H, m), 1.85-1.70 (1H, m), 1.65-1.50 (1H, m), 1.40-1.25 (9H, m), 0.90 (3H, d, J=4 Hz), 0.65 (3H, d, J=4 Hz); MS m/e 603.2 [M+H]+, 529.2, 503.2.
Example 25 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarhonyl)amino-4- hydroxy-N-methyl-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(imidazol-2- yl)methane
Following the procedure of Example 1 (a), except
substituting N-methyl-Cbz-(L)-valinal for Cbz-(L)-valinal, the title compound was prepared. NMR(CDCl3) δ 7.45-7.30 (5H, m), 6. 90 (2H, s), 5 . 12 (2H, s), 4 . 60 (1H, d, J=6 Hz), 2 . 95 (3H, s), 2 .70-2 .53 (1H, m), 1 . 02 (3H, d, J=3 Hz), 0. 85 (3H, d, J=3 Hz) . b) (1S) -1-methylamino-1-isopropyl-1-(imidazol-2-yl)methane Following the procedure of Example 1 (b), except using the compound of Example 25 (a), the title compound was prepared. NMR(CDCl3) δ 6.95 (2H, s), 3.52 (1H, d, J=3 Hz), 2.30 (3H, s), 2.10-1.90 (1H, m), 0.98 (3H, d, J=3 Hz), 0.82 (3H, d, J=3 Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-methyl-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c), except using the compound of Example 25(b), the title compound was prepared. NMR(CDCl3) δ 7.40-6.72 (12H, m), 4.82 (1H, d, J=5
Hz), 3.95 (1H, q, J=4 Hz), 3.82-3.75 (1H, m), 2.95-2.70 (5H, m), 2.51 (2H, s), 2.50-2.38 (1H, m), 2.08 (1H, s), 1.87-1.68 (2H, m), 1.38 (9H, s), 0.95 (9H, s), 0.88 (3H, d, J=3 Hz), 0.75 (3H, d, J=3 Hz), 0.05 (6H, d, J=7 Hz). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- methyl-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 9 (d), except using the compound of Example 28(c), the title compound was prepared. NMR(CDCl3) δ 7.35-6.82 (12H, m), 4.90-4.72 (1H, m), 3.70-3.00 (2H, m), 2.92-2.50 (8H, m), 1.90-1.60 (2H, m), 1.40-1.30 (9H, m), 0.95-0.70 (6H, m).
MS m/e 549.2 [M+H]+.
Example 26 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [1'-isopropyl-1'-(4-carbomethoxyimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- trimethoxymethylimidazol-2-yl)methane.
Sodium methoxide (8 mL, 25% in methanol, 37.5 mmol) was added to a solution of the compound of Example 27(a) (640 mg, 1.88 mmol) in anhydrous methanol (10 mL). The resulting mixture was heated at 55°C overnight, cooled, and
concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and H2O, and the organic extract was dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 2% methanol/dichloromethane) to afford the title compound (545 mg, 77%). NMR(CDCl3) δ 7.40-7.20 (5H, m), 6.98
(1H, br s), 5.90 (1H, br s), 5.08 (2H, s), 4.50 (1H, br s), 3.15 (9H, s), 2.00 (1H, m (br) ), 1.00-0.80 (6H, m); MS m/e 378.2 [M+H]+, 346, 332, 271, 195. b) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- carbomethoxyimidazol-2-yl)methane
A solution of the compound of Example 26(a) (540 mg) in 1:1 methanol/aqueous HCl (10 mL) was stirred at room
temperature for 2 h, and concentrated under reduced pressure. The residue was partitioned between aqueous Na2CO3 and dichloromethane, and the organic extract was dried over
Na2CO3 and concentrated in vacuo to afford the title compound (470 mg, 75%). NMR(CDCl3) δ 7.55 (1H, br s), 7.35 (5H, s),
5.90-5.65 (1H, m), 5.10 (2H, t, J=4 Hz), 4.60-4.42 (1H, m), 3.88 (3H, s), 2.40 (1H, br s), 1.00-0.80 (6H, m); MS m/e 332.2 [M+H]+. c) (1S)-1-amino-1-isopropyl-1-(4-carbomethoxyimidazol-2- yl)methane
Following the procedure of Example 1 (b), except using the compound of Example 26(b), the title compound was
prepared. NMR(CDCl3) δ 7.62 (1H, s), 3.97 (1H, d, J=4 Hz), 3.82 (3H, s), 2.27-2.05 (1H, m), 0.95-0.75 (6H, m). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-carbomethoxyimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c), except using the compound of Example 26(c), the title compound was prepared. NMR(CDCl3) δ 7.45-6.90 (12H, m), 6.48 (1H, d, J=4
Hz), 4.72 (1H, d, J=6 Hz), 4.35 (1H, s br), 4.02-3.87 (1H, m), 3.85 (3H, s), 3.75-3.60 (1H, m), 2.90-2.40 (5H, m), 1.90- 1.60 (2H, m), 1.42 (9H, s), 0.90 (9H, s), 0.72 (6H, d, J=4 Hz), 0.10 (6H, d, J=3 Hz). e) (2R, 4S, 5S, 1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [1'-isopropyl-1'-(4-carbomethoxyimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 9 (d), except using the compound of Example 26(d), the title compound was prepared. NMR(CDCl3) δ 7.40-6.80 (12H, m), 4.90 (1H, d, J=5
Hz), 4.50 (1H, br s), 3.90 (3H, s), 3.80-3.60 (2H, m), 2.95- 2.68 (5H, m), 2.45-2.30 (1H, m), 1.80-1.60 (2H, m), 1.40 (9H, s), 0.72 (6H, d, J=4 Hz); MS m/e 593.2 [M+H]+, 537.2, 519.2, 493.2, 475.2.
Example 27 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [1'-isopropyl-1'- (-4methylcarbonylimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S) -1-carbobenzyloxyamino-1-isopropyl-1-(4- hydroxymethylimidazol-2-yl)methane.
The compound of Example 26(b) (0.314 g, 1.0 eq) was stirred in anhydrous toluene at -78°C under an argon
atmosphere. Diisobutylaluminum hydride (3.8 mL, 1.0M in hexanes, 4.0 eq) was added and the solution stirred at -78°C for 1 h. The reaction was quenched with methanol (0.2 mL, 1.0 eq). The solution was then diluted with Rochelles salt solution (sat.) and stirred for 1 h. The solution was extracted with dichloromethane twice and the combined organic extracts were washed successively with saturated aqueous Rochelles salt and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to give the title compound as a white solid. (0.27 g, 94%). NMR(CDCl3) δ 7.25 (5H, s), 6.69 (1H, s), 6.14 (1H, d), 5.01 (2H, dd), 4.52 (2H, s), 4.37 (1H, t), 2.19 (1H, m), 0.92 (3H, d), 0.73 (3H, d); MS m/e 304.0 [M+H]+. b) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- formylimidazol-2-yl)methane.
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(CDCl3) δ 9.57
(1H,S), 7.54 (1H, s), 7.12 (5H, s), 6.43 (1H, d), 4.96 (2H , dd), 4.43 (1H, t), 2.08 (1H , m), 0.91 (3H, d), 0.62 (3H, t); MS m/e 302.0 [M+H]+. c) (1S,1'RS)-1-carbobenzyloxyamino-1-isopropyl-1-(4-(1'- hydroxyethyl)imidazol-2-yl)methane.
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(CDCl3) δ 7.19 (5H, s), 6.59
(1H, s), 6.42 (1H, d), 4.92 (2H, dd), 4.73 (1H, m), 2.09 (1H, m), 1.37 (3H, d), 0.82 (3H, d), 0.66 (3H, d). d) (1S, 1'RS)-1-amino-1-isopropyl-1-(4-(1'- hydroxyethyl)imidazol-2-yl)methane.
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(CDCl3) δ 6.63
(1H, s), 4.72 (1H, dd), 3.61 (1H, d), 1.92 (1H, m), 1.49 (3H, d), 0.84 (3H, d), 0.67 (3H, d). e) (2R,4S,5S,1'S,1"RS)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(1''-hydroxyethyl)- imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
To a solution of (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4- t-butyldimethylsiloxy-6-phenyl-2-phenylmethylhexanoic acid (0.131 g, 1.0 eq) in anhydrous dimethylformamide, the
compound of Example 27(d) (50 mg, 1.1 eq), BOP reagent
(0.11 g, 1.0 eq), and triethylamine (0.04 mL, 1.0 eq) were added. The solution was stirred at room temperature for 16 h. The solution was diluted with water and extracted three times with dichloromethane. The combined organic extracts were washed with water, then brine. The solution was dried over magnesium sulfate, filtered, and evaporated to give a white foam. The foam was chromatographed (silica, 4% methanol/dichloromethane) to afford the title compound as a white foam (0.11 g, 65%). NMR(CDCl3) δ 7.31-6.54 (12H, m), 4.72 (1H, d), 4.48 (2H, d), 3.82 (1H, q), 3.61 (1H, m), 2.81- 2.3 (6H, m), 1.65 (3H, m), 1.48 (3H, d), 1.22 (9H, s), 0.89 (9H, s), 0.70 (3H, d), 0.61 (3H, d), 0.06 (6H, s); MS m/e 693.4 [M+H]+. f) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethyIsiloxy-N-(1'-isopropyl-1'-(4-methylcarbonyl- imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
The compound of Example 27(e) (45 mg, 1.0 eq) was stirred in dry dichloromethane under an inert argon
atmosphere. Manganese dioxide (23 mg, 4.0 eq) was added and the mixture was stirred at room temperature for 16 h. An additional 2.0 eq of manganese dioxide was added and the reaction was complete by TLC after 2.5 h. The mixture was filtered through a pad of Celite® and the filter cake was washed with dichloromethane. The organic solvent was evaporated to give the title compound as a white solid
(0.038 g, 85%). NMR(CDCl3) δ 7.49-6.76 (11H, m), 6.30 (1H, br d), 4.71 (2H, m), 3.86 (1H, q), 3.61 (1H, dd), 2.77-2.41 (5H, m), 2.31 (3H, s), 1.58 (2H, m), 1.20 (9H, s), 0.83 (9H, s), 0.69 (6H, dd), 0.04 (6H,d) ; MS m/e 691.4 [M+H]+. g) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl- 2-phenylmethyl-hexanamide
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%).
NMR(CDCl3) δ 7.14 (5H, m), 6.86 (5H, m), 5.14 (1H, d), 4.42
(1H, d), 3.58 (1H, q), 3.45 (1H, d), 2.80-2.50 (5H, m), 1.91 (1H, m), 1.63 (2H, m), 1.26 (9H, s) (rotamer observed), 0.70 (3H, d), 0.57 (3H, d); MS m/e 577.2 [M+H]+. Example 28
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [1'-isopropyl-1'- (-4isopropylcarbonylimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S, 1'RS)-1-carbobenzyloxyamino-1-isopropyl-1-(4-(1'- hydroxy-2'-methyl)propylimidazol-2-yl)methane.
Following the procedure of Example 27 (c), except using isopropyl magnesium bromide (1.024 mL, 2.0M solution, 4.0 eq) in place of methyl magnesium bromide, to yield a crude product. The crude product was chromatographed (silica, 4% methanol/dichloromethane) to yield the title compound as a white solid (0.155 g , 88%).NMR(CDCl3) δ 7.19 (5H, m), 6.58 (1H, s), 4.91 (2H, m), 4.38 (1H, q), 4.20 (1H, dd), 2.11 (1H, m), 1.83 (1H, m), 0.72 (12H, m); MS m/e 346.2 [M+H]+; 328.2, 279.0 , 254.0, 205.0, 177.0, 149.0, 118.0. b) (1S,1'RS)-1-amino-1-isopropyl-1-(4-(1'-hydroxy-2'- methyl)propylimidazol-2-yl)methane
Following the procedure of Example 27 (d) , using the compound of Example 31(a), the title compound was prepared as a white foam (96 mg , 100%). NMR(CDCl3) δ 6.65 (1H, s),
4.21 (1H, d), 3.90 (1H, s), 2.22 (1H, m), 1.94 (1H, m), 0.93 (6H, m), 0.64 (6H, m); MS m/e 302.0 [M+H]+. c) (2R,4S,5S,1'S,1''RS)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(1''-hydroxy-2''- methyl)propylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 27 (e), except using the compound of Example 31(b) (96 mg, 1.1 eq), substituting dimethyl formamide as the solvent instead of dichloromethane, and purifying the product by chromatography, the title compound was prepared (168 g, 57%). NMR(CDCl3) δ 7.22-6.81
(11H, m), 6.62 (1H, d), 4.71 (1H, dd), 4.53 (1H, t), 4.19 (1H, d), 3.82 (1H, q), 3.58 (1H, dd), 2.71-2.30 (5H, m), 2.03 (1H, m), 1.70 (1H, m), 1.57 (1H, m), 1.14 (9H, s), 0.91 (3H, d), 0.88 (9H, s), 0.78 (3H, d), 0.67 (3H, d), 0.59 (3H, d), 0.03 6H, d); MS m/e 721.4 [M+H]+. d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyl- dimethylsiloxy-N-[1'-isopropyl-1'-(4-isopropylcarbonyl- imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
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%). NMR(CDCl3) δ 7.20-6.76 (11H, m), 5.05 (1H, br m), 3.88 (1H, q), 3.61 , m), 3.19 (1H, m), 2.80-2.46 (5H, m), 2.22 (1H, m), 2.07 (1H, m ), 1.63 (1H, m), 1.15 (16H, m), 0.89 (9H, s), 0.74 (6H, m), 0.08 (6H, d); MS m/e 719.4 [M+H]+. e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-isopropylcarbonylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 27 (g), except using the compound of Example 31(d) (132 mg), the title compound was prepared as a white foam (90 mg, 81%) . NMR(CDCl3) δ 7.48
(1H, s), 7.11 (5H, m), 6.82 (5H, m), 5.29 (1H, d), 4.46 (1H, m ), 3.54 (1H, q), 3.48 (1H, m), 3.14 (1H, m), 2.74-2.44 (5H, m), 1.90 (1H, m), 1.61 (2H, m), 1.28 (9H, s) (rotamers observed), 1.13 (6H, m), 0.69 (3H, d), 0.48 (3H, d); MS m/e 605.2 [M+H]+.
Example 29 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [ 1'-isopropyl-1'-(4-phenylcarbonyl-imidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S,1'RS)-1-carbobenzyloxyamino-1-isopropyl-1-(4-(1'- hydroxy)benzylimidazol-2-yl)methane
Following the procedure of Example 27 (c), except
substituting phenylmagnesium bromide (0.45 mL, 3.0M solution, 4.0 eq) for methyl magnesium bromide, and chromatographing the crude product (silica, 3% methanol/dichloromethane) the title compound was prepared as a white solid (175 mg, 96%). NMR(CDCl3) δ 7.26 (1H, d), 7.11 (10H, m), 6.39 (1H, dd), 6.08
(1H, d), 5.63 (1H, d), 4.82 (2H, m), 4.29 (1H, m), 2.01 (1H, m), 0.76 (3H, m), 0.59 (3H, d). b) (1S,1'RS)-1-amino-1-isopropyl-1-(4-(1'-hydroxy)benzyl- imidazol-2-yl)methane
Following the procedure of Example 27 (d), except using the compound of Example 29(a) (98 mg) the title compound was prepared as a tacky white foam (65 mg, 98%). c) (2R,4S,5S,1'S,1''RS)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-(4-(1''- hydroxy)benzylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 27 (e), except using the compound of Example 29(b) (0.065 g, 1.1 eq), and
chromatographing the crude product (2% methanol/
dichloromethane) the title compound was prepared as a white solid (109 mg, 55%). NMR(CDCl3) δ 7.48-6.79 (16H, m), 4.77
(1H, m), 3.88 (1H, m), 3.61 (1H, m), 2.65 (4H, m), 2.39 (1H, m), 2.15 (1H, m), 1.94 (1H, m), 1.75 (1H, m), 1.56 (1H, m), 1.21 (9H, s) (rotamers observed), 0.86 (9H, s), 0.68 (6H, dd), 0.07 (6H, s); MS m/e 755.4 [M+H]+. d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyl- dimethyIsiloxy-N-[1'-isopropyl-1'-(4-phenylcarbonylimidazol- 2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
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%).
NMR(CDCl3) δ 7.49-6.84 (17H, m), 3.88 (1H, q), 3.63 (1H, t),
2.87-2.49 (6H, m), 2.11 (2H, m), 1.64 (1H, m), 1.11 (9H, s), 0.82 (9H, s), 0.71 (6H, dd), 0.06 (6H, d); MS m/e 753.4 {M+H]+. e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-phenylcarbonylimidazol-2-yl)]methyl-6-phenyl- 2-phenylmethyl-hexanamide
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%).
NMR(CDCl3) δ 7.84-6.77 (16H, m), 4.48 (1H, d), 3.59 (1H, m),
3.42 (1H, m), 2.80-2.54 (5H, m), 1.99 (1H, m), 1.63 (2H, m), 1.26 (9H, s) (rotamers observed), 0.73 (3H, d), 0.59 (3H, d); MS m/e 639.2 [M+H]+.
Example 30
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [1'-isopropyl-1'-(4-formylimidazol-2-yl)lmethyl-6- phenyl-2-phenylmethyl-hexanamide a) (1S,1'RS)-1-amino-1-isopropyl-1-(4-(hydroxy)methyl- imidazol-2-yl)methane.
Following the procedure of Example 27 (d), except using the compound of Example 27(a) (90 mg), the titled compound was prepared (50 mg, 100%). NMR(CDCl3) δ 6.85 (1H, s), 4.62
(2H, s), 3.85 (1H, d, J=4 Hz), 2.20-2.05 (1H, m), 0.88 (6H, d, J=5 Hz). b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-(hydroxy)methyl- imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 27 (e), except using the compound of Example 30(a) (50 mg), and chromatographing the crude product (silica, 2% methanol/dichloromethane) the title compound was prepared (130 mg, 65%). NMR(CDCl3) δ
7.30-6.95 (11H, m), 4.82 (1H, d), 4.50-4.60 (1H, m), 4.40 (1H, d), 3.90-4.00 (1H, m), 3.60-3.68 (1H, m), 2.45-2.80 (5H, m), 2.20-2.30 (1H, m), 1.75-1.85 (1H, m), 1.60-1.70 (1H, m), 1.30 (9H, s), 0.95 (9H, s), 0.75 (3H, d), 0.62 (3H, d), 0.05 (6H, d). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4-formylimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 27 (f), except using the compound of Example 30(b) (50 mg), the title compound was prepared (20 mg, 40%). NMR(CDCl3) δ 9.80 (0.5H, s), 9.64
(0.5H, s), 7.50-6.90 (11H, m), 6.52-6.42 (1H, m), 4.88-4.70 (2H, m), 4.42-4.32 (1H, m), 4.02-3.93 (1H, m), 3.78-3.71 (1H, m), 2.90-2.40 (5H, m), 2.30-2.19 (1H, m), 1.87-1.62 (2H, m), 1.45 (9H, s), 0.95 (9H, s), 0.87-0.72 (6H, m), 0.05 (6H, m) (rotamers). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-formylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide
Following the procedure of Example 27 (g), except using the compound of Example 30 (c) (20 mg), the title compound was prepared (12 mg, 71%). NMR(CD3OD) δ 9.60 (1H, s), 7.65 (1H, s), 7.20-6.90 (10H, m), 4.52 (1H, d), 3.60 (1H, m), 3.45 (1H, d), 2.80-2.45 (5H, m), 2.00-1.88 (1H, m), 1.75-1.65 (1H, m), 1.62-1.45 (1H, m), 1.27 (9H, s), 0.82 (3H, d), 0.62 (3H, d); MS m/e 563.4, 242.2, 204.8.
Example 31
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4-(hydroxymethyl)-imidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedure of Example 27 (g), except using the compound of Example 30(b) (40 mg), the title compound was prepared (20 mg). NMR(CD3OD) δ 7.27-6.92 (10H, s), 6.72 (1H, s), 4.52 (1H, d), 3.64-3.60( 1H, m), 3.48( 1H, d), 2.82-2.50 (5H, m), 2.03-1.92 (1H, m), 1.78-1.67 (1H, m), 1.63-1.49 (1H, m), 1.28 (9H, s), 0.80 (3H, d), 0.65 (3H, d); MS m/e 565.4. Example 32
Preparation of (2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4- yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedures of Example 14 (a) -14 (c), except using 4-hydroxytetrahydrothiopyran in place of 2- benzyloxyethanol, the title compound was prepared.
Analytical data for the intermediates of this synthesis were: a) (tetrahydrothiopyran-4-yl)-(4-nitro) phenylcarbonate.
NMR(CDCl3) δ 8.26 (1H, s), 8.22 (1H, s), 7.38 (1H, s), 7.33
(1H, s), 4.79 (1H, m), 2.90-2.75 (2H, m), 2.70-2.52 (2H, m), 2.31-2.16 (2H, m), 2.10-1.90 (2H, m). b) (2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4-yl)oxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide. NMR(CD3OD) δ 7.12-6.65 (10H, m), 6.64 (2H, s), 5.60 (1H, d), 4.36 (2H, m), 3.58 (1H, q), 3.49 (1H, d), 2.68-2.48 (6H, m), 2.44-2.30 (3H, m), 1.93- 1.74 (3H, m), 1.70-1.40 (4H, m), 0.61 (3H, d), 0.50 (3H, d).
Example 33
Preparation of (2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4- yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide Following the procedures of Example 14 (a) -14(c), except using 4-hydroxytetrahydro-4H-pyran in place of 2- benzyloxyethanol, the title compound was prepared.
Analytical data for the intermediates of this synthesis were: a) (tetrahydro-4H-pyran-4-yl)-(4-nitro)phenylcarbonate.
NMR(CDCl3) δ 8.32 (1H, s), 8.28 (1H, s), 7.41 (1H, s), 7.38
(1H, s), 5.00 (1H, m), 4.05-2.90 (2H, m), 3.68-3.49 (2H, m), 2.17-2.00 (2H, m), 1.95-1.75 (2H, m). b) (2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide. NMR(CD3OD) δ 7.16-6.89
(10H, m), 6.79 (2H, s), 4.54 (2H, m), 3.82-3.70 (2H, m),
3.69-3.62 (1H, m), 3.50-3.46 (1H, m), 3.45-3.35 (2H, m),
2.79-2.65 (4H, m), 2.64-2.45 (3H, m), 2.00 (1H, m), 1.82-1.62
(3H, m), 1.55-1.45 (2H, m), 1.37 (1H, m), 0.79 (3H, d), 0.63 (3H, d).
Example 34
Preparation of (2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
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
dissolved in DMF, and 4-picolinium- (p-nitro) phenyl carbonate p-nitrophenylate (23 mg, 1 eq) and triethylamine (0.04 mL, 5 eq) were added. The mixture was stirred under Ar for 17 h. Water was added and the mixture was extracted with
dichloromethane. The organic extracts were concentrated and the residue was triturated with ether to yield the title compound (20 mg, 61%). NMR(CD3OD) δ 8.52 (2H, d), 7.10 (14H, m), 6.87 (2H, s), 5.07 (2H, dd), 4.61 (1H, d), 3.80 (1H, m), 3.59 (1H, m), 2.77 (5H, m), 2.05 (1H, m), 1.83 (1H, m), 1.60
(1H, m), 0.84 (3H, d), 0.59 (3H, d).
MS m/e570.5 [M+H]+.
Example 35
Preparation of (2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- ( 4 , 4 ,4-trifluorobut-1-yl)hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3- (4,4,4-trifluorobut-1-yl)-tetrahydrofuran-2-one
To a solution of lithium diisopropyl amide (1.8 mL of a 1.5M solution, 2.2 eq) in tetrahydrofuran (10 mL) was added (5S, 1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl- tetrahydrofuran-2-one (0.50 g; 1.0 eq) in anhydrous THF (2 mL) at -78°C. After stirring for 15 min at -78°C,
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.
After 2 h at -78°C, the reaction mixture was quenched with a 10% aqueous HCl and extracted with dichloromethane. The organic extracts were combined and evaporated to a clear oil. The oil was chromatographed (silica, 2% methanol/
dichloromethane) to give the title compound as a white foam (0.248 g, 37%). NMR: (CDCl3) δ 7.18 (5H , m), 4.57 (1H; d),
4.41 (1H , dd), 3.95 (1H , q), 2.82 (2H, d), 2.55 (2H , m), 2.49-1.49 (7H , m), 1.32 (9H , s); MS m/e 438.0 (M+Na)+. b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl- siloxy-6-phenyl-2-(4,4,4-trifluorobut-1-yl) hexanoic acid
Following the procedure of Example 12 (b), except using the compound of Example 35 (a) (245 mg), the title compound was prepared (215 mg, 67%). NMR(CDCl3) δ 7.18 (5H, m), 4.70
(1H, d), 3.88 (1H, q), 3.69 (2H, m), 2.73 (1H, m), 2.38 (1H, m), 1.91 (2H, m), 1.45 (6H, m), 1.31 (9H, s) (rotamers observed), 0.90 (9H, s), 0.08 (6H, d); MS m/e548.2 [M+H]+. c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-(4,4,4-trifluorobut-1-yl) hexanamide
Folowing the procedure of Example 1 (c), except using the compound of Example 35(b) (100 mg) and (1S)-1-imidazol-2-yl- 2-methylpropylamine, the title compound was prepared (83 mg, 68%). NMR(CDCl3) δ 7.22 (5H, m), 7.03 (1H, d), 6.89 (2H, s),
4.72 (1H, d), 4.51 (1H, t), 3.91 (1H, q), 3.65 (1H, m), 2.78 (2H, d), 2.33 (2H, m), 1.82 (4H, m), 1.48 (4H, m), 1.36 (9H, two singlets; rotamers present), 0.99 (9H, s), 0.91 (3H, d), 0.79 (3H, d), 0.07 (6H, d) ; MS m/e669.4 [M+H]+. d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(4,4,4- trifluorobut-1-yl)hexanamide
Following the procedure of Example 9 (d), except using the compound of Example 35(c) (83 mg), the title compound was prepared (40 mg, 58%). NMR(CD3OD) δ 7.19 (5H, m), 6.92 (2H, s), 4.61 (1H, d), 3.64 (1H, q), 3.48 (1H, m), 2.79 (2H, m), 2.49 (1H, m), 2.13 (4H, m), 1.60 (5H, m), 1.36 (9H, s), 0.90 (3H, d), 0.71 (3H, d); MS m/e555.2 [M+H]+.
Example 36
Preparation of (2R,4S,5S,1'S)-5-((tetrahydro-4-hydroxy-5-(t- butoxycarbonyl)amino-4-phenyl-N-(1'-isobutyl -1'-imidazol-2- yl)methyl -hexnamide hydrochloride a) 2-(1'-carbobenzyloxyamino-1'-isobutyl)methyl-imidazole
Following the procedure of Example 1 (a), except
substituting Cbz-isoleucinal (1.83 g) for Cbz-valinal, the title compound was prepared (0.658 g, 31%). NMR(CDCl3) δ
6.96 (2H, s), 5.31 (1H, d), 4.48 (1H, dd), 2.15 (1H, m), 1.44 (9H, s), 1.17 (2H, m), 0.92 (3H, t), 0.82 (3H, d) ; MS
(DCI/NH3) m/e 254.2 [M+H]+. b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t- butoxycarbonyl)amino-6-phenyl-N-(1'-isobutyl-1'-(imidazo-2- yl))methyl-hexanamide hydrochloride
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) δ 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
(2H, m), 1.30 (9H, s), 1.17 (2H, m), 0.78 (3H, t), 0.63 (3H, d) ; MS (DCI/NH3) m/e 549.7 [M+H]+. Example 37
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-(4- ( (1RS)-1-hydroxyethyl)- imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
The t-butyldimethylsiloxy-protected alcohol from Example 30(e) (20 mg, 1.0 eq) was stirred in anhydrous THF under an argon atmosphere at room temperature. Tetrabutyl ammonium fluoride (0.33 mL of a 1.0M solution in THF, 6.0 eq) was added and the solution stirred for 16 h. The solution was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water and
evaporated to a white solid. The solid was covered with diethyl ether and decanted twice to give the title compound as a white solid. (0.012 g, 72%). NMR(CDCl3) δ 7.22-6.84
(10H, m), 6.61 (1H, s), 5.42 (1H, d), 4.69 (1H, m), 4.41 (1H, d), 3.58 (1H, m), 3.45 (1H, m), 2.78-2.40 (5H, m), 1.91 (1H, m), 1.59 (2H, m), 1.41 (3H, d), 1.26 (9H, s) (rotamers observed), 0.71 (3H, d), 0.59 (3H, d); MS m/e 579.2 [M+H]+.
Example 38 Preparation of (2R,4S,5S,1'S)-5-(1,1-dimethyl-2- hydroxyethoxycarhonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) 2-t-butyldimethylsiloxy-1,1-dimethylethyl-(4- nitrophenyl) carbonate
A mixture containing bis (4-nitrophenyl) carbonate
(0.996 g, 3.28 mmol), 2-t-butyldimethylsiloxy-1,1- dimethylethanol (0.67 g, 1 eq) and 4-dimethylaminopyridine (0.4 g, 1 eq) in dichloromethane (50 mL) was stirred at room temperature for 5 d. The mixture was diluted with
dichloromethane and washed successively with H2O and
saturated aqueous NaCl, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (35%). NMR(CDCl3) δ 8.25 (2H, m), 7.35
(2H, m), 3.76 (2H, s), 1.53 (6H, s), 0.94 (9H, s), 0.09
(6H, s). b) (2R,4S,5S,1'S)-5-(2-t-butyldimethylsiloxy-1,1-dimethyl- ethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenyϊmethyl-hexanamide
A solution of 2-t-butyldimethylsiloxy-1,1-dimethylethyl- 4-nitrophenyl carbonate (137 mg, 0.372 mmol), (2R, 4S,5S, 1'S)- 5-amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide (102 mg, 0.186 mmol) and DMAP (45 mg, 0.372 mmol) in methylene choride was stirred at 20°C under Ar for 24 h. The solution was washed with aqueous Na2CO3, dried over solid Na2CO3 and concentrated. Flash chromatography (4% methanol/dichloromethane) provided the intermediate (2R,4S,5S,1*S)-5-(2-t-butyldimethylsiloxy- 1,1-dimethylethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N- (1'-isopropyl-1'-(1-(2-t-butyldimethylsiloxy-1,1- dimethylethoxycarbonyl)imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide, which was dissolved in ether, washed with 10% NaOH, dried over Na2CO3, and concentrated to provide the title compound (110 mg, 78% overall). NMR(CDCl3) δ 7.37-
6.70 (13H, m), 6.39 (1H, d), 4.84 (1H, d), 4.55 (1H, t), 3.96 (1H, q), 3.69 (2H, s), 3.60-3.42 (2H, m), 2.94 (1H, s (br)), 2.85-2.44 (4H, m), 2.39 (1H, q), 1.90-1.60 (2H, m), 1.31 (6H, d), 1.02-0.85 (18H, m), 0.83 (6H, t), 0.98 (12H, m). c) (2R,4S,5S,1'S)-5-(1,1-dimethyl-2-hydroxyethoxy- carbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
A mixture containing the compound of Example 38(b) (110 mg) and tetra-n-butylammonium fluoride (6 eq of IM solution in THF) under an argon atmosphere was allowed to stir at room temperature overnight. The solution was diluted with
dichloromethane and washed with water, and the organic layer was concentrated. The residue was purified by flash
chromatography (4% methanol/dichloromethane) to afford the title compound (0 . 05 g, 66%) . NMR (CDCl3, CD3OD) δ 7 .30-6 .78 (12H, m), 4 . 42 (1H, d), 3 .75-3 .38 (4H, m), 2 . 97-2 .50 (5H, m), 2 . 08 (1H, m), 1 .70-1.56 (2H, m), 1. 30 ( 6H, s), 0 . 90-0 .55 ( 6H, dd) .
Example 39
Preparation of (2R,4S,5S,1'S)-5-(1,1-dimethyl-2-hydroxyethoxycarbonyl)amino-4-hvdroxy-N-(1'-isopropyl-1,-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide hydrochloride
A IM solution of HCl in ether (63.5 mL) was added to a solution of the compound of Example 38(c) (35 mg, 0.064 mmol) in methanol (5 mL). The solvent was removed by rotary evaporation at 20°C, and the solid residue was triturated with ether and dried to afford the title compound as the hydrochloride salt (35 mg, 95%). NMR(CD3OD) δ 7.37-6.85
(12H, m), 4.56 (1H, d), 3.59 (1H, m), 3.48-3.33 (3H, m), 2.85-2.48 (6H, m), 2.04 (1H, septet), 1.72-1.49 (2H, m), 1.22 (6H, d), 0.88 (3H, d), 0.61 (3H, dd).
Example 40
Preparation of (2R,4S,5S,1'S)-5-_2-hydroxyethoxyoarhonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethylhexanamide a) benzyloxyethyl-(4-nitro) phenylcarbonate
To a solution of 2-benzyloxyethanol (2.5 g, 16.4 mmol) and bis (4-nitrophenyl) carbonate (5.0 g, 1 eq) in
dichloromethane (200 mL), N-methylmorpholine (1.81 mL, 1 eq) was added. The resulting mixture was allowed to stir at room temperature for 3 d. The reaction mixture was washed
successively with H2O and saturated aqueous NaCl and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 20% ethyl acetate/hexanes) to afford the title compound (4.38 g, 84%). NMR(CDCl3) δ 8.26 (2H, m), 7.34 (7H, m), 4 . 62 (2H, s), 4.49 (2H, t), 3.70 (2H, t). b) (2R,4S,5S,1'S)-5-(2-benzyloxyethoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(N'-(2- benzyloxyethoxy)carbonyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
To a solution of (2R, 4S, 5S,1'S)-5-amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-phenylmethyl-hexanamide (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 Na2CO3, H2O, aqueous Na2CO3 and H2O, and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound (180 mg, 82%). NMR(CDCl3) δ 7.45-
6.80 (22H, m), 6.62 (1H, d), 5.60 (1H, t), 5.06 (1H, d), 4.60 (2H, s), 4.52 (2H, s), 4.50 (2H, m), 4.31 (1H, m), 4.07 (2H, m), 3.80 (2H, t), 3.68 (1H, q), 3.57 (1H, q), 2.85 (1H, m), 2.77-2.41 (4H, m), 2.09 (1H, m), 1.90 (1H, m), 1.73 (1H, m), 0.95 (9H, s), 0.81 (6H, dd), 0.11 (6H, d). c) (2R,4S,5S,1'S)-5-(2-hydroxyethoxycarbonyl)amino-4-t-butyl- dimethyIsiloxy-N-[1'-isopropyl-l'-(N'-2-benzyloxyethoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
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%). NMR(CDCl3) δ 7.36-
6.72 (12H, m), 5.03 (1H, d), 4.80 (1H, dd), 4.50-4.32 (2H, m), 4 . 07-3.52 (5H, m), 2. 96-2 .32 (6H, m), 1. 98-1.85 (2H, m), 0 . 95 ( 9H, s), 0. 90-0.75 (6H, dd), 0 .05 ( 6H, d) . d) (2R,4S,5S,1'S)-5-(2-hydroxyethoxycarbonyl)amino-4-hydroxy- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
To a solution of the compound of of Example 40 (c) in methanol, excess aqueous HCl (approx. 5 equiv.) was added. The resulting solution was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was diluted with H2O, and made basic with aqueous Na2CO3. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over Na2.CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford the title compound.
NMR(CD3OD) δ 7.28-6.85 (12H, m), 4.55 (1H, d), 3.95 (1H, m),
3.73-3.40 (4H, m), 2.86-2.47 (5H, m), 1.99 (1H, m), 1.71 (1H, m), 1.22 (1H, m), 0.84 (3H, d), 0.62 (3H, d). Example 41
Preparation of (2R,4S,5S,1'S)-5-((IRS)-1-methyl-2- hydroxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) 2-t-butyldimethylsiloxy-1-methylethyl-(4-nitrophenyl)- carbonate
A mixture containing bis (4-nitrophenyl) carbonate
(3.20 g, 10.5 mmol), 2-t-butyldimethylsiloxy-1-methylethanol (2.0 g, 10.5 mmol) and 4-dimethylaminopyridine (1.30 g, 1 0.5 mmol) in dichloromethane (200 mL) was stirred at room
temperature for 5 d. The mixture was then diluted with dichloromethane and washed successively with H2O and
saturated aqueous NaCl and dried over Na2CO3. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to afford the title compound (88%). NMR(CDCl3) δ 8.28 (2H, m), 7.39 (2H, m), 4 . 98 (1H, m), 3 .75 (2H, d), 1 .38 (3H, s), 0 . 92 ( 9H, s), 0. 11 (6H, s) . b) (2R,4S,5S,1'S)-5-(2-t-butyldimethylsiloxy-1-methyl- ethoxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 38 (b), except substituting the compound of Example 4 (a) for 2-t- butyldimethylsiloxy-1,1-dimethylethyl-4-nitrophenyl
carbonate, the title compound was prepared. NMR(CDCl3) δ
7.40-7.00 (10H, m), 6.90 (1/2H, s), 6.72 (1/2H, s), 6.45 (1H, dd), 4.92 (1H, dd), 4.84-4.61 (2H, m), 4.10 (1H, m), 3.76 (1H, m), 3.58 (1H, m), 2.92-2.73 (3H, m), 2.70-2.45 (3H, m), 1.78 (2H, m), 1.22-1.08 (3H, m), 1.04-0.81 (24H, m), 0.17- 0.09 (12H, m). c) (2R,4S,5S,1'S)-5-((IRS)-1-methyl-2-hydroxyethoxycarbonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 38 (c), except using the compound of Example 4(b), the title compound is prepared. NMR(CD3OD) δ 7.15-6.68 (12H, m), 5.72-5.60 (1H, dd), 4.58
(1H, m), 4.38 (1H, dd), 4.06 (1H, m), 3.62 (1H, m), 3.41 (1H, m), 2.79-2.55 (5H, m), 2.49 (1H, dd), 1.92 (1H, m), 1.67 (1H, m), 1.08-0.98 (3H, dd), 0.69 (3H, dd), 0.58 (3H, dd).
Example 42
Preparation of (2R,4S,5S,1'S)-5-(2-hydroxy-1- cyclopentyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide a) (trans)-2-(t-butyldimethysiloxy)-cyclopentanol
To a mixture of t-butyldimethylsilyl chloride (5.08 g, 33.7 mmol) and imidazole (2.30 g, 33.7 mmol) in DMF (10 mL), a solution of trans-1,2-cyclopentanediol in DMF (4 mL) was added. The reaction mixture was stirred overnight at 25°C. The reaction mixture was diluted with ice water and extracted with ether. The ether extract was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo . The residue was purified by flash
chromatography (silica, 9:1 hexane: ethyl acetate) to the title compound as an oil (3.44 g, 49%). b) ((trans)-2-(t-butyldimethysiloxy)-cyclopentyl)-(4- nitrophenyl)carbonate
To a solution of the compound of Example 42(a) (1.08 g, 5 mmol) and DMAP (0.611 g, 5 mmol) in dichloromethane (12 mL), bis (4-nitrophenyl) carbonate (1.52 g, 5 mmol) was added. The solution was stirred overnight at 25°C. The reaction mixture was diluted with dichloromethane (15 mL), and washed with water and brine. The organic extract was dried over magnesium sulfate, filtered, and the solvent was removed at reduced pressure. The residue was triturated with
hexane:ethyl acetate (1:1) and filtered. The filtrate was evaporated to an oil and purified by flash chromatography (silica, 9:1 hexane:ethyl acetate) to yield the title
compound as an oil (1.75 g, 92%). c) 5-((trans)-2-t-butyldimethylsiloxy-cyclopentyloxy- carbonyl)amino-4-t-butyldimethysiloxy-N-[1'-isopropyl-1'-(1- (2-t-butyldimethysiloxy-cyclopentyloxycarbonyl))imidazol-2- yl]methyl-6-phenyl-2-phenylmethyl-hexanamide
A solution of 5-amino-4-t-butyldimethylsiloxy-N-[1'- isopropyl-1'-imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide (171 mg, 0.311 mmol), DMAP (76.1 mg, 0.623 mmol) and the compound of Example 42(b) (238 mg, 0.623 mmol) in dichloromethane (9 mL) was stirred overnight at 25°C. The reaction mixture was diluted with dichloromethane, washed with water and saturated sodium bicarbonate solution, and dried with magnesium sulfate. The organic extract was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica, 4:1
hexane: ethyl acetate) to yield the title compound as an oil (150 mg, 47%). d) 5-((trans)-2-hydroxy-cyclopentyloxycarbonyl)amino-4- hydroxy-N-[1'-isopropyl-1'-imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide
To a solution of the compound of Example 42(c) (150 mg, 0.145 mmol) in methanol (5 ml), 3N HCl (3 mL) was added. The solution was stirred overnight at 25°C. The methanol was evaporated in vacuo, and the residue was diluted with water and extracted with ether. The aqueous solution was
neutralized with 5% sodium carbonate (~pH 7) and a solid precipitated. The solid was filtered, washed with water and dried in vacuo to yield the title compound (51.5 mg, 63%) . NMR(CD3OD, 400 MHz) δ 7.0-7.3 (m, 10H), 6.87 (s, 2H), 4.63
(m, 2H), 3.88 (m, 1H), 3.55 (d, 1H), 2.5-2.9 m, 5H), 1.4-2.1 (br, 9H), 0.88 (d, 3H), 0.71 (d, 3H); TLC Rf 0.27 (silica, 8% methanol/chloroform).
Example 43
Preparation of (2R,4S,5S,1'S)-5-(4-hydroxyhutanoyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imiriazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide a) t-butyldimethylsilyl 4-(t-butyldimethylsiloxy)-butanoate
To a suspension of t-butyldimethylsilyl chloride (29.9 g, 198 mmol) in dry DMF (20 mL), 4-hydroxybutyric acid, sodium salt (5.0 g, 397 mmol) and imidazole (27.0 g, 0.397 mol) were added. The reaction mixture was stirred overnight at 25°C. The solvent was removed under reduced pressure and the residue was diluted with 10% aqueous citric acid (200 mL). The residue was extracted with ether. The ether solution was dried with magnesium sulfate, filtered and evaporated to yield the title compound as an oil. b) 4-t-butyldimethylsiloxy-butanoic acid
A solution of the compound of Example 43(a) (5.0 g) was dissolved in acetic acid:tetrahydrofuran:water (2:2:1, 50 mL) solution and stirred for 2.5 h. The solution was diluted with water and extracted with ether. The ether solution was dried with magnesium sulfate, filtered and evaporated to an oil. The oil was purified by flash chromatography (silica, hexane-ethyl acetate, 9:1) to yield the title compound as an oil (180 mg). c) (2R,4S,5S,1'S)-5-(4-t-butyldimethylsiloxy-butanoyl)amino- 4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide
A solution of (2R,4S,5S,1'S)-5-amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-phenylmethyl-hexanamide (175 mg, 0.319 mmol), 4-t- butyldimethylsiloxy-butanoic acid (84 mg, 0.41 mmol), BOP reagent (148, 0.335 mmol), triethylamine (46 μL, 0;335 mmol) and dichloromethane (4 mL) were stirred at 20°C under Ar for 24 h. The reaction mixture was diluted with dichloromethane, washed with aqueous Na2CO3, water and brine, and dried over solid magnesium sulfate. The organic phase was filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica, 2% methanol/chloroform) to provide the title compound. d) (2R,4S,5S,1'S)-5-(4-hydroxybutanoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide
A solution of the compound of Example 43(c) (177 mg,
0.236 mmol) and tetra-n-butylammonium fluoride (2.84 mL, 2.84 mmol, IM solution in THF) was stirred under an argon
atmosphere at room temperature overnight. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, and water, and the organic layer was concentrated. The residue was precipitated from the ethyl acetate solution to afford the title compound. NMR δ (CD3OD,
400 MHz) 7.0-7.3 (m, 10H), 6.86 (s, 2H), 4.62 (d, 1H), 4.05 (m, 1H), 3.43 (t, 2H), 2.55-2.90 (m, 4H), 2.60 (m, 1H), 2.17 (m, 2H), 2.05 (m, 1H), 1.76 (m, 1H), 1.67 (m, 2H), 1.55 (m, 1H), .88 (d, 3H), .72 (d, 3H); TLC Rf 0.40 (silica, 10% methanol/chloroform). Example 44
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5- (benzyloxycarbonyl)valylamino-6-phenyl-N-(1'-isobutyl-1'- imidazo-2-yl)methyl-hexanamide
(a) (2R,4S,5S,1'S)-2-phenylmethyl-4-butyldimethylsiloxy-5- (benzyloxycarbonyl)valylamino-6-phenyl-N-(1'-isobutyl-1'- (imidazo-2-yl))methyl-hexanamide.
A solution of carbobenzyloxy-(L)-valine (50.4 mg, 0.20 mmol), the product of Example 13(a) (110 mg, 0.20 mmol), BOP reagent (88.7 mg, 0.20 mmol) and triethylamine (28 μl, 0.20 mmol) in methylene chloride (4 mL) was stirred at 25°C for 4 d. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate and the organic layer was concentrated. The product was purified by flash chromatography (silica gel, 4% CH2CI2/ MeOH) to give the title compound (104 mg, 67%). (b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-
(benzyloxycarbonyl-valyl)amino-6-phenyl-N-(1'-isobutyl-1'- imidazo-2-yl)methyl-hexanamide.
To a solution of the compound of Example 44(a) (104 mg, 0.133 mmol) in MeOH (8 mL), 3N HCl (2 mL) was added. The solution was stirred for 16 hrs at 25°C. The methanol was removed at reduced pressure and 10% sodium carbonate was added to pH ~7.5. Ether (10 mL) was added and the solid product was filtered and dried in vacuo to provide the title compound (58 mg, 65%). NMR(CDCl3) δ 0.62 (d, 3H), 0.78 (d, 3H), 0.82 (d, 3H), 0.90 (d, 3H), 1.62 (m, 2H), 1.96 (m, 1H), 2.06 (m, 1H), 2.55 (m, 1H), 2.77 (m, 4H), 3.38 (s, 1H), 3.53 (m, 1H), 3.91 (M,1H), 3.99 (m, 1H), 4.47 (d, 1H), 5.11 (s, 2H), 5.78 (d, 1H), 6.85 (s, 2H), 6.92-7.34 (m, 15H);
MS m/e 667 [M+H]+. Example 45
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(N- acetylvalyl)amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2- yl)methyl-hexanamide
(a) (2R,4S,5S,1'S)-2-phenylmethyl-4-t-butyldimethylsil)oxy-5- (N-acetyl-valyl)amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2- yl)methyl-hexanamide
To a solution of N-acetyl-(L)-valine (40.3 mg, 0.253 mmol) in dry THF (8 mL) at -40°C was added n-methylmorpholine (55.7 μl, 0.506 mmol) followed by isobutyl chloroformate (33.5 μl, 0.253 mmol). The reaction mixture was stirred for 15 min, and the compound of Example 13(b) (139 mg, 0.253 mmol) in THF (3 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 d. The reaction was diluted with ethyl acetate, and washed with water and brine. The organic solution was dried with sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography (silica, 4% methanol/chloroform) to give the product as an oil (47 mg, 27%).
(b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(N- acetylvalyl)amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2- yl)methyl-hexanamide.
To a solution of the compound of Example 45(a) (47 mg,
0.0681 mmol) in methanol (3 mL), 3N HCl (0.5 mL) was added.
The reaction was stirred for 16 h at 25°C. The methanol was removed under reduced pressure and the solution was diluted with water and neutralized with 5% sodium carbonate. The solid product was filtered, washed with water and ether, and dried in vacuo to yield the title compound (29.5 mg, (75%).
NMR (CD3OD) δ 0.70 (d, 3H), 0.88 (m, 9H), 1.57 (m, 1H), 1.70 (m, 1H), 1.92 (s, 3H), 2.05 (m, 1H), 2.55 (q, 1H), 2.77 (m, 4H), 3.57 (d, 1H), 4.03 (m, 2H), 4.60 (d, 1H), 6.87 (s, 2H), 6.95-6.20 (m, 10H); MS m/e 575 [M+H]+. Example 46
Preparation of (2R,4S,5S,1'S)-5-[(imidazol-2- yl)methyloxycarbonyl]amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-Phenyl-2-phenvlmethyl-hexanamide a) (1-(benzyloxymethyl)imidazol-2-yl)methyl-(4- nitrophenyl)carbonate
A mixture of bis (4-nitrophenyl) carbonate, (1- benzyloxymethyl) imidazol-2-yl)methanol and 4- dimethylaminopyridine was reacted according to the procedure of Example 14(a) to afford the title compound (58%).
NMR(CDCl3, 400 MHz) δ 8.18 (d, 2 H, J=8.38 Hz), 7.44-7.23 (m,
7H), 7.11 (s, 1H), 7.13 (s, 1H), 5.48 (s, 2H), 5.44 (s, 2H), 4.49 (s, 2H). b) (2R,4S,5S,1'S)-5-((1-benzyloxymethyl)imidazol-2- yl)methyloxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide.
A mixture of the compound of Example 46(a),
(2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide, and 4- dimethylaminopyridine was reacted according to the procedure of Example 14(b) to afford the title compound (32%) .
NMR(CDC13) δ 7.50-6.60 (m, 19H), 5.25 (m, 2H), 5.11 (d, 2H,
J=11.03 Hz), 4.68 (m, 1H), 4.39 (m, 2H), 3.97 (m, 1H), 3.67 (m, 1H), 2.88 (m, 1H), 2.72-2.28 (m, 6H), 1.85 (m, 1H), 1.60 (m, 1H), 0.92-0.81 (m, 15H), 0.80 (s, 3H), 0.06 (s, 3H) ;
MS(ES) m/e 793 [M+H]+. c) (2R, 4S, 5S, 1'S)-5-(imidazoyl-2-yl- methyloxycarbonyl)amino-4-t-butyldimethylsiloxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide
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 H2 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%
MeOH/CH2Cl2) to yield the title compound (28 mg, 57%).
NMR(CDCl3) δ 7.29-6.83 (m, 14H); 5.05 (d, 1H, J=11.2 Hz),
4.91 (d, 1H, J=11.2 Hz), 4.71 (m, 1H), 3.92 (m, 1H), 3.61 (m, 1H), 3.02 (m, 1H), 2.81-2.54 (m, 4H), 2.36 (m, 1H), 1.93 (m, 1H), 1.59 (m, 1H), 0.91 (d, 3H, J=7.1 Hz), 0.89 (s, 9), 0.69 (d, 3H, J=7.1 Hz), 0.84-0.05 (m, 6H) ; MS(ES) m/e 673 [M+H]+. d) (2R,4S,5S,1'S)-5-(imidazol-2-yl-methyloxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
The compound of Example 46(c) (24 mg, 0.035 mmoL), 95% aqueous EtOH (0.50 mL), and concentrated aqueous HCl (0.050 mL) were stirred at 23°C for 24 h. The solution was diluted with H2O (5 mL) washed with EtOAc and then the aqueous phase was made basic by addition of solid K2CO3. Extraction with EtOAc, concentration of the organic extract and trituration with CH2CI2 afforded the title compound (14 mg, 72%). NMR (CDCI3) δ 7.33-6.85 (m, 14H), 5.11 (d, 1H, J=10.8 Hz), 4.96
(d, 1H, J=10.8 Hz), 4.47 (m, 1H), 3.72 (m, 1H), 3.38 (m, 1H), 2.81 (m, 4H), 2.59 (m, 1H), 2.07 (m, 1H), 1.72 (m, 1H), 1.62 (m, 1H), 0.78 (d, 3H, J=6.63 Hz), 0.67 (d, 3H, J=6.63 Hz); (m, 6H); MS(ES) m/e 559 [M+H]+.
Example 47
Preparation of (2R,4S,5S,1'S,1"RS)-5-( (1"-(imidazol-2-yl)-2"- methyl)propyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethvl-hexanamide a) (1RS)-1-((1-benzyloxymethylimidazol-2-yl)-2- methyl)propyl-(4-nitrophenyl) carbonate
A mixture of bis (4-nitrophenyl) carbonate, (1RS)-1-((1- benzyloxymethylimidazol-2-yl)-2-methyl) propanol and 4- dimethylammopyridine was reacted according to the procedure of Example 14(a) to afford the title compound (61%) . NMR (CDCI3) δ 8.18 (d, 2H, J=8.31 Hz), 7.38-7.21 (m, 7H), 7.13 (s, 1H), 6.94 (s, 1H), 5.74 (d, 1H, J-11.1 Hz), 5.47 (d, 1H, J=10.2 Hz), 5.28 (d, 1H, J=10.2 Hz), 4.53 (d, 1H, J=11.3 Hz), 4.41 (d, 1H, J=11.3 Hz), 2.64 (m, 1H), 1.18 (d, 3H, J=6.02 Hz), 0.87 (d, 3H, J=6.02 Hz); MS(ES) m/e 426 [M+H]+. b) (2R,4S,5S,1'S,1"RS)-5-((1"-(1-benzyloxymethylimidazol-2- yl)-2"-methyl-propyl)oxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-(1-(1"-(1- benzyloxymethylimidazol-2-yl)-2"- methylpropyl)oxycarbonyl)imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
A mixture of the compound of Example 47(a) (145 mg, 0.33 mmol), the compound of Example 13(a) (75.9 mg, 0.14 mmol), 4- dimethylammopyridine (41 mg, 0.33 mmol) and DMF (0.5 mL) was stirred under argon for 18 h. The DMF was evaporated in vacuo and the residue was combined with 10% aq K2CO3 (10 mL) and extracted with EtOAc. The combined extracts were washed with saturated aq NaHCO3, dried (K2CO3), filtered and
concentrated in vacuo. The residue was flash chromatographed (silica, step gradient, 0-4% MeOH/CH2Cl2) to afford the title compound (96.1 mg, 57%). NMR (CDCI3) δ 7.38-6.78 (m, 26H), 5.67 (m, 1H), 5.61-5.00 (m, 6H), 4.58-4.27 (m, 5H), 3.97-3.61 (m, 3H), 2.78-2.10 (m, 8H), 1.95-1.51 (m, 2H), 1.10-0.55 (m, 27H), 0.50-0.05 (m, 6H). c) (2R,4S,5S,1'S,1"RS)-5-[(1"-(1-benzyloxymethyl- imidazol-2-yl)-2"-methyl-propyl)oxycarbonyl]amino-4-hydroxy- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
A solution of the compound of Example 47(b) (81 mg, 0.07 mmol), CH3OH (0.75 mL), and 3N aqueous HCl (0.25 mL) was stirred at 23°C for 20 h. The reaction mixture was diluted with H2O (10 mL) and washed with EtOAc (3 x 15mL). Solid K2CO3 was added to give a basic solution (pH>12), which was extracted with EtOAc. The extracts were dried (K2CO3), filtered, concentrated and flash chromatographed (silica, step gradient, 0-8% CH3OH/CH2CI2) to give the title compound (34.9 mg, 65%) . 1H NMR (CDCl3) δ 7.43-6.79 (m, 9H), 5.87, 5.66 (2d, 1H, J=10.66, 10.85 Hz), 5.28 (m, 2H), 4.68 (m, 1H), 4.42 (m, 2H), 3.71 (m, 1H), 3.58 (m, 1H), 2.90-2.31 (m, 6H) , 2.11 (m, 1H), 1.75, 1.51 (2m, 2H), 1.05, 0.97 (2d, 3H,
J=6.32,6.45), 0.68 (m, 9H) . d) (2R,4S,5S,1'S,1"RS)-5-((1"-(imidazol-2-yl)-2"- methyl) propyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide.
A mixture of the compound of Example 47 (c) (34 mg,
0.047 mmol), CH3OH (4 mL), and 10% Pd/C (34 mg), was stirred under H2 (1 atm) for 26 h. The suspension was filtered through Celite®, concentrated, and triturated with CH2CI2 to yield the title compound (4 mg, 14%). 1H NMR (CDCI3/CD3OD) δ 7.7.32-6.71 (m, 14H), 5.38 (m, 1H), 4.55 (m, 1H), 3.72 (m, 1H), 3.55 (m, 1H), 2.78 (m, 4H), 2.55 (m, 1H), 2.15 (m, 2H), 1.60 (m, 2H), 1.03-0.61 (m, 12H).
Example 48
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [1'-isopropyl-1'-(4-(imidazol-2-yl)imidazol-2- yl)]methyl-6-phenvl-2-phenylmethyl-hexanamide (a) (1'S)-1'-(carbobenzyloxy)amino-1'-isopropyl-1'-(4- (imidazol-2-yl)imidazol-2-yl) methane
Cbz-(L)-valinal (0.45 g, 1.4 mmol) was stirred in anhydrous methanol at 0°C under argon. Glyoxal (40% in water) (0.22 mL, 1.4 mmol) and ammonium hydroxide (29% NH3) (0.88 mL, 14 mmol) were added and the mixture was allowed to stir at 0°C for 1 h. The cooling bath was removed and the solution stirred at room temperature for 16 h. The methanol was evaporated in vacuo and the residue was diluted with 5% aqueous HCl. After extracting with dichloromethane, the aqueous layer was made basic with solid sodium carbonate and extracted with dichloromethane. The combined organic
extracts were dried over sodium carbonate, filtered, and evaporated to a solid which was chromatographed (silica, 4% methanol/dichloromethane) to give the title compound (0.216 g, 43%) as a white solid. NMR (CDCI3) δ 7.15 (6H, s (br)),
6.88 (2H, s), 6.30 (1H, d), 4.89 (2H, dd), 4.52 (1H, t), 2.05 (1H, m), 0.73 (3H, d), 0.62 (3H, d). MS m/e 340.2 [M+H]+
(b) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [1'-isopropyl-1'-(4-(imidazol-2-yl)imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
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%).
This compound was combined with the compound of Example 13(a) (0.334 g, 0.63 mmol), BOP reagent (0.28 g, 0.63 mmol), and triethylamine (0.13 mL, 0.945 mmol) in DMF (1 mL) and allowed to stir under Ar for 3 d. The DMF was evaporated in vacuo and the residue was diluted with dichloromethane. The solution was washed with water and brine. The organic layer was dried over sodium carbonate, filtered, and evaporated to yield (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethysiloxy-N-[1'-isopropyl-1'-(4-(imidazol-2- yl)imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl hexanamide as a white solid.
A portion of the solid (0.100 g, 0.14 mmol) was stirred in THF at room temperature under argon. Tetrabutylammonium fluoride (0.84 mL, 0.84 mmol) was added and the mixture was allowed to stir for 16 h. The solution was diluted with water and extracted twice with dichloromethane. The combined organic extracts were washed with water and evaporated to an oily residue. The residue was dissolved in THF and several drops of diethyl ether were added until a white precipitate formed. The precipitate was collected by filtration and dried in vacuo to yield the title compound as a white solid (76 mg, 90%). NMR (CD3OD) δ 7.37-6.84 (13H, m), 4.61 (1H, d), 3 . 69 (2H, m), 3 . 54 (1H, d), 2 . 84-2 .52 (5H, m), 2 . 06 (1H, m), 1 . 83 (2H, m), 1 . 57 (1H, m), 1 .30 ( 9H, s), 0 . 87 (3H, d), 0 . 69 (3H, d) ; MS m/e 601.2 [M+H] + Example 49
Preparation of (2R,4S,5S,1'S)-5-[di(hydroxymethyl)- methoxycarbonyl]amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenvl-2-phenylmethyl-hexanamide a) di(t-butyldimethylsiloxymethyl) methyl-(4-nitrophenyl) carbonate
A mixture containing bis (4-nitrophenyl) carbonate (1.89 g, 6.21 mmol), di (t-butyldimethylsiloxymethyl) methanol (2.00 g, 1 eq) and 4-dimethylaminopyridine (757 mg, 1 eq) in dichloromethane (100 mL) was stirred at room temperature for 2 d. The mixture was diluted with dichloromethane and washed with saturated aqueous Na2CO3, brine, and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica, 10% ethyl
acetate/hexanes) to afford the title compound (75%). NMR (CDCI3) δ 8.29 (2H, m), 7.37 (2H, m), 3,96 (1H, m), 3.85
(2H, d), 3.82 (2H, d), 0.89 (18H, s), 0.09 (12H, s). b) (2R,4S,5S,1'S)-5-(di(t- butyldimethylsiloxymethyl)methyloxycarbonyl]amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-phenylmethyl-hexanamide
A solution of di(t-butyldimethylsiloxymethyl)-methyl 4- nitrophenyl carbonate (475 mg, 0.974 mmol), the compound of Example 13(a) (178 mg, 0.325 mmol) and dimethylammopyridine (119 mg, 0.974 mmol) in methylene choride was stirred at 20°C under Ar for 24 h. The solution was washed with aqueous Na2CO3, dried over solid Na2CO3 and concentrated in vacuo. Flash chromatography (silica, 4% methanol/dichloromethane) of the residue provided the intermediate (2R,4S,5S,1'S)-5-(di(t- butyldimethylsiloxymethyl) methyloxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-(1-(di(t- butyldimethylsiloxymethyl) methyloxycarbonyl) imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide, which was dissolved in ether, washed with 10% NaOH, dried over Na2CO3, and concentrated to provide the title compound (197 mg, 71%). NMR (CDCI3) δ 7.43-7.05 (10H, m), 6.90 (2H, s), 6.65 (1H, bs), 5.09 (1H, d), 4.78 (1H, bd), 4.08 (1H, m), 3.89-3.50 (7H,m) 3.00-2.80 (4H, m), 2.65 (1H, m), 2.55 (2H, m), 1.90 (1H, m), 1.78 (1H, m), 1.10-0.85 (33H, m), 0.20-0.06 (18H, m). c) (2R,4S,5S,1'S)-5-(di(hydroxymethyl)methoxycarbonyl)amino- 4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
A mixture containing the compound of Example 49(b) (50 mg) and ethereal HCl (4 eq) was allowed to stir in
methanol:water (9:1) at room temperature overnight. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous Na2CO3. The product was purified by flash chromatography (silica, 4% methanol/dichloromethane) to afford the title compound
(29 mg, 94%). NMR (CD3OD) δ 7.20-6.80 (10H, m), 6.71 (2H, s) , 4 .50 (1H, d) , 3. 90 (1H, m) , 3. 65-3.34 (5H, m) , 2 .82-2.45 (6H, m), 1.99 (1H, m), 1.74 (1H, m), 1.52 (1H, m) , 0.78 (3H, d), 0.60 (3H, d).
Example 50
Preparation of (2R,4S,5S,1'S)-5- (1-oxo-thian-4- yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethylhexanamide
Reacting the compound of Example 32(b) (81 mg, .133mmol) with m-chloro perbenzoic acid (23 mg, 0.133mmol)in CH2CI2 yielded the title compound. NMR (CD3OD) δ 7.20-6.85 (10H, m), 6.78 (2H, s), 4.51 (1H, d), 3.66 (1H, m), 3.42(1H, m), 2.95-2.41 (9H, m), 2.32-2.01 (2H, m), 1.99-1.63 (4H, m),
1.60-1.41 (2H, m), 0.78 (3H, d), 0.60 (3H, d); MS m/e 595.2 [M+H]+. Example 51
Preparation of (2R,4S,5S,1'S)-5-((tetrahydrosulfonylpyran-4- yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethylhexanamide
Reacting the compound of Example 50 (31 mg, 49.2μmol) with m-chloro perbenzoic acid (10 mg, 59.2 μmol) in methylene chloride yielded the title compound. NMR (CD3OD) δ 7.20-6.85 (10H, m), 6.76 (2H, s), 4.48 (1H, d), 3.68 (1H, m), 3.44 (1H, m), 2.96-2.42 (9H, m), 2.32-2.04 (2H, m), 1.97-1.62 (4H, m), 1.61-1.43 (2H, m), 0.79(3H, d), 0.60 (3H, d); MS m/e 611.2 [M+H] + .
Example 52
Preparation of (2R,4S,5S,1'S)-5-(1,1-dimethyl-2- acetoxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide (a) (2R,4S,5S,1'S)-5-(1,1-dimethyl-2- hydroxyethoxycarbonyl)amino-4-(t-butyldimethylsilyl)oxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
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 Na2CO3. 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 (CDCI3) 5 7.38-6.81 (12H, m), 4.93 + 4.65
(1H, d, rotamers), 4.81+ 4.48 (1H, t, rotamers), 4.15 + 4.08 (1H, d, rotamers), 3.90 (1H, q), 3.72 (2H, m), 3.50+3.38 (1H, d, rotamers), 2.98-2.48 (5H, m), 2.35 (1H, m), 1.98 (1H, m),
1.79 (1H, m), 1.60 (1H, m), 1.30 (3h, s), 1.29 (3H,s), 1.09
-0.85 (15H, m), 0.79 (3H, d), 0.11 (6H, m). (b) (2R, 4S, 5S, 1 ' S) -5- (1, 1-dimethyl-2- acetoxyethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
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%
methanol/dichloromethane).
The resulting 4-t-butyldimethylsiloxy intermediate (105 mg, 0.140 mmol) was stirred in methanol :water (9:1) with IM HCl in ether (0.14 mL, 1 eq). The solvents were removed in vacuo, the residue was diluted with dichloromethane, and the solution was washed with aqueous Na2CO3. The organic layer was concentrated and the residue was purified by flash chromatography (silica, 5% methanol/dichloromethane) to provide the title compound (82 mg, 91%). NMR (CD3OD) δ 7.29-
6.90 (10H, m), 6.81 (2H, s), 4.51 (1H, d), 4.05 (2H, s), 3.59 (1H, m), 3.42 (1H, m), 2.80-2.45 (5H, m), 2.00 (1H, m), 1.98 (3H, s), 1.72 (1H, m), 1.50 (1H, m), 1.34 (6H, d), 0.81 (3H, d), 0.60 (3H, d).
Example 53 Preparati on of (2R, 4S , 5S, 1 ' S ) -5- ( ( 1 , 1 -dimethyl -2- (benzyloxy- carbonyl glycyloxy) ethoxycarbonyl ) amino-4-hydroxy-N- (1' - isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide hydrochloride salt a) (2R,4S,5S,1'S)-5-((1,1-dimethyl-2- carbobenzyloxyglycyloxy)ethoxycarbonyl)amino-4-(t- butyldimethylsilyloxy)-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
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%
methanol/dichloromethane) to provide the title compound (95 mg, 73%). NMR (CDCI3) δ 7.41-6.71 (17H, m), 6.62 (1H, bs),
6.00 (1H, m) , 5 .20 (1H, m) , 5. 15 (2H, s) , 4.83 + 4 .55 (1H, d, rotamers), 4.65+ 4.48 (1H, t, rotamers), 4.81 + 4.38 (1H, q, rotamers), 4.03 (1H, q), 4.02 (2H, d), 3.85+3.68 (2H, d, rotamers), 2.85-2.48 (5H, m), 2.38 (1H, m), 1.90 (1H, m), 1.55 (1H, m), 1.38 (3h, s), 1.29 (3H,s), 0.90 (9H, m), 0.85 (3H, d), 0.70 (3H, d), 0.11 (6H, m). b) (2R,4S,5S,1'S)-5-((1,1-dimethyl-2-
(benzyloxycarbonyl)ethoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide hydrochloride salt
The compound of Example 53(a) (12 mg, 0.014 mmol) was stirred in methanol:water (9:1) with IM HCl (2 eq) in ether overnight. The solvents were removed in vacuo to give the title compound (8 mg, 73%). NMR(CD3OD) δ 7.35 (2H,s), 7.31-
6.85 (15H, m), 5.00 (2H, s), 4.59 (1H, d),4.15 (1H, d, rotamers), 4.65+ 4.48(1H, t, rotamers), 4.81 + 4.38 (2H, dd), 3.80 (2H,d), 3.59 (1H, m), 3.40 (1H, d), 2.85-2.48 (5H, m), 2.00 (1H, m), 1.60 (1H, m), 1.55 (1H, m), 1.31 (3h, s), 1.29 (3H,s), 0.91 (3H, d), 0.60 (3H, d), Example 54
Preparation of (2R,4S,5S,1'S)-5-((1,1-dimethyl-2- glycyloxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide dihydrochloride salt a) (2R,4S,5S,1'S)-5-(1,1-dimethyl-2- glycyloxyethoxycarbonyl)amino-4-(t-butyldimethylsilyl) oxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
The compound of Example 53(a) (58 mg, .0678mmol) was stirred in methanol with 10% Pd/C (50 mg) under 1 atm
hydrogen overnight. The reaction mixture was filtered through Celite® and the solvents were removed in vacuo to yield the title compound (48 mg, 98%). NMR(CD3OD) δ 7.32-7.02
(10H, m), 6.99 (2H, s), 4.68 (1H, d),4.40-4.28 (2H, dd), 3.81
(2H, d), 3.80-3.67 (2H, m), 2.90-2.49 (5H, m), 2.15 (1H, m), 1.97 (1H, m), 1.48 (1H, m), 1.40 (3H, s), 1.39 (3H,s), 1.15
(3H, d), 0.95 (9H, s), 0.70 (3H, d), 0.11 (6H, d). b) (2R,4S,5S,1'S)-5-((1,1-dimethyl-2-glycyloxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isoproρyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide dihydrochloride salt
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%). NMR(CD3OD) δ 7.35 (2H, s),
7.30-6.92 (10H, m), 4.60 (1H, d), 4.25 (2H, dd), 3.75 (2H, d), 3.59 (1H, m),3.49 (1H, m), 2.90-2.51 (6H, m), 2.10 (1H, m), 1.65 (1H, m), 1.54 (1H, m), 1.30 (6H, s), 0.90 (3H, d), 0.60 (3H, d).
Example 55
Preparation of (2R,4S,5S,1'S)-5-((1,1-dimethyl-2- hydroxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-(4- isopropylcarbonylimidazol-2-yl))methyl-6-phenyl-2- phenylmethyl-hexanamide dihydrochloride salt a) (2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-[1'- isopropyl-1'-(4-isopropylcarbonyl-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
Using the procedure of Example 13(a), except
substituting the compound of Example 28 (d), the title compound was prepared. b) (2R,4S,5S,1'S)-5-((1,1-dimethyl-2- hydroxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-(4- isopropylcarbonylimidazol-2-yl))methyl-6-phenyl-2- phenylmethyl-hexanamide dihydrochloride salt
Following the procedures of Example 38 (b) -38 (c), except substituting the compound of Example 55 (a) for
(2R,4S,5S,1'S)-5-amino-4-t-butyldimethylsiloxy-N-('- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide, the title compound was prepared. NMR (CDCI3) δ
7.49 (1H, s), 7.13 (5H, m), 6.84 (5H, m), 5.53 (1H, d), 4.47
(1H, d), 3.79 (1H, m), 3.60 (1H, m), 3.44 (2H, m), 3.16 (1H, m), 2.81-2.50 (5H, m), 1.92 (1H, m), 1.62 (2H, m), 1.18 (14H, m), 0.72 (3H, d), 0.58 (3H, d); MS m/e 621.4 [M+H]+.
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) δ 7.38-6.90 (10H, m), 6.83 (2H, s), 4.58 (2H, m),
3.61 (1H, m), 3.34 (3H, m), 2.82-2.44 (5H, m), 2.00 (1H, m), 1.66 (1H, m), 1.52 (1H, m), 1.08 (3H, d), 0.85 (3H, d), 0.60 (3H, d).
Example 57
Preparation of (2R,4S,5S,1'S)-5-((1R)-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 (R)-t-butyldimethylsiloxy-1-methylethanol in 41(a), the title compound was prepared. NMR(CD3OD) δ 7.39-6.88 (10H, m), 6.82 (2H, s), 4.56 (2H, m), 3.60 (1H, m), 3.36 (3H, m), 2.81-2.45 (5H, m), 1.99 (1H, m), 1.65 (1H, m), 1.51 (1H, m), 1.03 (3H, d), 0.84 (3H, d), 0.60 (3H, d). Example 58
Preparation of (2R,4S,5S,1'S)-5-((1-acetyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethylhexanamide
The title compound was prepared by the procedure of Example 13 (a)-(c), except substituting acetic anhydride in place of isopropyl chloroformate. NMR(CD3OD) δ 7.21-6.90
(10H, m), 6.81 (2H, -s), 4.58 (1H, d), 3.98 (1H, m), 3.51 (1H, m), 2.85-2.49 (5H, m), 1.99 (1H, m), 1.68 (3H, s), 1.61 (3H, m), 1.50 (1H, m), 0.80 (3H, d), 0.60 (3H, d).
Example 59 Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- henzyloxyphenylmethyl) hexanamide a) (3R,5S,1'S)-(1'-t-butoxycarbonylamino-2'-phenyl)ethyl-3- (4-benzyloxy)phenylmethyl-tetrahydrofuran-2-one
Following the procedure of Example 12 (a), except using (4-benzyloxy) benzyl bromide, the title compound was prepared (284 mg, 27%). NMR(CDCl3) δ 7.48-6.72 (14H, m), 4.94 (2H, s), 4.43 (1H, d), 4.12 (1H, dd), 3.83 (1H, q), 2.97-2.62 (5H, m), 2.12 (1H, m), 1.85 (1H, m), 1.27 (9H, s). b) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-t-butyldimethyl- siloxy-6-phenyl-2-(4-benzyloxyphenylmethyl) hexanoic acid
Folowing the procedure of Evans et al . , J. Org. Chem. 50, 4615 (1985), except substituting the compound of Example 59(a) for benzyl bromide, the title compound was prepared. NMR(CDCl3) δ 7.42-6.76 (14H, m), 4.99 (2H, s), 4.69 (1H, d),
3.91 (1H, q), 3.66 (1H, m), 2.98-2.36 (5H, m), 1.85 (1H, m), 1.52 (1H, m), 1.30 (9H, s), 0.88 (9H, s), 0.04 (6H, m). c) (2R,4S;5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-(4-benzyloxyphenylmethyl) hexanamide Following the procedure of Example 12 (c), except using (b), the title compound was prepared (284 mg, 92%).
NMR(CDCl3) δ 7.42-6.74 (16H, m), 5.04 (2H, s), 4.99 (1H, d),
4.77 (1H, d), 4.51 (1H, dd), 3.93 (1H, q), 3.69 (1H, m), 2.80-2.39 (5H, m), 1.81 (1H, m), 1.62 (1H, m), 1.33 (9H, s), 0.92 (9H, s), 0.75 (6H, dd), 0.07 (6H, d). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(4- benzyloxyphenylmethyl)hexanamide
Following the procedure of 12 (d), except using (c), the title compound was prepared (100 mg, 94%). NMR(CD3OD) δ
7.41-7.09 (10H, m), 6.85 (2H, d), 6.79 (2H, s), 6.58 (2H, d), 5.41 (1H, d), 4.90 (2H, s), 4.47 (1H, d), 3.62 (1H, q), 3.48 (1H, d), 2.79-2.48 (6H, m), 2.02 (1H, m), 1.62 (2H, m), 1.33 (9H, s), 0.74 (3H, d), 0.61 (3H, d).
Example 60 Preparation of (2R,4S,5S,1'S)-S-(t-butoxycarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- hydroxyphenylmethyl) hexanamide
Following the procedure of Example 4 (b), except using the compound of 59(d), the title compound was prepared (56 mg, 86%). NMR(CD3OD) δ 7.18 (5H, m), 6.84 (2H, s), 6.73 (2H, d), 6.44 (2H, d), 5.32 (1H, d), 4.45 (1H, d), 3.61 (1H, q), 3.42 (1H, m), 2.80-2.42 (5H, m), 2.04 (1H, m), 1.61 (2H, m), 1.31 (9H, s), 0.70 (3H, d), 0.61 (3H, d).
Example 61
Preparation of (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4- hydroxy-2-phenylmethyl-6-phenyl-N- [1'-cyclopropyl-1'- imidazol-2-yl]methyl-hexanamide a) α-(t-butoxycarbonyl)-amino-α-cyclopropylacetonitrile To a solution of cyclopropylmethanol (10.2 g, 141 mmol) in methylene chloride (250 mL) sodium acetate (1 g) and 20 g of Celite® were added. Pyridinium chlorochromate (30 g, 140 mmol) was added in small portions over a period of 30 m.
After 1 h the reaction mixture was diluted with ether
(100mL), filtered through Celite® and washed with ether. The combined organic extracts (1 L) were concentrated in vacuo at 15-18°C to yield formyl cyclopropane.
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 MgSO4. Filtration and evaporation of the solvent in vacuo yielded α-amino-α-cyclopropyl acetonitrile as an oil.
To a solution of the crude aminonitrile (2 g) in THF (20 mL) di-tert-butyldicarbonate (1.53 g, 7 mmol) was added. The reaction was stirred overnight. Removal of the solvent in vacuo followed by flash chromatography (silica, 1:8 ethyl acetate:hexane) yielded the title compound (2.8 g). 1H
NMR(CDCl3, 200 MHz) δ 5.0 (bs, 1H), 4.4 (bs, 1H), 1.4 (s,
9H), 1.2 (m, 1H), 0.7 (m, 2H), 0.5 (m, 2H). b) α-(t-butoxycarbonyl)-amino-α-cyclopropylacetaldehyde
To a solution of the compound of Example 61(a) (1 g, 5.1 mmol) in THF (20 mL), diisobutylaluminium hydride (10.5 mL, 10.5 mmol, IM in THF) was added at -78°C, over 5 min. The reaction mixture was allowed to warm to 0°C over a period of 2 h, and stirred at 0°C for an additional 1 h. The reaction mixture was quenched with MeOH (2 mL), and saturated
potassium sodium tartrate solution (100 mL) was added.
Extraction with ether, drying over MgSO4 and removal of solvents in vacuo yielded an oil. Flash chromatography
(silica, 1:10 ethyl acetate:hexane) gave the title compound as a colorless solid (225 mg). NMR(CDCl3, 400 MHz) δ 9.45
(bs, 1H), 4.95 (bs, 1H), 3.5 (bs, 1H), 1.3 (s, 9H), 0.7 (m, 1H), 0.3-0.6 (m, 4H). c) 1-(t-butoxycarbonyl)amino-1-(imidazol-2-yl)-1-cyclopropyl- methane
A mixture of the compound of Example 61(b) (178 mg, 0.89 mmol), glyoxal (150 mL, 1 mmol, 40% aq), ammonium hydroxide (5 mL, 28% aq) and MeOH (5mL) was stirred at room temperature for 10 h. The solvents were removed in vacuo and the residue was titurated with ether to yield a brown solid (53 mg). The solid was passed through Florisil® and eluted with 5%
MeOH/methylene chloride. Removal of the solvent in vacuo followed by trituration provided the title compound as a colorless solid (19 mg). MS(CI/NH3) m/e 238.3 [M+H]+· 1H NMR(CD3OD, 200 MHz) δ 6.9 (s, 2H), 4.1 (bd, 1H), 1.4 (s, 9H) ,
1.3 (m, 1H), 0.6 (m, 2H), 0.4 (m, 2H). d) 1-amino-1-(imidazol-2-yl)-1-cyclopropyl-methene,
trifluoroacetate
The compound of Example 61(c) (15 mg) was dissolved in 1 mL of TFA and stirred at room temperature for 20 min.
Solvents removed in vacuo to give the title compound as a semisolid residue. 1H NMR(CD3OD, 200 MHz) δ7.1 (s, 2H), 3.8
(d, 1H, J=7 Hz), 1.5 (m, 1H), 0.5-0.8 (m, 4H). e) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-(t-butyldimethyl)- siloxy-2-phenylmethyl-6-phenyl-N-[1'-cyclopropyl-1'-imidazol-
2-yl]methyl-hexanamide
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
temperature for 24 h. The reaction was diluted with ethyl acetate (100 mL), washed with aqueous sodium bicarbonate and dried over anhydrous potassium carbonate. Removal of
solvents in vacuo, followed by flash chromatography (silica, 5% methanol/methylene chloride) yielded the title compound as a mixture of diastereomers (25 mg). f) (2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2- phenylmethyl-6-phenyl-N-[1'-cycloρropyl-1'-imidazol-2- yl]methyl-hexanamide
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
overnight and methylene chloride (100 mL) and water (10 mL) were added. The organic layer was dried over potassium carbonate, and the solvent was removed in vacuo to give an oil. Flash chromatography (silica, 5% methanol/methylene chloride) gave a colorless solid which was a 1:1
diastereomeric mixture of the title compound. Example 62
Preparation of (2R, 4S, 5S, 1 'R) -5- (t-butoxycarhonyl) amino-4- hydroxy-2-phenylmethyl-6-phenyl-N- [1 '-cyclopropyl -1 ' - imidazol-2-yl]methyl-hexanamide; and
(2R, 4S , 5S , 1 ' S , -5- (t-bntoxycarbonyl) amino-4-hyriroxy-2- phemylmethyl -6-phenyl-N- [1'-cyclopropyl-1 '-i midazol-2- yl]methyl-hexanamide a) Purification of the 125 mg of the compound of Example 61(e) by flash chromatography (silica, 3% methylene
chloride/methanol), yielded 48 mg of isomer 1, 15 mg of isomer 2 and 20 mg of combined fractions. 1H NMR for isomer 1 (CDCl3, 400 MHz) δ7.1-7.4 (m, 10H), 6.95 (s, 2H), 6.1 (d, 1H), 4.85 (d, 1H), 4.15 (dd, 1H), 3.75 (q, 1H), 3.6 (m, 1H), 2.9(dd, 1H), 2.7 (d, 2H), 2.6 (dd, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.6 (m, 1H), 1.4 (m, 1H), 1.35 (s, 9H), 0.95 (s, 9H), 0.7 (m, 1H), 0.4 (m, 1H), 0.25 (m, 1H), 0.1 (m, 1H), 0.2 (s, 3H), 0.1 (s, 3H), 1H NMR for isomer 2 (CDCI3, 400 MHz) δ 7.1-
7.4 (m, 10H), 6.8 (s, 2H), 6.26 (d, 1H), 4.6 (d, 1H), 4.0 (m, 2H), 2.5-3.0 (m, 4H), 1.8 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.4 (s, 9H), 1.0 (s, 9H), 0.7 (m, 2H), 0.2 (m, 2H), 0.1 (2 overlapping singlets, 6H). b) Following the procedure of Example 61 (f), except
substituting the compounds of Example 62 (a) yielded the title compounds. 1H NMR for isomer 1 (CD3OD, 400 MHz) δ 7.1-7.3 (m,
10H), 6.95 (s, 2H), 4.25 (d, 1H), 3.5-3.7 (m, 2H), 2.5-3.0 (m, 5H), 1.7 (m, 2H), 1.4 (s, 9H), 1.1 (m, 1H), 0.6 (m, 1H), 0.25-0.4 (m, 2H), 0.05 (m, 1H); MS(ESMS) m/e 533.2 [M+H]+; 1H NMR for isomer 2 (CD3OD) δ 7.1-7.4 (m, 10H), 6.85 (s, 2H),
4.25 (d, 1H), 3.5-3.7 (m, 2H), 2.5-2.9 (m, 5H), 1.5-1.8 (m, 2H), 1.4 (s, 9H), 1.1 (m, 1H), 0.2-0.6 (m, 4H); MS(ESMS) m/e 533.4 [M+H]+.
Example 63
Preparation of (2R,4S,5S,1'S)-5-((isopropylthiol)carbonyl)- amino-4-hydroxy-2-phenylmethyl-6-phenyl-N-[1-isopropyl-1'- imidazol-2-yl]methyl-hexanamide a) 5-((isopropylthiol)carbonyl)amino-4-(t- butyldimethylsiloxy)-2-phenylmethyl-6-phenyl-N-[1'-isopropyl- 1'-(1-(isopropylthiol)carbonyl-imidazol-2yl)]methyl- hexanamide
To a solution of (2R,4S,5S,1'S)-5-amino-4-t- butyldimethylsiloxy-2-phenylmethyl-6-phenyl-N- [1'-isopropyl- 1'-imidazol-2-yl]methyl-hexanamide (81 mg, 148 mmol) and DMAP (37 mg, 303 mmol) in dichloromethane (8 mL),
isopropylthiolchloroformate (42 mg, .303 mmol) in
dichloromethane (1 mL) was added. The solution was stirred for 20 h and an additional equivalent of the chloroformate and DMAP were added. The reaction mixture was stirred for an additional 20 h, diluted with dichloromethane, and washed with saturated sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered and evaporated to an oil. The oil was dissolved in chloroform and purified by flash chromatography (silica, 1% methanol/chloroform) to give the title compound as an oil (79.5 mg). b) (2R,4S,5S,1'S)-5-((isopropylthiol)carbonyl)amino-4- hydroxy-2-phenylmethyl-6-phenyl-N-[1-isopropyl-1'-imidazol-2- yl]methyl-hexanamide
To a solution of the compound of Example 63(a) (79 mg, 105 mmol) in methanol (8 mL), 10% hydrochloric acid (3 mL) was added. The reaction mixture was stirred overnight at 25°C. The methanol was evaporated in vacuo, and the residue was diluted with water. The solution was neutralized with 5% aqueous sodium carbonate, and a solid precipitated. The solid was filtered, washed with water, and triturated with ether. The solid was dried at high vacuum to yield the title compound (27 mg, 48%). NMR(CDCl3, 250 MHz) δ 6.9-7.3 (m,
10H), 6.85 (s, 2H), 6.20 (d, 1H), 4.42 (d, 1H), 4.22 (m, 1H), 4.0 (m, 1H), 3.55 (m, 3H), 2.5-3.0 (m, 6H), 1.65 (t, 2H), 1.27 (m, 7H), .71 (d of d, 6H); MS (FAB) m/e 537 [M+H]+; TLC Rf 0.30 (silica, 4% methanol/chloroform).
Example 64 Preparation of (2R,4S,5S,1'S)5-(1-hydroxymethyl- oyclopentyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methvl-6-phenyl-2-phenylmethyl-hexamide a) 1-(t-butyldimethysiloxy)methyl-cyclopentanol
iTo a solution of 1-hydroxymethyl-1-cyclopentanol (4.07 g, 0.035 mole) in dichloromethane (30 mL) t-butyldimethylsilyl chloride (5.28 g, 0.035 mol) in dichloromethane (30 mL) was added. Triethylamine (5.37 mL, 0.0385 mol) and DMAP (0.171 g, 0.0014 mol) were added and the solution was stirred overnight at 25°C. The solution was diluted with
dichloromethane (30 mL) and washed with water and saturated ammonium chloride solution. The organic solution was dried over sodium sulfate, filtered and the solvent removed at reduced pressure. The product was purified by flash
chromatography (silica, 19:1 hexane:ethyl acetate) to yield the title compound as a colorless oil (6.95 g, 86%). b) 1-(t-butyldimethylsiloxy)methyl-cyclopentyl 4-nitrophenyl carbonate
A solution of the compound of 64(a) (1.15 g, 5 mmol), DMAP (0.611 g, 5 mmol) and bis (4-nitrophenyl) carbonate (1.52 g, 5 mmol) in dichloromethane (16 mL) was stirred overnight at 25°C. The reaction mixture was diluted with
dichloromethane and washed with 5% sodium carbonate. The solvent was removed at reduced pressure and the residual oil was triturated with hexane:ethyl acetate (3:2) and filtered. The product was purified by flash chromatography (silica, 19:1 hexane:ethyl acetate) to give a colorless oil (0.599 g, 30%). c) (2R,4S,5S,1'5)-5-[1-(t-butyldimethylsiloxy)methyl- cyclopentyloxycarbonyl]amino-4-t-butyldimethylsiloxy-N-[1'- isoρropyl-1'-(t-butyldimethylsiloxy)methyl- cyclopentyloxy)imidazol-2-yl]-6-phenyl-2-phenylmethyl- hexanamide
A solution of the compound of Example 13(a) (173 mg, 0.316 mmol), DMAP (81 mg, 0.663 mmol) and the compound of
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,
4 : lhexane : ethyl acetate) to yield the title compound as an oil (200 mg, 60%). d) (2R,4S,5S,1'S)5-(1-hydroxymethyl-cyclopentyloxy- carbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexamide
A solution of the silated derivative (200 mg, 0.188 mmol) in methanol (7 mL) and 3N HCl (2.5 mL) was stirred overnight at 25°C. The methanol was removed at reduced pressure and the solution was diluted with water (15 mL) and extracted with ether (25 mL). The aqueous solution was neutralized with 5% sodium carbonate solution to pH 7-7.5 and the product precipitated as a solid. The solid was filtered, washed with water and dried in vacuo to yield the title compound (51 mg, 47%). NMR (CD3OD. 400 MHz) δ 7.0-7.3 (m,
10H), 6.87 (s, 2H), 4.62 (d, 1H), 3.70 (m, 3H), 3.55 (d, 1H), 2.5-2.9 (m, 5H), 2.05 (m, 1H), 1.5-2.0 (br, 10H), 0.88 (d, 3H), 0.70 (d, 3H); TLC Rf 0.50 (silica, 8%
methanol/chloroform).
Example 65 Preparation of (2R,4S,5S,1'S)-5-[3-(R)-(1H-imidazol-2-yl)-3- hydroxy-4-methylpentylamido]-4-hydroxy-N-(1'-isopropyl-1'- imidazol-2-yl)methyl-6-phenyl-2-phenylmethγl-hexanamide: and (2R,4S,5S,1'S)-5-[3-(S)-(1H-imidazol-2-yl)-3-hydroxy-4- methylpentylamidol-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide a) 1-(1-benzyloxymethylimidazol-2-yl)-2-methyl-1-propanol
1-benzyloxymethylimidazole prepared according to the procedure of Ngochindo, R., J. Chem. Res . (S), 58 (1990)) (3.76 g, 20 mmol), and THF (40 mL) at -40°C, was treated dropwise with n-BuLi (8.4 mL, 21 mmol, 2.5M in hexane). The resulting solution was stirred at -40°C for 15 min, and i- butyraldehyde (2.0 mL, 22 mmol) was added dropwise. The reaction was stirred at -40°C for 1.5 h, 0°C for 1 h, warmed to 23°C, poured into H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Trituration of the residue with
Et2O/hexane gave a white solid which was dried in vacuo overnight to afford of the title compound (3.57 g, 69%). 1H NMR(CDCl3, 400 MHz) δ 7.28 (m, 5H), 6.97 (s, 1H), 6.92 (s, 1H), 5.23 (d, 1H, J=12 Hz), 5.42 (d, 1H, J=12 Hz), 4.48 (s, 2H), 4.44 (d, 1H, J=9 Hz), 2.21 (m, 1H), 1.02 (d, 3H, J=7 Hz), 0.83 (d, 3H, J=7 Hz). b) 1-(benzyloxymethylimidazol-2-yl)-2-methyl-propan-1-one
The compound of Example 65(a) (1.0 g/ 3.88 mmol), MnO2, (1.69 g, 19.4 mmol), and CH2CI2 (75 mL) were combined and stirred for 1 d. Additional Mnθ2 (1.69 g, 19.4 mmol) was added and stirring was continued for an additional 2 d.
Filtration through Celite®, concentration and flash
chromatography (silica, 0-1% CH3OH/CH2CI2) afforded the title compound (0.773 g, 77%). % NMR(CDCl3, 400 MHz) 7.28 (m, 6H), 7.18 (s, 1H), 5.85 (s, 2H), 4.52 (s, 2H), 3.94 (m, 1H), 1.21 (d, 2H, J=5 Hz). c) t-butyl 3-(1-benzyloxymethylimidazol-2-yl)-3-hydroxy-4- methyl-pentanoate
Diisopropylamine (83 μL, 0.59 mmol) and THF (1.5 mL) were cooled to -40°C and n-BuLi (188 μL, 0.47 mmol, 2.5M in hexane) was added. The reaction mixture was warmed to -10°C and stirred for 15 m, recooled to -70°C and t-butyl acetate (63 μL, 0.47 mmol) was added. The reaction was stirred for 5 m, and HMPA (254 μL, 1.41 mmol) was added. The reaction was stirred at -70°C for 5 m and 1-(benzyloxymethylimidazol-2- yl)-2-methyl-propan-1-one (100 mg, 0.39 mmol) in THF (1.5 mL) was added dropwise. The mixture was stirred at -70°C for 30 m, -40°C for 30 m, -10°C for 30 m, warmed to 23°C, poured into 10% aqueous K2CO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried (K2CO3), concentrated and flash chromatographed (silica gel, step gradient, 0-20% EtOAc/hexanes) to afford the title compound (131 mg, 90%). 1H NMR(CDCl3, 400 MHz) δ 7.25 (m, 5H), 6.96 (s, 1H), 6.91 (s, 1H), 5.69 (d, 1H, J=10 Hz), 5.65 (d, 1H,
J=10 Hz), 4.53 (d, 1H, J=11 Hz), 4.48 (d, 1H, J=11 Hz), 3.23 (d, 1H, J=6 Hz), 2.57 (d, 1H, J=6 Hz), 2.14 (m, 1H), 1.39 (s, 9H); 0.97 (d, 3H, J=7 Hz), 0.75 (d, 3H, J=7 Hz); MS(ES) m/e 375 [M+H]+. d) 3-(1-benzyloxymethylimidazol-2-yl)-3-hydroxy-4-methyl pentanoic acid triflouroacetate.
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%). 1H NMR(CDCl3, 400 MHz) 7.30 (m, 7H); 6.06 (d, 1 H, J=9 Hz),
5.74 (d, 1H, J=1 Hz), 4.67 (d, 1H, J=9 Hz), 4.61 (d, 1H, J=9 Hz), 3.62 (d, 1H, J=12 Hz), 2.93 (d, 1H, J=12 Hz), 2.04 (m, 1H), 0.92 (d, 3H, J=12 Hz), 0.88 (d, 3H, J=12 Hz); MS(ES) m/e 319 [M+H]+. e) (2R,4S,5S,1' S)-5-[3-(RS)-(l-benzyloxymethylimidazol-2-yl)- 3-hydroxy-4-methylpentanoyl]amino-4-t-butyldimethylsilyloxy- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide
A mixture of the compound of Example 65(d) (1.0 eq) (2R,4S,5S,1'S)-5-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide (1.1 eq), BOP reagent (1.1 eq), and triethylamine (4 eq) were reacted according to the procedure of Example 1(c). The product was purified by flash chromatography to afford the title compound (57%) (silica, step gradient, 0-4% CH3OH/CH2CI2). 1H
NMR(CDCl3, 400 MHz) δ 7.36-6.76 (m, 19H), 5.65 (m, 2H), 4.66
(m, 1/2H), 4.51 (m, 2H), 4.39 (m, 1/2H), 4.30 (m, 1/2H), 4.02 (m, 1/2H), 3.68 (m, 1H), 3.28 (m, 1H), 2.90-2.35 (m, 6H), 2.13 (m, 1H), 1.76 (m, 1/2H), 1.68 (m, 1/2H), 1.40 (m, 1/2H), 1.00-0.70 (m, 21H), 0.10-0.00 (m, 6H); MS (ES) m/e 849 [M+H]+. f) (2R,4S,5S,1'S)-5-[3-(RS)-(1-benzyloxymethylimidazol-2-yl)- 3-hydroxy-4-methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide
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%). 1H NMR(CDCl3, 400 MHz) δ 7.40-
6.80 (m, 19H), 5.75 (m, 2H), 4.97 (m, 1/2H), 4.78 (m, 1/2H),
4.51 (m, 2H) 3.94 (m, 1/2H), 3.85 (m, 1/2H), 3.51 (m, 1H),
3.21 (m, 1H), 2.97-2.43 (m, 6H);2.00 (m, 1H), 1.60 (m, 1H), 1.43 (m, 1H), 0.97-0.49 (m, 12H); MS(ES) m/e 735 [M+H]+. g) (2R,4S,5S,1'S)-5-[3(R)-(imidazol-2-yl)-3-hydroxy-4- methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide; and
(2R,4S,5S,1'S)-5-[3-(S)-(imidazol-2-yl)-3-hydroxy-4- methylpentanoyl]amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol- 2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide Using the procedure of Example 47 (d), the compound of Example 65(f) (72 mg, 0.98 mmol) was hydrogenated to afford a diastereomeric mixture of the title compounds . The mixture was purified by flash chromatography (silica, step gradient, 0-8% CH3OH/CH2CI2) to afford tail fractions containing the pure diastereomers (35 mg total, 58%).
Isomer 1, last eluting, (2R,4S,5S,1'S)-5-[3-(R)-(1H- Imidazol-2-yl)-3-hydroxy-4-methylpentylamido]-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide. 1H NMR(CDCl3, 400 MHz) δ 7.35-6.82
(m, 10H), 6.93 (s, 1H), 6.84 (s, 1H), 4.42 (d, 1H, J=9 Hz), 3.77 (m, 1H), 3.40 (m, 1H), 3.00-2.40 (m, 5H), 2.14 (m, 1H), 1.99 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 0.93-0.64 (m, 12H); MS(ES) m/e 615 [M+H]+.
Isomer 2, first eluting, (2R,4S,5S,1'S)-5-[3(S)-(1H- Imidazol-2-yl)-3-hydroxy-4-methylpentylamido]-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide. 1H NMR(CDCl3, 400 MHz) δ 7.35-6.81
(m, 10H), 6.83 (s, 1H), 6.81 (s, 1H), 4.46 (d, 1 H, J=9 Hz), 3.93 (m, 1H), 3.40 (m, 1H), 3.00-2.40 (m, 5H), 2.13 (m, 1H), 1.91 (m, 1H), 1.41 (m, 1H), 1.10 (m, 1H), 0.93-0.64 (m, 12H); MS(ES) m/e 615 [M+H]+.
Example 66
Preparation of (2R,4S,5S,1'S)-5-[(4-methoxyphenoxy)carbonyl]- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenyl-2-phenylmethyl-hexanamide a) (2R,4S,5S,1'S)-5-[(4-methoxyphenoxy)carbonyl]amino-4-t- butyldimethyIsiloxy-N-(1'-isopropyl-1'-(N'- methoxycarbonyl)imidazol-2-yl]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13 (b), except using p-methoxyphenyl chloroformate and (2R,4S,5S,1'S)-5-amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenyl-2-phenylmethyl-hexanamide (114 mg, 0.21 mmol), the title compound was prepared (63%). NMR(CDCl3), δ 7.44-6.76 (m, 20H), 5.66 (m, 1H), 5.18 (d, 1H ), 4.40 (m, 1H), 3.83 (s,3H), 3.76 (m, 1H), 3.73 (s, 3H), 2.96-2.50 (m, 5H), 2.05 (m, 5H), 1.60 (m, 1H), 0.94 (s, 9H) , 0.79 (d, 3 H, J=7 Hz), 0.74 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H) .. b) (2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 13 (c), except using the compound of Example 66(a), the title compound was prepared (32%). NMR(CDCl3/CD3OD), δ 7.36-6.84 (m, 16H), 4.49
(d, 1H, J=9 Hz), 3.79 (s, 3H), 3.37 (m, 1H), 2.92-2.60 (m, 5H), 2.10-1.70 (m, 3H), 0.78 (d, 3H, J=7 Hz), 0.67 (d, 3H, J=7 Hz); MS(ES) m/e 585 [M+H]+.
Example 67
Preparation of (2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino -4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide a) (2R,4S,5S,1'S)5-(t-butylaminocarbonyl)amino-4-(t- butyldimethylsiloxy)-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenylmethyl-hexamide
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(CDCl3), δ7.35-7.05 (12H, m), 6.85 (2H, s), 4.69 (1H, d,
J=9 Hz), 4.60 (1H, t, J=8 Hz), 4.38 (1H, br), 4.24 (1H, q, J=8 Hz), 3.66 (1H, dd, J=4 Hz, 10 Hz), 2.95 (1H, dd, J=9Hz, 13Hz), 2.73 (2H, m), 2.54 (1H, dd, J=5 Hz, 13 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.67 (1H, m), 1.22 (9H, s), 0.93 (9H, s), 0.84 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 0.08 (3H, s), 0.07 (3H, s); MS(ES) m/e 648.4 [M+H]+. b) (2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl- hexanamide.
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 (MgSO4). 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(CD3OD) δ 7.37-6.90 (10H, m), 6.90 (2H, s), 4.58
(1H, d, J=9 Hz), 3.71 (1H, t, J=7 Hz), 3.52 (1H, d, J=9 Hz), 2.75 (4H, m), 2.53 (1H, dd, J=4 Hz, 12 Hz), 2.03 (1H, m), 1.76 (1H, m), 1.66 (1H, m), 1.22 (9H, S), 0.79 (3H, d, J=7 Hz), 0.67 (3H, d, J=7 Hz); MS (ES) m/e 534 [M+H] +.
Example 68 Preparation of (2R,4S,5S,1'S)-5-(methylaminocarhonyl)- amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide.
Following the procedure of Examples 67 (a) -67 (b), except substituting methyl isocyanate for t-butylisocyanate, the title compound was prepared (0.075 mg, 51%). Mp 253°C (dec);
NMR(DMSOd6) δ7.78 (1H, d, J=9 Hz), 7.80-6.96 (11H, m), 6.88
(2H, s), 5.78 (1H, d, J=5 Hz), 5.72 (1H, d, J=9 Hz), 4.84 (1H, d, J=4 Hz), 4.65 (1H, m), 3.68 (1H, q, J=7 Hz), 3.44 (1H, br), 2.74 (3H, m), 2.58 (1H, dd, J=7 Hz, 13 Hz), 2.50 (3H, s), 2.41 (1H, d, J=8 Hz), 1.92 (1H, m), 1.46 (2H, m), 0.72 (3H, d, J=7 Hz), 0.63 (3H, d, J=7 Hz); MS(ES) m/e 492 [M+H]+.
Example 69
Preparation of (2R, 4S , 5S , 1 ' S) -5- (phenylammocarbonyl ) amino-4- hydroxy-N- (1 ' -isopropyl -1 ' -i mi dazol -2-yl ) methyl -6- phenylmethyl-hexamide . Following the procedure of Examples 67 (a) -67(b), except substituting phenyl isocyanate for t-butylisocyonate, the title compound was prepared (87 mg, 79%). Mp 273°C (dec); NMR(DMSO-d6), 8.50 (1H, s), 7.81 (1H, d, J=9 Hz), 7.34-6.83 (18H, m), 6.07 (1H, d, J=9 Hz), 4.99 (1H, d, J=4 Hz), 4.65 (1H, t, J=8 Hz), 3.75 (1H, m), 3.52 (1H, br), 2.77 (3H, m), 2.66 (1H, m), 2.42 (1H, d, J=7 Hz), 1.89 (1H, m), 1.50 (2H, m), 0.68 (3H, d, J=7 Hz), 0.61 (3H, d, J=7 Hz); MS (DCI/NH3) m/e 554.3 [M+H]+.
Example 70
(2R,4S,5S,1'S)-5-N-(propylaminocarhonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl- hexamide.
Following the procedure of Examples 67 (a), except substituting n-propyl isocyanate for t-butylisocyanate, the title compound was prepared (0.048 g, 54%). Mp 247-9°C
(dec); NMR(DMSO-d6) δ7.75 (1H, d, J=8 Hz), 7.23-6.94 (11H, m), 6.85 (2H, s), 5.87 (1H, t, J=5 Hz), 5.65 (1H, d, J=9 Hz), 4.82 (1H, d, J=4 Hz), 4.64 (1H, t, J=8 Hz), 3.66 (1H, m), 3.38 (1H, br), 2.87 (2H, q, J=6 Hz), 2.74 (3H, m), 2.56 (1H, dd, J=7 Hz, 13 Hz), 2.39 (1H, d, J=7 Hz), 1.91 (1H, m), 1.43 (2H, m), 1.28 (2H, q, J=7 Hz), 0.77 (3H, t, J=7 Hz), 0.71 (3H, d, J=7 Hz), 0 . 62 (3H, d, J=7 Hz) ; MS (CI) m/e 520.2
[M+H] + .
Example 71 Preparation of (2R , 4S , 5S , 1 ' S) -5- (n-propylaminothiono) amino-4- hydroxy-N- (1 ' isopropyl -1 ' -imidazol-2-yl ) methyl -6- phenylmethyl-hexamide.
Following the method of Example 67 (a) -67(b), except using n-propyl thioisocyanate, the title compound was prepared (0.012 g, 21%). Mp 195-7°C (dec); NMR (CD3OD) δ
7.32-6.86 (12H, m), 4.59 (1H, m), 3.64 (1H, br), 3.34 (2H, br), 2.79 (5H, m), 2.03 (1H, m), 1.73 (1H, m), 1.58 (3H, m), 0 . 92 (3H, t, J=7Hz), 0 .83 (3H, d, J=7Hz), 0 , 68 (3H, d, J=7 Hz) ; MS (Cl) m/e 536.2 [M+H] +.
Exampl e 72
Preparation of (2R,4S,5S,1'S)-5-(isopropylaminocarbonyl)- amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexamide
Following the method of Example 67 (a) -67 (b), except substituting isopropyl isocyanate for t-butyl isocyanate, the title compound was prepared (0.034g, 46%). NMR(DMSO-d6) δ
7.78 (1H, d, J=8 Hz), 7.24-6.97 (11H, m), 6.85 (2H, s), 5.74 (1H, d, J=8 Hz), 5.57 (1H, d, J=9 Hz), 4.83 (1H, d, J=4 Hz), 4.66 (1H, d, J=7 Hz), 3.62 (2H, m), 3.43 (1H, br), 2.73 (3H, m), 2.57 (1H, dd, J=7 Hz, 13.5 Hz), 2.41 (1H, d, J=7 Hz),
1. 91 (1H, m) , 1.45 (2H, m) , 0 . 95 (3H, d, J=6.5 Hz) , 0 . 93 (3H, d, J=6.5 Hz) , 0 .72 (3H, d, J=6.5 Hz) , 0 . 63 (3H, d, J=6.5 Hz) ; MS (Cl) m/e 520 .2 [M+H] + . Example 73
Preparation of (2R,4S,5S,1'S)-5-(aminocarbonyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexamide
The compound of Example 67 (a) (0.050 g, 0 .094 mmol) was dissolved in triflouroacetic acid (2 mL) and stirred at 50°C for 2 h. After cooling, the reaction mixture was poured into saturated sodium bicarbonate solution (50 mL) and was
extracted into ethyl acetate (100 mL). The organic solution was washed with brine, dried (MgSO4) and the solvent removed under reduced pressure. Chromatography of the residue
(silica, 19:1 dichloromethane:methanol) gave the title compound as a white solid (0.036 g, 80%). Mp 235°C (dec); NMR(DMSO) δ 7.82 (1H, d), 7.30-6.90 (11H, m), 6.85 (2H, d), 5.88 (1H, m), 4.86 (1H, d), 4.67 (1H, t), 3.67 (1H, m), 3.45
(1H, m), 2.75 (3H, m), 2.60 (1H, m), 2.43 (1H, m), 1.94 (1H, m), 1, 49 (2H, m), 0.73 (3H, d), 0.62 (3H, d); MS (Cl) m/e 478 [M+H]+. Example 74
Preparation of (2R,4S,5S,1'S)-5-(6-quinolinylmethyloxy- carhonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenylmethyl-hexanamide
Using the procedure of Example 34, except substituting (6-quinolinylmethyl)-(4-nitrophenyl) carbonate for (4- picolinyl)-(4-nitrophenyl) carbonate, the title compound was prepared.
Example 75
Preparati on of (2R, 4S , 5S, 1 ' S) -5- (benzoyl ) ami no-4-hydroxy-N- (1 '-isopropyl -1 '-imidazol -2-yl) methyl -6-phenylmethyl - hexanamide a) (2R,4S,5S,1'S)-5-benzoyl)amino-4-t- butyldimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl- 6-phenylmethyl-hexamide.
The compound of Example 13(a) (0.11 g, 0.2 mmol), benzoyl chloride (0.025 g, 2.2 mmol) and
di (isopropyl) ethylamine (0.026 g, 0.2 mmol) were stirred together in dichloromethane (4 mL) at ambient temperature for 48hr. The solvent was removed under reduced pressure and the residue chromatographed (silica, 1:1 ethyl acetate:hexane) to yield the title compound as a white solid (0.080 g, 61%). NMR (CDCl3) 7.53 (2H, d), 7.40-7.04 (11H, m), 6.93 (2H, d),
6.69 (2H, s), 6.59 (1H, d), 6.37 (1H, d), 4.54 (2H, m), 3.68 (1H, t), 2.78 (2H, m), 2.66 (2H, m), 2.39 (1H, dd), 2.13 (1H, m), 1.62 (2H, t), 0.87 (9H, s), 0.53 (3H, d), 0.48 (3H, d), 0.02 (3H, s), 0.00 (3H, s). b) (2R,4S,5S,1'S)-5-(benzoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide The compound of Example 75 (a) (0.080 g, 0.12 mmol) was dissolved in THF (1 mL) and to this was added tetrabutyl- ammomium fluorrde, 0.16 mL, 0.16 mmol, 1M solution in THF). After stirring at 40°C for 24 hr, the solvent was removed under reduced pressure and the residue was chromatographed (silica, step gradient, 1:1 ethyl acetate:hexane, 9:9:2 ethyl acetate:hexane:methanol) to give the title compound as a white solid (0.051 g, 79%). Mp 253-6°C; NMR(DMSO-d6) δ 7.99
(1H, d), 7.91 (1H, d), 7.72 (2H, d), 7.50-7.02 (13H, m), 6.94 (2H, s), 4.83 (1H, br), 4.68 (1H, d), 4.14 (1H, m), 3.58 (1H, d), 2.82 (4H, m), 2.49 (1H, m), 1.92 (1H, m), 1.73 (1H, t), 1.40 (1H, m), 0.73 (3H, d), 0.63 (3H, d); MS (ES) m/e 539.2 [M+H]+.
Example 76
Preparation of (2R,4S,5S,1'S)-5-(2-furylcarbonyl)amino-4- hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide
Following the procedure of Example 75 (a), except using furoyl chloride in place of benzoyl chloride, the title compound was prepared as a white solid (0.019 g, 18%). Mp 212-3°C (dec); NMR(CDCl3/CD3OD) δ 7.46 (1H, s), 7.30-6.88
(12H, m), 6.85 (2H, s), 6.49 (1H, m), 4.48 (1H, d), 4.20 (1H, m), 3.67 (1H, m), 2.96 (4H, m), 2.77 (2H, m), 2.58 (1H, d), 2.07 (1H, m), 1.71 (2H, m), 0.74 (3H, d), 0.65 (3H, d);
MS(ES) m/e 528.32 [M+H]+.
Example 77
Preparation of (2R,4S,5S,1'S)-5-(4-methoxybenzoyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide
Following the procedure of Example 75 (a), except using 4-methoxybenzoyl chloride in place of benzoyl chloride, the title compound was prepared as a white solid (32%). Mp 235- 7°C (dec); NMR(CDCl3/CD3OD) δ 7.64 (2H, d), 7.22-6.87 (14H, m), 6.80 (2H, m), 4.52 (1H, d), 4.16 (1H, m), 3.81 (3H, s),
3.62 (1H, d), 2.92 (2H, d), 2.72 (2H, m), 2.53 (1H, dd), 1.98
(1H, m), 1.73 (1H, m), 1.63 (1H, m), 0.71 (3H, d), 0.62 (3H, d); MS(ES) m/e 569.4 [M+H]+. Example 78
Preparation of (2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexamide. a) (2R,4S,5S,1'S)-5-benzylcarbonyl)amino-4-t-butyldimethyl siloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl -hexanamide.
Following the procedure of Example 75 (a), except using phenylacetyl chloride in place of benzoyl chloride and triethylamine in place of di (isopropyl) ethylamine, the title compound was prepared as a white solid (20%). NMR(CDCl3) δ 7.40-6.75 (19H, m), 5.40 (1H, d), 4.73 (1H, t), 4.41 (1H, q), 3.68 (1H, m), 3.48 (2H, s), 2.96 (1H, dd), 2.69 (1H, m), 2.49 (4H, m), 1.61 (2H, m), 0.92 (6H, t), 0.77 (9H, s), 0.04 (3H, s), 0.00 (3H, s). b) (2R,4S,5S,1'S)-5-benzylcarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide The product of Example 78 (a) (0.018 g, 0.03 mmol) was dissolved in methanol (5 mL) and 2N hydrochloric acid (0.027 mL, 0.06 mmol) was added. After stirring at ambient
temperature for 18 h the solvent was removed under reduced pressure and the residue was chromatographed (silica, gradient, dichloromethane/methanol) to yield the title compound (0.011 g, 66%). Mp 240-2°C; NMR(CDCl3/CD3OD) δ
7.38-7.06 (18H, m), 6.98 (2H, s), 4.72 (1H, d), 4.14 (1H, m), 3.67 (1H, m), 3, 54 (2H, s), 2.99 (4H, m), 2.67 (1H, m), 2.14 (1H, m), 1.87 (1H, m), 1.63 (1H, m), 0.94 (3H, d), 0.79 (3H, d); MS (ES) m/e 553.2 [M+H]+.
Example 79
Preparation of (2R,4S,5S,1'S)-5-(4-hydroxybenzoyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide a) (2R,4S,5S,1'S)-5-(4-acetoxyphenyl)-4-t-butyl
dimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide.
The compound of Example 13(a) (0.11 g, 0.2 mmol) was dissolved in dichloromethane (2 mL), and BOP reagent (0.089 g, 0.2 mmol), triethylamine (0.028 mL, 0.2 mmol) and 4- acetoxybenzoic acid (0.043 g, 0.24 mmol) were added. After stirring at ambient temperature overnight the solvent was removed under reduced pressure. The residue was
chromatographed (silica, 49:1 dichloromethane:methanol) to give the title compound as a white solid (0.11 g, 78%).
NMR(CDCl3) δ 7.53 (2H, d), 7.28-6.97 (13H, m), 6.83 (1H, d),
6.78 (2H, s), 6.44 (1H, d), 4.54 (2H, m), 3.72 (1H, dd), 2.79 (4H, m), 2.49 (1H, dd), 2.24 (3H, s), 2.20 (1H, m), 1.70 (2H, m), 0.91 (9H, s), 0.66 (3H, d), 0.57 (3H, d), 0.07 (3H, s), 0.02 (3H, s). b) (2R,4S,5S,1'S)-5-(4-hydroxybenzoyl)amino-4-t-butyl dimethylsiloxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide
The product from reaction 79(a) (0.11 g, 0.15 mmol) was dissolved in methanol (5 mL) and powdered potassium carbonate (0.12 g, 0.9 mmol) was added. After stirring the suspension vigorously for 2 h, the mixture was filtered and the solvent removed from the filtrate at reduced pressure.
Chromatography of the residue (silica, 19:19:2 ethyl
acetate:hexane:methanol) gave the title compound as a white solid (0.066 g, 66%). NMR(CDCl3) δ 7.35 (2H, d), 7.24-6.98 (12H, m), 6.67 (4H, m), 6.32 (1H, d), 4.63 (2H, m), 3.76 (1H, dd), 2.78 (4H, m), 2.44 (1H, d), 2.12 (1H, m), 1.64 (2H, m),
0.88 (9H, s), 0.44 (3H, d), 0.32 (3H, d), 0.05 (3H, s), 0.01 (3H, s). c) (2R,4S,5S,1'S)-5-(4-hydroxybenzoyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide Following the procedure of Example 75 (b), except using the compound of Example 79(b) in place of the compound of Example 75 (a), the title compound was prepared as a white solid (57%). Mp 267-8°C (dec); NMR(CDCl3/CD3OD) δ 7.57 (2H, d), 7.33-6.75 (17H, m), 4.48 (1H, d), 4.14 (1H, m), 3.58 (1H, d), 2.90 (2H, m), 2.82 (1H, m), 2.73 (1H, m), 2.53 (1H, dd), 2.04 (1H, m), 1.65 (2H, m), 0.73 (3H, d), 0.58 (3H, d); MS (ES) m/e 555.2 [M+H]+.
Example 80 Preparation of (2R, 4S, 5S, 1 ' S) -5- (cinnamoyl) amino-4-hydroxy-N- ( 1 ' -isopropyl -1 '- imidazol-2-yl ) methyl-6-phenyl methyl - hexanamide
Following the procedure of Example 75 (a), except using cinnamoyl chloride in place of benzoyl chloride, the title compound was prepared as a white solid (25%). Mp 273°C;
NMR(CDCl3/CD3OD) δ 7.55-6.91 (19H, m), 6.86 (2H, s), 6.53 (1H, d), 4.37 (1H, d), 4.15 (1H, dt), 3.62 (1H, d), 2.91 (2H, m), 2.78 (2H, m), 2.59 (1H, dd), 2.04 (1H, m), 1.76 (1H, m), 1.65 (1H, m), 0.79 (3H, d), 0.69 (3H, d); MS (ES) m/e 565.2
[M+H]+.
Example 81
Preparation of (2R,4S,5S,1'S)-5-(2-hydroxybenzoyl)amino-4- hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6- phenylmethyl-hexanamide
Following the procedure of Example 79(a), except using
2-acetoxybenzoic acid in place of 4-acetoxybenzoic acid, the title compound was prepared (50%). Mp 197°C; NMR(CD3OD) δ 7.77 (1H, d), 7.42-6.78 (17H, m), 4.62 (1H, d), 4.32 (1H, dt), 3.71 (1H, m), 2.94 (2H, m), 2.78 (2H, m), 2.57 (1H, m),
2.03 (1H, m), 1.84 (1H, m), 1.67 (1H, m), 0.82 (3H, d), 0.68
(3H, d); MS (ES) m/e 555.2 [M+H]+. Example 82
Preparation of (2R, 4S , 5S , 1 ' S) -5- (imidazoyl-4-yl-acetyl) amino- 4-hydroxy-N- (1 ' -isopropyl-1 ' -imidazol-2-yl) methyl-6- phenylmethyl-hexanamide
Following the procedure of Example 79 (a) -79 (c), except using (imidazol-4-yl) acetic acid in place of 4-acetoxy benzoic acid, the title compound was prepared . Example 83
Preparation of (2R, 4S , 5S , 1 ' S) -5- ( t-butoxycarbonyl) amino-4- hydroxy-N- [1 '-isopropyl-1 '- (4-oarbomethoxyethylimidazol-2- yl) ] methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S) 1-carbobenzyloxyamino-1-isopropyl-1-[(4-(E- carbomethoxyethylene)imidazol-2-yl)]methane
The compound of Example 27(b) (100 mg, 0.33 mmol), lithium chloride (28 mg, 0.66 mmol) and
trimethylphosphonoacetate (61 mg, 0.33 mmol) were dissolved in anhydrous acetonitrile (2 mL). 1,8-Diazabicyclo [5.4.0]- undec-7-ene (55 mg, 0.36 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silicaa, 2% methanol/ dichloromethane to afford the title compound (72 mg, 61%). NMR(CDCl3) δ 7.60-7.10 (6H, m), 6.50 (1H, br s), 6.10 (1H, br s), 5.15-4.95 (2H, m), 4.50 (1H, br m), 3.75 (3H, s), 2.30
(1H, br m), 1.10-0.80 (6H, m); MS m/e 358.2 [M+H]+. b) (1S)-1-amino-1-isopropyl-1-(4-carbomethoxyethylimidazol-2- yl)methane
Following the procedure of Example 1 (b), except
substituting the compound of Example 82 (a) for the compound of Example 1(a), the title compound was prepared. NMR(CDCl3) δ 6.65 (1H, s), 4.40 (2H, br s), 3.82 (1H, d, J=3 Hz), 3.65
(3H, s), 2.90-2.55 (4H, m), 2.05 (1H, m), 0.90 (6H, d,
J=3Hz). c) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t-butyldi- methylsiloxy-N-[1'-isopropyl-1'-(4-carbomethoxyethylimidazol- 2yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 1 (c) except using the compound of Example 82 (b), the title compound was prepared. NMR(CDCl3) δ 7.35.-6.90 (12H, m), 6.55 (1H, s),
4.75 (1H, d, J=4 Hz), 4.45 (1H, m) 3.95 (1H, m), 3.70 (3H, s), 2.90-2.40 (9H, m), 1.90-1.60 (2H, m), 1.38 (9H, s), 0.90-0.70 (15H, m), 0.10 (6H, d, J=2 Hz). d) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-
[1'-isopropyl-1'-(4-carbomethoxyethylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide.
Following the procedure of Example of 9(d) except using the compound of Example 83 (c), the title compound was
prepared. NMR(CDCl3) δ 7.30-6.90 (10H, m), 6.55 (1H, s),
5.00 (1H, d, J=4 Hz), 4.45 (1H, m), 3.70 (3H, s), 2.95-2.50 (9H, m), 2.25 (1H, m), 1.80-1.60 (2H, m), 0.85 (9H, s), 0.70 (6H, d, J=3 Hz); MS m/e 621.4 [M+H]+.
Example 84
Preparation of (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4- hydroxy-N- [ 1'-isopropyl-1'-[4-carboxamidoimidazol-2- yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide a) (1S) -1-carbobenzyloxyamino-1-isoρropyl-1-[(4- (hydrazinocarbonyl) imidazol-2-yl) ]methane
Anhydrous hydrazine (47 μL, 1.5 mmol) was added to a solution of the compound of Example 26(b) (100 mg, 0.30 mmol) in anhydrous methanol. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 and the organic extract was dried over Na2CO3 and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, 4%
methanol/dichloromethane) to afford the title compound (52 mg, 52%). NMR(CD3OD) δ 7.50 (1H, s), 7.30-7.20 (5H, m), 5.00-4.90 (2H, m), 4.45 (1H, d, J=6 Hz), 2.10 (1H, br m), 0.95-0.75 (6H, m); MS m/e 332.2 [M+H]+ b) (1S) -1-carbobenzyloxyamino-1-isopropyl-1-[(4- azidocarbonyl) imidazol-2-yl]methane
The compound of Example 83 (a) was dissolved in 2N HCl (1 mL) and glacial acetic acid (0.2 mL) and cooled in an ice bath. A solution of sodium nitrite (11 mg, 0.16 mmol) in H2O (200 μL) was added dropwise. The reaction mixture was stirred for 0.5 h, neutralized with cold concentrated
ammonium hydroxide and extracted with ethyl acetate. The organic extract was dried over Na2C03 and the solvent removed in vacuo to yield the title compound (54mg. 100%).
NMR(CDCl3) δ 7.75 (1H, s), 7.35-7.20 (5H, m), 5.20-5.00 (2H, m), 4.62 (1H, br m), 2.60 (1H br m), 1.10-0.80 (6H, m); IR 2123cm-1 (CON3). c) (1S)-1-carbobenzyloxyamino-1-isopropyl-1-(4- carboxamidoimidazol-2-yl)methane
The compound of Example 83 (b) was dissolved in 2 mL of ethyl acetate and stirred with of concentrated ammonium hydroxide (1 mL) at 0°C for 0.5 h, then at room temperature overnight. The reaction mixture was diluted with H2O, extracted with ethyl acetate, and dried over Na2CO3. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica, 4% methanol/ dichloromethane) to afford the title compound (50mg, 100%). NMR(CDCl3) δ 7.45
(1H, s), 7.25-7.10 (5H, m), 5.00-4.85 (2H, m), 4.35 (1H, d, J=3 Hz), 2.00 (1H, br m), 0.90-0.70 (6H, m); MS m/e 317.2
[M+H]+. d) (1S)-1-amino-1-isopropyl-1-(4-carboxamidoimidazol-2- yl)methane.
Following the procedure of Example 1 (b), except
substituting the compound of Example 83(c) for the compound of Example 1(a), the title compound was prepared. NMR(CDCl3) Example 85
δ 7.45 (1H, s), 3.47 (1H, d, J=3 Hz), 1.80 (1H, br m), 0.75- 0.60 (6H, m). e) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-t- butyldimethylsiloxy-N-[1'-isopropyl-1'-(4- carboxamidoimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl- hexanamide
Following the procedure of Example 1 (c), except using the compound of Example 83 (d), the title compound was prepared. NMR(CDCl3) δ 7.50 (1H, s), 7.45-6.90 (11H, m),
6.25 (1H, d, J=4 Hz), 4.50 (1H, d, J=6Hz), 4.10 (1H, br m), 3.60 (1H, m), 2.90-2.40 (5H, m), 1.90 (1H, br m), 1.70-1.50 (2H, br m), 1.35 (9H, s), 0.90 (9H, s), 0.70-0.60 (6H, m), 0.10 (6H, m). f) (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N- [1'-isopropyl-1'-(4-carboxamidoimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide
Following the procedure of Example 9(d) except using the compound of Example 83(e) the title compound was prepared. NMR(CD3OD) δ 7.45 (1H, s), 7.25-6.85 (10H, m), 4.50 (1H, d,
J=6 Hz), 4.10 (1H, m), 3.60 (1H, m), 2.85-2.50 (5H, m), 2.00 (1H, br m), 1.80-1.50 (2H, m), 1.30 (9H, s), 0.80-0.65 (6H, m); MS m/e 578.2 [M+H]+.
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5- (1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide a) (2R,4S,5S,1'S)-2-phenylmethyl-4-t-butyldimethyl-siloxy-5- thioureido-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl- hexanamide
A solution of benzoyl isothiocyanate (prepared from ammonium thiocyanate (147 mg, 1.93 mmol) and benzoyl chloride (257 mg, 1.84 mmol) in of acetone (10 mL) according to the procedure of J. Amer. Chem. Soc , 56, 1408 (1934)) was treated with a solution of (2R,4S,5S,1'S)-2-phenylmethyl-4-t- butyldimethylsiloxy-5-amino-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide (1.0 g, 1.83 mmol) in acetone. After 20 min at 23°C, the solvent was evaporated, and the residue was dissolved in diethyl ether. The ether extract was washed with water, dried, and the solvent was evaporated. This residue was dissolved in of MeOH (25 mL), treated with 2.5N NaOH (0.1 mL) and heated to 50°C for 30 min. The solvent was evaporated, and the residue was dissolved in EtOAc. The organic solution was washed with water, dried, and the solvent evaporated. The residue was chromatographed (silica, 5% MeOH/CHCl3) to yield the title compound (520 mg, 47%). NMR(DMSO) δ 7.80 (1H, d), 7.35 (1H, d), 6.70-7.20 (15H, m), 4.69 (1H, t), 4.54 (1H, m), 3.78 (1H, m), 2.72-2.86 (3H, m), 2.54 (lh, dd), 2.42 (1H, dd), 2.04 (1H, m), 1.82 (1H, m), 1.30 (1H, m), 0.92 (9H, s), 0.86 (3H, d), 0.74 (3H, d), 0.15 (6H, d). b) dimethylformamidino derivative of (2R,4S,5S,1'S)-2- phenylmethyl-4-dimethyl-t-butyl silyloxy-5-thioureido-6- phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide
A solution of the compound of Example 85(a) (122 mg, 0.2 mmol) and dimethylformamide dimethylacetal (26 mg, 0.22 mmol) in CHCI3 (2 mL) was stirred at 23°C for 16 h. The solvent and excess reactant was removed under high vacuum, and the residue was chromatographed (Florisil®, 2% MeOH/CHCL3) to yield the title compound (100 mg, 76%). NMR(CDCl3) δ 8.82 (1H, s), 7.05-7.40 (12H, m), 6.76 (1H, br s), 6.60 (1H, d), 5.32 (1H, m), 4.66 (1H, dd), 3.88 (1H, dd), 3.14 (3H, s),
3.05 (3H, s), 2.70-3.04 (4H, m), 2.40 (2H, m), 1.68 (2H, m), 1.00 (9H, s), 0.80 (6H, dd), 0.14 (6H, d). c). (2R,4S, 5S, 1'S)-2-phenylmethyl-4-dimethyl-t-butyl silyloxy-5-(5-(1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N- (1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide
A solution of the compound of Example 85(b) (100 mg, 0.15 mmol), 1-bromo-2-butanone (25 mg, 0.165 mmol), and triethylamine (33 mg, 0.165 mmol) in acetonitrile (10 mL) was heated at 80°C for 3.5 h. The solvent was evaporated, and the residue shaken with a mixture of diethyl ether and aqueous NaHCO3. The ether was seperated, washed with water, dried, and the solvent was evaporated. The residue was recrystallized from a mixture of CHCI3 and hexane to yield the title compound (59 mg, 57%). NMR(CDCl3) δ 7.75 (1H, s),
7.02-7.38 (10H, m), 6.88 (2H, m), 6.80 (1H, br s), 6.70 (1H, d), 6.60 (1H, d), 4.62 (1H, t), 3.96 (1H, m), 3.78 (1H, t), 2.82 (3H, m), 2.72 (2H, q), 2.54 (2H, m), 2.20 (1H, m), 2.04 (1H, m), 1.66 (1H, m), 1.15 (3H, t), 0.96 (9H, s), 0.72 (6H, t), 0.10 (6H, d). d). (2R,4S, 5S, 1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1- oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide
A solution of the compound of Example 85(c) (50 mg, 0.07 mmol) in (2 mL) of THF was treated with) of tetrabutylammonium fluoride (0.2 mL, IN solution in THF) 58°C for 1 h. The solvents were evaporated, and the residue dissolved in ether. The ether was washed with water, dried, and the solvent evaporated. The residue was chromatographed (neutral alumina. Activity V, impurities removed with 2% MeOH/EtOAc, product eluted with 5% MeOH/CHCl3) to yield the title
compound (22 mg, 55%). NMR(DMSO) δ 7.75 (1H, s), 7.66 (1H, d), 6.80-7.30 (13H, m), 4.93 (1H, br s), 4.78 (1H, t), 3.78 (1H, m), 3.68 (1H, dd), 3.00 (1H, dd), 2.92 (1H, dd), 2.86 (1H, m), 2.80-2.90 (1H, br), 2.76 (2H, q), 2.56 (2H, m), 2.12 (1H, m), 1.74 (1H, m), 1.69 (1H, m), 1.20 (3H, t), 0.80 (3H, d), 0.73 (3H, d).
Example 86
Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5- (1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide a) (2R,4S,5S,1'S)-2-phenylmethyl-4-dimethyl-t-butyl silyloxy- 5-(2-thiazolylamino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide.
The compound of Example 85(a) (50 mg, 0.08 mmol) in CHCI3 (2 mL) was treated with chloroacetaldehyde (50 mg, 0.64 mmol). After 20 min the solvent and excess reagent were evaporated. The residue was dissolved in EtOAc, washed with aqueous NaHCO3 dried and the solvent evaporated. The residue was chromatographed (Florisil®, 60% EtOAc/hexane) to yield the title compound (42 mg, 83%). NMR(CDCl3) δ 7.12-
7.30 (10H, m), 7.02 (1H, d), 6.92 (2H, m), 6.82 (1H, br), 6.62 (1H, br), 6.38 (1H, d), 5.86 (1H, br), 4.58 (1H, t), 4.00 (1H, m), 3.86 (1H, m), 2.85 (3H, m), 2.52 (2H, m), 2.26 (1H, m), 2.16 (1H, m), 1.68 (1H, m), 0.98 (9H, s), 0.70 (6H, t), 0.12 (6H, d). b) (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1- oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide.
Following the procedure of Example 85 (d), except
substituting the compound of Example 86(a) for the compound of Example 85(c), the title compound was prepared.
NMR (CDCI3/DMSO) δ 6.80-7.42 (14H, m), 6.40 (2H, m), 5.18 (1H, br), 4.74 (1H, t), 3.70 (1H, m), 3.62 (1H, m), 3.00 (2H, m), 2.88 (2H, m), 2.58 (1H, m), 2.18 (1H, m), 1.80 (2H, m), 1.72 (6H, dd).
Example 87 Preparation of (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5- propyl-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide a) (2R,4S,5S,1'S)-2-phenylmethyl-4-t-butyldimethylsilyloxy-5- (5-propyl-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'- (imidazo-2-yl))methyl-hexanamide.
A solution of the compound of Example 85(a) (120 mg, 0.2 mmol) in CHCI3 (5 mL) was treated with 2-bromovaleraldehyde (100 mg, 0.6 mmol) and warmed to 60°C for 30 min and 80°C for 5 min. The solvent and excess reagent were removed under reduced pressure. The residue was dissolved in EtOAc, washed with aqueous K2CO3, dried, and the solvent evaporated. The residue was chromatographed (silica, 3% MeOH/CHCl3) to yield the title compound (55 mg, 41%). NMR(CDCl3) δ 7.10-7.30 (10H, m), 6.88 (2H, m), 6.72 (1H, br), 6.68 (1H, s), 6.60 (1H, br), 5.60 (1H, br), 4.62 (1H, t), 3.94 (1H, m), 3.78 (1H, t), 2.82 (3H, m), 2.50 (4H, m), 2.26 (1H, m), 2.04 (1H, m), 1.66 (1H, m), 1.55 (2H, sextet), 0.94 (9H, s), 0.92 (3H, t), 0.70 (6H, dd), 0.08 (6H, d). b). (2R,4S, 5S, 1'S)-2-phenylmethyl-4-hydroxy-5-(5-propyl-2- thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2- yl))methyl-hexanamide.
Following the procedure of Example 85 (d), except
substituting the compound of Example 87 (a) for the compound of Example 85(c), the title compound was prepared. NMR(CDCl3) δ 7.50 (1H, br), 6.90-7.24 (10H, m), 6.78 (2H, s), 6.60 (1H, s), 6.18 (1H, br), 5.76 (1H, br), 4.60 (1H, t), 3.68 (1H, m), 3.52 (1H, m), 3.05 (1H, dd), 2.95 (2H, m), 2.82 (1H, dd), 2.62 (1H, m), 2.58 (2H, t), 2.32 (1H, m), 1.86 (2H, m), 1.60 (2H, sextet), 0.96 (6H, t), 0.75 (6H, dd). Example 88
Preparation of (2R,4S,5S,1'S)-5-(nicotinyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide Following the procedure of Example 75 (a), except using nicotinoyl chloride in place of benzoyl chloride, the title compound was prepared as a white solid (43%). Mp 233-4°C (dec); NMR(CDCl3/CD3OD) 58.81 (1H, d), 8.59 (1H, dd), 7.99
(1H, m), 7.35-6.86 (14H, m), 6.79 (2H, s), 4.44 (1H, d), 4.19 (1H, dt), 3.59 (1H, m), 2.90 (2H, d), 2.68 (2H, m), 2.52 (2H, m), 1.96 (1H, m), 1.71 (1H, m), 1.58 (1H, m), 0.70 (3H, d), 0.58 (3H, d); MS(ES) m/e 540.2 [M+H]+. The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular embodiments described
hereinabove, but includes all modifications thereof within the scope of the following claims.

Claims

What is claimed is :
1 . A compound of the formula (I) :
Figure imgf000133_0001
wherein :
R1 and R3 are each independently Q, Q-C1-6alkyl,
Q-C2-6alkenyl, Q-C2-6alkynyl or C1-6alkyl substituted by one to five fluorine atoms, each optionally substituted by R23;
Q is H, C3-6cycloalkyl, C5-6cycloalkenyl, Ar or Het
R2 is H or OH;
R4 is R6-NR11- or CONR1 1CHR6R7;
R5 is R6-NR11- or R10-NR13-; R6 is
Figure imgf000133_0002
X is NR11, O or S;
R7 is Q, Q-C1-6alkyl or Q-C2-6alkenyl;
R8 and R9 are each independently H, OH, halo, NO2, COR12, CF3, Ar, Chalky 1-R15, or R17 (R18R19C) m, or together form a fused C2-4alkylene, aryl or heteroaryl moiety;
R10 is A- (B) n- ;
R11 is H or C1 -4alkyl;
R12 is R7, OR7, NR7R11 or an amino acid or amino alcohol; B is an amino acid;
A is H, Ar, Het, R17 (R18R19C)m, Ar-W, Het-W or
R17(R18R19C)m-W, or phthaloyl each optionally substituted by one to three groups chosen from R15 or C1-6alkyl-R15;
W is C=O, OC(=O), NR11C(=O), SC(=O), HR11C (=S), SO2, NR11SO2 or P(=O) (OR22);
R15 is H, nitro, C1-6alkoxy, Chalkylthio, O(C=O)R16,
C=OR22, CO2R22, CON(R16)2, N(R22)2, NHC (=N) NH-A, I, Br, Cl, F, OR10, or OH, provided that when R15 is a substituent of the carbon adjacent to W, R15 is not halogen or OH when W is OC(=O) or NHCO;
R16 is H or C1-6alkyl; R17, R18 and R19 are independently: i) H, R15 or
C1-4alkyl, C2-6alkenyl, phenyl, naphthyl, C3-6cycloalkyl or
Het, each optionally substituted by one to three R15 or
R^-Cx-galkyl groups, or ii) R17 is as above and (R18R19C) are joined together to form a phenyl, naphthyl, C3-6cycloalkyl or Het ring, or iii) R17 is as above and R18 and R19 together are =O;
R22 is H, C1-6alkyl, phenyl or phenyl-C1-4alkyl;
R23 is -X'-(CH2)qNR24R25, X"[((CH2)rO)S]R26,
CH2X" [ ( (CH2)rO)s]R26, or benzofuryl, indolyl, azacycloalkyl, azabicyclo C7_ncycloalkyl or benzopiperidinyl, optionally substituted with Ci-galkyl;
q is 2-5;
s is 1-6 and r is 1-3 within each repeating unit s;
X' is CH2, O, S or NH;
X" is CH2, NR', O, S, SO or SO2;
R24 and R25 are i) C1-6alkyl, optionally substituted by OH, C1-3alkoxy, 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, SO2, said heterocycle optionally substituted with C1-4alkyl, iii) aromatic heterocycle, optionally substituted with
C1-4alkyl or N(R')2,
R' is H or C1-4alkyl;
R26 is H, C1-4alkyl, C(=O)R27, C(=O)U[ (CH2)mO]nR',
P(=O) (0M)2, CO2R27, C(=O)NR27R28, where M is a mono or
divalent metal ion, and U is NR' or O;
R27 is C1-6alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, C1-3alkoxy, CONR'2, NR'2, CO2R', SO2NR'2. CH2NR2, NR'COR', NR'SO2R', X"[(CH2)rO]sR' or CH2X"[(CH2)rO]sR';
R28 is H, C1-6alkyl or together with R27 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
m is 1-4; and
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein:
R1 and R3 are C1-6alkyl, Ar-C1-6alkyl, Ar-C2-6alkenyl, Ar-C2-6alkynyl, or C1-6alkyl optionally substituted by one to five fluorine atoms;
X is N-R11;
R4 is CONR11CHR6R7;
R5 is R10-NR11;
R7 is H, C1-6alkyl, C3-6cycloalkyl, phenyl or benzyl; R8 is H, C1-6alkyl, COR12, NO2 or Br;
R9 is H, NO2, Br, COR12, CF3, Ar, C1-6alkyl or
C1-6alkyl-R15, wherein R12 is H, C1-6alkyl, Ar, OC1-6alkyl, NH2, and R15 is OH;
A is H, Het, R17(R18R19C)m-W or Het-W;
B is absent or Val;
R17, R18 and R19 are H, or C1-4alkyl, Het or Ar, each optionally substituted by one or two R15 or R15C1-6alkyl groups, or (R18R19C) are joined together to form a phenyl, C3-6cycloalkyl or Het ring; and
W is C=O, OC(=O), NHC(=O), NHC(=S) or SC (=O) .
3. A compound according to claim 1 wherein R4 is
CONR11CHR6R7 and X is N-H.
4. A compound according to claim 3 wherein R8 is H and R9 is H or COR12.
5. A compound according to claim 4 wherein R7 is C1-6alkyl.
6. A compound according to claim 3 wherein R1 is benzyl and R3 is benzyl, 4-hydroxy-benzyl or phenylpropenyl.
7. A compound according to claim 3 wherein A is
R17(R18R19C)m-W, and R17, R18 and R19 are H, or C1-4alkyl, Het or Ar.
8. A compound according to claim 3 wherein B is absent and A is C1-6alkylOC (=O).
9. A compound according to claim 3 wherein W is C=O.
10. A compound according to claim 1 wherein the compound is: (2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl- hexanamide hydrochloride;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-isopropyl-1'-(4-aminocarbonyl-thiazo-2- yl)]methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-isopropyl-1'-(thiazo-2-yl)]methyl- hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-(1'-imidazo-2-yl)methyl-hexanamide
hydrochloride;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-methyl-1'-(imidazo-2-yl)] methyl- hexanamide hydrochloride;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)- amino-6-phenyl-N-[1'-benzyl-1'-(imidazo-2-yl)]methyl- hexanamide hydrochloride;
(2R,4S,5S,1'S)-5-(carbobenzyloxy)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dimethyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(N'-methyl)imidazol-2-yl]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3- phenyIpropargyl) hexanamide;
(2R,4S,5S,1'S)-5-(isopropoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide; (2R,4S,5S,1'S)-5-(benzyloxyethoxycarbonyl) amino-4-hydroxy-N-
(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(methoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(ethoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyϊ-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(3-phenyl-2- propenyl) hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-nitroimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- ethyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- propyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl- hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-bromoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4,5-dibromoimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-methylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-trifluoromethylimidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-methyl- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2- phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-carbomethoxyimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-methylcarbonylimidazol-2-yl)]methyl-6-phenyl- 2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-isopropylcarbonyl-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-phenylcarbonyl-imidazol-2-yl)]methyl-6- phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-formylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'- isopropyl-1'-(4-(hydroxymethyl)-imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-((tetrahydrothiopyran-4-yl)oxycarbonyl)-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-((tetrahydro-4H-pyran-4-yl)oxycarbonyl)-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(4-picolinyloxy)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-(4,4,4-trifluorobut-1-yl)hexanamide ;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-isopropyl-1'-(4-((IRS)-1-hydroxyethyl)-imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-(1-methyl)propyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(propylaminocarbonyl)amino-4-hydroxy-N-[1'-isopropyl-1'-(imidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(4-hydroxybutanoyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(benzyloxy-carbonyl)valylamino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2-yl)methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(N-acetylvalyl)-amino-6-phenyl-N-(1'-isobutyl-1'-imidazo-2-yl)methyl-hexanamide;
(2R,4S,5S,1'S)-5-[(imidazol-2-yl)methyloxycarbonyl]amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S,1-RS)-5-((1"-(imidazol-2-yl)-2"-methyl)-propyloxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-isopropyl-1'-(4-(imidazol-2-yl)imidazol-2-yl)]methy1-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(l-oxo-thian-4-yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1"-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)-5-((tetrahydrosulfonylpyran-4-yl)oxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide;
(2R,4S,5S,1'S)-5-((1,1-dimethyl-2-(benzyloxycarbonyl-glycyloxy)ethoxycarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamidehydrochloride salt;
(2R,4S,5S,1'S)-5-((1,1-dimethyl-2-glycyloxy)ethoxycarbonyl)-amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamidedihydrochloridesalt;
(2R,4S,5S,1'S)-5-((1-acetyl)amino-4-hydroxy-N-(1'-isopropyl- 1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethylhexanamide; (2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- benzyloxyphenylmethyl)hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'imidazol-2-yl)methyl-6-phenyl-2-(4- hydroxyphenylmethyl)hexanamide;
(2R,4S,5S)-5-(t-butoxycarbonyl)amino-4-hydroxy-2- phenylmethyl-6-phenyl-N-[1'-cyclopropyl-1'-imidazol-2- yl]methyl-hexanamide;
(2R,4S,5S,1'S)-5-((isopropylthiol)carbonyl)-amino-4-hydroxy- 2-phenylmethyl-6-phenyl-N-[1-isopropyl-1'-imidazol-2- yl]methyl-hexanamide;
(2R,4S,5S,1'S)-5-[3-(1H-imidazol-2-yl)-3-hydroxy-4- methylpentylamido]-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2- yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-[(4-methoxyphenoxy)carbonyl]amino-4-hydroxy- N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenyl-2-phenylmethyl-hexanamide;
2R,4S,5S,1'S)-5-(t-butylaminocarbonyl)amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(methylaminocarbonyl)-amino-4-hydroxy-N-(1'- isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-phenylaminocarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; (2R,4S,5S,1'S)-5-N-(propylaminocarbonyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
(2R,4S,5S,1'S)-5-(n-propylaminothiono)amino-4-hydroxy-N- (1'isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;2R,4S,5S,1'S)-5-(isopropylammocarbonyl)-amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide;
(2R,4S,5S,1'S)-5-(aminocarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; (2R,4S,5S,1'S)-5-(6-quinolinylmethyloxy-carbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R, 4S, 5S, 1'S) -5- (benzoyl) amino-4-hydroxy-N- (1 ' -isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(2-furylcarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(4-methoxybenzoyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-benzylcarbonyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide; (2R,4S,5S,1'S)-5-(4-hydroxybenzoyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(cinnamoyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(2-hydroxybenzoyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide; (2R,4S,5S,1'S)-5-(imidazoyl-4-yl-acetyl)amino-4-hydroxy-N- (1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-isopropyl-1'-(4-carbomethoxyethylimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-5-(t-butoxycarbonyl)amino-4-hydroxy-N-[1'-isopropyl-1'-(4-carboxamidoimidazol-2-yl)]methyl-6-phenyl-2-phenylmethyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-(1-oxopropyl)-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide;
(2R,4S,5S,1'S)-2-phenylmethyl-4-hydroxy-5-(5-propyl-2-thiazolyl)amino)-6-phenyl-N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide; and
(2R,4S,5S,1'S)-5-(nicotinyl)amino-4-hydroxy-N-(1'-isopropyl-1'-imidazol-2-yl)methyl-6-phenylmethyl-hexamide.
11. A compound according to claim 1 which is (2R, 4S, 5S, 1 ' S)5- ( t-butoxycarbonyl) amino-4-hydroxy-N- [ 1 ' -isopropyl-1 ' - (4- isopropylcarbonylimidazol-2-yl)]methyl-6-phenyl-2- phenylmethyl-hexanamide
12. A compound according to claim 1 which is (2R, 4S, 5S,1'S)- 2-phenylmethyl-4-hydroxy-5-(t-butoxycarbonyl)-amino-6-phenyl-
N-(1'-isopropyl-1'-(imidazo-2-yl))methyl-hexanamide.
13. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.
14. A pharmaceutical formulation comprising a compound according to Claim 1 and an oil.
15. A method of treating disease states associated with HIV infection comprising administering an effective amount of a compound according to Claim 1.
16. The use of a compound according to Claim 1 in the manufacture of a medicament.
17. A compound of the formula:
Figure imgf000142_0001
wherein Pr2 is an amino protecting group, and R7', R8' and R9' are as defined in Claim 1 with any reactive groups protected.
18. A compound of formula:
Figure imgf000142_0002
wherein : R1 and R3 are each independently C1-6alkyl,
Ar-C1-6alkyl, Het-C1-6alkyl, C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6alkenyl, C3-6cycloalkyl-C1-6alkyl or
C3-6cycloalkenyl-C1-6alkyl;
R2 is H or OH;
R4 is R6-NH-, or
Figure imgf000143_0001
R5 is R6-NH- or R10-NH;
R6 is
Figure imgf000143_0002
wherein:
X is NR11, O, or S,
R11 is H or C1-3alkyl;
R8 and R9 are each independently H, OH, halo, acyl, or substituted alkyl; or R6 is
Figure imgf000143_0003
wherein:
X is NH, O, or S;
Y is a fused C2-4 alkylene, aryl or heteroaryl moiety;
R7 is C1-6alkyl, Ar-C1-6alkyl, Het-C1-6alkyl,
C2-6alkenyl, Ar-C2-6alkenyl, Het-C2-6alkenyl,
C3-6cycloalkyl-C1-6 alkyl or C3-6cycloalkenyl-C1-6alkyl;
R10 is a moiety A-(B)n-, where n = 0 or 1; and B is, independently, an α-amino acid chosen from the group: Ala, Asn, Cys, Trp, Gly, Gin, lie. Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A and the carboxy group of B is bonded to the structure;
A is covalently attached to the amino group of the adjacent residue B or to the amino group of the structure if n = 0 and is:
1) trityl,
2 ) hydrogen,
3) C1-6alkyl,
4) R14-CO-wherein R14 is : a) hydrogen,
b) C1-6alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms,
c) phenyl or naphthyl unsubstituted or
substituted with one or more substituents R15 wherein R15 is:
i) C1-4alkyl,
ii) halogen, where halogen is F, Cl, Br or I,
iii) hydroxyl,
iv) nitro,
v) C1-3alkoxy, or
vi) -CO-N(R16)2 wherein R16 is,
independently, H or C1-4alkyl; or
d) a 5-7 member heterocycle such as pyridyl,
furyl, or benzisoxazolyl;
5) phthaloyl wherein the aromatic ring is
unsubstituted or substituted with one or more substituents R15;
6) R17(R18R19C) m-CO- wherein m = 1-3 and R17, R18, and R19 are independently:
a) hydrogen,
b) chlorine or fluorine,
c) C1-3alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups,
d) hydroxyl,
e) phenyl or naphthyl unsubstituted or
substituted with one or more substituents R15, f) C1-3alkoxy,
g) a 5-7 member heterocycle, or
h) R17, R18, and R19 may be independently joined to form a monocylic, bicyclic, or tricycle ring system each ring of which is C3-6
cycloalkyl;
7) R17 (R18R19C)m-W- wherein m = 1-3 and W is OCO or SO2 and R17, R18, and R19 are as defined above. except R17, R18, and R19 are not chlorine, fluorine or hydroxyl if they are adjacent to W;
8) R20-W-wherein R20 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
9) R21-W- wherein R21 is phenyl or naphthyl
unsubstituted or substituted with one or more subsituents R15;
10) R17-(R18R19C)m-P(0) (OR22)- wherein R22 is C1-4
alkyl or phenyl;
11) R20-p O) (OR22)-; or
12) R21-P(O) (OR22)-;
or pharmaceutically acceptable salt thereof.
PCT/US1992/006047 1991-07-17 1992-07-17 Retroviral protease inhibitors WO1993002057A1 (en)

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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
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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
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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
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CA2113644A1 (en) 1993-02-04
EP0602069A4 (en) 1995-05-03
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AP9200410A0 (en) 1992-07-31
MX9204233A (en) 1994-06-30

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