EP0538396A1 - Inhibitors of retroviral proteases - Google Patents

Inhibitors of retroviral proteases

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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
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Prior art keywords
substituted
alkyl
unsubstituted
groups
compound
Prior art date
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EP91914409A
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German (de)
English (en)
French (fr)
Other versions
EP0538396A4 (enrdf_load_stackoverflow
Inventor
Geoffrey Bainbridge Dreyer
Jeffrey Charles Boehm
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0538396A1 publication Critical patent/EP0538396A1/en
Publication of EP0538396A4 publication Critical patent/EP0538396A4/xx
Withdrawn legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • 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.

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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
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
DE69333270T2 (de) 1992-03-11 2004-08-05 Narhex Ltd. Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
NZ249789A (en) * 1992-03-11 1997-07-27 Narhex Ltd Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
EP0575097B1 (en) * 1992-06-19 2000-11-02 Eli Lilly And Company 2,3-Bis-carboxamidomethyl substituted oxiranes as inhibitors of HIV protease and their use for the treatment of AIDS
WO1994013629A1 (en) * 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
KR100333016B1 (ko) * 1992-12-29 2002-11-22 아보트 러보러터리즈 레트로바이러스성프로테아제억제화합물,이의제조방법및이를함유하는약제학적조성물
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
WO1999029311A1 (en) * 1997-12-08 1999-06-17 The Scripps Research Institute 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
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