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WO1993023373A1 - HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX - Google Patents

HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX Download PDF

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Publication number
WO1993023373A1
WO1993023373A1 PCT/EP1993/000592 EP9300592W WO9323373A1 WO 1993023373 A1 WO1993023373 A1 WO 1993023373A1 EP 9300592 W EP9300592 W EP 9300592W WO 9323373 A1 WO9323373 A1 WO 9323373A1
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Prior art keywords
alkyl
product
cycloalkyl
hydroxy
dmso
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PCT/EP1993/000592
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English (en)
Inventor
Colin William Greengrass
Geoffrey William Gymer
David William Thomas Hoople
Stephen Derek Albert Street
Peter John Whittle
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Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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Priority to JP5519802A priority Critical patent/JPH07503482A/ja
Priority to EP93906530A priority patent/EP0641319A1/fr
Publication of WO1993023373A1 publication Critical patent/WO1993023373A1/fr
Priority to FI945438A priority patent/FI945438A0/fi
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to certain peptide derivatives containing a heterocyclic group which are useful in the treatment or prophylaxis of human retroviral infections.
  • HIV human immunodeficiency virus
  • Infection with HIV is characterised by progressive breakdown of the immune system and CNS dysfunction. Severely immune deficient patients suffer from a wide range of opportunistic infections (e.g. pneuroocvstis carinii, human cyteimegalovirus, or Candida), and cancers such as Kaposi's sarcoma. Loss of cells, particularly
  • CD4 + lymphocytes following infection with HIV is an important factor in the progressive impairment of immune function.
  • the infection of cells of raor ⁇ x-yte/macrophage lineage with HIV also contributes to the observed pathology. Unas, successful infection of CD4 cells by HIV is a key step in the disease process.
  • HIV is a retrovirus; it encodes its genetic information in RNA, which is converted into DNA after the virus enters the host cell.
  • An essential step in the retroviral replication cycle is the processing of an initial polypeptide precursor into mature structural and replicative proteins. This processing is carried out by a virus-coded protease and, in the absence of this enzyme activity, viral replication is blocked.
  • proteases both in a cell-free assay and in infected cells and, in addition, show antiviral activity in tissue culture assays. This activity renders such compounds useful for the treatment and prophylaxis of retroviral infections, in particular, those caused by HIV.
  • the invention provides cxfmp ⁇ unds of the formula:-
  • R 1 is C 1 -C 6 alkyl C 3 -C 8 cycloalkyl, aryl, heterocyclyl or R 7 R 8 NCO;
  • R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl (C 1 -C 4 )alkyl, aryl (C 1 -C 4 ) alkyl, or heterocyclyl (C 1 -C 4 ) alkyl;
  • R 3 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 4 )- alkenyl, heterocyclyl(C 1 -C 4 )alkyl or heterocyclyl- (C 2 -C 4 )alkenyl;
  • R 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl or heterocyclyl;
  • R 5 and R 6 are each independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkyl substituted by C 1 -C 4 alkoxy, hydroxy or NR 7 R 8 ; or R 5 and R 6 are linked to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, piperazine or N-(C 1 -C 4 alkyl)piperazine group;
  • each of R 7 and R 8 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl or R 7 and R 8 may be joined together to form, with the nitrogen to which they are attached, a 4 to 8 membered nitrogen-containing heterocyclic group; each of R 9 , R 10 , R 11 and R 12 is independently H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, or R 6 and R 10 , or R 11 and R 12 may be joined together to form a 3 to 8 membered carbocyclic ring;
  • X is a 4-10 membered mono- or bicyclic heterocyclic group containing carbon ring atoms and one ring nitrogen atom through which the group is attached to the adjacent carbonyl group; the group may be saturated or partially unsaturated and, in addition to the -(CR 11 R 12 ) -NR 5 R 6 substituent, it may be substituted by up to 4 further substituents each independently chosen from F, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, OH, C 1 -C 6 alkoxy or NR 7 R 8 ;
  • heterocyclyl means a 4 to 6 membered heterocyclic group containing as
  • heteroatoms up to four nitrogen atoms, or an oxygen or sulphur atom optionally with one or two nitrogen atoms.
  • the ring may be aromatic, or fully or partially saturated and may optionally be benzo-fused or substituted by C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, C 2 -C 5 alkanoyl, C 1 -C 4 alkoxy, halo, hydroxy, oxo or aryl.
  • Preferred heterocyclyl groups are pyridyl, pyrimidinyl, thienyl, isoquinolyl and tetrazolyl.
  • aryl means phenyl optionally substituted with from 1 to 3 substituents each independently selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkoxy, C 2 -C 5 alkanoyl, hydroxy, halo, C 1 -C 4 alkyl fully or partially substituted by fluorine, C 1 -C 4 alkoxy fully or partially substituted by fluorine, phenyl, phenoxy, benzyl, benzoyl, phenylSO 2 -, pyridyl, tetrazolyl, phenyltetrazolyl, NR 7 R 8 or
  • Halo means fluoro, chloro, bromo or iodo.
  • Alkyl and alkoxy groups containing 3 or more carbon atoms may be branched or straight-chain. Any alkyl, alkoxy or cycloalkyl group included in the above definitions may optionally be fully or partially substituted by fluorine.
  • bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a corpound of the formula (I).
  • examples include ester derivatives formed between the free hydroxy group in the compound of formula (I) and, for example, an amino acid (such as L-valine).
  • aryl is preferably phenyl and heterocyclyl is preferably oxetan-3-yl or 1,1-dioxothietan-3-yl.
  • R 1 is preferably t-butyl, isopropyl, oxetan-3-yl or 1,1-dioxothietan-3-yl and (CR 9 R 10 ) is absent; or R 1 is phenyl and
  • n is CH 2 ; or R 1 is H 2 NCO-, CH 3 NHCO- or (CH 3 ) 2 NCO- and
  • (CR 9 R 10 ) n is CH 2 or CH(CH 3 ) .
  • Particularly preferred are compounds wherein R 1 is t-butyl, isopropyl or oxetan-3-yl and n is 0, most particularly where R 1 (CR 9 R 10 ) - is t-butyl.
  • aryl is preferably phenyl and heterocyclyl is for example pyridyl, pyrimidinyl or thienyl.
  • R 2 is preferably aryl(C 1 -C 4 ) alkyl; benzyl is particularly preferred.
  • aryl is preferably phenyl and heterocyclyl is preferably pyridyl, pyrimidinyl or thienyl.
  • R 4 is preferably C 1 -C 6 alkyl; particularly preferred are isopropyl and sec-butyl (valine or isoleucine derivatives).
  • the heterocyclic group X is preferably a 4-6 membered saturated or mor-ounsaturated group and is most preferably an azetidine, pyrrolidine, tetrahydropyridine or piperidine group; piperidine being particularly preferred.
  • R 7 and R 8 are preferably H and m is preferably 0 or 1.
  • aryl is phenyl, unsubstituted or substituted as defined in the term aryl above, and heterocyclyl is for example pyridyl, pyrimidinyl, lsoquinolyl or thienyl.
  • R 3 is preferably aryl(C 1 -C 4 )alkyl or aryl(C 2 -C 4 )alkenyl; R 3 is most preferably benzyl optionally substituted in the phenyl ring by methyl, chloro, trifluoromethyl, trifluoromethoxy, pivaloyl, OH,
  • CONMe 2 phenoxy, phenylsulphonyl or pyridyl or is 3-phenylpropyl or 3-phenyl-prop-2-enyl.
  • Particular and preferred individual compounds include:
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament, especially for use in the treatment or prophylaxis of human retroviral
  • the invention also includes the use of a compound of the formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prophylaxis or treatment of retroviral infections.
  • the invention further includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the antiviral activity of the compounds of general formula (I) is established using in vitro assay systems.
  • the co ⁇ rpounds of formula (I) are able to completely protect human T-cell line H9 for 7 days from the progressive effects of HIV infection.
  • Untreated virus-infected cells display typical cytopathic effects such as formation of syncytia and cell death, m addition, virus particles produced from virus-infected cells treated with a compound of formula (I) are non-infectious.
  • infections which may be treated or prevented fcy the compounds of formula (I) include those caused by human or animal refcroviruses, especially EHV-1.
  • Clinical conditions which may therefore be treated or prevented include AIDS, ARC, and HEV related dementia.
  • the compounds may also be used to block disease progression in symptomless infected individuals.
  • the compounds of formula (I) can be prepared using the coupling and protection techniques which are familiar to those skilled in the art of peptide chemistry.
  • 4-ketopiperidine group is carried through to the coupling stage and the reductive animation conducted on the coupled, protected product (XII) to give the product (IX) which is then deprotected to give the final product as before.
  • the process can be performed with the appropriate group present in the starting material of formula (II), or it can be performed using a coitpound of formula (IV) wherein R 1 is t-butyl (BOC derivative), and this is then removed after coupling to the intermediate (VIII) for exairple by treatment with trifluoroacetic acid.
  • the free amine is then reacylated, for exairple, in the case where R 1 is oxetanyl and n is O, by reaction with 3-oxetanyloxycarbonyloxysuccinimide, before final removal of the protecting groups.
  • the above sequences can be adapted as appropriate to be performed with any of the variants claimed for R 1 to R 12 by appropriate selection of starting materials.
  • amino-protecting groups include but are not limited to aryloxycarbonyl such as benzyloxycarbonyl; substituted or unsubstituted aralkyl such as benzyl, trityl, benzhydryl and 4-nitrobenzyl; benzylidene;
  • arylthio such as phenylthio, nitrqphenylthio and trichlorophenylthio
  • phosphoryl derivatives such as dimethylphosphoryl and O,O-dibenzylphosphoryl
  • trialkylsilyl derivatives such as trimethylsilyl
  • the preferred amino protecting group for use in the above sequence is t-butoxycarbonyl.
  • Procedures for substituting said group on a given amino group are well known. In general they comprise acylating the appropriate amino compound with the corresponding carbonyl chloride or anhydride in a reaction inert solvent, e.g. water, methylene chloride or tetrahydrofuran, in the presence of a base (acid acceptor) e.g., sodium or potassium hydroxide when water is solvent; and, when an organic solvent is used, in the presence of a tertiary amine such as a triethylamine or pyridine.
  • a reaction inert solvent e.g. water, methylene chloride or tetrahydrofuran
  • a base e.g., sodium or potassium hydroxide when water is solvent
  • a tertiary amine such as a triethylamine or pyridine.
  • pH of the reaction is typically held at about pH 8-10
  • the protected amino groups are converted to the unprotected amino groups by procedures known to those skilled in the art as appropriate to the particular group employed.
  • the t-butoxycarbonyl group is, for exairple, readily removed by treatment with dichloromethane saturated with hydrogen chloride gas.
  • hydroxy-protecting groups are also known and are described in the literative sources already cited above.
  • a preferred hydroxy protecting group is t-butyldimethylsilyl. This is introduced as previously described and is readily removed by treatment with tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature.
  • esters derived from N-hydroxyphtoalimide, N-hydroxysuccinimide or 1-hydroxybenzotriazole are used in peptide syntheses.
  • a dehydrative coupling agent is used to form the activated ester.
  • Such coupling agents are 1-cyclohexyl-3-(2-morpholincethyl)carbodiimide, N,N'dicyclohejylcarbodiimide, N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, ethoxyacetylene, diphenylketene and N-ethyl-5-phenyl-isoxazoliner-3'-sulfonate.
  • the reaction conditions for using such coupling agents are well described in the literature.
  • the various protecting groups can be removed by the appropriate techniques previously discussed, and the compounds of the formula (I) isolated and purified using conventional procedures such as recrystallisation or column dircimatography.
  • N-t-butoxycarbonyl (BOC-) derivatives of the naturally occurring amino acids used in the synthesis of the compounds of the formula (V) are commercially available as are their
  • hvdroxysuccinimido esters The corresponding intermediates derived from unnatural amino acids can be prepared by standard procedures (see, for exairple, M. J. O'Donnell et. al., J. Amer. Chem. Soc., 1989, 111, 2353).
  • the co ⁇ p ⁇ unds of formula (II) can be prepared from the corresponding t-butyloxycarbonyl-protected amino-aldehydes (see D. H. Rich et. al., J. Org. Chem., 1978, 43, 3624 and Y. Hamada et. al., Chem. Pharm. Bull.. 1982, 30(5), 1921) by reaction with ethyl propiolate (see A. H. Fray et. al., J. Org. Chem., 1986, 51, 4828), followed by reduction to give the
  • Compounds of formula (XIII) can be prepared by conventional synthetic methods, for example by coupling a N-protected amino acid with a N-substituted or N-protected 4-aminomethyl piperidine derivative.
  • the invention includes a process for preparing a compound of the formula (I) which comprises removing the protecting groups from a compound of the formula:
  • X 1 is either H or a selectively removable hydroxy- protecting group and Y 1 is either R 6 , or a selectively removable nitrogen-protecting group and R 1 to R 6 are as previously defined with the proviso that at least one of X 1 and Y 1 is a protecting group, and isolating the compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.
  • the preferred protecting group for X is t-butyldimethylsilyl; this is removed by treatment with tetra-n-butylammonium fluoride in an organic solvent, preferably tetrahydrofuran.
  • the preferred protecting group for Y is benzyloxycarbonyl; this is removed by catalytic hydrogenation.
  • novel intermediates of formulae (IX) , (XI) , (XII) and (XIV) also form part of this invention.
  • Examples of pharmaceutically acceptable salts of the ccarpounds (I) are acid-addition salts, e.g. sulfates, bisulfates, phosphates, acetates, lactates, maleates, mesylates, fumarates, citrates, succinates and gluconates.
  • acid-addition salts e.g. sulfates, bisulfates, phosphates, acetates, lactates, maleates, mesylates, fumarates, citrates, succinates and gluconates.
  • the compounds (I) will be administered by any suitable route, e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal) , rectal, nasal, topical (including buccal and sublingual) or vaginal routes.
  • parenteral e.g. subcutaneous, intravenous, int ramuscular, or intradermal
  • nasal including buccal and sublingual
  • vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal)
  • nasal, topical (including buccal and sublingual) or vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intradermal)
  • nasal including buccal and sublingual
  • vaginal routes e.g. by the oral, parenteral (e.g. subcutaneous, intravenous, int ramuscular, or intra
  • Rectal formulations will be in suppository form, and vaginal formulations as, for example, tampons, creams or foams.
  • formulations will be in sterile form, e.g. as vials for injection containing aqueous or non-aqueous diluents, buffers and
  • the appropriate dose of the anti-retroviral agents of the formula (I) will be from 1-50 mg/kg/day, preferably 1-25 mg/kg/day given in up to six divided doses per day. There may be of course instances where higher or lower dosages are merited according to the age, weight, degree of illness and response of the patient, and appropriate therapy will be as determined by the medical practitioner.
  • the c ompounds of formula (I) may be used in combination with other drugs, same of which may potentiate their activity.
  • drugs include the following:- (a) Reverse transcriptase inhibitors such as AZT, ddI, ddC, foscarnet, TIBO compounds, dipyridodiazepinones or
  • gp120-CD4 blockers such as dextran sulphate and soluble CD4, including its combination with toxic agents such as
  • interleukins or colony sti-mulating factors e.g. GM-CSF.
  • the compounds of the invention were evaluated for antiviral activity by dissolving the test compound in 50 ⁇ l of DMSO and diluting in REMI 1640, a complex salts solution with a pH of 7.2, to 1 mg/ml. Testing was performed at 0.001, 0.01, 0.1, 1 and 10 as ⁇ g/ml against HIV 1 (strain IIIB) in a human T-cell line (H9) . Untreated control infections were initiated at the same time.
  • tissue culture supernatants were titrated for the presence of infectious virus on C8166 cells (human T-cell line).
  • C8166 cells human T-cell line
  • 5 and 7 cultures were examined for appearance of syncytia.
  • Control infections, untreated with drug, show typical viral cytopathic effects, including formation of syncytia and cell death.
  • the IC 100 quoted is the lowest test concentration affording coirplete protection to the culture. Using this test method, the compounds had an IC 100 values in the range 0.1 to 10.0 ⁇ g/ml.
  • intermediate (3b) by reductive amination of intermediate (3a) with metiiylamine.
  • sucoinimide esters were prepared from the appropriate alcohol using the method described above.
  • N,N- dimethylformamide (5 ml) was added to an active ester solution previously prepared by stirring together the product from
  • Example 3 The product from Example 3 (1.75 g) in tetrahydrofuran (150 ml) was treated with 1M tetra-n-butylammonium fluoride in
  • Example 7 The title compound was prepared by the same procedure as described for Example 7 by reacting the product from Example 6 with ammonium acetate, m.p.161°. Found: C,68.32; N,8.59; N,9.03.
  • Example 1 by reacting the amine derived from 1-(N-t-butoxycarbonyl)-(S)-valyl-4-(pyrrolidin-1-yl)piperidine with an active ester derived from the product from intermediate
  • the title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 12 with an active ester derived from the product from intermediate preparation (2b).
  • N.M.R. (DMSO-d 6 ) ⁇ 0.8(m,6H); 1.0(t,3H); 1.35(s,9H); 1.4-1.8(m,4H); 1.9(m,1H); 2.5(m,2H); 3.0-3.2 (m,2H); 3.9-4.3 (m,3H); 4.5(m,1H); 5.1(s,2H); 6.7 & 6.9(2x d,1H); 7.4(m,5H).
  • the title compound was prepared by the same procedure as described for Example 3 by reacting the amine derived from the product of Example 17 with an active ester derived from the product from intermediate preparation (2b).
  • Example 7 by reacting the product from Example 23 with methylamine.
  • the title compound was prepared from the product from Example 24 by the same procedure as described for Example 2, m.p. 149-151°.
  • the title compound was prepared from the product from Example 42 by the same procedure as described for Example 2, m.p. 145-147° .
  • CH 2 Cl 2 requires C,68.36; H,9.18; N,7.05%.
  • a solution of the product from Example 47 (45 g) in acetic acid (300 ml) was treated with platinum oxide (0.5 g) and was stirred under an atmosphere of hydrogen at 60 psi (4.1 bar) and 60°C for 24 hours before the solvent was removed by evaporation under vacuum.
  • a solution of the residue in methylene chloride (300 ml) was treated at room teiiperature with di-tert-butyl dicarbonate (50.2 g) and stirred for a further 18 hours.
  • N-t-butoxycarbonyl valine (1.91 g) , 1-hydroxybenzotriazole hydrate (1.31 g) , 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g) and N,N-diisopropylethylamine (7.7 ml) in methylene chloride (100 ml) for 30 minutes was treated with the product from
  • N.M.R. (DMSO-d 6 ) 5 0.8(m,6H) ; 1.0(m,2H) ; 1.35(s,9H) ; 1.65(m,3H) ; 1.9 (m,1H) ; 2.5(m,1H) ; 2.85-3.05 (m, 3H) ; 4.0(m,1H) ; 4.2 (m,1H) ;
  • Example 58 The title compound was prepared from the product of Example 58 by the same procedure as described for Example 49.
  • Example 59 The title compound was prepared from the product of Example 59 by the same procedure as described for Example 50. Purification fcy chromatography on silica-gel, eluting with hexane-ethyl acetate (3:2) gave the title compound as a colourless oil.
  • the title ccatpound was prepared from the product of Example 60 by the same procedure as described for Example 51, m.p. 193-196°.
  • N.M.R. (DMSO-d 6 ) ⁇ 0.1(s,6H); 0.8(m,6H); 0.9(s,9H); 0.95-1.25(m,3H); 1.3(s,9H); 1.6(m,2H); 1.75(m,3H); 1.95(m,1H); 2.4-2.95-3.1(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45-3.7 (m,2H) ; 3.9 (m,1H) ; 4.15 (m, 1H) ; 4.55 (m,1H) ; 6.75 (m,1H) ; 7.05-7.35 (m, 9H) ; 7.95 & 8.05 (2xd,1H) .
  • N.M.R. (EMSO-d 6 ) ⁇ 0.75(m,6H); 1.0(m,4H); 1.3(s,9H); 1.2-1.8(m,5H); 2.5-3.05(m,10H); 3.2(s,3H); 3.35(t,2H); 3.45(m,1H); 3.55(m,1H); 3.8(m,1H); 4.1(m,1H); 4.55(m,2H); 6.4(m,1H); 7.0-7.25(m,9H); 7.85(m,1H).
  • Example 79 The title compound was prepared from the product of Example 79 and the product from Intermediate Preparation (4b) by the same procedure as described for Example 3, m.p. 80-90° (glass) .
  • Example 80 The title compound was prepared from the product of Example 80 by the same procedure as described for Example 4, m.p. 188-190°.
  • N.M.R. (DMSO-d 6 ) ⁇ 0.8-1.4 (m,8H) ; 1.3 (s,9H) ; 1.4-1.85 (m,9H) ; 2.4-3.1(m,10H) ; 3.2(s,3H) ; 3.35(t,2H) ; 3.45(m,1H) ; 3.55(m,1H) ; 3.85(m,1H) ; 4.1(m,1H) ; 4.55(m,2H) ; 6.4(d,1H) ; 7.2 (m,10H) ;
  • the title compound was prepared from the product from Example 95 by the procedure as described for Example 73.

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Abstract

Composés représentés par la formule (I) dans laquelle R1 représente alkyle C¿1?-C6, cycloalkyle C3-C8, aryle, hétérocyclyle ou R?7R8NCO; R2¿ représente alkyle C¿1?-C6, alkyle C1-C4 cycloalkyle C3-C8, alkyle C1-C4 aryle, ou alkyle C1-C4 hétérocyclyle; R?3¿ représente alkyle C¿1?-C6, cycloalkyle C3-C8, alkyle C1-C4 cycloalkyle C3-C8, alkyle C1-C4 aryle, alcényle C2-C4 aryle, alkyle C1-C4 hétérocyclyle ou alcényle C2-C4 hétérocyclyle; R?4¿ représente alkyle C¿1?-C6, cycloalkyle C3-C8, aryle ou hétérocyclyle; R?5 et R6¿ représentent chacun indépendamment H, alkyle C¿1?-C6, cycloalkyle C3-C7 ou alkyle C1-C6 substitué alcoxy C1-C4, hydroxy ou NR?7R8¿; ou bien R5 et R6 sont reliés de façon à constituer avec l'atome d'azote auquel ils sont fixés, un groupe de pyrrolidine, de pipéridine, de morpholine, de pipérazine ou de pipérazine N-alkyle C¿1?-C4; chacun de R?7 et R8¿ représente indépendamment H, alkyle C¿1?-C6 ou cycloalkyle C3-C8 ou R?7 et R8¿ peuvent être reliés, de façon à constituer, avec l'atome d'azote auquel ils sont fixés, un groupe hétérocyclique contenant de l'azote et comportant de 4 à 8 éléments; chacun de R?9, R10, R11 et R12¿ représentent indépendamment H, alkyle C¿1?-C6 ou cycloalkyle C3-C8; ou R?9 et R10¿ ou bien R?11 et R12¿ peuvent être réunis, de façon à constituer un noyau carbocyclique comportant de 3 à 8 éléments; X représente un groupe hétérocyclique mono- ou bis-cyclique à 4-10 éléments contenant des atomes à noyau de carbone et un atome à noyau d'azote par l'intermédiaire duquel le groupe est fixé au groupe carbonyle contigu; le groupe peut être saturé ou partiellement insaturé et, en complémentarité au substituant de -(CR11R12)m -NR5R6, il peut être substitué par 4 autres substituants au maximum sélectionnés chacun indépendamment à partir de F, alkyle C¿1?-C6, cycloalkyle C3-C8, OH, alcoxy C1-C6 ou NR?7R8¿; n et m sont chacun indépendamment 0, 1 ou 2; et où tout groupe alkyle ou cycloalkyle compris dans les définitions ci-dessus peut être éventuellement substitué, totalement ou partiellement, par fluor; lesdits composés sont des inhibiteurs de protéases rétrovirales et présentent une efficacité dans le traitement et la prophylaxie des infections par rétrovirus chez l'homme.
PCT/EP1993/000592 1992-05-20 1993-03-13 HETEROCYCLES A SUBSTITUTION N-[N'-(5-AMINO-4-HYDROXY-ACYLOYL)-α-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX Ceased WO1993023373A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP5519802A JPH07503482A (ja) 1992-05-20 1993-03-13 Ｎ−〔Ｎ’−（５−アミノ−４−ヒドロキシ−アシロイル）−α−アミノアシロイル〕置換された複素環式化合物および抗ウイルス物質としての使用
EP93906530A EP0641319A1 (fr) 1992-05-20 1993-03-13 HETEROCYCLES A SUBSTITUTION N- N'-(5-AMINO-4-HYDROXY-ACYLOYL)-$g(a)-AMINOACYLOYL] ET LEUR UTILISATION COMME AGENTS ANTIVIRAUX
FI945438A FI945438A0 (fi) 1992-05-20 1994-11-18 N-/N'-(5-amino-4-hydroksiasyloyyli)-alfa aminoasyloyyli/substituoidut heterosyklit ja niiden käyttö antiviraalisina aineina

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GB929210744A GB9210744D0 (en) 1992-05-20 1992-05-20 Antiviral peptides
GB9210744.0 1992-05-20

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5538997A (en) * 1993-03-12 1996-07-23 Sandoz Ltd. 2,4-diamino-3-hydroxycarboxylic acid derivatives
US5717093A (en) * 1993-07-08 1998-02-10 Merrell Pharmaceuticals Inc. Difluoro statone analogs
US5831094A (en) * 1993-09-09 1998-11-03 Merrell Pharamceuticals Inc. Difluoro statone antiviral analogs
US6114380A (en) * 1995-12-18 2000-09-05 Merrell Pharmaceuticals Inc. Difluoro statone analogs
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2850377B1 (fr) * 2003-01-23 2009-02-20 Sanofi Synthelabo Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0312157A2 (fr) * 1987-10-13 1989-04-19 Merck & Co. Inc. Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux
EP0386611A2 (fr) * 1989-03-06 1990-09-12 F. Hoffmann-La Roche Ag Dérivés d'acides aminés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0312157A2 (fr) * 1987-10-13 1989-04-19 Merck & Co. Inc. Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux
EP0386611A2 (fr) * 1989-03-06 1990-09-12 F. Hoffmann-La Roche Ag Dérivés d'acides aminés

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5538997A (en) * 1993-03-12 1996-07-23 Sandoz Ltd. 2,4-diamino-3-hydroxycarboxylic acid derivatives
US5717093A (en) * 1993-07-08 1998-02-10 Merrell Pharmaceuticals Inc. Difluoro statone analogs
US5831094A (en) * 1993-09-09 1998-11-03 Merrell Pharamceuticals Inc. Difluoro statone antiviral analogs
US5948778A (en) * 1993-09-09 1999-09-07 Merrel Pharmaceuticals Inc. Difluoro statone antiviral analogs
US6114380A (en) * 1995-12-18 2000-09-05 Merrell Pharmaceuticals Inc. Difluoro statone analogs
US7462639B2 (en) 2005-04-14 2008-12-09 Hoffmann-La Roche Inc. Aminopyrazole derivatives

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AU3748293A (en) 1993-12-13
JPH07503482A (ja) 1995-04-13
CA2133583A1 (fr) 1993-11-25
FI945438A7 (fi) 1994-11-18
GB9210744D0 (en) 1992-07-08
FI945438A0 (fi) 1994-11-18
EP0641319A1 (fr) 1995-03-08

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