WO1993005026A1 - Peptide isoters containing a heterocycle as h.i.v. inhibitors - Google Patents

Peptide isoters containing a heterocycle as h.i.v. inhibitors Download PDF

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Publication number
WO1993005026A1
WO1993005026A1 PCT/US1992/007747 US9207747W WO9305026A1 WO 1993005026 A1 WO1993005026 A1 WO 1993005026A1 US 9207747 W US9207747 W US 9207747W WO 9305026 A1 WO9305026 A1 WO 9305026A1
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Prior art keywords
hydroxy
phenylpentyl
benzyl
amino
alkyl
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PCT/US1992/007747
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French (fr)
Inventor
Geoffrey Bainbridge Dreyer
John Gerald Gleason
Thomas Downing Meek
Scott Kevin Thompson
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Smithkline Beecham Corporation
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Priority to JP5505523A priority Critical patent/JPH06510766A/en
Priority to EP92920181A priority patent/EP0603309A1/en
Publication of WO1993005026A1 publication Critical patent/WO1993005026A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the 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 complexes, and many others.
  • RSV Rous sarcoma virus
  • MMV murine leukemia virus
  • MMTV mouse mammary tumor virus
  • FeLV fel
  • transcriptase such as 3'-azido-3'-deoxythymidine and 2',3'- dideoxycytidine. These treatments have not proven effective to arrest or reverse the disease, they may have adverse side effects, and they may lose their efficacy over time.
  • Virally-encoded proteases function in many of these viruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins.
  • the proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has" been
  • retroviruses which lack a 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 Debouck et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987). Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.
  • This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating infection by the human
  • This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a
  • This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).
  • R 1 is A-(B) t ;
  • B is an amino acid, SCH(R 7 )CO or OCH(R 7 )CO;
  • E is O or S ;
  • R 2 and R 3 are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, Ar, Het, T-C 1-6 alkyl, T-C 2-6 alkenyl or
  • T-C 2-6 alkynyl optionally substituted by R 10 ;
  • T is Ar, Het or C 3-7 cycloalkyl
  • R 5 , R 6 and R 7 are independently H, C 1-6 alkyl
  • Q is OH or NH 2 ;
  • U' and U" are H or OH
  • V is N or C-Y'
  • W is NR 11 or S
  • Y and Y' are H, halogen, CF 3 , Ar, NO 2 , C 1-6 alkyl, CO-Z or (CR 8 R 9 ) n -R', or together Y and Y' form a five or six-membered alkyl, aryl or heterocyclic ring substituted at any stable position by R 8 or R 9 ;
  • Z is H, C 1-6 alkyl, OH, NR'R 5 , OR 5 or an amino acid with a blocked or unblocked carboxy terminus;
  • R 9 is independently H, C 1-4 alkyl, C 2-6 alkenyl, CO-Z,
  • R' is H, C 1-4 alkyl, Ar-C 1-4 alkyl;
  • R 10 is -X' - (CH 2 ) q NR 12 R 13 , X" [ ( (CH 2 ) r O) s ] R 14 ,
  • R 11 is H, C 1-4 alkyl, Ar-C 1-4 alkyl, or together with Y forms a five or six-membered cycloalkyl, aryl or heterocyclic ring substituted at any stable position by R 8 or R 9 ;
  • R 12 and R 13 are i) C 1-6 alkyl, optionally substituted by
  • heterocycle optionally substituted with C 1-4 alkyl, iii) aromatic heterocycle, optionally substituted with
  • R" is H or C 1-4 alkyl
  • R 15 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 16 is H, C 1-6 alkyl or together with.
  • R 15 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
  • R 17 is R 6 , R 6 CO or R 6 SO 2 ;
  • X' is CH 2 , O, S or NH
  • X" is CH 2 , NR', O, S, SO or SO 2 ;
  • n 2-5;
  • n 1 to 6;
  • s is 1-6 and r is 1-3 within each repeating unit s; and t is 0 or 1; or
  • W is S.
  • W is N and V is C-Y.
  • R 1 is R 6 CO, R 6 OCO or R 6 SO 2 , or Ala, Val or Thr substituted on the amino group by R 6 CO, R 6 OCO or R 6 SO 2 .
  • A is butyloxycarbonyl, carbobenzyloxy, pyridinylmethyloxycarbonyl.
  • R 2 is CH 2 -T.
  • R 3 is C 1-4 alkyl or CH 2 -T.
  • Z is H, NH 2 or Ph.
  • R 9 is H, C 1-4 alkyl or Ph.
  • R 2 and R 3 are benzyl.
  • U and U' are H and Q is OH.
  • Representative compounds of this invention are:
  • Preferred compounds are :
  • More preferred compounds are:
  • a substituted imidazole, 1,3,5-tritzole and 1,3-thiazole constitute suitable moieties for replacement of the amide moiety for the amino acid in the P1' position in a non- hydrolyzable mimetic of a peptide substrate for the HIV-1 protease enzyme.
  • the compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunodeficiency virus.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo .
  • C 1-4 alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • C 1-6 alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • C 2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 2-6 alkenyl includes
  • C 2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C 2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • a substituent on a C 1-6 alkyl, C 2-6 alkenyl orC 2-6 alkynyl, such as R 8 , R 9 or R 10 may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.
  • Halogen indicates a fluorine, chlorine, bromine and iodine atom.
  • M indicates a mono- or divalent alkaline or earth metal ion, such as potassium, sodium, lithium, calcium or
  • T-C 1-6 alkyl refers to a C 1-6 alkyl group wherein in any position a carbon-hydrogen bond is replaced by a carbon-T bond.
  • T-C 2-6 alkenyl and T-C 2-6 alkynyl have a similar meaning with respect to C 2-6 alkenyl and C 2-6 alkynyl.
  • C 3-7 cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
  • Typical of C 3-7 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
  • C 3-11 cycloalkyl indicates a stable mono- or bi-cyclic ring of 3 to 11 carbon atoms, which may be saturated or unsaturated, and may be substituted with one to three
  • C 3-11 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, tetralinyl, indanyl, phenyl and naphthyl.
  • Azacycloalkyl indicates a C 3-7 cycloalkyl group wherein a carbon atom is replaced by a nitrogen atom, such as aziridine, azetidine, pyrrolidine, piperidine or
  • Azabicyclo-C 7-11 cycloalkyl indicates a C 7-11 cycloalkyl group wherein one of the carbon atoms is replaced by a nitrogen atom.
  • Ar or aryl, as applied herein, means phenyl or
  • naphthyl or phenyl or naphthyl substituted by one to three C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio, trifluoroalkyl, guanidino, amidino, HetC 1-4 alkoxy, HetC 1-4 alkyl, OH, Cl, Br or I.
  • Het, or heteroaryl indicates a five or six membered aromatic ring, or a nine or ten-membered aromatic ring, containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
  • heterocycles are morpholine, tetrazole, imidazole,
  • Het ring may optionally be substituted on the carbon or heteroatom by one to three C 1-4 alkyl, C 1-4 alkenyl, hydroxyC 1-4 alkyl group, carboxyl, aminocarbonyl,
  • alkoxycarbonyl carboxyC 1-6 alkyl, aminocarbonylC 1-6 alkyl, alkoxycarbonylC 1-6 alkyl, or a phenylC 1-6 alkyl group
  • Ar-C 1-6 alkyl and Ar-C 2-6 alkenyl mean C 1-6 alkyl or C 2-6 alkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Ar bond.
  • Het-C 1-6 alkyl and Het-C 2-6 alkenyl mean
  • Boc refers to the t-butyloxycarbonyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • Bzl refers to the benzyl radical
  • Ac refers to acetyl
  • Ph refers to phenyl
  • tbs refers to t-butyldimethylsilyl
  • EDTA is ethylenediamine tetraacetic acid
  • BOP refers to benzotriazol-1-yloxy- tris (dimethylamino)phosphonium hexafluorophosphate
  • DIEA diisopropyl ethylamine
  • DBU is 1,8 diazobicyclo[5.4.0]undec- 7-ene
  • DMSO dimethylsulfoxide
  • DMF is -dimethyl formamide
  • MeOH is methanol
  • pyr is pyridine
  • DMAP 4-dimethylamino pyridine
  • Lawesson's reagent
  • 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).
  • Y or R 9 are CO-Z and Z is an amino acid
  • the amino acid is joined by an amide bond via its amino terminus to the carbonyl group, and the carboxy terminus of the amino acid is blocked or unblocked.
  • An unblocked carboxy terminus is a free carboxyl group.
  • Typical blocking groups are esters and amides, such as NR'R 5 or OR 5 , wherein R 5 is as defined in formula (I).
  • t is 1 and B is an amino acid
  • the amino acid is joined via its carboxy terminus to the amino group of the isostere, and the amino terminus is substituted by A.
  • R 8 is NR'R 18 and R 18 is an amino acid
  • the amino acid is joined to the nitrogen atom via its carbonyl group, and the amino terminus of the amino acid may be blocked or unblocked.
  • Valine, threonine and alanine are useful amino acids.
  • Cbz Val, and 2-quinolinylcarbonyl-Val are illustrative blocked amino acids.
  • An unblocked amino terminus is an unsubstituted amino group.
  • Typical blocking groups for the amino terminus are R 6 , R 6 CO, R 6 OCO, R 6 OCH(R 7 )CO, R 6 NHCH(R 7 ) CO, R 6 SCH(R 7 )CO, R 6 SO 2 or R 6 SO, wherein R 6 and R 7 are as defined in formula (I).
  • Acetyl, Boc, Cbz, pyridinylmethyloxycarbonyl and 3- quinolinylmethyloxycarbonyl are illustrative of the A
  • R 1 , R 2 , R 3 , R 11 , R', Q, U', U", V, W and Y are as defined for formula (I), may be prepared by deprotecting a compound of the formula:
  • Q* is a protected amino or hydroxyl group
  • U* are independently H or a protected hydroxyl group.
  • Suitable protecting groups for the amino and hydroxyl group, and reagents for deprotecting these functional groups are
  • acetyl 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 hydrolyis.
  • a fluoride reagent such as a tetra-alkyl ammonium fluoride
  • R 1 is an amino-protecting group or R 1 , with a compound of the formula R-CH(X)-CHO, wherein X is a suitable displaceable group and R is Y or a group which may be converted by common synthetic methods into Y.
  • Suitable displaceable groups are those which are displaced by a sulfur nucleophile, such as chloride, bromide, iodide, mesylate, p-tolunesufonate, and the like. Introduction of substituents at the 4 position of the thiazole may be accomplished by conducting the reaction with a ketone of the formula X-CH 2 -C(O)R.
  • Oxazoles wherein W is 0 and V is CY', are prepared in an analogous manner, by reacting the corresponding
  • 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. If the protecting group is not the desired group R 1 , the protecting group may be
  • amino group may be alkylated or acylated to append the desired group as described hereinafter.
  • thioamide (IV) is dissolved in chloroform, or another suitable halocarbon or hydrocarbon solvent, and refluxed with five to ten equivalents of a suitably substituted ⁇ -halo-aldehyde for from 12 to 24 hours.
  • the product is generally purified by chromatography.
  • R 1 is a protecting group (eg. , Boc, Cbz, Ac), but is not the desired substituent R 1 , the protecting group may be removed and the desired
  • Typical halomethyl carbonyl reagents are 2-bromo- acetophenone, chloroacetaldehyde, iodoacetamide, 2-oxo-1- bromo-butane, methyl 3-bromopyruvate and the like.
  • the CO-R" substituent of the thiazole may be converted by common methods of chemistry to the group CO-Z or CO-(CR 8 R 9 ) (n-1)-R'.
  • the R"CO substituent may be converted to the corresponding 5-(substituted) hydroxymethyl-thiazole, wherein Y is
  • ⁇ -halo aldehydes, R-CH(X)-CHO, and the halomethyl carbonyl compounds, R"CO-CH2-X, of this invention are commercially available or available by common synthetic methods .
  • the ⁇ -halo aldehydes may be prepared by reduction of the corresponding ⁇ -halo ester, for example, with diisobutyllithiumaluminum hydride .
  • the intermediate thioamide of formula (IV) is prepared according to Scheme 3 from a 5-amino-4-hydroxy-2,5- disubstituted-pentanoate ester, acid or corresponding ⁇ - lactone.
  • a compound of formula (III) wherein W is NH and V is N is a triazole and is prepared according to Scheme 4.
  • Carboximide (VIII), prepared as described in Scheme 3, is treated with dimethylformamide dimethyl acetal to yield the carboximidate (XIV).
  • the carboximidate (XIV) is subsequently treated with hydrazine which, in the presence of an acid, cyclizes to yield the triazine ring. Deprotection of the hydroxyl group yields the final triazine product.
  • Compounds of formula (III), wherein W is O and V is N are 1,3,4 oxadiazoles, and may be prepared by reacting the lactone of formula (VI) with hydrazine, acylating the resulting hydrazide with a compound (RCO) 2 to form a diacyl hydrazide, which is then cyclized via acid catalysis. If necessary, the group R is then converted to the desired substituent Y by conventional techniques.
  • thioamide (XI) is treated with an alkylating agent, such as methyl iodide, to yield a thioimide (XII), which is further reacted with ammonium acetate to yield the
  • Chloroacetaldehyde is a suitable reagent for producing the imidazole wherein Y is H. Deprotection of the hydroxyl group with mild base, and optionally deprotecting the imidazole yields a compound of this invention .
  • the acyl product of this method is amendable to
  • substituent Y may be modified by methods common in the art.
  • alcohols may be prepared by reduction of a carbonyl group, such as by reduction of an aldehyde or ketone with sodium borohydride.
  • an alcohol may be prepared by reduction of an ester, such as with LiAlH4, or reduction of an acid, such as with diborane.
  • a diol may be prepared by oxidation of a double bond in an alkylene substituent with osmium tetroxide.
  • a carbonyl group may be prepared from an alcohol by oxidation with manganese oxide, or by the Swern method (DMSO, TFAA and triethylamine).
  • DMSO manganese oxide
  • TFAA TFAA
  • triethylamine triethylamine
  • an aldehyde or ketone may be prepared by oxidation of the double bond in an alkylene group, for instance with osmium tetroxide and sodium periodate in an ether-water solution (the Lemieux-Johnson procedure).
  • a bromo or chloro group may be prepared from an alcohol by reaction with thionyl chloride or bromide.
  • alkyl or alkylene group or a substituted alkyl or alkylene group, wherein any reactive functional groups are protected may be prepared by a nucleophilic addition
  • reaction such as by addition of a Grignard reagent (or other suitable organometallic reagent) to a carbonyl compound.
  • a Grignard reagent or other suitable organometallic reagent
  • This also constitutes a method for preparing an alcohol.
  • An ester may be prepared from an aldehyde by treatment with an alkali metal cyanide, followed by oxidation, for instance with manganese dioxide, in the presence of an alcohol, such as methanol.
  • a carboxamide may be prepared from an ester by treatment with ammonia or an organic amine.
  • a carboxylic acid may be prepared by hydrolysis of an ester by acid or base, such as either HCl or sodium hydroxide in methanol, or by oxidation of an aldehyde by permanganate or dichromate.
  • An oxime may be prepared from an aldehyde or ketone by treatment with hydroxylamine and a base, such as sodium carbonate, in an alcoholic solvent.
  • Amines may be prepared from a carbonyl compound by reductive amination with ammonium chloride or bromide and sodium cyanoborohydride.
  • an amine may be prepared by reduction of an oxime, either catalytically or with LiAlH 4 .
  • Scheme 7 is exemplary of such techniques.
  • a group other than the protecting group is desired for the substituent R 1 , then the protecting group is removed and the amino group is reacted with an appropriate alkylating or acylating reagent.
  • Alkyl halides, acyl halide, sulfonyl halides, anhydrides, activated esters, and the like, of the appropriate group R 1 are useful for this purpose.
  • carbamates may be prepared by reaction of the amino group with an appropriate chloro- or bromo-formate, such as R 6 OCO-Cl, 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.
  • Sulfonamides may be prepared by reaction of the amino group with a sulfonyl halide, such as R 6 SO 2 -Cl which may be prepared from the corresponding sulfonic acid.
  • a sulfonyl halide such as R 6 SO 2 -Cl which may be prepared from the corresponding sulfonic acid.
  • Ureas may be prepared by reaction of the amino group with an isocyanate, such as R 6 NCO.
  • the isocyanate may be prepared from reaction of the corresponding amine, R 6 NH 2 , with phosgene.
  • a thiourea may be prepared by reaction of the amino group with a thiocyanate, such as R 6 NCS.
  • the isothiocyanate may be prepared by reaction of the corresponding amine, R 6 NH 2 , with thiophosgene.
  • Thiocarbamates may be prepared by reaction of the amino group with phosgene followed by a thiol, such as R 6 -SH.
  • Guanidines may be prepared by reaction of the amino group with O-methylisourea hydrogen sulfate, or S-methyl- pseudothiourea hydrogen sulfate, in the presence of a base, which may optionally be subsequently alkylated or acylated.
  • a base which may optionally be subsequently alkylated or acylated.
  • the amino group may be reacted with a cyanamide reagent, such as R 6 NCN, which may in turn be prepared from the corresponding amine, R 6 NH 2 , and cyanogen bromide.
  • Acyl groups may be added by reaction of the amino group with an acyl halide, such as R 6 CO-Cl, or an activated
  • Compounds wherein Q is amino are prepared from the corresponding 4-hydroxy intermediate by methods common in the art for converting a hydroxyl group into an amino group, such as by oxidation of the hydroxyl and subsequent reductive animation.
  • the alcohol may be oxidized via the Swern method, with DMSO, trifluoroacetic anhydride and triethylamine in methylene chloride solution, and the corresponding ketone reduced with sodium cyanoborohydride and ammonium bromide in an alcohol/water solution.
  • R 1 , R 2 , R 3 and R 11 are as defined for formula (I);
  • R 20 is H or C 1-6 alkyl
  • Q* is a protected amino group or a protected hydroxyl group; are useful in the preparation of the protease- inhibiting compounds of this invention.
  • R 2 and R 3 are benzyl or C 1-6 alkyl.
  • R 1 is R'O(CO) or R'CO.
  • R 1 is t-butyloxy,
  • R 11 is H.
  • Q' is R'CO-NH, R'CO-O or (R') 3 Si-O.
  • Q' is acetyl.
  • an acid addition salt may be prepared.
  • Acid addition salts of the 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 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.
  • compounds of formula (I) When compounds of formula (I) are administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded. Accordingly, the compounds of formula (I) are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment.
  • the method of treatment comprises the administration orally, parenterally, buccally, trans- dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably
  • Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of
  • dosage units may be administered one to ten times daily for acute or chronic infection.
  • the compounds of this invention are particularly useful for the treatment of HIV-1. No unacceptable toxicological effects are expected when
  • compositions of the compounds of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral
  • 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 polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral
  • compositions may be added to enhance or stabilize the
  • Liquid carriers include syrup, peanut oil, olive oil,
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • 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.
  • the preparation 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 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.
  • Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention.
  • anti-viral agents examples 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 one preferred agent.
  • pharmaceutical compositions comprise an anti-viral agent, a protease
  • 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.
  • the Ki for the compounds of this invention are in the range of about 0.001 ⁇ M to about 50 ⁇ M.
  • Preferred compounds have Ki of less than 0.5 ⁇ M. More preferred compounds have Ki of less than 0.0b ⁇ M. The most preferred compounds have Ki of less than 0.01 ⁇ M.
  • Microsorb® SiO 2 refers to a silica gel
  • NMR electrospray ionization mass spectrometry.
  • ⁇ -halo-aldehydes used were generally prepared via reduction of the commercially available corresponding esters with one equivalent of diisobutyl aluminum hydride in
  • Example 1(c) The compound of Example 1(c) (60.5 mg, 0.13 mmol) was dissolved in CHCI 3 (10 ml) and to this was added freshly prepared 2-bromohexanal (115.0 mg, 0.65 mmol, 5.0eq.). The mixture was refluxed with stirring under Ar for 22.0 h. TLC (silica gel, 1:1 hexane:EtOAc) indicated no remaining
  • Example 1(d) The diasteromers of Example 1(d) (28.6 mg, 0.052 mmol) were dissolved in methanol (3.0 ml) and 3 drops of 2.5 N NaOH were added. The mixture was stirred for 2.0 h at room temperature. The reaction was concentrated in vacuo and the residue was chromatographed (silica gel, 2:1 hexane:EtOAc). The title isomeric alcohols were isolated as a white solid (18.0 mg, 68%).
  • 1 H NMR(CDCl 3 ) ⁇ 0.9-1.0 (t, 3H), 1.35 + 1.4 (2s, 9H), 1.55-1.75 (m, 4H), 1.8-2.15 (m, 2H), 2.7-3.2 (m,
  • Example 2 Using the procedure of Example 1, except substituting 2-bromobutanal for 2-bromohexanal in Example 1 (d) , the title compound was prepared .
  • 1 H NMR (CDCl 3 ) ⁇ 1 .25 (t, 3H) , 1 .35 +1.4 (2s, 9H), 1.75-1.95 (m, 2H) , 1.95-2.15 (m, 1H), 2.6-3.2 (m, 6H), 3.55-3.85 (m, 3H), 4.8-5.0 (br s, 1H), 6.95 + 7.05 (2m, 1H), 7.1-7.4 (m, 10H);
  • TLC R f 0.58, 0.53 (1:1
  • Example 2 Using the procedure of Example 1, except substituting 2-bromopentanal for 2-bromobutanal in Example 1 (d), the title compound was prepared.
  • 1 H NMR(CDCl 3 ) ⁇ 0.95 (2t, 3H), 1.4 + 1.45 (2s, 9H), 1.55-1.75 (m, 4H), 1.8-1.95 (m, 1H), 1.95-2.15 (m, 1H), 2.65-3.25 (m, 6H), 3.35-3.8 (m, 2H), 4.85-5.0 (br m, 1H), 6.95 + 7.05 (2m, 1H), 7.1-7.4 (m, 10H);
  • TLC R f 0.55, 0.50 (1:1 hexane:EtOAc); MS m/e 495 [M+H] + ; HPLC RT 3.9 min (46%), 5.6 min (54%) (Microsorb® Si ⁇ 2 , 4.6 x 250 mm column, 50.48.2 CH 2 CI 2 :hexane
  • Example 5 The compound of Example 5 (a) was dissolved in glacial acetic acid (0.5 mL) and hydrazine monohydrate (6.1 mg, 0.12 mmol, 5.9 ⁇ L) was added. The mixture was heated at 90°C for 1.5 h. The slightly pink solution was cooled, diluted with ethyl acetate, and 15% aqueous sodium hydroxide was added until the aqueous layer reached pH 11. The organic layer was dried (magnesium sulfate), filtered, and concentrated to afford a slightly yellow oil. The crude material was
  • (+)-valine (1.76 g, 2.02 mmol) in 2 N NaOH (15.75 mL, 31.5 mmol) at 10°C was added isopropyl chloroformate (16.5 mL of 1 M solution in toluene, 16.5 mmol). After stirring for 30 min, the pH was adjusted to pH 10, and the phases were separated. The aqueous phase was washed with Et 2 O. The pH was then adjusted to pH 2 by the addition of 3 N HCl, and the aqueous phase was extracted with Et 2 O (3x). The combined organic extracts were dried over
  • TFA salt (90.4 mg, 0.178 mmol) was diluted with DMF (10 mL), cooled to 0°C, and diisopropylamine (23 mg, 0.178 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • a suitable dosage form for intravenous administration is prepared by dissolving the compound of Example 1 (25 mg) in dimethyl sulfoxide or formamide (1 mL), diluting to 20 mL with a 70% propylene glycol/30% ethanol solution, and
  • This solution is also suitable for use in other methods of administration, such as addition to a bottle or bag for IV drip infusion.
  • a capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

Abstract

Novel compounds containing a heterocyclic isostere of formula (I) are disclosed, which inhibit the replication of the Human Immunodeficiency Virus.

Description

TITLE
PEPTIDE ISOTERS CONTAINING A HETEROCYCLE AS H.I.V. inhibitors
FIELD OF THE INVENTION
This invention relates to inhibitors of proteases encoded in retroviruses, in particular, to inhibitors of the virally encoded protease of the Human Immunodeficiency Virus. BACKGROUND
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.
Current treatments for viral diseases generally involve administration of compounds which inhibit reverse
transcriptase, such as 3'-azido-3'-deoxythymidine and 2',3'- dideoxycytidine. These treatments have not proven effective to arrest or reverse the disease, they may have adverse side effects, and they may lose their efficacy over time.
Accordingly, new treatments for viral disease are needed.
Virally-encoded proteases function in many of these viruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins. The proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has" been
demonstrated that retroviruses which lack a 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 Debouck et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987). Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease.
Methods to express retroviral proteases in E. coli have been disclosed by Debouck et al . , Proc. Natl . Acad. Sci . USA, 8903-06(1987) and Graves et al. , Proc. Natl. Acad. Sci. USA, 85, 2449-53(1988) for the HIV-1 virus. The crystal structure of an HIV-1 protease has been disclosed by Miller et al . , Science, 246, 1149 (1989).
The method of 'dipeptide' isosteric replacement has been disclosed as a strategy for the development of protease inhibitors for HIV-1. Published European Patent applications EP-A 337 714, EP-A 352 000 and EP-A 357 332, EP-A 346 847, EP-A 342 541 and EP-A 393 445 are representative. DeSolms et al., J. Med. Chem. , 34, 2852 (1991) disclose compounds which employ such isosteres. Similar strategies have also been reported for inhibition of renin in U.S. Patents 4,713,445 and 4, 661, 473. Other inhibitors of the HIV protease, which contain a symmetrical isostere are reported in EP-A 402 646. There remains a need for protease-inhibiting compounds which have a favorable balance of potency and pharmacokinetic properties.
SUMMARY OF THE INVENTION
This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating infection by the human
immunodeficiency virus and Acquired Immunodeficiency Syndrome (AIDS).
This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a
pharmaceutically acceptable carrier.
This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are given by formula (I):
Figure imgf000005_0001
wherein
R1 is A-(B)t;
A is R6, R6C(=E), R6OC(=E), R6NR'C(=E), R6SC(=E),
R17NR'C(=NR'), R6OCH(R7)CO, R6NHCH (R7) CO, R6SCH(R7)CO, R6SO2, or R6SO;
B is an amino acid, SCH(R7)CO or OCH(R7)CO; E is O or S ;
R2 and R3 are independently H, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, Ar, Het, T-C1-6alkyl, T-C2-6alkenyl or
T-C2-6alkynyl, optionally substituted by R10;
T is Ar, Het or C3-7cycloalkyl;
R5, R6 and R7 are independently H, C1-6alkyl,
C3-11cycloalkyl, Ar, Het, T-C1-6alkyl, T-(CH2)nCH(T)(CH2)n, optionally substituted by one or two halogen, SR1, OR1, NR'2, C(=NR')NR,R17, NR'C(=NR,)NR,R17, or C1-4alkyl;
Q is OH or NH2;
U' and U" are H or OH;
V is N or C-Y';
W is NR11 or S;
Y and Y' are H, halogen, CF3, Ar, NO2, C1-6alkyl, CO-Z or (CR8R9)n-R', or together Y and Y' form a five or six-membered alkyl, aryl or heterocyclic ring substituted at any stable position by R8 or R9;
Z is H, C1-6alkyl, OH, NR'R5, OR5 or an amino acid with a blocked or unblocked carboxy terminus;
R8 is independently H, OH, NR'R17, NR'C(=NR')NR'R17,
NR'-NR'2, C1-4alkyl, (CH2)pAr or (CH2)qHet;
R9 is independently H, C1-4alkyl, C2-6alkenyl, CO-Z,
(CH2) pAr or (CH2) qHet, or, taken together, R8 and R9 are =O,
=N-OR ' or =N-NR' 2;
R' is H, C1-4alkyl, Ar-C1-4alkyl;
R10 is -X' - (CH2) qNR12R13, X" [ ( (CH2) rO) s] R14,
CH2X" [((CH2)rO)s]R14, or benzofuryl, indolyl, azacycloalkyl, azabicycloC7_11cycloalkyl or benzopiperidinyl, optionally substituted with C1-4alkyl;
R11 is H, C1-4alkyl, Ar-C1-4alkyl, or together with Y forms a five or six-membered cycloalkyl, aryl or heterocyclic ring substituted at any stable position by R8 or R9;
R12 and R13 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;
R14 is H, C1-4alkyl, C(=O)R15, C (=O)U'" [(CH2)mO]nR', P (=O) (OM)2, CO2R15, C(=O)NR15R16, where M is a mono or divalent metal ion, and U'" is NR' or O;
R15 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';
R16 is H, C1-6alkyl or together with. R15 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
R17 is R6, R6CO or R6SO2;
X' is CH2, O, S or NH;
X" is CH2, NR', O, S, SO or SO2;
m is 2-5;
n is 1 to 6;
p and q are 0 to 2;
s is 1-6 and r is 1-3 within each repeating unit s; and t is 0 or 1; or
a pharmaceutically acceptable salts thereof.
Suitably W is S. Preferably W is N and V is C-Y.
Suitably R1 is R6CO, R6OCO or R6SO2, or Ala, Val or Thr substituted on the amino group by R6CO, R6OCO or R6SO2.
Suitably Y is H, C1-6alkyl, CO-(CHR8)(n-1)-R', CO-Z, (CHR9)n-OH, C (=NOH)-C1-6alkyl or CHOH(CHR8)(n-1)-R'.
Preferably A is butyloxycarbonyl, carbobenzyloxy, pyridinylmethyloxycarbonyl.
Suitably R2 is CH2-T.
Suitably R3 is C1-4alkyl or CH2-T.
Suitably Z is H, NH2 or Ph.
Suitably R9 is H, C1-4alkyl or Ph.
Preferably R2 and R3 are benzyl.
Preferably U and U' are H and Q is OH.
Representative compounds of this invention are:
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-butyl-thiazole; 2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-ethyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-1,3,5-triazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy~5- phenylpentyl]-4(5)-acetylimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(1-hydroxyethyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-formylimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-propionylimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methylpropionyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(1-hydroxy-2-methylpropyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(1-oxobutyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methyl-1-oxobutyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-carbomethoxyimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(N-methylaminocarbonyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-(1-oxo-3- phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole; 2- { (1R, 3S, 4S) -1-benzyl-3-hydroxy-4- [N- (3-methyl-l- oxobutyl)]amino-5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-L- valyl]amino-5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-D- valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-benzyloxycarbonyl)-
L-threonyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,3'S,4S)-1-benzyl-3-hydroxy-4-{l'-[5'-hydroxy-3'-(1- methylethyl)-2'-oxo-l'pyrrolidinyl]}-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,3'R,4S)-1-benzyl-3-hydroxy-4-{l'-[5'-hydroxy-3'-(1- methylethyl) -2' -oxo-l'pyrrolidinyl] }-5-phenylpentyl }-4 (5) - (2- methylpropionyl) imidazole;
2- [ (IR, 3S, 4S) -1-benzyl-4-benzenesulfonylamino-3-hydroxy-5- phenylpentyl] -4 (5 ) - (2-methylpropionyl) imidazole;
2- { (1R, 3S, 4S) -1-benzyl-3-hydroxy-4- [N- (N ' -methanesulfonyl) -L- valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-4-[N-(N'-tert-butoxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-[(1R,3S,4S) -1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethyl-3-butenoyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethylbutanoyl)-imidazole;
3-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-6,6-dimethyl-5-hydroxy-pyrrolo-[1,2-c]- imidazol-7-one;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpentyl]-4(5)-(cyclopentylcarbony1)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-
5-phenylpentyl]-4(5)-benzoylimidazlle; 2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpentyl]-4(5)-(2-ethylbutanoyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpentyl]-4(5)-(E)-1-(hydroxyimino)-2- methylpropyl)]imidazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-benzoyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(α-hydroxybenzyl)-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-aminocarbonyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-hydroxymethyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-formyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1-hydroxypropyl)-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyll-5-(3-hydroxypropyl)-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1,2-dihydroxyethyl)-thiazole;
2-[(3S,4S)-1-benzyl-4-(benzyloxycarbonyl-alanyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;
2-[(3S,4S)-1-benzyl-4-(benzyloxycarbonyl-valyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propionyl-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-carboxy-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(2-methyl-1-hydroxy-propyl)-thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(N'-benzyloxycarbonyl-guanidino)carbonyl- thiazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1-methoxycarbonyl)propyl-thiazole; 2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1-methoxy)propyl-thiazole; and
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-(1-aminocarbonyl)propyl-thiazole.
Preferred compounds are :
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-
5-phenylpentyl]-4(5)-(cyclopentylcarbonyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy-
5-phenylpentyl]-4(5)-(E)-1-(hydroxyimino).-2- methylpropyl)]imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethylbutanoyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethyl-3-butenoyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-D- valyl]amino-5-phenylpentyl}-4(5)-(2-methylpropionyl)- imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(3-methyl-1- oxobutyl)]amino-5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methylpropionyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(1-oxobutyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpenty1]-4(5)-propionylimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-acetylimidazole; and
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole.
More preferred compounds are:
2-[(3S,4S)-1-benzyl-4-(benzyloxycarbonyl-valyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-methanesulfonyl)-L- valyl]amino-5-phenylpentyl}-4(5)-(2-methylpropionyl)- imidazole; 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-ethylbutanoyl)-imidazole; and
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methyl-1-oxobutyl)imidazole.
The most preferred compounds are:
2-[(1R,3S,4S)-1-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-(1-oxo-3- phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-L- valyl]amino—5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole; and
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-benzyloxycarbonyl)- L-threonyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole.
According to this invention, it has been found that a substituted imidazole, 1,3,5-tritzole and 1,3-thiazole constitute suitable moieties for replacement of the amide moiety for the amino acid in the P1' position in a non- hydrolyzable mimetic of a peptide substrate for the HIV-1 protease enzyme. The compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunodeficiency virus.
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 .
The definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Formula (I) is intended to encompass all unique nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule.
C1-4alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C1-6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6alkenyl includes
ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
C2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
A substituent on a C1-6alkyl, C2-6alkenyl orC2-6 alkynyl, such as R8, R9 or R10, may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.
Halogen indicates a fluorine, chlorine, bromine and iodine atom.
M indicates a mono- or divalent alkaline or earth metal ion, such as potassium, sodium, lithium, calcium or
magnesium.
T-C1-6 alkyl refers to a C1-6 alkyl group wherein in any position a carbon-hydrogen bond is replaced by a carbon-T bond. T-C2-6 alkenyl and T-C2-6alkynyl have a similar meaning with respect to C2-6alkenyl and C2-6alkynyl.
C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention. C3-11cycloalkyl indicates a stable mono- or bi-cyclic ring of 3 to 11 carbon atoms, which may be saturated or unsaturated, and may be substituted with one to three
C1-4alkyl, C1-4alkoxy, C1-4alkthio, trifluoroalkyl, guanidino, amidino, OH, NR'2, Cl, Br or I groups. C3-11cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl, tetralinyl, indanyl, phenyl and naphthyl. Azacycloalkyl indicates a C3-7cycloalkyl group wherein a carbon atom is replaced by a nitrogen atom, such as aziridine, azetidine, pyrrolidine, piperidine or
tetrahydroazepine. Azabicyclo-C7-11cycloalkyl indicates a C7-11cycloalkyl group wherein one of the carbon atoms is replaced by a nitrogen atom.
Ar, or aryl, as applied herein, means phenyl or
naphthyl, or phenyl or naphthyl substituted by one to three C1-4alkyl, C1-4alkoxy, C1-4alkthio, trifluoroalkyl, guanidino, amidino, HetC1-4alkoxy, HetC1-4alkyl, OH, Cl, Br or I.
Het, or heteroaryl, indicates a five or six membered aromatic ring, or a nine or ten-membered aromatic ring, containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative
heterocycles are morpholine, tetrazole, imidazole,
benzimidazole, pyrrole, pyrazinyl, pyrazolyl,
pyrazolidinyl,pyrazolinyl, indole, pyridine, pyrimidine, pyrimidone, quinoline, benzofuran, furan, benzothiophene or thiophene. The Het ring may optionally be substituted on the carbon or heteroatom by one to three C1-4alkyl, C1-4alkenyl, hydroxyC1-4alkyl group, carboxyl, aminocarbonyl,
alkoxycarbonyl, carboxyC1-6alkyl, aminocarbonylC1-6alkyl, alkoxycarbonylC1-6alkyl, or a phenylC1-6alkyl group
substituted by one to three C1-4alkyl, C1-4alkoxy, C1-4alkthio, trifluoroalkyl, OH, Cl, Br or I groups.
Any accessible combination of up to three substituents on the phenyl, naphthyl or Het ring which is available by chemical synthesis and is stable is within the scope of this invention. Ar-C1-6alkyl and Ar-C2-6alkenyl mean C1-6alkyl or C2-6alkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Ar bond. Het-C1-6alkyl and Het-C2-6alkenyl mean
C1-6alkyl or C2-6alkenyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond.
Boc refers to the t-butyloxycarbonyl radical, Cbz refers to the benzyloxycarbonyl radical, Bzl refers to the benzyl radical, Ac refers to acetyl, Ph refers to phenyl, tbs refers to t-butyldimethylsilyl, EDTA is ethylenediamine tetraacetic acid, BOP refers to benzotriazol-1-yloxy- tris (dimethylamino)phosphonium hexafluorophosphate, DIEA is diisopropyl ethylamine, DBU is 1,8 diazobicyclo[5.4.0]undec- 7-ene, DMSO is dimethylsulfoxide, DMF is -dimethyl formamide, MeOH is methanol, pyr is pyridine, DMAP is 4-dimethylamino pyridine, Lawesson's reagent is 2,4-bis (4-methoxyphenyl)-1,3- dithia-2,4-diphosphetane-2,4-disulfide and THF is
tetrahydrofuran.
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 or valine. Typically, lipophilic amino acids are preferred. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
When Y or R9 are CO-Z and Z is an amino acid, the amino acid is joined by an amide bond via its amino terminus to the carbonyl group, and the carboxy terminus of the amino acid is blocked or unblocked. An unblocked carboxy terminus is a free carboxyl group. Typical blocking groups are esters and amides, such as NR'R5 or OR5, wherein R5 is as defined in formula (I).
When t is 1 and B is an amino acid, the amino acid is joined via its carboxy terminus to the amino group of the isostere, and the amino terminus is substituted by A. When R8 is NR'R18 and R18 is an amino acid, the amino acid is joined to the nitrogen atom via its carbonyl group, and the amino terminus of the amino acid may be blocked or unblocked. Valine, threonine and alanine are useful amino acids. Cbz Val, and 2-quinolinylcarbonyl-Val are illustrative blocked amino acids. An unblocked amino terminus is an unsubstituted amino group. Typical blocking groups for the amino terminus are R6, R6CO, R6OCO, R6OCH(R7)CO, R6NHCH(R7) CO, R6SCH(R7)CO, R6SO2 or R6SO, wherein R6 and R7 are as defined in formula (I). Acetyl, Boc, Cbz, pyridinylmethyloxycarbonyl and 3- quinolinylmethyloxycarbonyl are illustrative of the A
substituent and blocking groups for the amino terminus- The compounds of this invention are prepared by
conventional methods of organic chemistry.
The compounds of this invention of the formula (I):
Figure imgf000016_0001
wherein R1, R2, R3, R11, R', Q, U', U", V, W and Y are as defined for formula (I), may be prepared by deprotecting a compound of the formula:
Figure imgf000016_0002
wherein Q* is a protected amino or hydroxyl group, and U* are independently H or a protected hydroxyl group. Suitable protecting groups for the amino and hydroxyl 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 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 hydrolyis.
Compounds of formula (III), wherein W is S and V is CH are thiazoles and may be prepared according to Scheme 1 by reacting a thioamide of the formula (IV), wherein
Figure imgf000017_0001
R1 is an amino-protecting group or R1, with a compound of the formula R-CH(X)-CHO, wherein X is a suitable displaceable group and R is Y or a group which may be converted by common synthetic methods into Y. Suitable displaceable groups are those which are displaced by a sulfur nucleophile, such as chloride, bromide, iodide, mesylate, p-tolunesufonate, and the like. Introduction of substituents at the 4 position of the thiazole may be accomplished by conducting the reaction with a ketone of the formula X-CH2-C(O)R.
Oxazoles, wherein W is 0 and V is CY', are prepared in an analogous manner, by reacting the corresponding
carboxamide (eg., (VII)) with an a-halo ketone or aldehyde.
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. If the protecting group is not the desired group R1, the protecting group may be
removed, and the amino group may be alkylated or acylated to append the desired group as described hereinafter.
In a typical reaction, thioamide (IV) is dissolved in chloroform, or another suitable halocarbon or hydrocarbon solvent, and refluxed with five to ten equivalents of a suitably substituted α-halo-aldehyde for from 12 to 24 hours.
The product is generally purified by chromatography.
An alternate method for preparing compounds of formula (III), wherein W is S and Y is CO-Z, CO- (CR8R9) (n-1)-R', (CHR9) (n-1)CR9R'-OH' or CHOH-(CR8R9) (n-1)-R' is given by Scheme 2. Accordingly, the thioamide (IV) is reacted with
Figure imgf000018_0001
N,N-dimethylformamide dimethyl acetal to yield the
thioamidino intermediate (V). This intermediate is
subsequently reacted with a suitably substitued halomethyl carbonyl reagent of the formula, R"CO-CH2-X, to yield the corresponding 5-acyl thiazole. If R1 is a protecting group (eg. , Boc, Cbz, Ac), but is not the desired substituent R1, the protecting group may be removed and the desired
substituent R1 may be appended by common methods of
acylation, sulfonylation or alkylation as described
hereinafter.
Typical halomethyl carbonyl reagents are 2-bromo- acetophenone, chloroacetaldehyde, iodoacetamide, 2-oxo-1- bromo-butane, methyl 3-bromopyruvate and the like. The CO-R" substituent of the thiazole may be converted by common methods of chemistry to the group CO-Z or CO-(CR8R9) (n-1)-R'. The R"CO substituent may be converted to the corresponding 5-(substituted) hydroxymethyl-thiazole, wherein Y is
CHOH-(CR8R9) (n-1)-R', by reduction. The α-halo aldehydes, R-CH(X)-CHO, and the halomethyl carbonyl compounds, R"CO-CH2-X, of this invention are commercially available or available by common synthetic methods . For instance the α-halo aldehydes may be prepared by reduction of the corresponding α-halo ester, for example, with diisobutyllithiumaluminum hydride .
The intermediate thioamide of formula (IV) is prepared according to Scheme 3 from a 5-amino-4-hydroxy-2,5- disubstituted-pentanoate ester, acid or corresponding γ- lactone.
Figure imgf000019_0001
A compound of formula (III) wherein W is NH and V is N is a triazole and is prepared according to Scheme 4.
Carboximide (VIII), prepared as described in Scheme 3, is treated with dimethylformamide dimethyl acetal to yield the carboximidate (XIV). The carboximidate (XIV) is subsequently treated with hydrazine which, in the presence of an acid, cyclizes to yield the triazine ring. Deprotection of the hydroxyl group yields the final triazine product.
Figure imgf000020_0001
Compounds of formula (III), wherein W is O and V is N are 1,3,4 oxadiazoles, and may be prepared by reacting the lactone of formula (VI) with hydrazine, acylating the resulting hydrazide with a compound (RCO)2 to form a diacyl hydrazide, which is then cyclized via acid catalysis. If necessary, the group R is then converted to the desired substituent Y by conventional techniques.
Compounds of formula (III), wherein W is N-R' and V is CH are imidazoles and are prepared according to Scheme 5. Preparation of the substituted thioamide (XI) proceeds in a fashion analogous to thioamide (IV) of Scheme 3, where R11 is a protecting group or an incipient imidazole substituent.
The thioamide (XI) is treated with an alkylating agent, such as methyl iodide, to yield a thioimide (XII), which is further reacted with ammonium acetate to yield the
substituted amidine (XIII). Reaction of the amidine with a compound of the formula R-CH(X)-CHO, wherein X is a suitable displaceable group and R is Y or a group which may be converted by common synthetic methods into Y, causes
cyclization to yield the imidazole ring. Chloroacetaldehyde is a suitable reagent for producing the imidazole wherein Y is H. Deprotection of the hydroxyl group with mild base, and optionally deprotecting the imidazole yields a compound of this invention .
Figure imgf000021_0001
An alternate method for preparing an imidazole is given by Scheme 6.
Figure imgf000021_0002
The acyl product of this method is amendable to
modification by routine chemical techniques, such as
oxidation, reduction, nucleophilic addition, such as by a Grignard or other organometallic reagent, alkylation, acylation and sulfonylation. Generally, the substituent Y may be modified by methods common in the art. For instance, alcohols may be prepared by reduction of a carbonyl group, such as by reduction of an aldehyde or ketone with sodium borohydride. Alternately, an alcohol may be prepared by reduction of an ester, such as with LiAlH4, or reduction of an acid, such as with diborane. A diol may be prepared by oxidation of a double bond in an alkylene substituent with osmium tetroxide.
A carbonyl group may be prepared from an alcohol by oxidation with manganese oxide, or by the Swern method (DMSO, TFAA and triethylamine). Alternatively, an aldehyde or ketone may be prepared by oxidation of the double bond in an alkylene group, for instance with osmium tetroxide and sodium periodate in an ether-water solution (the Lemieux-Johnson procedure).
A bromo or chloro group may be prepared from an alcohol by reaction with thionyl chloride or bromide.
An alkyl or alkylene group or a substituted alkyl or alkylene group, wherein any reactive functional groups are protected, may be prepared by a nucleophilic addition
reaction, such as by addition of a Grignard reagent (or other suitable organometallic reagent) to a carbonyl compound.
This also constitutes a method for preparing an alcohol.
An ester may be prepared from an aldehyde by treatment with an alkali metal cyanide, followed by oxidation, for instance with manganese dioxide, in the presence of an alcohol, such as methanol.
A carboxamide may be prepared from an ester by treatment with ammonia or an organic amine.
A carboxylic acid may be prepared by hydrolysis of an ester by acid or base, such as either HCl or sodium hydroxide in methanol, or by oxidation of an aldehyde by permanganate or dichromate. An oxime may be prepared from an aldehyde or ketone by treatment with hydroxylamine and a base, such as sodium carbonate, in an alcoholic solvent.
Amines may be prepared from a carbonyl compound by reductive amination with ammonium chloride or bromide and sodium cyanoborohydride. Alternatively, an amine may be prepared by reduction of an oxime, either catalytically or with LiAlH4.
Combinations and variations of these methods and other conventional reactions will be apparent to one routinely skilled in the art.
Scheme 7 is exemplary of such techniques.
Figure imgf000023_0001
If a group other than the protecting group is desired for the substituent R1, then the protecting group is removed and the amino group is reacted with an appropriate alkylating or acylating reagent. Alkyl halides, acyl halide, sulfonyl halides, anhydrides, activated esters, and the like, of the appropriate group R1 are useful for this purpose.
For instance, carbamates may be prepared by reaction of the amino group with an appropriate chloro- or bromo-formate, such as R6OCO-Cl, 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.
Sulfonamides may be prepared by reaction of the amino group with a sulfonyl halide, such as R6SO2-Cl which may be prepared from the corresponding sulfonic acid.
Ureas may be prepared by reaction of the amino group with an isocyanate, such as R6NCO. The isocyanate may be prepared from reaction of the corresponding amine, R6NH2, with phosgene.
A thiourea may be prepared by reaction of the amino group with a thiocyanate, such as R6NCS. The isothiocyanate may be prepared by reaction of the corresponding amine, R6NH2, with thiophosgene.
Thiocarbamates may be prepared by reaction of the amino group with phosgene followed by a thiol, such as R6-SH.
Guanidines may be prepared by reaction of the amino group with O-methylisourea hydrogen sulfate, or S-methyl- pseudothiourea hydrogen sulfate, in the presence of a base, which may optionally be subsequently alkylated or acylated. Alternately, the amino group may be reacted with a cyanamide reagent, such as R6NCN, which may in turn be prepared from the corresponding amine, R6NH2, and cyanogen bromide.
Acyl groups may be added by reaction of the amino group with an acyl halide, such as R6CO-Cl, or an activated
anhydride, or with the corresponding acid in the presence of a coupling agent. Scheme 8 is exemplary of such techniques.
Figure imgf000025_0001
Methods for preparing protected 5-amino-4-hydroxy-2,5- disubstituted-pentanoate esters and acids, and the
corresponding γ-lactones and amides (VI), (VII) and (VIII), 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) and Szelke et al . , WO 84/03044, all of which are incorporated herein by reference.
Compounds wherein Q is amino are prepared from the corresponding 4-hydroxy intermediate by methods common in the art for converting a hydroxyl group into an amino group, such as by oxidation of the hydroxyl and subsequent reductive animation. For example, the alcohol may be oxidized via the Swern method, with DMSO, trifluoroacetic anhydride and triethylamine in methylene chloride solution, and the corresponding ketone reduced with sodium cyanoborohydride and ammonium bromide in an alcohol/water solution.
The compounds of formula (I), wherein U' or U" are OH, are also prepared by methods common in the art, such as those disclosed in U.S. Patent 4,864,017, Thaisrivongs et al . , J. Med. Chem. , 30, 976 (1987), Dellaria et al . , WO 87/04349, and Dellaria et. al . , J. Med. Chem. , 30, 1978, (1987).
As is clear from the foregoing description, intermediate compounds of the formula (XVII) and (XVIII):
Figure imgf000026_0001
wherein
R1, R2, R3 and R11 are as defined for formula (I);
R20 is H or C1-6alkyl;
Q* is a protected amino group or a protected hydroxyl group; are useful in the preparation of the protease- inhibiting compounds of this invention.
Suitably R2 and R3 are benzyl or C1-6alkyl. Suitably R1 is R'O(CO) or R'CO. Preferably R1 is t-butyloxy,
benzyloxycarbonyl or acetyl. Suitably R11 is H. Suitably Q' is R'CO-NH, R'CO-O or (R')3Si-O. Preferably Q' is acetyl.
If a final compound (I) of this invention contains a basic group, an acid addition salt may be prepared. Acid addition salts of the 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.
When compounds of formula (I) are administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded. Accordingly, the compounds of formula (I) are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment. The method of treatment comprises the administration orally, parenterally, buccally, trans- dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably
dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of
administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection. The compounds of this invention are particularly useful for the treatment of HIV-1. No unacceptable toxicological effects are expected when
compounds of the invention are administered in accordance with the present invention.
Pharmaceutical compositions of the compounds of this 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 polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternately, these compounds may be encapsulated, tableted or prepared in an 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, peanut oil, olive oil,
glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. 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.
For intra-vaginal or 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. These and other pharmaceutically acceptable formulations are found in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, Pennsylvania (1990).
Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this 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 one preferred agent. Suitably pharmaceutical compositions comprise an anti-viral agent, a protease
inhibiting compound of this invention and a pharmaceutically acceptable carrier.
The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. 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. The Ki for the compounds of this invention are in the range of about 0.001 μM to about 50 μM. Preferred compounds have Ki of less than 0.5 μM. More preferred compounds have Ki of less than 0.0b μM. The most preferred compounds have Ki of less than 0.01 μM.
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 Examples which follow serve to further illustrate this invention. The Examples are intended to in no way 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. Microsorb® SiO2 refers to a silica gel
chromatographic support manufactured by Rainin Instruments Co., Woburn, Mass. FAB indicates fast atom bombardment mass spectrometry. FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment. ESMS
indicates electrospray ionization mass spectrometry. NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer. 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.
Preparation of α-halo-aldehydes.
The α-halo-aldehydes used were generally prepared via reduction of the commercially available corresponding esters with one equivalent of diisobutyl aluminum hydride in
tetrahydrofuran solution at -78°C. Choloracetaldehyde was obtained commercially and purified by distillation. Example 1
Preparation of 2- [ (1R, 3S , 4S) -1-benzyl -4-t- butpχycarbonyIamino-3-hydroxy-5-phenylpentyl] -5-bu t yl- thiaz ole a) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-hydroxy-2- phenylmethyl-(1-oxo)hexyl-amide
5-[1-(t-Boc-amino)-2-phenylethyl]-3-(phenylmethyl)- dihydrofuran-2 (3H)-one, 1, was prepared according to the method disclosed by Evans, et al . , J. Org. Chem., 50, 4615 (1985).
A solution of benzyl lactone 1 (0.26 g, 0.67 mmol) in methanol (4 mL) was cooled to 0°C. A steady stream of ammonia was bubbled directly into the solution until
saturation was reached. The reaction flask was sealed with a rubber septum and allowed to warm to room temperature overnight. The flask was vented with a syringe needle and concentrated in vacuo to give the title compound as a white solid (0.27 g, 99%). 1H NMR(CDCl3) δ1.35 (s, 9H), 1.75 (m, 1H), 2.6-3.3 (m, 6H), 3.55-3.8 (m, 3H), 4.75-4.85 (d, 1H), 5.2-5.4 (br s, 1H), 5.6-5.75 (br s, 1H), 7.05-7.35 (m, 10H); IR (film): 3400 (br), 2900-3080, 1650 (s), 1525 (m), 1170 (m) cm-1; MS m/e 413 [M+H]+; TLC: Rf 0.56 (100% EtOAc) ; 13C
NMR(CDCl3) δ28.3, 37.4, 38.8, 40.2, 46.2, 57.7, 70.8, 80.0, 127.1, 127.2, 129.3-130.4, 140.3, 140.9, 158.2, 180.5. b) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-acetoxy-2- phenylmethyl-(1-oxo)hexyl-amide
To a solution of the compound of Example 1(a) (0.27 g, 0.66 mmol) in methylene chloride (10 mL) was added acetic anhydride (0.136 g, 1.33 mmol), triethylamine (0.135 g, 1.33 mmol), and 4-dimethylaminopyridine (0.008 g, 0.066 mmol). The mixture was stirred overnight at room temperature. The solution was quenched with methanol (2.0 mL) and stirred for 20 min. The reaction mixture was washed with 1.0 N HCl, water, dried over MgSO4, filtered and concentrated in vacuo to yield, as a white sticky solid, the title compound (0.26g, 86%). 1H NMR(CDCl3) δl.35 (s, 9H), 1.7-1.85 (m, 1H), 1.85-
2.05 (m, 1H), 2.1 (s, 3H), 2.4-2.55 (br m, 1H), 2.57-2.75 (m, 3H), 2.95-3.1 (m, 2H), 4.05-4.2 (m, 1H), 4.6-4.75 (d, 1H),
4.85-4.95 (br m, 1H), 5.05-5.15 (br, 1H), 7.05-7.35 (m, 10H); IR (film, cm-1): 3310 (br), 2910-3030, 1685 (s), 1500 (m), 1365 (m), 1235 (m), 1165 (m); MS m/e 477 [M+Na]+; TLC Rf 0.6 (2:1 EtOAc:hexane); 13C NMR(CDCl3) δ21.0, 28.3, 3.50, 38.0, 39.0, 44.5, 53.5, 73.5, 80.0, 127.0, 127.5, 128.4-129.1, 138.0, 140.0, 156.0, 171.0, 177.0. c) (5S,4S,2R) 6-phenyl-5-t-butoxycarbonylamino-4-acetoxy-2- phenylmethyl-(1-thiono)hexyl-amide
To a solution of the compound of Example 1(b) (0.25 g, 0.56 mmol) in benzene (10 mL) was added Lawesson's Reagent (0.113 g, 0.28 mmol). Warmed at 80°C for 1.0 h. Diluted with ether, washed with 5% NaHCO3, H2O, and saturated brine, dried over MgSO4, filtered and concentrated to a crude white solid. This material was chromatographed (silica gel, 40% EtOAc:hexane) to yield the title compound as a sticky white solid (0.142 g, 54%). 1H NMR(CDCl3) δl.35 (s, 9H) , 1.8-2.05 (m, 2H), 2.1 (s, 3H), 2.65-2.95 (m, 4H), 3.15-3.3 (m, 1H), 4.05-4.20 (br m, 1H), 4.65 (d, 1H), 4.8-4.95 (m, 1H), 7.1- 7.35 (m, 10H); IR (film) 3300 (br), 2910-3010, 1700 (s), 1260, 1130 cm-1; MS m/e 471 [M+H]+; TLC Rf 0.42 (1:1 hexane:EtOAc), single component; 13C NMR(CDCl3) δ22.5, 28.3, 37.0, 38.0, 42.0, 53.0, 57.5, 61.0, 127.0-129.0, 138.0, 167.0 d) 2- [(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-acetoxy-5- phenylpentyl]-5-butyl-thiazole
The compound of Example 1(c) (60.5 mg, 0.13 mmol) was dissolved in CHCI3 (10 ml) and to this was added freshly prepared 2-bromohexanal (115.0 mg, 0.65 mmol, 5.0eq.). The mixture was refluxed with stirring under Ar for 22.0 h. TLC (silica gel, 1:1 hexane:EtOAc) indicated no remaining
thioamide. The reaction was concentrated in vacuo and the brown oily reside was chromatographed (silica gel, 60% hexane:EtOAc). The 5-butyl-thiazole acetate diastereomers were isolated as a yellow oil (28.6 mg, 40%). 1H NMR(CDCl3) indicated two absorptions for Boc (δl.35 and 1.40) and for OAc (δ2.0 and 2.05) and a peak at δ7.0 corresponding to the 4-H thiazole; TLC Rf 0.6 (silica gel, 1:1 hexane:EtOAc). e) 2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-5-butyl-thiazole
The diasteromers of Example 1(d) (28.6 mg, 0.052 mmol) were dissolved in methanol (3.0 ml) and 3 drops of 2.5 N NaOH were added. The mixture was stirred for 2.0 h at room temperature. The reaction was concentrated in vacuo and the residue was chromatographed (silica gel, 2:1 hexane:EtOAc). The title isomeric alcohols were isolated as a white solid (18.0 mg, 68%). 1H NMR(CDCl3) δ0.9-1.0 (t, 3H), 1.35 + 1.4 (2s, 9H), 1.55-1.75 (m, 4H), 1.8-2.15 (m, 2H), 2.7-3.2 (m,
6H), 3.35-3.8 (m, 3H), 4.25 (br s, 1H), 4.95 (br m, 1H), 6.9 + 7,05 (2m, 1H), 7.1-7.4 (m, 10H); TLC Rf 0.56, 0.51 (1:1 hexane:ethyl acetate); MS m/e 509 [M+H]+; HPLC RT 4.24 min (46%), 5.95 min (54%) (Microsorb® Siθ2, 4.6 x 250 mm column, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min).
Example 2
Preparation of 2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3- hγdroxy-5-phenylpentyl]-thiazole
Using the procedure of Example 1, except substituting chloroacetaldehyde for 2-bromohexanal in Example 1(d), the title compound was prepared. 1H NMR(CDCl3) δl.35 + 1.4 (2s,
9H), 1.55-1.7 (m, 1H), 1.8-1.95 (m, 1H), 1.95-2.2, (m, 1H), 2.7-2.9 (m, 2H), 2.92-3.15 (m, 2H), 3.45-3.65 (m, 2H), 3.7- 3.85 (m, 1H), 4.85-4.95 (d, 1H), 6.95 + 7.05 (2m, 1H), 7.1- 7.35 (m, 10H), 7.65(d, 1H); TLC Rf 0.42, 0.36 (1:1
hexane:ethyl acetate); MS m/e 453 [M+H]+; HPLC RT. 6.52 min (44%), (10.5 min, 56%) (Microsorb® SiO2, 4.6 x 250 mm column, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min).
Example 3
Preparati on of 2- [ (3S , 4R ) -1 -benzyl -4-t-butoxycarbonyl amino-3- hydroxy-5-phenylpentyn -5-ethyl-thi azol e
Using the procedure of Example 1, except substituting 2-bromobutanal for 2-bromohexanal in Example 1 (d) , the title compound was prepared . 1H NMR (CDCl3) δ 1 .25 (t, 3H) , 1 .35 +1.4 (2s, 9H), 1.75-1.95 (m, 2H) , 1.95-2.15 (m, 1H), 2.6-3.2 (m, 6H), 3.55-3.85 (m, 3H), 4.8-5.0 (br s, 1H), 6.95 + 7.05 (2m, 1H), 7.1-7.4 (m, 10H); TLC Rf 0.58, 0.53 (1:1
hexane:ethyl acetate); MS m/e 481 [M+H] +; HPLC RT. 4.8 min (46%), 7.0 min (54%) (Microsorb® Siθ2, 4.6 x 250 mm column,
50:48:2 CH2CI2:hexane:isopropanol, 2.0 ml/min).
Example 4 Preparation of 2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3- hydrgxy-5-phenylpentyl]-5-propyl-thiazole
Using the procedure of Example 1, except substituting 2-bromopentanal for 2-bromobutanal in Example 1 (d), the title compound was prepared. 1H NMR(CDCl3) δ0.95 (2t, 3H), 1.4 + 1.45 (2s, 9H), 1.55-1.75 (m, 4H), 1.8-1.95 (m, 1H), 1.95-2.15 (m, 1H), 2.65-3.25 (m, 6H), 3.35-3.8 (m, 2H), 4.85-5.0 (br m, 1H), 6.95 + 7.05 (2m, 1H), 7.1-7.4 (m, 10H); TLC Rf 0.55, 0.50 (1:1 hexane:EtOAc); MS m/e 495 [M+H]+; HPLC RT 3.9 min (46%), 5.6 min (54%) (Microsorb® Siθ2, 4.6 x 250 mm column, 50.48.2 CH2CI2:hexane:isopropanol, 2.0 ml/min).
Example 5
Preparation of 2-[(3S,4S)-1-henzyl-4-t-hutoxycarhonylaιnino-3- hydroxy-5-phenylpentyl]-1,3,5-triazole a) N-2-[(5S,4S,2R)-6-phenyl-5-t-butoxycarbonylamino-4- acetoxy-2-phenylmethyl-(1-oxo)hexy1]-(N',N'-dimethyl)- formamidine
A solution of the compound of Example 1(b) (50 mg, 0.11 mmol) in dimethyl formamide dimethyl acetal (2 mL) was allowed to stir at 25°C for 2 h. The volatiles were removed in vacuo to leave a slightly yellow oil. The crude material was used without further purification. b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-acetoxy- 5-phenylpentyl]-1,3,5-triazole
The compound of Example 5 (a) was dissolved in glacial acetic acid (0.5 mL) and hydrazine monohydrate (6.1 mg, 0.12 mmol, 5.9 μL) was added. The mixture was heated at 90°C for 1.5 h. The slightly pink solution was cooled, diluted with ethyl acetate, and 15% aqueous sodium hydroxide was added until the aqueous layer reached pH 11. The organic layer was dried (magnesium sulfate), filtered, and concentrated to afford a slightly yellow oil. The crude material was
purified by choromatography (silica gel, .2:1 ethyl acetate) to provide the title compound as a colorless oil (38.2 mg, 73%). c) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-l,3,5-triazole
To a stirred solution of the compound of Example 5 (b) (28.9 mg, 60 μmol) in methanol (400 μL), 3N aqueous potassium hydroxide (400 μL) was added. After stirring 1 h, the solution was diluted with water (2 mL), saturated with solid sodium chloride and extracted with ethyl acetate (10 mL).
The extract was dried (magnesium sulfate), filtered, and the volatiles were removed in vacuo to yield the title compound as a white solid (23.6 mg, 90%). mp 187-188.5°C; 1H NMR(CDCl3, 250 MHz) δ 1.36 (s, 9 H), 1.84-2.05 (m, 2 H), 2.82 (d, 2 H,
J=7.5 Hz), 2.95 (dd, 1 H, J=6.8, 13.5 Hz), 3.09 (dd, 1 H, J-8.6, 13.5 Hz), 3.48 (m, 3H), 4.88 (d, 1 H, J=9.7 Hz), 6.97 (d, 2 H, J=7.5 Hz), 7.12-7.24 (m, 8 H), 7.91 (s, 1 H). Example 6
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-pheny]pentyl]-4(5)-acetylimidazole a) (2R,4S,5S)-2-benzyl-5-t-butoxycarbonylamino-4-t- butyldimethylsiloxy-N-(5-methylisoxazol-4-yl)-6- phenylhexanamide
To a mixture containing (2R,4S,5S)-2-benzyl-5-t- butoxycarbonylamino-4-t-butyldimethylsiloxy-6-phenylhexanoic acid (270 mg, 0.51 mmol), 1-hydroxybenzotriazole hydrate (13.8 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (107.9 mg, 0.56 mmol) in DMF was added 4-amino-5-methylisoxazole (55 mg, 0.56 mmol). The resulting yellow solution was allowed to stir at room temperature for 24 h, then was poured into H2O (25 mL) and extracted with EtOAc (25 mL). The organic extract was washed successively with 0.1 N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 1:4 EtOAc:hexanes) to afford the title compound (185.8 mg, 60%) as a white solid, m.p. 58- 60°C; NMR(CDCl3) δ 8.37 (s, 1H), 7.60 (s, 1H), 7.38-7.19 (m,
8H), 4.75 (d, 1H), 4.12-4.03 (m, 1H), 3.68 (dd, 1H), 3.08 (dd, 1H), 2.82-2.50 (m, 4H), 2.23 (s, 3H),. 1.87-1.69 (m, 2H), 1.25 (s, 9H), 0.95 (s, 9H), 0.12 (s, 3H), 0.10 (s, 1H). b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-acetylimidazole
A mixture containing the compound of Example 6(a) (185.8 mg, 0.31 mmol) and 10% palladium on activated carbon (93 mg) in EtOH (3 mL) was stirred under a hydrogen atmosphere for 5 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. To the residue in EtOH (2.7 mL) was added 1 M NaOH (0.4 mL in EtOH, 0.4 mmol). The resulting mixture was heated at reflux overnight, then was partitioned between EtOAc and aqueous NH4CI. The organic extract was washed with saturated aqueous NaCl and dried over MgSO4. The solvent was removed under reduced pressure, and the oily residue was purified by flash chromatography (silica gel, 1:2 EtOAc:hexanes) to afford the title compound (136.8 mg, 76%) as a yellow solid, m.p. 74- 76°C; NMR(CDCl3) δ (tautomers) 7.58 (s, 1H), 7.47 (d, 1H), 7.34-7.07 (m, 18H), 7.00 (d, 2H), 4.78 (d, 1H), 4.67 (d, 1H), 4.08 (m, 2H), 3.65-3.59 (m, 1H), 3.49-3.40 (m, 2H), 3.30-3.22 (m, 2H), 3.06 (m, 1H), 2.86-2.78 (m, 2H), 2.71-2.64 (m, 4H), 2.53 (s, 3H), 2.36 (s, 3H), 1.84-1.61 (m, 4H), 1.36 (s, 9H) , 1.35 (s, 9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H), 0.00 (s, 6H) . c) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4(5)-acetylimidazole
A solution containing the compound of Example 6(b) (61.6 mg, 0.10 mmol) in 1 M tetra-n-butylammonium fluoride (1.25 mL in THF, 1.25 mmol) was heated at 50°C for 5 h. The solution was then poured into EtOAc, washed successively with H2O (2x) and saturated aqueous NaCl and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 2:1
EtOAc :hexanes) to afford the title compound (41.7 mg, 84%) as a white solid. NMR(CDCl3) δ 7.60 (br s, 1H), 7.24-7.13 (m,
8H), 6.92 (m, 2H), 4.92 (m, 1H), 3.61 (d, 2H), 3.37 (m, 1H), 3.10-3.02 (m, 1H), 2.91-2.84 (m, 3H), 2.42 (s, 3H), 1.98-1.81 (m, 2H), 1.36 (s, 9H); MS(ES) m/e 478.2 [M+H]+; IR(CHCl3) 3430, 3220, 3000-2860, 1700, 1660, 1500 cm-1.
Example 7
Preparation of 2-[(1R,3S,4S,-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentγl]-4(5)-(1-hydroxyethyl)- imidazole To a solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)- acetylimidazole (20.8 mg, 0.044 mmol) in EtOH (0.5 mL) was added excess NaBH4. After stirring for 15 min, the reaction was quenched by the addition of aqueous NH4CI, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with EtOAc to afford the title compound (16.3 mg, 78%) as a white solid, m.p. 85-87°C;
NMR(CDCl3) δ (diastereomers) 7.31-7.17 (m, 16H), 6.90-6.88 (m,
4H), 6.66 (s, 2H), 5.01 (d, 2H), 4.84 (m, 2H), 3.62 (m, 4H), 3.24 (m, 2H), 3.01-2.86 (m, 8H), 1.97 (m, 2H), 1.75 (m, 2H), 1.51 (d, 3H), 1.48 (d, 3H), 1.36 (s, 18H); MS (ES) m/e 480.4 [M+H]+; Anal. Calcd for C28H37N3O4·1/2 H2O: C, 66.83; H, 7.84; N, 8.60. Found: C, 68.89; H, 7.61; N, 8.46.
Example 8
Preparation of 2-[(1R,3S,4S)-1-henzyl-4-t-bntoxycarbonyl- 3mino-3-hydroxy-5-phenylpentyl]-4(5)-formylimidazole a) (2R,4S,5S)-2-benzyl-5-t-butoxycarbonylamino-4-t- butyldimethylsiloxy-N-(isoxazol-4-yl)-6-phenylhexanamide
The title compound was prepared according to the
procedure in Example 6, step (a), except using 4- aminoisoxazole. m.p. 59-61°C; NMR(CDCl3) δ 8.91 (s, 1H), 8.34
(br s, 1H), 8.24 (s, 1H), 7.37-7.18 (m, 8H), 7.02 (d, 2H), 4.75 (d, 1H), 4.11-4.01 (m, 1H), 3.64 (dd, 1H), 3.16 (dd, 1H), 2.81-2.50 (m, 4H), 1.85-1.65 (m, 4H), 1.32 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole
The title compound was prepared according to the
procedure in Example 6, step (b), except using the compound of Example 8(a). m.p. 70-72°C; NMR(CDCl3) δ (tautomers) 10.71
(br s, 1H), 10.47 (br s, 1H), 9.86 (s, 1H), 9.56 (s, 1H), 7.66 (s, 1H), 7.51 (d, 1H), 7.36-6.99 (m, 20H), 4.77 (d, 1H), 4.70 (d, 1H), 4.14-4.04 (m, 2H), 3.60 (t, 1H), 3.49-3.41 (m, 1H), 3.35-3.08 (m, 2H), 2.90-2.62 (m, 6H), 1.83-1.75 (m, 4H) 1.36 (s, 9H), 1.35 (s, 9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.05- 0.02 (m, 12H). c) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4(5)-formylimidazole
The title compound was prepared according to the procedure in Example 6, step (c), except using the compound of Example 8(b). m.p. 90-92°C; NMR(CDCl3) δ (tautomers) 9.85
(s, 1H), 9.54 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.35-7.16 (m, 16H), 6.99-6.91 (m, 4H), 4.86-4.82 (m, 2H), 4.47 (m, 1H), 4.02 (m, 1H), 3.61 (m, 4H), 3.36 (m, 2H), 3.08 (dd, 2H), 2.92-2.83 (m, 4H), 1.89-1.81 (m, 4H), 1.37 (m, 18H); MS(ES) m/e 464.2 [M+H]+; Anal. Calcd for C27H33N3O4 ·1/2 H2O: C,
68.62; H, 7.25; N, 8.89. Found: C, 68.63; H, 7.15; N, 8.76.
Example 9 Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-bntoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5) - (2-methylpropionyl) - imidazole a) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-(l-hydroxy-2- methylpropyl)imidazole
To a solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4 (5)-formylimidazole (138.4 mg, 0.24 mmol) in 1 : 1 Et2O:THF (0.5 mL) was added 3 N isopropylmagnesium bromide (0.48 mL in THF, 1.44 mmol). After stirring for 15 min, the reaction was quenched by the addition of aqueous NH4CI, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 1:1 EtOAc :hexanes) to afford the title compound as a white solid. NMR(CDCl3) δ
(diastereomers) 7.28-6.58 (m, 11H), 4.80-4.54 (m, 1H), 4.29 (m, 1H), 4.02 (m, 1H), 3.64-3.55 (m, 2H), 3.25 (m, 1H), 3.02 (m, 1H), 2.72-2.54 (m, 3H), 1.77 (m, 2H), 1.35-1.23 (m, 9H), 1.00-0.81 (m, 15H), 0.10-0.00 (m, 6H). b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole
To a solution of the compound of Example 10(a) (77.6 mg, 0.12 mmol) in CH2CI2 (1 mL) was added MnO2 (775 mg), and the resulting suspension was allowed to stir at room temperature for 5 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography, (silica gel, 1:2 EtOAc:hexanes) to afford the title compound (70 mg, 90%) as a white foam. NMR(CDCl3). δ (tautomers) 7.60
(s, 1H), 7.48 (d, 1H), 7.34-6.98 (m, 20H), 4.77-4.66 (m, 2H), 4.10-4.03 (m, 2H), 3.64-3.59 (m, 3H), 3.23-3.04 (m, 5H), 2.87-2.60 (m, 6H), 1.84-1.75 (m, 4H), 1.36 (s, 9H), 1.33 (s, 9H), 1.24-1.14 (m, 12H), 0.91 (s, 18H), 0.05-0.00 (m, 12H). c) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4(5)-(2-methylpropionyl)imidazole
The title compound was prepared according to the
procedure in Example 6, step (c), except using the compound of Example 10(b). m.p. 76-78°C; NMR(CDCl3) δ 7.62 (s, 1H),
7.34-7.04 (m, 8H), 6.91-6.88 (m, 2H), 5.11-4.91 (m, 2H), 3.61-3.52 (m, 2H), 3.43-3.40 (m, 1H), 3.19 (septet, 1H), 3.10-3.02 (m, 1H), 3.07-2.83 (m, 3H), 1.98-1.94 (m, 1H), 1.81-1.75 (m, 1H), 1.35 (s, 9H), 1.21 (d, 3H), 1.19 (d, 3H); MS(ES) m/e 506.2 [M+H]+; Anal. Calcd for C30H39N3O4·1/2 H2O: C, 70.01; H, 7.83; N, 8.16. Found: C, 69.64; H, 7.77; N, 7.78. Example 10
Preparation of 2-[(1R,3S,4S,-1-benzyl-4-t-butoxycarbonyl- am ino-3-hydroxy-5-phenylpentγl]-4(5)-propionylimidazole The title compound was prepared according to the
procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and ethylmagnesium bromide in step (a). m.p. 80-82°C; NMR(CDCl3) δ 7.60 (s, 1H), 7.21-6.90 (m, 10H), 5.07-4.87 (m, 2H), 3.60-
3.40 (m, 3H), 2.83-2.76 (m, 5H), 1.97-1.75 (m, 2H), 1.35-1.19 (m, 12H); MS(ES) m/e 492.2 [M+H]+.
Example 11
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-(2-methylpropionyl) - imidazole, hydrochloride salt
To a solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole (36.9 mg, 73 μmol) in Et2O (2.5 mL) was added 1 M HCl (80 μL in Et2θ, 80 μmol). The mixture was concentrated under reduced pressure to afford the title compound (39.6 mg, 100%) as a white solid, m.p. 122-124°C; NMR(MeOH-d4) δ 8.20 (s, 1H), 7.14-7.09 (m, 8H), 6.95 (d, 2H),
3.62-3.49 (m, 2H), 3.20-3.11 (m, 2H), 3.03 (dd, 1H), 2.91 (dd, 1H), 2.69 (dd, 1H), 2.57 (dd, 1H), 1.97-1.82 (m, 2H),
1.23 (s, 9H), 1.09 (d, 6H) ; Anal. Calcd for C30H40CIN3O4·1/2 H2O: C, 65.38; H, 7.50; N, 7.62. Found: C, 65.43; H, 7.34; N, 7.75. Example 12
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-(1-hydroxy-2- methylpropyl)imidazole
The title compound was prepared according to the
procedure in Example 6, step (c), except using 2-[(1R,3S,4S)- 1-benzyl-4-t-butoxycarbonylamino-3-t-butyldimethylsiloxy-5- phenylpentyl]-4(5)-(l-hydroxy-2-methylpropyl)imidazole. m.p. 82-84°C; NMR(CDCl3) δ 7.26-7.15 (m, 8H), 6.90 (m, 2H), 6.63
(m, 1H), 5.04 (m, 1H), 4.34 (m, 1H), 3.61 (m, 2H), 3.27 (m, 1H), 2.85 (m, 4H), 1.96 (m, 2H), 1.75 (m, 2H), 1.35 (s, 9H), 0.99-0.80 (m, 6H) ; MS(ES) m/e 508.2 [M+H]+; Anal. Calcd for C30H41N3O4·H2O: C, 68.54; H, 8.24; N, 7.99. Found: C, 68.50; H, 7.90; N, 7.55.
Example 13
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl1-4(5)-(1-oxobutyl)imidazole
The title compound was prepared according to the procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylaraino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and 1-propylmagnesium bromide in step (a). m.p. 70-72°C;
NMR(CDCl3) δ 7.60 (s, 1H), 7.20-7.12 (m, 8H), 6.90 (s, 2H), 4.96 (m, 2H), 3.59-3.41 (m, 3H), 3.05-2.70 (m, 5H), 1.96-1.74 (m, 4H), 1.35 (s, 9H), 0.98 (m, 3H); MS (ES) m/e 506.2 [M+H]+; Anal. Calcd for C30H39N3O4·1/2. H2O: C, 70.01; H, 7.83; N, 8.16. Found: C, 69.68; H, 7.65; N, 8.05. Example 14
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentγl]-4(5)-(2-methyl-1- oxobiityl)imidazole
The title compound was prepared according to the
procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and 2-butylmagnesium bromide in step (a). m.p. 79-84°C;
NMR(CDCl3) δ 7.61 (s, 1H), 7.26-7.12 (m, 8H), 6.89 (m, 2H),
4.96 (m, 1H), 3.62-3.42 (m, 3H), 3.06-2.84 (m, 4H), 1.98-1.71 (m, 3H), 1.52-1.15 (m, 14H), 0.90 (t, 3H); MS(ES) m/e 520.2 [M+H]+; Anal. Calcd for C31H41N3O4·3/4 H2O: C, 69.83; H, 8.03; N, 7.88. Found: C, 70.02; H, 7.67; N, 7.97. Example 15
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-bntoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-carbomethoxyimidazole a) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)- carbomethoxyimidazole
To a solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4 (5)-formylimidazole (10 mg, 17 μmol) in MeOH (0.3 mL) was added potassium cyanide (5.6 mmol, 87 μmol) and MnO2 (30.1 mg, 0.35 mmol). The resulting mixture was allowed to stir at room temperature for 2 h, at which time additional MnO2 (70 mg, 0.80 mmol) and potassium cyanide (13 mg, 0.20 mmol) were added. After stirring at room temperature for 20 h, the mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The colorless oily residue was chromatographed (silica gel, 1:2 EtOAc: hexanes) to afford the title compound (10.1 mg, 96%) as a colorless oil. NMR(CDCl3) δ 7.55 (s, 1H), 7.34-7.04 (s, 10H), 4.73 (d, 1H), 4.05-3.98 (m, 1H), 3.86 (s, 3H), 3.41 (m, 2H), 3.16 (m, 1H), 2.86 (dd, 1H), 2.67-2.64 (m, 2H), 1.80 (m, 2H), 1.34 (s, 9H), 0.88 (s, 9H), 0.00 (s, 6H). b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4(5)-carbomethoxyimidazole
The title compound was prepared according to the procedure in Example 6, step (c), except using the compound of Example 15(a). m.p. 91-93°C; NMR(CDCl3) δ 7.52 (s, 1H),
7.26-7.16 (m, 8H), 6.96-6.93 (m, 2H), 4.89 (d, 1H), 3.85 (s, 3H), 3.56 (m, 2H), 3.35 (m, 1H), 3.15-3.06 (m, 1H), 2.92-2.83 (m, 3H), 1.85 (m, 2H), 1.36 (s, 9H); MS(ES) m/e 494.2 [M+H]+. Example 16
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-hutoxycarbonyl- amino-3-hydrnxy-5-phenylpentyl]-4(5)-(N-methylaminocarbonyl)- imidazole a) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-(N- methylaminocarbonyl)imidazole
Into a solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4(5)-carbomethoxyimidazole (10.2 mg, 17 μmol) in MeOH (1 mL) at 0°C was bubbled methylamine. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 6 d. The mixture was then concentrated under reduced pressure and used without further purification. NMR(CDCl3) δ
7.40 (s, 1H), 7.33-7.14 (m, 8H), 7.01 (d, 2H), 4.78 (d, 1H),
4.11-4.07 (m, 1H), 3.49-3.47 (m, 1H), 3.30 (dd, 1H), 3.03 (m, 1H), 2.97 (d, 3H), 2.88-2.50 (m, 3H), 2.20-1.97 (m, 1H), 1.86-1.70 (m, 2H), 1.35 (s, 9H), 0.90 (s, 9H), 0.00 (s, 6H). b) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy- 5-phenylpentyl]-4(5)-(N-methylaminocarbonyl)imidazole
The title compound was prepared according to the
procedure in Example 6, step (c), except using the compound of Example 16(a). m.p. 101-103°C; NMR(CDCl3) δ 7.26-6.93 (m,
11H), 4.90 (d, 1H), 3.65 (m, 1H), 3.52 (m, 1H), 3.29 (m, 1H), 3.15-3.06 (m, 1H), 2.99 (d, 3H), 2.89-2.81 (m, 3H), 1.80 (m, 2H), 1.36 (s, 9H); MS(ES) m/e 493.2 [M+H]+.
Example 17
Prepa rat i on of 2- [ ( 1 R , 3S , 4S) -1 -ben zyl-4- [ N- (benzyloxycarbonyl ) -L -valyl ] ami no-3-hydroxy-5-phenyl pentyl ] - 4 (5) - (2-meth ylpropion yl) imidazole a) 2-[(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]- 4(5)-(2-methylpropionyl) imidazole
A solution containing 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl) imidazole (200.4 mg, 0.40 mmol) in TFA (1 mL) was stirred at room temperature for 5 min, then was
concentrated under reduced pressure. The residue was
partitioned between EtOAc and 10% aqueous NaOH, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound (160.5 mg, 100%) as a white solid, m.p. 80-82°C; NMR(CDCl3) δ 7.61 (s, 1H), 7.26-7.05 (m, 10H),
3.45 (m, 1H), 3.18 (m, 3H), 2.89-2.82 (m, 3H), 2.44 (m, 1H), 2.06 (m, 1H), 1.83 (m, 1H), 1.16 (d, 6H). b) 2-[(1R,3S,4S)-1-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole
A mixture containing 2-[(1R,3S,4S)-4-amino-1-benzyl-3- hydroxy-5-phenylpentyl]-4(5)-(2-methylpropionyl)imidazole (3.7 mg, 9 μmol), carbobenzyloxy-L-valine (2.3 mg, 9 μmol), 1-hydroxybenzotriazole hydrate (0.2 mg, 2 μmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 mg, 10 μmol) in DMF (0.2 mL) was allowed to stir at room temperature overnight. The reaction mixture was poured into EtOAc and washed successively with H2O, 0.1 N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 4% MeOH/CH2Cl2) to afford the title compound (5.5 mg, 94%) as a white solid, m.p. 89-91°C; NMR(CDCl3) δ 7.55 (s, 1H), 7.31-6.68 (m, 16H),
5.44 (d, 1H), 5.18-5.04 (m, 2H), 4.01-3.92 (m, 2H), 3.60 (d, 1H), 3.42 (m, 1H), 3.18-3.02 (m, 2H) , 2.85 (m, 3H), 2.03-1.74 (m, 3H), 1.18 (d, 6H), 0.81 (d, 3H), 0.74 (d, 3H); MS(ES) m/e 639.4 [M+H]+; Anal. Calcd for C38H46N4O5·1/4 H2O: C, 70.95; H, 7.29; N, 8.71. Found: C, 70.93; H, 7.15; N, 8.63. Example 18
Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole a) (S)-N-(isopropoxycarbonyl)valine
To a solution of (+)-valine (1.76 g, 2.02 mmol) in 2 N NaOH (15.75 mL, 31.5 mmol) at 10°C was added isopropyl chloroformate (16.5 mL of 1 M solution in toluene, 16.5 mmol). After stirring for 30 min, the pH was adjusted to pH 10, and the phases were separated. The aqueous phase was washed with Et2O. The pH was then adjusted to pH 2 by the addition of 3 N HCl, and the aqueous phase was extracted with Et2O (3x). The combined organic extracts were dried over
MgSO4, and the solvent was removed in vacuo . The title compound was obtained (2.73 g, 89%) and used without further purification. NMR(CDCl3) δ 5.13 (d, 1H), 4.94-4.89 (m, 1H),
4.32 (dd, 1H), 2.23 (m, 1H), 1.24 (d, 6H), 1.01 (d, 3H), 0.94 (d, 3H). b) 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole
The title compound was prepared according to the procedure in Example 17, step (b), except using 2-
[(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)-
(2-methylpropionyl) imidazole, 1-hydroxybenzotriazole hydrate,
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and (S) -N- (isopropoxycarbonyl) valine . m.p . 90-92°C;
NMR(CDCl3) δ 7 .57 (s, 1H), 7 .18-6. 91 (m, 10H), 5 .23 (m, 1H),
4.85 (m, 1H), 4.02-3.90 (m, 2H) , 3.58 (d, 1H), 3.44 (m, 1H), 3.20 (m, 1H), 3.12-3.03 (m, 1H), 2.86 (m, 3H), 1.99-1.74 (m, 3H), 1.21 (d, 12H), 0.81 (d, 3H), 0.75 (d, 3H); MS (CI/NH3) m/e 591.5 [M+H]+; Anal. Calcd for C34H46N4O5·1/2 H2O: C,
68.09; H, 7.90; N, 9.34. Found: C, 68.25; H, 7.84; N, 9.18. Example 19
Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-(1- oxo-3-phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole a) (S)-N-phenylethylcarbonylvaline
To a solution of (S)-valine (1.76 g, 15 mmol) in 1:1 Et2O:2N NaOH (31.5 mL) was added dropwise over 5 min
phenylpropanoyl chloride (2.45 mL, 16.5 mmol). The
temperature was maintained at 10°C during the addition, then was allowed to warm to room temperature and stirred for 30 min. The aqueous phase was adjusted to pH 10 and then extracted with Et2O (4x8 mL). The aqueous layer was adjusted to pH 2 by the addition of 3 N HCl, and the solid which formed was collected by filtration and dried in vacuo to afford the title compound as a white solid (3.66 g, 98%).
NMR(CDCl3) δ 7.16 (m, 5H), 4.29 (d, 1H), 2.92 (apparent t,
2H), 2.58 (apparent dt, 2H), 2.09 (m, 1H), 0.88 (d, 6H). b) 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-(1-oxo-3- phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole
The title compound was prepared according to the
procedure in Example 17, step (b), except using 2-
[(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)-
(2-methylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and (S)-N-phenylethylcarbonylvaline. m.p. 99-101°C;
NMR(CDCl3) δ (diastereomers) 7.64 (s, 1H), 7.59 (s, 1H), 7.18-
6.96 (m, 15H), 4.58-4.06 (m, 2H), 3.44-2.44 (m, 11H), 1.82 (m, 3H), 1.23-1.10 (m, 6H), 0.72-0.59 (m, 6H); MS(ES) m/e 637.2 [M+H]+; Anal. Calcd for C39H48N4O4·1/2 H2O: C, 72.53; H, 7.65; N, 8.68. Found: C, 72.20; H, 7'.34; N, 8.56. Exampl e 20
Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(3- methyl-1-oxobutyl)lamino-5-phenylpentyl1-4(5)-(2-methyl- propionyl)imidazole
The title compound was prepared according to the procedure in Example 17, step (b), except using 2- [(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)- (2-methylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3-methylbutanoic acid. m.p. 74-76°C; NMR(CDCl3) δ 7.57
(s, 1H), 7.20-6.93 (m, 10H), 4.08-4.05 (m, 1H), 3.52 (m, 2H), 3.18-3.09 (m, 2H), 2.88 (m, 3H), 1.97 (m, 5H), 1.23 (d, 3H), 1.21 (d, 3H), 0.75 (m, 6H); MS(ES) m/e 490.2 [M+H]+; Anal. Calcd for C30H39N3O3·1/2 H2O: C, 72.26; H, 8.08; N, 8.43.
Found: C, 71.88; H, 7.87; N, 8.28.
Example 21
Preparation of 2-{ (1R, 3S , 4S) -1-benzyl-3-hydroxy-4- [N- (N' - acetyl) -L-valyl] amino-5-phenylpentyl 1-4 (5) - (2-m ethyl - propionyl)imidazole To a solution containing 2-[(1R,3S,4S)-4-amino-1-benzyl- 3-hydroxy-5-ρhenylpentyl]-4(5)-(2-methylpropionyl)imidazole (30.0 mg, 74 μmol), (S)-N-acetylvaline (13.0 mg, 81 μmol) and BOP reagent (36.0 mg, 81 μmol) in CH2CI2 (37 μL) was added Et3N (11.3 μL, 81 μmol). The resulting solution was allowed to stir at room temperature for 24 h, then was diluted with EtOAc and washed successively with H2O and 0.1 N HCl. The acidic wash was made basic by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl and dried over
MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (silica gel, 6% MeOH/CH2Cl2) to afford a white solid (30.8 mg, 76%). This material was further purified by preparative HPLC (R.P., 70:30 MeOH:H2O) to afford the title compound (15.6 mg, 39%). m.p. 122-24°C; NMR(CDCl3) δ 7.68 (s, 1H), 7.14-6.89 (m, 10H), 4.11-4.02 (m,
2H), 3.44 (d, 2H), 3.22-3.17 (m, 2H), 2.96-2.82 (m, 3H), 2.12 (s, 3H), 1.90-1.82 (m, 3H), 1.23 (d, 3H), 1.22 (d, 3H), 0.87 (d, 3H), 0.75 (d, 3H) ; MS(ES) m/e 547.2 [M+H]+; Anal. Calcd for C32H42N4O4·3/4 H2O: C, 68.61; H, 7.83; N, 10.00. Found: C, 68.66; H, 7.59; N, 9.87. Example 22
Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- acetyl)-D-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole
The title compound was obtained from the preparative HPLC separation in Example 21 (4.8 mg, 12%). m.p. 123-25°C; NMR(CDCl3) δ 7.62 (s, 1H), 7.20-6.97 (m, 10H), 4.25 (m, 2H),
3.46 (m, 2H), 3.19 (m, 2H), 2.82 (m, 3H), 1.82 (m, 6H), 1.19 (m, 6H) , 0.77 (d, 3H), 0.62 (d, 3H); MS(ES) m/e 547.2 [M+H]+.
Example 23
Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- benzyloxycarbonyl)-L-threonyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole
The title compound was prepared according to the procedure in Example 17, step (b), except using 2- [(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)- (2-methylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-benzyloxycarbonyl-L-threonine. m.p. 89-91°C;
NMR(CDCl3) δ 7.56 (s, 1H), 7.31-7.13 (m, 12H), 6.93 (m, 3H), 5.81 (d, 1H), 5.06 (d, 1H), 5.04 (d, 1H), 4.14-4.04 (m, 3H), 3.60 (m, 1H), 3.43 (m, 1H), 3.15-3.07 (m, 2H), 2.88-2.79 (m, 3H), 1.84 (m, 2H), 1.16 (d, 3H), 1.15 (d, 3H), 1.07 (d, 3H); MS(ES) m/e 641.4 [M+H]+; Anal. Calcd for C37H44N4O6·H2O: C, 67.46; H, 7.04; N, 8.50. Found: C, 67.53; H, 6.98; N, 8.31.
Example 24
Preparation of 2-{(1R,3S,3'S,4S)-1-benzyl-3-hydroxy-4-{1'-
[5'-hydroxy-3'-(1-methylethyl)-2'-oxo-1'pγrrolidinyl]}-5- phenylpentyl}-4(5)-(2-methylpropionyl)imidazole The title compound was prepared according to the procedure in Example 21, except using 2-[(1R,3S,4S)-4-amino- 1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole, BOP reagent, triethylamine and (2S)-2-(1-methylethyl)-4-oxobutanoic acid. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexanes), then with (2:1 ethyl acetate :hexanes) to afford the title compound. NMR(CDCl3) δ 7.60 (s, 1H), 7.26-
7.16 (m, 6H), 7.05 (d, 2H), 6.97 (d, 2H), 5.14 (t, 1H), 4.05 (dd, 1H), 3.80 (m, 1H), 3.44 (m, 1H), 3.23 (m, 2H), 2.99 (m, 1H), 2.80 (dd, 1H), 2.68 (m, 1H), 2.42 (dd, 1H), 2.27-2.23
(m, 2H), 1.84-1.81 (m, 1H), 1.68 (m, 2H), 1.43 (m, 1H), 1.24 (d, 3H), 1.22 (d, 3H), 0.96 (d, 3H), 0.86 (d, 3H); MS (ES) m/e 514.2 (M-H2O+H)+. Example 25
Preparation of 2- { (1R,3S,3'R,4S)-1-benzyl-3-hydroxy-4-{1'- [5'-hydroxy-3'-(1-methylethyl)-2'-oxo-1'pyrrolidinyl]}-5- phenylpentyl}-4(5)-(2-methylpropionyl)imidazole
The title compound was obtained from the chromatographic separation in Example 24. NMR(CDCl3) δ 7.69 (s, 1H), 7.23-
7.19 (m, 7H), 7.02 (m, 3H), 4.76 (m, 1H), 3.82 (q, 1H), 3.64
(m, 1H), 3.29 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.89-2.75 (m, 3H), 2.52 (m, 1H), 2.05-2.00 (m, 4H), 1.72 (m 2H), 1.23
(d, 3H), 1.22 (d, 3H), 0.94 (d, 3H), 0.87 (d, 3H); MS(ES) m/e 514.2 (M-H2O+H)+. Example 26
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-benzenesnlfonylamino- 3-hydroxy-5-phenylpentyl]-4(5)-(2-methylpropionvl)imidazole
To a stirring solution of 2-[(1R,3S,4S)-4-amino-1- benzyl-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole (10.0 mg, 0.025 mmol) and
triethylamine (3.0 mg, 0.03 mmol, 4.2 μL) in CH2CI2 (0.125 mL) was added benzenesulfonyl chloride (4.8 mg, 0.027 mmol, 3.5 μL). After stirring at room temperature for 1h, the solution was diluted with CH2CI2, washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexanes) to provide the title compound (4.7 mg,
25%). m.p. 108-110°C; NMR(CDCl3) δ 7.74 (d, 2H), 7.56 (s, 1H), 7.50 (t, 1H), 7.41 (t, 2H), 7.15 (m, 6H), 7.01 (d, 2H),
6.83 (m, 2H), 5.35 (d, 1H), 3.68 (d, 1H), 3.30 (m, 2H), 3.21
(m, 1H), 2.95 (dd, 1H), 2.81 (m, 2H), 2.55 (dd, 1H), 1.95 (m, 1H), 1.67 (m, 1H), 1.22 (d, 3H), 1.20 (d, 3H); MS (ES) 546.0 [M+H]+.
Example 27 Preparation of 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- methanesnlfonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole
The title compound was prepared according to the
procedure in Example 26, except using 2-[(1R,3S,4S)-4-amino- 1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl) imidazole, (2S)-2-methanesulfonylamino-3- methylbutanoyl chloride, and triethylamine for 22h. m.p.
248-250°C; NMR(CDCl3/CD3OD) δ 7.60 (m, 2H), 7.22-7.15 (m, 8H), 7.03 (d, 2H), 4.08 (m, 1H), 3.55 (d, 1H), 3.35-3.30 (m, 4H),
3.06 (dd, 1H), 2.90-2.87 (m, 2H), 2.72 (dd, 1H), 2.34 (s,
3H), 1.82 (m, 3H), 1.20 (d, 3H), 1.18 (d, 3H), 0.88 (d, 3H),
0.73 (d, 3H); MS(ES) 583.2 [M+H]+. Example 28
Preparation of 2-{(1R,3S,4S)-1-benzyl-4-[N-(N'-tert- butoxycarbonyl)-L-valyl]amino-3-hydroxy-5-phenylpentyl}-4(5)- (2-methylpropionyl)imidazole
The title compound was prepared according to the procedure in Example 17, step (b), except using 2- [(1R,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-4(5)- (2-methylpropionyl)imidazole, 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-tert-butoxycarbonyl-L-valine. m.p. 101.5-104.5°C;
NMR(CDCl3) δ 7.57 (s, 1H), 7.23-7.12 (m, 8H), 6.90 (d, 2H), 6.63 (bs, 1H), 5.06 (s, 1H), 3.99 (q, 1H), 3.85 (dd, 1H), 3.62 (d, 1H), 3.44 (m, 1H), 3.22 (m, 1H), 3.06 (dd, 1H), 2.89-2.84 (m, 3H), 2.03 (m, 1H), 1.93 (m, 1H), 1.75 (m, 1H), 1.38 (s, 9H), 1.21 (d, 3H), 1.19 (d, 3H), 0.82 (d, 3H), 0.74 (d, 3H); Anal. Calcd for C35H48N4O5·3/4 H2O: C, 67.99; H, 8.07; N, 9.06. Found: C, 67.73; H, 7.92; N, 9.39.
Example 29
Preparation of 2-T(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-(2 ,2-dimethyl-3- butenoyl)imidazole
The title compound was prepared according to the
procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and 3-methyl-2-butenylmagnesium bromide in step (a). m.p. 73- 75°C. NMR(CDCl3) δ 7.65 (s, 1H), 7.25-7.14 (m, 8H), 6.89 (bs,
2H), 6.12 (m, 1H), 5.26 (d, 1H), 5.21 (d, 1H), 4.95 (d, 1H), 3.63 (m, 2H), 3.38 (m, 1H), 3.00 (m, 1H), 2.85 (m, 3H), 2.05 (m, 1H), 1.78 (m, 1H), 1.35 (s, 6H); MS (ES) 532.4 [M+H]+;
Anal. Calcd for C32H41N3O4·1/2 H2O: C, 71.08; H, 7.83; N, 7.77. Found: C, 71.30; H, 7.75; N, 7.74. Example 30
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-t-bntoxycarbonyl- amino-3-hydroxy-R-phenylpentyl]-4(5)-(2,2-dimethylbutanoyl)- imidazole a) 2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-(2,2-dimethyl-3- butanoyl)imidazole.
To a solution of 2-[(1R,3S,4S)-1-beιjzyl-4-t- butoxycarbonylamino-3-t-butyldimethylsiloxy-5-phenylpentyl]- 4(5)-(2,2-dimethyl-3-butenoyl)imidazole (26 mg, 0.04 mmol) in ethanol (0.4 mL) was added 5% palladium on carbon (6.5 mg). The suspension was stirred vigorously under a balloon of hydrogen for 16h. The suspension was filtered through a bed of celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 1:4 ethyl acetate :hexanes) to provide the title compound (13.8 mg, 53%). NMR(CDCl3) δ 7.60 (s, 1H), 7.31-7.15 (m, 8H), 6.97 (d,
2H), 4.69 (d, 1H), 4.01 (m, 1H), 3.61 (m, 1H), 3.17 (m, 1H), 2.81 (m, 1H), 2.69 (m, 1H), 1.85 (m, 2H), 1.74 (q, 2H), 1.32 (m, 9H), 1.26 (s, 3H), 1.24 (s. 3H), 0.91 (s, 9H), 0.75 (t, 3H), 0.05 (s, 6H). b) 2-[(1R,(S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3- hydroxy-5-phenylpentyl]-4(5)-(2,2-dimethylbutanoyl)-imidazole
The title compound was prepared according to the procedure in Example 6, step (c), except using 2-[(1R,3S,4S)- 1-benzyl-4-t-butoxycarbonylamino-3-t-butyldimethylsiloxy-5- phenylpentyl]-4(5)-(2,2-dimethyl-3-butanoyl) imidazole. m.p. 78-80°C; NMR(CDCl3) δ 7.59 (s, 1H), 7.26-7.15 (m, 8H), 6.89
(bs, 2H), 4.94 (d, 1H), 3.67 (m, 1H), 3.60 (m, 1H), 3.38 (m, 1H), 3.01 (m, 1H), 2.87 (m, 3H), 1.99 (m, 1H), 1.79 (m, 3H), 1.35 (s, 9H), 1.27 (s, 3H), 1.26 (s, 3H), 0.77 (t, 3H);
MS(ES) 534.4 [M+H]+. Example 31
Preparation of 3-[(1R,3S,4S)-1-benzyl-4-t-butoxγcarbonyl- amino-3-hydroxy-5-phenylpentγl]-6,6-dimethyl-5-hydroxy- pyrrolo-[1,2-c]-imidazol-7-one
A solution of 2-[(1R,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2,2- dimethyl-3-butenoyl)imidazole (5.0 mg, 9.4 μmol) and sodium periodate (4.4 mg, 0.02 mmol) in 1:1 dioxane:H2O (0.34 mL), containing 7.9 μL of a 1% aqueous solution of osmium
tetroxide, was allowed to stir at room temperature for 6h. The mixture was diluted with ethyl acetate, washed
sequentially with water and saturated brine, dried (MgSO4), filtered and concentrated. The residue was purified by preparative TLC, developed with 2:1 ethyl acetate:hexanes, to provide the title compound (3.4 mg, 68%). m.p. 88-90°C;
NMR(CDCl3) δ 7.52 (s, 1H), 7.26-7.13 (m, 8H), 6.96 (d, 2H),
6.31 (bs, 1H), 4.90 (bs, 1H), 4.79 (d, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 3.31 (m, 1H), 3.14 (m, 1H), 2.99 (m, 2H), 2.83 (dd, 1H), 2.14 (m, 2H), 1.39 (s, 9H), 1.17 (s, 3H) , 0.70 (s, 3H); MS(ES) 534.2 [M+H]+.
Example 32
Preparation of 2-[ (1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl- amino-3-hydroxγ-5-phenylpentyl]-4(5)-(cyclopentylearbonyl)- imidazole The title compound was prepared according to the
procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-tert- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and cyclopentylmagnesium bromide in step (a). NMR(CDCl3) δ 7.58 (s, 1H), 7.20 (m, 9H), 6.91 (m, 2H), 4.97 (d, 1H), 3.61 (m, 2H), 3.41 (m, 2H), 3.06 (m, 1H), 2.89 (m, 1H), 2.86 (d, 2H), 1.80 (m, 11H), 1.37 (s, 9H); MS(ES) 532.4 [M+H]+. Example 33
Preparation of 2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-benzoylimidazole
The title compound was prepared according to the procedure in Example 9, steps (a-c), except using 2- [(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and phenylmagnesium chloride in step (a). NMR(CDCl3) δ 7.89 (d,
2H), 7.62 (t, 1H), 7.58 (s, 1H), 7.52 (t, 2H), 7.20 (m, 8H),
6.93 (d, 2H), 4.97 (d, 1H), 3.64 (m, 2H), 3.53 (m, 1H), 3.12
(m, 1H) , 2.93 (m, 1H), 2.86 (d, 2H), 2.02 (d, 1H), 1.87 (d, 1H), 1.40 (s, 9H); MS (ES) 540.2 [M+H]+.
Example 34
Preparation of 2-[(1R,3S,4fi)-1-benzyl-4-t.ert.-butoxycarbonyl- amino-3-hydroxy-5-phenylpentyl]-4(5)-(2-ethylbutanoyl)- imidazole
The title compound was prepared according to the procedure in Example 9, steps (a-c), except using 2-
[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-t- butyldimethylsiloxy-5-phenylpentyl]-4(5)-formylimidazole and 3-pentylmagnesium bromide in step (a). NMR(CDCl3) δ 7.60 (s, 1H), 7.22 (m, 9H), 6.90 (d, 2H), 4.94 (d, 1H), 3.67 (d, 1H), 3.62 (m, 1H), 3.42 (m, 1H), 3.07 (m, 1H), 2.90 (m, 1H), 2.88 (d, 2H), 2.00 (m, 1H), 1.83 (m, 1H), 1.72 (m, 2H), 1.57 (m, 2H), 1.36 (s, 9H), 0.83 (t, 6H); MS(ES) 534.2 [M+H]+.
Example 35
Preparation of 2- [ (1R, 3S , 4S) -1-henzyl -4-tert-butoxycarbonyl - amino-3-hydroxy-5-phenylpentyl l -4 ( 5) - (E) -1- (hydroxyimino) -2- methylpropyl) l imidazole To a stirring solution of hydroxylamine hydrochloride (25 mg, 0.36 mmol) in ethanol (0.5 mL) at 0°C was added potassium carbonate (25 mg, 0.18 mmol) in water (0.5 mL). The solution was stirred for 10 minutes and added to a solution of 2-[(1R,3S,4S)-1-benzyl-4-tert- butoxycarbonylamino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl) imidazole in ethanol (1 mL) at 55-60°C.
After stirring for 24 hours the reaction mixture was diluted with water and ethyl acetate, extracted with ethyl acetate (2X). The combined extracts were washed with saturated brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography on 230-400 mesh (silica gel, 3:2 ethyl acetate:hexanes) to provide the title compound. NMR(CDCl3) δ 7.23 (m, 10H), 6.96 (d, 2H), 5.01 (d, 1H), 3.63 (m, 2H), 3.42 (m, 1H), 3.00 (m, 2H), 2.90 (m, 1H), 2.87 (d, 2H), 2.00 (m, 1H), 1.80 (m, 1H), 1.38 (s, 9H), 1.27 (m, 6H); MS (ES) 521.2 [M+H]+.
Example 36
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoyl-thiazole a) N-dimethylaminomethylidene-(2R,4S,5S)-2-phenylmethyl-4- acetoxy-5-t-butoxycarbonylamino-6-phenylhexanethioamide.
A solution of the compound of Example 1(c) (134 mg, 0.29 mmol) in CHCl3 (1 mL) was treated with dimethylformamide dimethylacetal (1.2 equiv) and activated 4A molecular sieves, and stirred for 30 min. The reaction was filtered, the solvent thoroughly evaporated, and the residue
chromatographed (silica gel, 75% EtOAc/hexane), to yield the title compound (133 mg, 89%). NMR(CDCl3) δ 8.32 (1H, s),
7.06-7.32 (10H, m), 5.00 (1H, m), 4.58 (1H, d), 3.92 (1H, m), 3.12 (3H, s), 2.96 (3H, s), 2.50-3.34 (4H, m), 2.02 (3H, s), 1.76-2.32 (3H, m), 1.35 (9H, s). b) (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoylthiazole
A mixture of the compound of Example 36(a) (111 mg, 0.21 mmol), phenacyl bromide (65 mg, 0.33 mmol), and Et3N (45 mg, 0.45 mmol) in MeCN (3 mL) was heated to 90°C for 30 min. The solvent was evaporated, and the residue taken up in EtOAc. The extracts were washed with 0.05N HCl, and water, dried, and the solvent removed. The residue was chromatographed (silica gel, EtOAc/hexane/CH2Cl2) to yield the title
compound. NMR(CDCl3) δ 8.10 (1H, s), 7.82 (2H, d), 7.48-7.66
(3H, m), 7.00-7.30 (10H, m), 4.92 (1H, m)., 4.65 (1H, d), 3.98 (1H, m), 3.48 (1H, m), 2.40-3.12 (2H, m), 2.56-2.75 (2H, m), 1.94-2.34 (2H, m), 2.08 (3H, s), 1.38 (9H, s). c) (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoyl-thiazole
A solution of the compound of Example 36(b) (25 mg) in MeOH (3 mL) was treated with aqueous K2CO3 at ambient
temperature for 4 h. The solution was diluted with H2O, and filtered. The filtrate was acidified and extracted with Et2θ. The extracts were washed with H2O, dried, and the solvent removed to yield the title compound (13.2 mg, 59%). NMR(CDCl3) δ 8.06 (1H, s), 7.80 (2H, dd), 7.62 (1H, m), 7.52
(2H, m), 7.00-7.26 (10H, m), 4.80 (1H, d), 3.76 (1H, m), 3.60 (1H, m), 3.52 (1H, m), 3.05 (2H, m), 2.82 (2H, m), 2.06 (1H, m), 1.82 (1H, m), 1.70 (1H, broad s), 1.40 (9H, s).
Example 37 Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-benzoylthiazole
A solution of the compound of Example 3D (86 mg, 0.14 mmol) in a mixture of THF (8 mL) and Et2θ (8 mL) was cooled to 0°C and treated with a solution of LiAlH4 (1 mmol) in THF (1 mL). The reaction was stirred at 0°C for 30 min, and ambient temperature for 40 min, then quenched with cold, dilute HCl. The mixture was extracted with Et2O, the extracts washed with water, dried, and the solvent removed. The residue was chromatographed (Florisil, EtOAc/hexane/MeOH) to yield the title compound. NMR(CDCl3/CD3OD) δ 6.92-7.42
(16H, m), 6.00 (1H, s), 4.90 (1H, d), 3.50-3.70 (2H, m), 3.20-3.30 (1H, m), 2.74-3.08 (4H, m), 2.00 (1H, m), 1.68 (1H, m), 1.40 (9H, s).
Example 38
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-aminocarbonylthiazole
A solution of the compound of Example 39(a) (20 mg) in MeOH (4 mL) was cooled to 0°C and saturated with NH3. The reaction was closed with a vented cap, allowed to come to ambient temperature and stirred overnight. The solvent was evaporated, the residue taken up in EtOAc, washed with water, dried, and the solvent evaporated. The residue was
crystallized from a mixture of acetone and hexane to yield the title compound (9.3 mg, 46%). NMR(CDCl3/Me2CO-D6/CD3OD) δ 8.12 (1H, s), 7.02-7.28 (10H, m), 5.35 (1H, d), 3.30-3.73
(3H, m), 3.06 (2H, m), 2.78 (2H, m), 1.80-2.10 (2H, m), 1.38 (9H, s).
Example 39
Preparati on of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-hydroxymethylthiazole a) (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-carbomethoxythiazole
Using the procedure of Example 36(b), except
substituting methyl bromoacetate for phenacyl bromide, the title compound was prepared. NMR(CDCl3) δ 8.28 (1H, s),
6.95-7.30 (10H, m), 4.88 (1H, m), 4.60 (1H, d), 3.96 (1H, m), 3.86 (1H, m), 3.40 (1H, m), 2.88-3.08 (2H, m), 2.55-2.74 (2H, m), 2.08-2.30 (2H, m), 2.06 (3H, s), 1.40 (9H, s). (b) (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-hydroxymethylthiazole Using the procedure of Example 37, except substituting the compound of Example 39(a), the title compound was
prepared. NMR (CDCI3/CD3OD) δ 7.42 (1H, s), 7.00-7.28 (10H, m), 5.30 (1H, d), 4.70 (2H, s), 3.50-3.68 (2H, m), 3.41 (1H, d), 2.90-3.08 (2H, m), 2.38 (2H, d), 1.98 (1H, m), 1.86 (1H, m), 1.34 (9H, s).
Example 40
Preparation of (1R,3S,45)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-formylthiazole
A solution of the compound of Example 39(b) (65 mg, 0.125 mmol) in CH2CI2 (3 mL) and CH3CN (3 mL) was treated with excess MnO2 and stirred at ambient temperature for 22 h.
The reaction was filtered, and the solvent evaporated to yield the title compound (59 mg, 91%). NMR(CDCl3) δ 9.92
(1H, s), 8.26 (1H, s), 7.00-7.28 (10H, m), 4.80 (1H, d), 3.76
(1H, m), 3.58 (1H, m), 3.48 (1H, m), 3.02 (2H, m), 2, 80 (2H, m), 2.06 (1H, m), 1.88 (1H, m), 1.79 (1H, s, broad), 1.40 (9H, s).
Example 41
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hγdroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-hydroxypropyl)- thiazole
A suspension of ethylmagnesium bromide (2 mmol) in Et2O (5 mL) at 23°C was treated with a solution of the compound of Example 40 (50 mg, 0.1 mmol) in Et2O (5 mL) and THF (0.5 mL). A dense precipatate formed, and after 5 min the reaction was quenched by the addition of aq NH4CI. The layers were separated, and the organic layer was dried and the solvent evaporated. The residue was chromatographed (Florisil, 49% EtOAc/49% hexane/2% MeOH) to yield the title compound (41 mg, 77%). NMR(CDCl3) δ 6.92-7.38 (11H, m), 4.92 (1H, d), 4.76
(2H, m), 3.48-3.68 (3H, m), 2.88-3.08 (2H, m), 2.82 (2H, d), 2.02 (1H, m), 1.62-1.92 (4H, m), 1.38 (9H, s), 0.92 (3H, q).
Example 42
Preparation of 2-[ (1S,3S,4S)-1-benzyl-4-t- butoxycarbonylamino-3-hydroxy-5-phenylpentγl]-5-propyl- thiazole; and
2-[ C1R,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole
The diastereomeric thiazoles of Example 4 were separated by chromatography (Microsorb® Siθ2, 10 x 250 mm column, 5 mL/min) to yield the following pure enantiomers:
2-[(1R or 1S,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole (isomer A).
1H NMR(CDCl3) δ 0.95 (t, 3H), 1.27 (m, 2H), 1.35 (s, 9H), 1.58-1.7 (m, 2H), 2.02 (t, 1H), 2.7 (t, 2H), 2.85-3.08 (m, 4H), 3.58 (m, 3H), 4.92 (d, 1H), 6.95 (m, 1H), 7.1-7.3 (m, 10H); TLC Rf 0.55 (1:1 hexane:EtOAc); HPLC RT 3.9 min
(Microsorb® SiO2, 4.6 x 250 mm column, 50:48:2
CH2CI2:hexane:isopropanol, 2.0 mL/min).
2-[(1R or 1S,3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole (isomer B)
1H NMR(CDCl3) δ 0.95 (t, 3H), 1.28 (m, 2H), 1.36 (s, 9H),
1.62 (m, 2H), 1.75-2.15 (2m, 1H), 2.7 (t, 2H), 2.75-3.15 (m, 4H), 3.4 (br m, 1H), 3.55 (br m, 1H), 3.75 (br m, 1H), 4.9 (d, 1H), 7.05 (d, 1H), 7.1-7.3 (m, 10H); TLC Rf 0.50 (1:1 hexane:EtOAc); HPLC RT 5.6 min (Microsorb® SiO2, 4.6 x 250 mm column, 50:48:2 CH2CI2:hexane:isopropanol, 2.0 mL/min).
Example 43
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(3-hydroxypropyl)- thiazole a) (1R,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t-butoxy- carbonylamino-5-phenylpentyl)-5'-(2-carboethoxyethenyl)- thiazole
A solution of triethylphosphonoacetate (224 mg, 1 mmol) in dimethoxyethane (10 mL) was treated with NaH (40mg of a 60% dispersion) at 0°C. 1.7 mL of this solution (.17 mmol) was added at 0°C to a solution of (1R,3S,4S)-2'-(1- phenylmethyl-3-hydroxy-4-t-butoxycarbonylamino-5- phenylpentyl)-5'-formylthiazole (29 mg, 0.056 mmol) in dimethoxyethane (2 mL). After 1 h, a mixture of water and dilute HCl was added, and the mixture was extracted with Et2O. The extracts were washed with water, dried, and the solvent removed. The residue was chromatographed (silica gel, 25% EtOAc/CH2Cl2), to yield the title compound (35 mg, 53%). NMR(CDCl3) δ 7.70 (1H, d), 7.68 (1H, s), 7.10-7.28
(8H, m), 7.00 (2H, m), 6.06 (1H, d), 4.88 (1H, d), 4.26 (2H, q), 4.06 (1H, m), 3.46-3.75 (3H, m), 3.00 (2H, m), 2.82 (2H, m), 2.04 (1H, m), 1.80 (1H, m), 1.40 (9H, s), 1.32 (3H, t). b) (1R,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t-butoxycarbonylamino-5-phenylpentyl)-5'-(3-hydroxypropyl)- thiazole.
A solution of LiAlH4 (0.6 mmol) in THF (2.5 mL) at 0°C was treated with a solution of (1R,3S,4S)-2'-(1-phenylmethyl- 3-hydroxy-4-t-butoxycarbonylamino-5-phenylpentyl)-5'-(2- carboethoxyethenyl)-thiazole (35 mg, 0.06 mmol) in THF (2.5 mL). After 1 h at 0°C an additional LiAlH4 (0.6 mmol) was added, and stirring continued for 20 min at ambient
temperature. Water was added, and enough HCl to dissolve all the solids. The mixture was extracted with Et2O, washed with H2O, dried, and the solvent removed. The resultant yellow solid was triturated with Et2O to yield the title compound (10.5 mg, 32%). NMR(CDCl3/CD3OD) δ 7.10-7.28 (9H, m), 7.00 (2H, m), 5.10 (1H, d), 3.60 (4H, m), 3.42 (1H, m), 3.00 (2H, m), 2.90 (4H, m), 2.00 (1H, m), 1.82 (2H, quintet), 1.68 (1H, m), 1.36 (9H, s). Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1, 2-dihydroxyethyl)- thiazole a) (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-ketocarboethoxy- thiazole.
A mixture of the compound of Example 36(b) (111 mg, 0.21 mmol), ethyl bromopyruvate (64 mg, 0.33 mmol), and Et3N (45 mg, 0.45 mmol) in CH3CN (3 mL) was heated to 90°C for 30 min. The solvent was evaporated, and the residue taken up in
EtOAc. The extracts were washed with 0.05N HCl, and water, dried, and the solvent removed. The residue was
chromatographed (silica gel, 30% EtOAc/68% hexane/2% CH2CI2), to yield the title compound (86 mg, 68%). NMR(CDCl3) δ 8.65
(1H, s), 6.96-7.28 (10H, m), 4.88 (1H, m), 4.60 (1H, d), 4.42 (2H, q), 3.98 (1H, m), 3.40 (1H, m), 3.02 (2H, m), 2.65 (2H, m), 2.10-2.30 (2H, m), 2.05 (3H, s), 1.45 (3H, t), 1.38 (9H, s). b) (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1, 2-dihydroxyethyl)- thiazole
A solution of the compound of Example 44(a) (86 mg, 0.14 mmol) in a mixture of THF (8 mL) and Et2O (8 mL) was cooled to 0°C and treated with a solution of LiAlH4 (1 mmol) in 1 mL of THF. The reaction was stirred at 0°C for 30 min, and ambient temperature for 40 min, then quenched with cold, dilute HCl. The mixture was extracted with Et2O, the
extracts washed with water, dried, and the solvent removed. The residue was chromatographed (Florisil, 40% EtOAc/58% hexane/2% MeOH) to yield the title compound (22 mg, 31%).
NMR(CDCl3/CD3OD) δ 7.40 (1H, d), 6.96-7.28 (10H, m), 4.98
(1H, m), 3.46-3.82 (5H, m), 2.88-3.08 (2H, m), 2.80 (2H, d), 2.00 (1H, m), 1.75 (1H, m), 1.40 (9H, s). Example 45
Preparation of (3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-alanyl)amino-5-phenylpentyl)-5'-propyl- thiazole
A solution of the compound of Example 4 (171 mg, 0.34 mmol) in 50% trifluoroacetic acid/methylene chloride (10 mL) was stirred at room temperature under argon for 3.5 h and then concentrated under reduced pressure to give the TFA salt of (3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-amino-5- phenylpentyl)-5'-propyl-thiazole as a white solid (176 mg, 100%).
The TFA salt (90.4 mg, 0.178 mmol) was diluted with DMF (10 mL), cooled to 0°C, and diisopropylamine (23 mg, 0.178 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (37.6 mg, 0.196 mmol), 1-hydroxybenzotriazole (28.9 mg, 0.214 mmol), and carbobenzyloxy-L-alanine (43.8 mg, 0.196 mmol) were added. The reaction mixture was allowed to stir and warm to room temperature overnight. The DMF was evaporated and the resulting oil was diluted with EtOAc, washed successively with 1.0N HCl, H2O, 5% NaHCO3, brine, and dried (MgSO4). Filtration, evaporation of the solvent and flash chromatography (silica gel, 33% hexane/ethyl acetate) yielded the title compound as a white solid (27 mg, 25%).
The diastereomeric mixture was separated by
chromatography (Microsorb® Si02, 50:48:2
CH2CI2:hexane:isopropanol) to yield the pure enantiomers.
(1R or 1S,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-alanyl)amino-5-phenylpentyl)-5'-propyl- thiazole (isomer 1). NMR(CDCl3), (250 MHz) δ 7.4-7.1 (m,
15H), 6.95 (d, 1H), 6.3 (d, 1H), 5.25 (d, 1H), 5.05 (s, 2H), 4.1 (m, 2H), 3.9 (m, 1H), 3.65 (m, 2H), 3.0 (m, 1H), 2.85 (m, 2H), 2.7 (m, 2H), 1.9-1.6 (m, 5H), 1.35 (m, 1H), 1.2 (d, 3H), 0.9 (t, 3H), 0.75 (d, 3H); TLC Rf 0.35 (2:1 EtOAc:hexane); HPLC RT 10.2 min (Microsorb® Siθ2, 50:48:2
CH2CI2:hexane:isopropanol, 2.0 mL/min); MS m/e 600 [M+H]+. (1R or 1S, 3S, 4S) -2 '- (1-phenylmethyl-3-hydroxy-4-
(benzyloxycarbonyl-L-alanyl)amino-5-phenylpentyl)-5'-propyl- thiazole (isomer 2). NMR(CDCl3, 250 MHz) δ 7.4-7.1 (m, 15H),
7.05 (d, 1H), 6.3 (d, 1H), 5.25 (d, 1H), 5.05 (s, 2H), 4.15 (m, 1H), 4.05 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 3.0 (m,
1H) , 2 .8 (m, 2H) , 2. 7 (m, 2H) , 2.0 (m, 2H), 1 . 8 (m, 1H) , 1.55 (m, 2H) , 1. 25 (m, 4H) , 0 . 9 (t, 3H) ; TLC Rf 0 .32 (2 : 1
EtOAc:hexane) ; HPLC RT 15 . 7 min (Microsorb® SiO2, 50 : 48 : 2 CH2CI2 :hexane : isopropanol, 2 .0 mL/min) ; MS m/e 600 [M+H] + .
Example 46
Preparation of (3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-valinyl)amino-5-phenylpentγl)-5'-propyl- thiazole
Following the procedure of Example 45, except
substituting the benzyloxycarbonyl-L-valine for
benzyloxycarbonyl-L-alanine, the title compounds are
prepared.
The diastereomeric thiazoles were separated by
chromatography (Zorbax® SiO2) to yield the pure enantiomers: (1R or 1S,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-
(benzyloxycarbonyl-L-valinyl)amino-5-phenylpentyl)-5'-propyl- thiazole (isomer 1). NMR(CDCl3, 250 MHz) δ 7.4-7.1 (m, 15H),
6.95 (d, 1H), 6.25 (d, 1H), 5.25 (d, 1H), 5.05 (s, 2H), 3.9 (m, 2H), 3.65 (m, 1H), 3.6 (m, 1H), 3.0 (m, 1H), 2.8 (m, 2H), 2.7 (m, 2H), 2.05-1.75 (m, 3H), 1.7-1.45 (m, 4H), 0.95 (t, 3H), 0.85 (d, 3H), 0.75 (d, 3H); TLC Rf 0.55 (2:1
EtOAc:hexane); MS m/e 628 [M+H]+.
(1R or 1S,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4- (benzyloxycarbonyl-L-valinyl)amino-5-phenylpentyl)-5'-propyl- thiazole (isomer 2). NMR(CDCl3, 250 MHz) δ 7.4-7.1 (m, 15H),
7.05 (d, 1H), 6.25 (d, 1H), 5.25 (d, 1H), 5.1 (s, 2H), 4.05 (m, 1H), 3.95 (m, 2H), 3.6 (m, 1H), 3.4 (m, 1H), 3.05 (m, 1H), 2.8 (m, 2H), 2.7 (m, 2H), 2.1-1.9 (m, 3H), 1.8-1.5 (m, 4H), 1.0-0.85 (dt, 3H), 0.7 (d, 3H); TLC Rf 0.50 (2:1
EtOAc:hexane); MS m/e 628 [M+H]+. Example 47
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxγ-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-oxo-propyl)- thiazole
Using the procedure of Example 40, except substituting the compound of Example 41, the title compoound was prepared. NMR(CDCl3) δ 8.14 (1H, s), 7.00-7.30 (10H, m), 4.82 (1H, d),
3.46-3.82 (3H, m), 2.98-3.10 (2H, m), 2.76-2.92 (4H, m), 2.06 (1H, m), 1.80 (1H, m), 1.38 (9H, s), 1.22 (3H, t).
Example 48 Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-carboxythiazole
A solution of the compound of Example 39(a) (25 mg, 0.045 mmol) in MeOH (3 mL) was treated with aqueous K2CO3 at ambient temperature for 4 h. The solution was diluted with H2O, and filtered. The filtrate was acidified and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent removed to yield the title compound (13.2 mg, 59%). NMR(CDCl3) δ 8.22 (1H, s), 6.88-7.30 (10H, m), 4.85 (1H, d),
3.72 (1H, m), 3.42-3.65 (3H, m), 3.02 (2H, m), 2.80 (2H, m), 2.02 (1H, m), 1.85 (1H, m), 1.30 (9H, s).
Example 49
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-hydroxy-2- methylpropyl)-thiazole Using the procedure of Example 41, except substituting the isoproyl magnesium bromide for ethyl magnesium bromide, the title compound was prepared. NMR(CD3OD) δ 7.32 (1H, d),
6.90-7.15 (10H, m), 6.10 (1H, d), 4.42 (1H, dd), 3.52 (2H, m) , 3 .32 (1H, m) , 2. 88 (2H, m) , 2 . 70 (1H, dd) , 2 .55 (1H, dd) , 1. 62-1. 90 (3H, m) , 1 .25 (9H, s) , 0 . 86 (3H, d) , 0 . 68 (3H, dd) .
Example 50
Preparation of (1R, 3S , 4S ) -2 ' - ( 1 -phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl) -5 '- (N'- benzyloxycarbonylguanidino) carbonylthiazole
A solution of the compound of Example 48 (70 mg, 0.13 mmol) in CH2CI2 (4 mL) was treated with N- hydroxybenzotriazole (18 mg, 0.13 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide (39 mg, 0.13 mmol), and carbobenzyloxyguanidine (25 mg, 0.13 mmol). After 2 h at ambient temperature, the solvent was evaporated, and the residue taken up in Et2O. The extracts were washed with 0.05N HCl, aq. NaHCO3, and aq. NaHS03. The extracts were dried, and the solvent evaporated, and the residue chromatographed (silica gel, 74% EtOAc/25% hexane/1% MeOH) to yield the title compound (58 mg). NMR(CDCl3) δ 8.88 (1H, broad s), 8.42 (1H, broad s), 8.16 (1H, s), 7.35 (5H, s),
7.10-7.30 (8H, m), 6.96 (2H, dd), 5.20 (2H, s), 4.84 (1H, d), 4.26 (1H, broads), 3.63 (2H, m), 3.52 (1H, d), 3.06 (1H, dd), 2.92 (1H, dd), 2.80 (2H, d), 2.02 (1H, m), 1.72 (1H, m), 1.62 (1H, broad s), 1.38 (9H, s).
Example 51
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxyoarbonylamino-5-phenylpentyl)-5'-(1- aminocarbonylpropyl)-thiazole a) (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-chloropropyl)- thiazole
A solution of (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4- t-butoxycarbonylamino-5-phenylpentyl)-5'-(1-hydroxypropyl)- thiazole (49 mg, 0.089 mmol) in CH2CI2 (5 mL) at 0°C was treated with Et3N (9 mg, 0.089 mmol), and thionyl chloride (11 mg, 0.089 mmol). After 30 min at 0°C, water was added, and the layers were seperated. The organic layer was washed with cold, dilute HCl, and water, and the extracts were dried and the solvent removed. The residue was chromatographed (silica gel, 5% EtOAc/CH2Cl2) to yield the title compound (20 mg, 41%). NMR(CDCl3) δ 7.52 (1H, d), 7.08-7.30 (8H, m), 6.98
(2H, m), 5.00 (1H, t), 4.90 (1H, m), 4.58 (1H, dd), 3.98 (1H, m), 3.34 (1H, m), 3.04 (1H, dd), 2.90 (1H, dd), 2.62 (2H, t), 2.10 (4H, m), 2.00 (3H, s), 1.38 (9H, s), 1.00 (3H, q). b) (1R,3S,4S)-2'-(l-phenylmethyl-3-acetoxy-4-t-butoxy- carbonylamino-5-phenylpentyl)-5'-(1-carbomethoxy-propyl)- thiazole
A solution of the compound of Example 51(a) (135 mg, 0.24 mmol) in DMF (3 mL) and MeOH (2 mL) was treated with Pd (OAc) 2 (14 mg, 0.0625 mmol), PI13P (33 mg, 0.125 mmol), and Et3N (48 mg, 0.48 mmol). Carbon monoxide was bubbled through the reaction for 30 min, the vessel was sealed, and heated overnight at 45°C. The mixture was cooled, diluted with water, acidified with dilute HCl, and extracted with Et2O. The extracts were washed with water, dried, and the solvent removed. The residue was chromatographed (silica gel 10% EtOAc/CHCl3) to yield the title compound (45 mg, 32%).
NMR(CDCl3) δ 7.75 (1H, m), 7.45 (1H, d), 7.04-7.40 (7H, m), 6.96 (2H, m), 4.90 (1H, m), 4.56 (1H, d), 3.96 (1H, m), 3.69 (3H, s), 3.32 (1H, m), 3.02 (1H, dd), 2.90 (1H, dd), 2.62 (2H, m), 2.00 (3H, s), 1.68-2.10 (4H, m), 1.32 (9H, s), 0.88 (3H, m).
Also isolated from this reaction and chromatography was (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t-butoxycarbonyl- amino-5-phenylpentyl)-5'-(1- methoxypropyl)-thiazole.
NMR(CDCl3) δ 7.50 (1H, s), 7.08-7.30 (8H, m), 6.94 (2H, d),
4.90 (1H, m), 4.58 (1H, d), 4.20 (1H, t), 3.96 (1H, m), 3.35 (1H, m), 3.18 (1.5H, s), 3.12 (1.5H, s), 3.00 (1H, dd), 2.90 (1H, dd), 2.69 (1H, dd), 2.58 (1H, dd), 2.18 (1H, m), 2.10 (1H, m), 2.02 (3H, s), 1.85 (1H, m), 1.60 (1H, m), 1.32 (9H, s), 0.84 (3H, q). c) (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-carboxypropyl)- thiazole
Following the procedure of Example 48, the compound of Example 51(b) was hydrolyzed to yield the title compound. d) (1R,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1- carbomethoxypropyl)-thiazole
A solution of (1R,3S,4S)-2'-(l-phenylmethyl-3-hydroxy-4- t-butoxycarbonylamino-5-phenylpentyl)-5'-(1-carboxypropyl)- thiazole in Et2O was treated with an excess of an ethereal solution of CH2N2. The solvent was evaporated to yield the title compound. NMRCCDCI3) δ 7.42 (1H, s), 7.12-7.28 (8H, m), 6.90 (2H, d), 4.90 (1H, d), 3.72 (3H, s), 3.58 (4H, m), 3.02 (1H, dd), 2.90 (1H, dd), 2.85 (2H, m), 2.00 (2H, m), 1.62-1.80 (2H, m), 1.32 (9H, s), 0.88 (3H, m).
Example 52
Preparation of (1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-methoxypropyl)- thiazole (1R,3S,4S)-2'-(1-phenylmethyl-3-acetoxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-methoxypropyl)- thiazole, isolated from the reaction of Example 51(b), was hydrolyzed according to the procedure of Example 48 to yield the title compound. NMR(CDCl3) δ 7.42 (1H, s), 7.10-7.28 (8H, m), 6.92 (2H, d), 4.90 (1H, d), 4.20 (1H, t), 3.58 (3H, m), 3.20 (1.5H, s), 3.14 (1.5H, s), 3.02 (1H, dd), 2.90 (1H, dd), 2.85 (2H, m), 2.04 (1H, m), 1.86 (1H, m), 1.68 (1H, dd), 1.60 (1H, dd), 1.35 (9H, s), 0.86 (1.5H, t), 0.82 (1.5H, t). Example 53
Preparation of 1R,3S,4S)-2'-(1-phenylmethyl-3-hydroxy-4-t- butoxycarbonylamino-5-phenylpentyl)-5'-(1-aminocarbonyl- propyl)-thiazole
A solution of the compound of Example 51(b) (30 mg, 0.05 mmol) in MeOH (5 mL) was cooled in an ice bath, and saturated with NH3 gas. The reaction vessel was sealed with a vented cap, allowed to come to ambient temperature, and stirred 16 h. The solvents were evaporated, and the residue taken up in EtOAc. The extract was washed with water and dilute HCl, dried, and the solvents evaporated. Trituration of the residue with Et2O gave the title compound (7.2 mg, 27%).
NMR(CDCl3) δ 7.42 (1H, s), 7.10-7.30 (8H, m), 6.92 (2H, m),
5.60 (1H, br s), 5.50 (1H, br s), 5.42 (1H, broad s), 4.92 (1H, d), 3.68 (1H, m), 3.42-3.60 (3H, m), 3.00 (1H, dd), 2.90 (1H, dd), 2.80 (2H, d), 1.92-2.14 (2H, m), 1.58-1.80 (2H, m), 1.32 (9H, s), 0.90 (3H, m).
Example 54
Parenteral Dosage Unit Composition
A suitable dosage form for intravenous administration is prepared by dissolving the compound of Example 1 (25 mg) in dimethyl sulfoxide or formamide (1 mL), diluting to 20 mL with a 70% propylene glycol/30% ethanol solution, and
filtering the resultant solution under sterile conditions. This solution is also suitable for use in other methods of administration, such as addition to a bottle or bag for IV drip infusion.
Example 55 Orall Dosage Unit Composition
A capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
The above description fully discloses how to make and use this invention. This invention, however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.

Claims

What is claimed is:
1. A compound of the formula:
wherein
R1 is A-(B)t;
A is R6, R6C(=E), R6OC(=E), R6NR'C(=E), R6SC(=E),
R17NR'C(=NR'), R6OCH(R7)CO, R6NHCH (R7) CO, R6SCH (R7) CO, R6SO2 or R6SO;
B is an amino acid, SCH(R7)CO or OCH(R7)CO;
E is O or S;
R2 and R3 are independently H, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, Ar, Het, T-C1-6alkyl, T-C2-6alkenyl or
T-C2-6alkynyl, optionally substituted by R10;
T is Ar, Het or C3-7cycloalkyl;
R5, R6 and R7 are independently H, C1-6alkyl,
C3-11cycloalkyl, Ar, Het, T-C1-6alkyl, T-(CH2)nCH(T) (CH2) n, optionally substituted by one or two halogen, SR', OR', NR'2, C(=NR')NR'R17, NR'C(=NR')NR'R17 or C1-4alkyl;
Q is OH or NH2;
U' and U" are H or OH;
V is N or C-Y';
W is NR11, O or S;
Y and Y' are H, halogen, CF3, Ar, Het, NO2, CO-Z,
(CR8R9)n-R' or C2-6alkylene substituted by R8 and R9, or Y and Y' together form a five or six-membered alkyl, aryl or heterocyclic ring substituted at any stable position by R8 or R9;
Z is H, C1-6alkyl, OH, NR'R5, OR5 or an amino acid with a blocked or unblocked carboxy terminus;
R8 is independently H, OH, NR'R18, NR'C (=NR')NR'R17, NR'-NR'2, C1-4alkyl, (CH2)pAr or (CH2)qHet; R9 is independently H, C1-4alkyl, C2-6alkenyl, CO-Z , (CH2)pAr or (CH2)qHet, or, taken together, R8 and R9 are =O, =N-OR' or =N-NR'2;
R' is H, C1-4alkyl, Ar-C1-4alkyl;
R10 is -X'-(CH2)qNR12R13, X" [((CH2)rO)s]R14,
CH2X"[((CH2)rO)s]R14, or benzofuryl, indolyl, azacycloalkyl, azabicycloC7-11cycloalkyl or benzopiperidinyl, optionally substituted with C1-4alkyl;
R11 is H, C1-4alkyl, Ar-C1-4alkyl, or together with Y forms a five or six-membered cycloalkyl, aryl or heterocyclic ring substituted at any stable position by R8 or R9;
R12 and R13 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;
R14 is H, C1-4alkyl, C(=O)R15, C(=O)U"'[(CH2)mO]nR',
P(=O) (OM)2, CO2R15, C(=O)NR15R16, where M is a mono or
divalent metal ion, and U'" is NR' or O;
R15 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,;
R16 is H, C1-6alkyl or together with R15 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S;
R17 is R6, R6CO or R6SO2;
R18 is R17 or an amino acid with a blocked or unblocked amino terminus;
X' is CH2, O, S or NH;
X" is CH2, NR', O, S, SO or SO2;
m is 2-5;
n is 1 to 6;
p and q are 0 to 2; s is 1-6 and r is 1-3 within each repeating unit s; and t is 0 or 1; or
a pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 in which U an U' are H.
3. A compound according to claim 2 in which W is S.
4. A compound according to claim 2 in which W is N and V is C-Y.
5. A compound according to claim 4 in which R2 is CH2-T.
6. A compound according to claim 5 in which R3 is C1-6alkyl or CH2-T, optionally substituted with R10.
7. A compound according to claim 6 in which R1 is R6CO, R6OCO or R6SO2, or Ala, Val or Thr substituted on the amino group by R6CO, R6OCO or R6SO2.
8. A compound according to claim 7 in which Y is H,
C1-6alkyl, CO-(CHR8)(n-1)-R' CO-Z, (CHR9)n-OH,
C(-NOH)-C1-6alkyl or CHOH(CHR8)(n-1)-R'.
9. A compound according to claim 1 which is:
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpenty1]-5-propyl-thiazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpentyl]-4(5)-(cyclopentylcarbonyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-tert-butoxycarbonyl-amino-3-hydroxy- 5-phenylpentyl]-4(5)-(E)-1-(hydroxyimino)-2- methylpropyl)]imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethylbutanoyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2,2-dimethyl-3-butenoyl)imidazole; 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-D- valyl]amino-5-phenylpentyl}-4(5)-(2-methylpropionyl)- imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(3-methyl-1- oxobutyl)]amino-5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(1-oxobutyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methylpropionyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-propionylimidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-acetylimidazole;
2-[(3S,4S)-1-benzyl-4-t-butoxycarbonylamino-3-hydroxy-5- phenylpentyl]-5-propyl-thiazole;
2-[(3S,4S)-1-benzyl-4-(benzyloxycarbonyl-valyl)amino-3- hydroxy-5-phenylpentyl]-5-propyl-thiazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-methanesulfonyl)-L- valyl]amino-5-phenylpentyl}-4(5)-(2-methylpropionyl)- imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-ethylbutanoyl)-imidazole;
2-[(1R,3S,4S)-1-benzyl-4-t-butoxycarbonyl-amino-3-hydroxy-5- phenylpentyl]-4(5)-(2-methyl-1-oxobutyl)imidazole;
2-[(1R,3S,4S)-1-benzyl-4-[N-(benzyloxycarbonyl)-L- valyl]amino-3-hydroxy-5-phenylpentyl]-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'- isopropoxycarbonyl)-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-(l-oxo-3- phenylpropyl))-L-valyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole;
2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-acetyl)-L- valyl]amino-5-phenylpentyl}-4(5)-(2-methyl- propionyl)imidazole; or 2-{(1R,3S,4S)-1-benzyl-3-hydroxy-4-[N-(N'-benzyloxycarbonyl) L-threonyl]amino-5-phenylpentyl}-4(5)-(2- methylpropionyl)imidazole.
10. The use of a compound according to claim 1 in the manufacture of a medicament .
11. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. A method of treating disease states associated with infection by a retrovirus which comprises administering an effective amount of a compound according to claim 1.
13. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a compound according to claim 1.
14. A method of treating disease states .associated with HIV infection which comprises administering an effective amount of a compound according to claim 1 and AZT.
15. A process for preparing a compound of the formula:
Figure imgf000075_0001
wherein R1, R2, R3, R11, R1, Q, U', U", V, W and Y are as defined in claim 1; which comprises deprotecting a compound of the formula:
wherein
Figure imgf000075_0002
Q* is a protected amino group or a protected hydroxyl group; and
U* are independently H or a protected hydroxyl group.
16. A compound of the formula.
Figure imgf000076_0001
wherein
R1, R2, R3 and R11 are as defined in claim 1; and
Q* is a protected amino group or a protected hydroxyl group.
17. A compound of the formula:
Figure imgf000076_0002
wherein
R1, R2, R3 and R11 are as defined in claim 1;
R20 is H or C1-6alkyl; and
Q* is a protected amino group or a protected hydroxyl group.
PCT/US1992/007747 1991-09-11 1992-09-11 Peptide isoters containing a heterocycle as h.i.v. inhibitors WO1993005026A1 (en)

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JP5505523A JPH06510766A (en) 1991-09-11 1992-09-11 H. I. V. Heterocycle-containing peptide isosteres as inhibitors
EP92920181A EP0603309A1 (en) 1991-09-11 1992-09-11 Peptide isoters containing a heterocycle as h.i.v. inhibitors

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US5888992A (en) 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
NZ249789A (en) * 1992-03-11 1997-07-27 Narhex Ltd Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
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