EP0603309A1 - Isosteres peptidiques contenant un heterocycle utilises comme inhibiteurs du v.i.h. - Google Patents

Isosteres peptidiques contenant un heterocycle utilises comme inhibiteurs du v.i.h.

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Publication number
EP0603309A1
EP0603309A1 EP92920181A EP92920181A EP0603309A1 EP 0603309 A1 EP0603309 A1 EP 0603309A1 EP 92920181 A EP92920181 A EP 92920181A EP 92920181 A EP92920181 A EP 92920181A EP 0603309 A1 EP0603309 A1 EP 0603309A1
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EP
European Patent Office
Prior art keywords
hydroxy
phenylpentyl
benzyl
amino
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92920181A
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German (de)
English (en)
Inventor
Geoffrey Bainbridge Dreyer
John Gerald Gleason
Thomas Downing Meek
Scott Kevin Thompson
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0603309A1 publication Critical patent/EP0603309A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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.

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Abstract

L'invention concerne de nouveaux composés contenant un isostère hétérocyclique de la formule (I), lesquels inhibent la réplication du virus de l'immunodéficience humaine.
EP92920181A 1991-09-11 1992-09-11 Isosteres peptidiques contenant un heterocycle utilises comme inhibiteurs du v.i.h. Withdrawn EP0603309A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US75775191A 1991-09-11 1991-09-11
US757751 1991-09-11
PCT/US1992/007747 WO1993005026A1 (fr) 1991-09-11 1992-09-11 Isosteres peptidiques contenant un heterocycle utilises comme inhibiteurs du v.i.h.

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EP0603309A1 true EP0603309A1 (fr) 1994-06-29

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EP (1) EP0603309A1 (fr)
JP (1) JPH06510766A (fr)
AU (1) AU2642492A (fr)
MX (1) MX9205222A (fr)
PT (1) PT100865A (fr)
WO (1) WO1993005026A1 (fr)
ZA (1) ZA926933B (fr)

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US6071895A (en) 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
ATE253050T1 (de) 1992-03-11 2003-11-15 Narhex Ltd Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
US5888992A (en) 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
EP0633881B1 (fr) * 1992-03-11 2003-10-29 Narhex Limited Derives amines d'hydrocarbures a substitution oxo et hydroxy
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
AU4953796A (en) * 1995-03-15 1996-10-02 Sanyko Company, Limited Dipeptide compounds having ahpba structure
NZ520075A (en) 2000-02-04 2004-02-27 Pfizer Prod Inc Heterocyclic amide derivatives
EP1450901A4 (fr) 2001-12-10 2005-05-25 Bristol Myers Squibb Co Composes de (1-phenyl-2-heteroaryl)ethyl-guanidine utiles en tant qu'inhibiteurs de la f1f0 atp hydrolase mitochondriale

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IL89900A0 (en) * 1988-04-12 1989-12-15 Merck & Co Inc Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them
IL91307A0 (en) * 1988-08-24 1990-03-19 Merck & Co Inc Hiv protease inhibitors and pharmaceutical compositions for the treatment of aids containing them
EP0594586A4 (en) * 1990-01-09 1994-08-17 Smithkline Beecham Corp Hiv protease inhibitors
CA2057369A1 (fr) * 1990-12-17 1992-06-18 Ann E. Decamp Production stereocontrolee de composes de type hydroxyester, hydroxyamide et lactone d'aldehydes chiraux de type –-aminoaldehydes

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Title
See references of WO9305026A1 *

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JPH06510766A (ja) 1994-12-01
MX9205222A (es) 1993-03-01
AU2642492A (en) 1993-04-05

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