EP0538396A1 - Inhibiteurs de proteases retrovirales - Google Patents

Inhibiteurs de proteases retrovirales

Info

Publication number
EP0538396A1
EP0538396A1 EP91914409A EP91914409A EP0538396A1 EP 0538396 A1 EP0538396 A1 EP 0538396A1 EP 91914409 A EP91914409 A EP 91914409A EP 91914409 A EP91914409 A EP 91914409A EP 0538396 A1 EP0538396 A1 EP 0538396A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
unsubstituted
groups
compound
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Withdrawn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
EP91914409A
Other languages
German (de)
English (en)
Other versions
EP0538396A4 (fr
Inventor
Geoffrey Bainbridge Dreyer
Jeffrey Charles Boehm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0538396A1 publication Critical patent/EP0538396A1/fr
Publication of EP0538396A4 publication Critical patent/EP0538396A4/xx
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compounds which are inhibitors of aspartic proteases, particularly of retroviruses.
  • 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
  • HIV-1 protease has been classified as an aspartic acid protease (Meek et al., Proc. Natl. Acad. Sci. USA. 88, 1841 (1989)).
  • the proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus.
  • retroviruses which lack the protease or contain a mutated form of it lack infectivity. See Katoh et al.,
  • Inhibitors of recombinant HIV protease have been reported (Dreyer et al., Proc. Natl. Acad. Sci USA. 86, 9752-56 (1989); Tomasselli et al. supra: Roberts et al.,
  • the limitations of current strategies for aspartic protease inhibition include ( 1 ) oral bioavailability; (2) plasma clearance lifetimes (e.g., through biliary excretion or
  • the present invention relates to a new inhibitors of retroviral and aspartic proteases. Unlike previously described inhibitors , the compounds of this invention are not analogues of peptide substrates possessing a scissile dipeptide mimetic. They also deviate substantially from peptide substrate-like structure in that they do not possess a conventional amino-to-carboxyl terminus orientation.
  • This invention comprises compounds having the structures particularly pointed out in the claims and described hereinafter which bind to retroviral proteases. These compounds are inhibitors of viral protease and are useful for treating disease related to infection by viruses.
  • This invention is also a pharmaceutical composition, which comprises an aforementioned compound and a pharmaceutically acceptable carrier therefor.
  • This invention further constitutes a method for treating viral diseases, which comprises administering to a mammal in need thereof an effective amount of an
  • B is, independently, an ⁇ -amino acid chosen from the group: Ala, Asn, Cys, Trp, Gly, Gln, lie, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or the carboxy group of the adjacent residue B, whichever is appropriate, and the carboxy group of B is bonded to the amino group of the adjacent residue B or the structure, whichever is appropriate; and
  • R 4 is:
  • halogen is F, Cl, Br or I, iii) hydroxyl
  • R 10 is, independently, H or C 1 -C 4 alkyl
  • a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl
  • R 5 (R 6 R 7 C)m-CO- wherein m 1-3 and R 5 , R 6 , and R 7 are independently: a) hydrogen,
  • R 5 , R 6 , and R 7 may be independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is C 3 -C 6 cycloalkyl;
  • R 5 (R 6 R 7 C)m W- wherein m 1-3 and W is OCO or SO 2 and R 5 , R 6 , and R 7 are as defined above, except R 5 , R 6 , and R 7 are not chlorine, fluorine or hydroxyl if they are adjacent to W;
  • R 8 -W- wherein R 8 is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
  • R 9 -W- wherein R 9 is phenyl or naphthyl unsubstituted or substituted with one or more substituents R 4 ;
  • N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R 4 ;
  • R 1 is C 1 -C 6 alkyl, benzyloxymethyl, 3-phenylpropyl or benzyloxy.
  • R 1 may be benzyloxymethyl or 3-phenylpropyl.
  • R 1 is benzyl.
  • X 1 is CbzAla, AlaAla, Val, CbzVal, Cbz or hydrogen.
  • the compounds of this invention are useful in the manufacture of a medicament, in particular, for a medicament for treating infection by retroviruses.
  • C 2 symmetric peptide compounds wherein R 1 and R 2 are C 1 -C 6 alkyl or aralkyl and X 1 and X 2 are single amino acids or mono- or dipeptides; these groups may be terminally substituted by common acyl groups or blocking groups commonly used in peptide synthesis, such as t-Boc or Cbz, are also preferred.
  • alkyl refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, l-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like; "alkoxy” represents an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom; "cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopen
  • heterocycle represents a stable 5- to 7-membered mono- or bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused " to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements examples include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl,
  • morpholinyl morpholinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, furyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sufone, and oxadiazolyl.
  • any variable e.g., A, B, R 1 , R 3 , ..., R 17 , heterocycle, substituted phenyl, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a geminal diol for example when R 6 and R 7 are simultaneously hydroxyl, is meant to be equivalent with a carbon-oxygen double bond.
  • the amino terminus is on the left and the carboxy terminus is on the right.
  • All chiral amino acids can occur as racemates, racemic mixtures, or individual enantiomers or diasteriomers, with all isomeric forms being included in the present invention.
  • ⁇ -Ala refers to 3-amino propanoic acid.
  • -Boc refers to the t-butyloxycarbonyl radical
  • Cbz refers to the carbobenzyloxy radical
  • i-Bu refers to isobutyl
  • Ac refers to the acetyl
  • Ph refers to phenyl
  • DCC refers to
  • DMAP refers to dimethylaminopyridine
  • HOBT refers to 1- hydroxybenzotriazole
  • NMM is N-methylmorpholine
  • DTT is dithiothreitol
  • EDTA is ethylenediamine tetraacetic acid
  • DIEA is diisopropyl ethylamine
  • DBU is 1, 8 diazobicyclo [5.4.0] undec-7-ene
  • DMSO is dimethylsulfoxide
  • DMF is dimethyl formamide
  • THF is tetrahydrofuran.
  • HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.
  • peptide moieties denoted by X 1 and X 2 are generally dipeptides or smaller. However, longer peptides which encompass the residues defined herein are also believed to be active and are considered within the scope of this invention.
  • residues or end groups may be used to confer favorable biochemical or physico-chemical properties to the compound.
  • hydrophilic residues may be used to confer desirable solubility properties or D-amino acids at the carboxy terminus may be used to confer resistance to exopeptidases.
  • Synthesis of compounds represented by the structure I can be achieved by pinacol coupling of N-protected alpha-amino aldehydes, P 2 NHCH(R - )CHO.
  • One representative procedure involves addition of the aldehyde to a mixture of TiCl 4 and magnesium-mercury amalgam in an inert solvent such as THF under inert atmosphere, as described by E. J. Corey, R. L. Danheiser, and s. Chandrasekaran, J. Org. Chem. 41, 260-266 (1976).
  • N-protected alpha-amino aldehydes are readily prepared from the respective N- protected alpha-amino acids P 2 N ⁇ CH(R 1 )CO 2 H, for example by reduction of the corresponding esters with diisobutyl aluminum hydride, by reduction of derived N-methyl, N-methoxy amides P2NHCH(R 1 )CONMe(OMe) with LiAlH4 (Fehrentz and Lau, Synthesis 676 (1983)), or by reduction to the N-protected alpha-amino alcohol followed by oxidation with DMSO-(COCl) 2 or SO 3 -pyridine (Review: Jurczak and Golebiowski,
  • the amino protecting group, P 2 is t-Boc-, Cbz-, p-toluenesulfonyl or another standard protecting group chosen as well know in the peptide art. Subsequent to pinacol coupling the protecting group P 2 can be removed and groups X 1 can be introduced. The foregoing procedures can be used to prepare all of the steroeoisomers of compounds represented by the structure.
  • compounds represented by the structure I can be prepared from D-(+)-mannitol by conversion to the diaziridine (compound B, Scheme 1).
  • the resulting diaziridine is reacted with appropriate nucleophiles such as (CH 3 ) 2 CuLi, to introduce the side-chain groups R 1 as illustrated in Scheme 1 and as detailed in the Examples.
  • the preparation of compound B has been disclosed by Y. Le Merrer et al., Heterocvcles 25, 541 - 548 (1987) and by A. Dureault, C. Greek and J.C. Depezay, Tet. Letters 27, 4157-4160 (1986).
  • R 1 CH 2 R 12
  • R 12 is hydrogen or is a group that forms a stableand reactive cuprate reagent, such as methyl, butyl, isopropyl, or other alkyl, alkenyl or aryl which is optionally substituted, for example with fluorine or alkoxy or protected hydroxyl.
  • compounds represented by the structure I can be prepared from D-(+)-mannitol by conversion to 1,6-ditosyl-3,4-(O-isopropylidene)mannitol as shown in Scheme 1, followed by treatment with a base such as KH or KOtBu in an inert solvent such as THF or ether to yield the diepoxide, 1,2:5,6-dianhydro-3,4-(O-isopropylidene)mannitol (compound C, Scheme 2).
  • a base such as KH or KOtBu
  • an inert solvent such as THF or ether
  • This diepoxide is reacted with appropriate carbon nucleophiles such as cuprate reagents (R 12 ) 2 CuLi or alkynylaluminum reagents to introduce the side-chain groups R 1 (Scheme 2).
  • cuprate reagents R 12
  • CuLi or alkynylaluminum reagents to introduce the side-chain groups R 1 (Scheme 2).
  • R 1 CH 2 R 12 where R 12 is a group that forms a stable and reactive cuprate reagent, as described above.
  • the resulting diol product is converted to the corresponding diamine with inversion of configuration at the alcohol carbons.
  • Either enantiomer of compounds of the structure can be prepared from the respective enantiomer of mannitol by the procedures shown in Schemes 1-2.
  • this invention is a process for preparing a compound of the formula:
  • N-benzimidazolyl where the fused benzene ring is unsubstituted or substituted by one or more substituents R 4 ;
  • R" and R'" are hydrogen, an amino-protecting group or taken together are N 2 , which comprises
  • Z is hydrogen, an alkali metal, such as Li, Na or K, or an earth metal, such as magnesium, or a transition metal, such as copper, aluminum, titanium, zinc or cadmium, or a species derived therefrom.
  • R'-Z are optionally substituted alkyl, aryl or heteroaryl lithium, alkyl, aryl or heteroaryl magnesium halides (eg. Grignard reagents), lithium dialkyl cuprate, lithium diaryl cuprate, or the alkali metal salts of optionally substituted alkyl alcohols, phenols or benzyl alcohols. Lithium diphenyl cuprate is especially useful.
  • the hydroxyls are converted to suitable displaceable groups, such as mesylate, tosylate, brosylate, benzoate, acetate and halide, by methods common in the art.
  • suitable displaceable groups such as mesylate, tosylate, brosylate, benzoate, acetate and halide.
  • the tosyl group is especially suitable and is formed by reacting the hydroxyl groups with tosyl chloride, for instance.
  • Suitable nitrogen nucleoph ⁇ es are those which are able to react with a displaceble group.
  • Unhindered organic amines or heterocyles, metal salts of amines, heterocycles or azide are useful.
  • an nitrogen containing group of the formula R'"R'vN-Z, wherein Z is as defined above and R"' and R'v are hydrogen, an amino-protecting group or taken together are N 2 (eg. azide) are useful.
  • a metal azide such as sodium or potassium azide, is preferable. Subsequent reduction of the azido groups provides amino groups.
  • Particularly useful intermediate compounds of this invention are:
  • R' is 1) R 12 , as defined for formula 1, 2) hydrogen, 3) C 1 -C 6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups or 4) C 3 -C 7 cycloalkyl.
  • the compounds of this invention are prepared by the solid phase technique of Merrifield (J. Am. Chem. Soc.85., 2149 (1964), or preferably by solution methods known to the art.
  • a combination of solid phase and solution synthesis may be used, as in a convergent synthesis in which di-, tri-, or tetra-peptide fragments may be prepared by solid phase synthesis and either coupled or further modified by solution synthesis.
  • the methods of peptide synthesis generally set forth in J. M. Stewart and J. D. Young, "Solid Phase Peptide Synthesis”. Pierce Chemical Company, Rockford, II (1984) or M. Bodonsky, Y.A. Klauser and M. A. Ondetti, "Peptide Synthesis” .
  • the tosyl or nitro group may be used for protection of the guanidine of Arg or the imidazole of His, and a suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ⁇ -amino group of lysine.
  • Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group.
  • Cysteine and other sulfur-containing amino acids may also be protected by formation of a disulfide with a thioalkyl or thioaryl group.
  • the protective groups are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment as known in the art.
  • the peptide is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide.
  • Solid phase synthesis is begun by covalently attaching the C terminus of a protected amino acid to a suitable resin, such as a benzhydrylamine resin (BHA), methylbenzhydrylamine resin(MBHA) or chloromethyl resin (CMR), as is generally set forth in U.S. Patent No.
  • a BHA or MBHA support resin is used for the carboxy terminus of the product peptide is to be a carboxamide.
  • a CMR support is generally used for the carboxy terminus if the produced peptide is to be a carboxyl group, although this may also be used to produce a carboxamide or ester.
  • Modification of the terminal amino group of the peptide is accomplished by alkylation or acetylation as is generally known in the art. These modifications may be carried out upon the amino acid prior to incorporation into the peptide, or upon the peptide after it has been synthesized and the terminal amino group liberated, but before the protecting groups have been removed.
  • acetylation is carried out upon the free amino group using the acyl halide, anhydride or activated ester, of the corresponding alkyl acid, in the presence of a tertiary amine.
  • Mono-alkylation is carried out most conveniendy by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a mild reducing agent, such as lithium or sodium cyanoborohydride.
  • Dialkylation as well as quatemization may be carried by treating the amino group with an excess of an alkyl halide in the presence of a base.
  • Solution synthesis of peptides is accomplished using conventional methods used to form amide bonds.
  • a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1 -hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • a suitable carbodiimide coupling agent such as N, N' dicyclohexyl carbodiimide (DCC)
  • catalysts such as 1 -hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP).
  • a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran (THF), in the presence of a base, such as N-methyl morpholine, or a trialkyl amine, with isobutyl chloroformate to form the mixed anhydride, which is subsequently reacted with the free amine of a second protected amino acid or peptide.
  • anhydrous solvent such as methylene chloride or tetrahydrofuran (THF)
  • a base such as N-methyl morpholine, or a trialkyl amine
  • the peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques.
  • the protecting groups may be removed as hereinbefore described, such as by hydrogenation in the presence of a palladium or platinum catalyst, treatment with sodium in liquid ammonia, hydrofluoric acid, trifluoroacetic acid or alkali.
  • Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be converted to carboxylic acids by treatment with an alkali metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an aqueousalcoholic solution. The acids may be converted to other esters via an activated acyl intermediate as previously described.
  • the amides and substituted amides of this invention are prepared from carboxylic acids of the peptides in much the same manner.
  • ammonia or a substituted amine may be reacted with an activated acyl intermediate of an amino-protected ⁇ -amino acid or oligopeptide to produce the amide.
  • Use of coupling reagents, such as DCC, is convenient for forming substituted amides from the carboxylic acid itself and a suitable amine.
  • the methyl esters of this invention may be converted to the amides, or substituted-amides, directly by treatment with ammonia, or a substituted amine, in methanol solution.
  • a methanol solution of the methyl ester of the peptide is saturated with ammonia and sti ⁇ ed in a pressurized reactor to yield the simple carboxamide of the peptides.
  • Procedures for the determination of the inhibition constant (Ki) by Dixon analysis are described in the art, e.g., in Dreyer, et al. Proc. Natl. Acad. Sci. U.S.A.. 86,9752-9756 (1989).
  • a peptidolytic assay is employed using the substrate Ac-Arg-AIa-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH 2 and recombinant HIV protease as in Strieker, et al.,
  • 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 excipient such as poly vinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • a preferred composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier.
  • Uposome may be formed by dispersion of the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization. A suitable method of making such compositions is more fully disclosed in copending Application Serial No. 06/763,484 and is incorporated herein by reference.
  • a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus.
  • An example of such a protein is the CD-4 T-cell glycoprotein, or a derivative thereof, such as sCD-4(soluble CD-4), which is reactive with the glycoprotein coat of the human
  • immunodeficiency virus HIV
  • proteins are disclosed in copending Application Serial No. 07/160,463, which is incorporated herein by reference. Similar targeting proteins could be devised, by methods known to the art, for other viruses and are considered within the scope of this invention.
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup or 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 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 glycerol monostearate or glycerol 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.
  • a liquid carrier 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 excipient such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipient such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the pulverized powders may also be compound with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • This invention is also a method for treating viral infection, particularly infection by retroviruses, which comprises administering a compound of formula I to a patient infected with a susceptible virus.
  • the method is particularly applicable to infection by the Human Immunodeficiency Virus, type 1.
  • the method of treatment comprises the administration orally, parenterally, bucally, trans-dermally, intravenously, intramuscularly, 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 selected from the range of 0.05 to 50 mg/kg of body weight. Dosage units will typically be from 50 to 1000 mg.
  • dosage units may be administered one to ten times daily for acute or chronic infection.
  • the dosage will be readily deterimined by one skilled in the art and will depend upon the age, weight and condition of the patient, and the route of administration. Combination therapy as described in Eur. PaL Appl. No. 337 714 at pages 42-47 are included herein.
  • Methyl lithium (18.9 mL, 23.6 mmol; 1.25 M in ether) was added slowly to a slurry of Cul (2.24 g, 11.8 mmol) in THF (25 mL) at -10°C for 15 min, then was cooled to -78°C.
  • a solution of compound B (265 mg, 0.59 mmol) in THF (2 mL) was added, and the mixture was maintained at -25°C overnight without stirring.
  • the mixture was -diluted with a solution of saturated NH 4 CI (100 mL) and concentrated aqueous NH 3 (10 mL), and extracted with ethyl acetate (3 ⁇ 25 mL).
  • the reaction mixture was stirred for 15 min and a solution of 51 mg (0.128 mmol) of the diamine 22 in 2.5 mL of DMF was added. The mixture was slowly warmed to room temperature and stirred overnight. Diluted with 75 mL of ethyl acetate, washed with 2 ⁇ 25 mL of 5% hydrochloric acid , 50 mL of 3 % sodium bicarbonate and solvents removed in vacuo. The residual oil was flash chromatographed (ethyl acetate: hexane 1 :4) to give 69 mg of 24 as a colorless solid.
  • the bisazide 29 was subjected to hydrogenation as usual over 25 mg of
  • a standard solution of isopropenyllithium was prepared by reacting 700 mg of lithium and 7 mL (75 mmol) of 2-bromopropene at 0° for Ih (in 75 mL of diethyl ether).16 mmol of this solution was added at -78° to a suspension of 1.5g (7.77 mmol) of copper(1) iodide and warmed to -45° over half hour. The dark brown mixture was recooled to -78° and a solution of 2.5 g (13.5 mmol) of the bisepoxide £ in 50 mL of diethyl ether was added. The reaction mixture was stirred at -78° for 1 h and slowly warmed to room temperature.
  • 1,6-Dibenzyloxy-3,4-O-isopropylidene-D-mannitol 42 (402 mg, 1.0 mmol), tosyl chloride (764 mg, 4.0 mmol) and pyridine (10 mL) were stirred for 3 days, poured into ice cold 3N HCl (30 mL) and extracted with EtOAc (3 ⁇ 25 mL). The extracts were washed with 3N HCl (3 ⁇ 25 mL), 5% NaHCO 3 (25 mL), and satd. aq.
  • MENDT buffer 50 mM Mes (pH 6.0; 2-(N-morpholino) ethanesulfonic acid), 1 m
  • reaction mixtures 37°C were quenched after 10-20 minutes with an equal volume of cold 0.6 N trichloroacetic acid, and, following centrifugation to remove precipitated material, peptidolysis products were analyzed by reverse phase HPLC (Beckman Ultrasphere ODS, 4.5 mm 25 mm; mobile phase; 5-20% acetonitrile/H 2 O - .1% TFA 915 min.), 20% acetonitrile/H 2 0 - .1% TFA (5 min) at 1.5 mlVmin, detection at 220 nm.
  • reverse phase HPLC Beckman Ultrasphere ODS, 4.5 mm 25 mm; mobile phase; 5-20% acetonitrile/H 2 O - .1% TFA 915 min.
  • 20% acetonitrile/H 2 0 - .1% TFA 5 min at 1.5 mlVmin, detection at 220 nm.
  • the compounds of this invention prefferably have Ki values less than 50 ⁇ M, preferably less than 10 ⁇ M and more preferably less than l ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Composés utiles en tant qu'inhibiteurs de protéases rétrovirales caractérisés par une structrue de la formule (I), dans laquelle les groupes X1 peuvent être consitués de 0 à 2 groupes d'acides aminés alpha substitués en fin de chaîne par de l'hydrogène ou par l'un parmi un certain nombre de groupes terminaux et le groupe R1 peut être sélectionné parmi un large éventail de radicaux d'hydrocarbure. On vise à obtenir des composés présentant une constante Ki d'inhibition de l'activité des protéases inférieure à 50.
EP91914409A 1990-07-06 1991-07-03 Inhibiteurs de proteases retrovirales Withdrawn EP0538396A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54945690A 1990-07-06 1990-07-06
US549456 1990-07-06

Publications (2)

Publication Number Publication Date
EP0538396A1 true EP0538396A1 (fr) 1993-04-28
EP0538396A4 EP0538396A4 (fr) 1994-04-13

Family

ID=24193103

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91914409A Withdrawn EP0538396A1 (fr) 1990-07-06 1991-07-03 Inhibiteurs de proteases retrovirales

Country Status (8)

Country Link
EP (1) EP0538396A1 (fr)
JP (1) JPH06501681A (fr)
AU (1) AU8320691A (fr)
IE (1) IE912379A1 (fr)
MX (1) MX9100120A (fr)
PT (2) PT98228A (fr)
WO (1) WO1992000948A1 (fr)
ZA (1) ZA915271B (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5354866A (en) * 1989-05-23 1994-10-11 Abbott Laboratories Retroviral protease inhibiting compounds
US5552558A (en) * 1989-05-23 1996-09-03 Abbott Laboratories Retroviral protease inhibiting compounds
US5362912A (en) * 1989-05-23 1994-11-08 Abbott Laboratories Process for the preparation of a substituted diaminodiol
DE69333270T2 (de) 1992-03-11 2004-08-05 Narhex Ltd. Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
RU2126794C1 (ru) * 1992-03-11 1999-02-27 Нархекс Лимитед Аминопроизводные оксо- или гидроксизамещенных гидразинов, способ их получения и фармацевтические композиции для ингибирования ретровирусной протеазы
CZ113393A3 (en) * 1992-06-19 1994-03-16 Lilly Co Eli Hiv protease inhibitor, useful for aids treatment, process of its preparation and pharmaceutical preparation in which said inhibitor is comprised
WO1994013629A1 (fr) * 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Derives de mannitol et leur utilisation comme inhibiteurs de l'aspartyle-protease
KR100187990B1 (ko) * 1992-12-29 1999-06-01 스티븐 에프. 웨인스톡 레트로바이러스성 프로테아제 억제 화합물 제조용 합성 중간체
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
AU1904599A (en) * 1997-12-08 1999-06-28 Scripps Research Institute, The Hiv/fiv protease inhibitors having a small p3 residue
US6803466B1 (en) * 1997-12-08 2004-10-12 The Scripps Research Institute HIV/FIV protease inhibitors having a small P3 residue
US6362165B1 (en) 1999-03-30 2002-03-26 Pharmacor Inc. Hydroxyphenyl derivatives with HIV integrase inhibitory properties
US6313177B1 (en) 1999-04-30 2001-11-06 Pharmacor Inc. D-mannitol derivatives as HIV aspartyl protease inhibitors
EP1406617A1 (fr) 2001-07-10 2004-04-14 Elan Pharmaceuticals, Inc. Diaminediols pour le traitement de la maladie d'alzheimer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0428849A2 (fr) * 1989-09-28 1991-05-29 Hoechst Aktiengesellschaft Inhibiteurs de protéases rÀ©trovirales
WO1991018866A2 (fr) * 1990-06-01 1991-12-12 The Du Pont Merck Pharmaceutical Company 1,4-diamino-2,3-dihydroxybutanes

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3855297A (en) * 1971-03-10 1974-12-17 Sterling Drug Inc 1,1{40 -bridged-bis{8 n-(alkyl)-2-aminoethanols{9
US3987029A (en) * 1974-01-23 1976-10-19 American Cyanamid Company Antibacterial antibiotics AM31α, AM31β and AM31γ
HU176101B (en) * 1977-12-29 1980-12-28 Gyogyszerkutato Intezet Process for producing bis-bracket-nitrozo-ureido-bracket closed-polyol derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0428849A2 (fr) * 1989-09-28 1991-05-29 Hoechst Aktiengesellschaft Inhibiteurs de protéases rÀ©trovirales
WO1991018866A2 (fr) * 1990-06-01 1991-12-12 The Du Pont Merck Pharmaceutical Company 1,4-diamino-2,3-dihydroxybutanes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMISCHE BERICHTE vol. 92 , 1959 , WEINHEIM DE pages 2506 - 2515 L. VARGHA ET AL. '1.2:5.6-Dianhydro-3.4-is opropyliden-d-sorbit und l-idit' *
JOURNAL OF ORGANIC CHEMISTRY vol. 54, no. 22 , 1989 , EASTON US pages 5324 - 5330 A. DUREAULT ET AL 'Nucleophilic opening of chiral bis(aziridines): a route to enantiomerically pure alpha amino aldehydes or acids and polysubstituted piperidines' *
See also references of WO9200948A1 *

Also Published As

Publication number Publication date
WO1992000948A1 (fr) 1992-01-23
ZA915271B (en) 1992-05-27
IE912379A1 (en) 1992-01-15
JPH06501681A (ja) 1994-02-24
PT98227A (pt) 1992-05-29
MX9100120A (es) 1992-02-28
PT98228A (pt) 1993-08-31
AU8320691A (en) 1992-02-04
EP0538396A4 (fr) 1994-04-13

Similar Documents

Publication Publication Date Title
EP0538366A1 (fr) Inhibiteurs de proteases retrovirales
EP0538396A1 (fr) Inhibiteurs de proteases retrovirales
EP0665215A1 (fr) 1,4-diamino-2,3-dihydroxybutanes
EP0352000A2 (fr) Peptides liant des protéases rétrovirales
IE922316A1 (en) Retroviral protease inhibitors
WO1990000399A1 (fr) Peptides de liaison de protease retrovirale
EP1165492A1 (fr) Derives d'hydroxyphenyle possedant des proprietes inhibitrices de l'integrase du vih
CA2001265C (fr) Nouveaux analogues de substrats de peptidase
AU666532B2 (en) Dithiolanylglycine-containing HIV protease inhibitors of the hydroxyethylene isostere type
EP0538383A1 (fr) Inhibiteurs de proteases aspartiques
EP0538374A1 (fr) Inhibiteurs de proteases aspartiques
OA12164A (en) Protease inhibitors and their pharmaceutical uses.
SAKURAI et al. Studies of HIV-1 Protease Inhibitors. I. Incorporation of a Reduced Peptide, Simple Aminoalcohol, and Statine Analog at the Scissile Site Substrate Sequences
WO1991010442A1 (fr) Inhibiteurs de protease de l'hiv (virus de l'immunodeficience humaine)
US6362165B1 (en) Hydroxyphenyl derivatives with HIV integrase inhibitory properties
AU8205491A (en) 1,4-diamino-2,3-dihydroxybutanes
EP1049481B1 (fr) Agents antineoplasiques synthetiques derives de la dolastatine 15 et leurs procedes de fabrication
WO1992015319A1 (fr) Agents inhibiteurs de protease de l'hiv
KR960000078B1 (ko) 인간 면역 결핍 바이러스 프로테아제의 억제 화합물 및 그의 제조방법
KR970011577B1 (ko) 항 에이즈(aids) 효과를 갖는 신규한 인간 면역 결핍 바이러스 프로테아제의 억제 화합물 및 그의 제조방법
WO1995021186A1 (fr) Derives de difluorostatone macrocyclique utiles en tant qu'agents antiviraux
CA2302144A1 (fr) Derives hydroxyphenyliques ayant des proprietes inhibitrices de vih-integrase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930120

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

RHK1 Main classification (correction)

Ipc: C07C271/22

A4 Supplementary search report drawn up and despatched

Effective date: 19940221

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19940526