EP0832110A1 - Antivirale peptoid-verbindungen - Google Patents

Antivirale peptoid-verbindungen

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Publication number
EP0832110A1
EP0832110A1 EP96917496A EP96917496A EP0832110A1 EP 0832110 A1 EP0832110 A1 EP 0832110A1 EP 96917496 A EP96917496 A EP 96917496A EP 96917496 A EP96917496 A EP 96917496A EP 0832110 A1 EP0832110 A1 EP 0832110A1
Authority
EP
European Patent Office
Prior art keywords
lower alkyl
amino
phenyl
narg
bivalent radical
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Withdrawn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
EP96917496A
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English (en)
French (fr)
Inventor
Eduard Felder
François HAMY
Gerhard Heizmann
Thomas Klimkait
Janis Karlis Lazdins
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.)
Novartis AG
Original Assignee
Ciba Geigy AG
Novartis AG
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Publication date
Application filed by Ciba Geigy AG, Novartis AG filed Critical Ciba Geigy AG
Publication of EP0832110A1 publication Critical patent/EP0832110A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16311—Human Immunodeficiency Virus, HIV concerning HIV regulatory proteins
    • C12N2740/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to antiviral compounds comprising a peptoid structure, processes for the preparation of said compounds, pharmaceutical preparations comprising said compounds, the compounds for the use in the therapeutic (including prophylactic) or diagnostic treatment of the animal or especially human body, and the use of said compounds for the therapeutic or diagnostic treatment of the animal or especially human body or for the manufacture of pharmaceutical preparations.
  • HIV-1 a virus which is regarded as causative agent for the complex disease process leading to AIDS, encodes two regulatory proteins, Tat and Rev, which act through mechanisms the knowledge of which was unprecedented in the scientific community to determine both the quantity and quality of HIV-1 gene expression. These novel regulatory pathways are controlled at the level of protein-RNA interaction.
  • Two classes of HIV mRNAs can be distinguished. The first of these consists of a doubly spliced, 2 kb mRNA species that encodes the viral regulatory proteins, including Tat and Rev. The second class consists of the unspliced (9 kb) and incompletely spliced (4 kb) viral mRNAs that encode the virion structural proteins. Tat induces a marked increase in the steady-state level of viral mRNA.
  • RNA transcripts are fully spliced by the cellular RNA processing machinery prior to export to the cytoplasm.
  • Rev unspliced (Gag) or partially spliced (Env) viral mRNAs evade processing - instead they are exported directly to the cytoplasm.
  • Rev induces the efficient export of viral RNA species that are otherwise excluded from the cell cytoplasm.
  • Tat and Rev recognize regulatory elements on the viral mRNA. Tat function is mediated through a sequence termed TAR (for trans-activation response region) that comprises part of the 5 '-noncoding region of all HIV mRNAs.
  • Rev protein is highly sequence specific and requires recognition of an RNA target sequence, the Rev Responsive Element (RRE), a highly conserved region in the middle of the viral env gene.
  • RRE Rev Responsive Element
  • the RNA binding sites of both Tat and Rev map to protein areas which are highly arginine rich (see Calnan, B.J., et al., Science 252, 1167-1171 (1991) and Tiley, L.S., et al., Proc. Natl. Acad. Sci. USA 89, 758-62 (1992)).
  • Tat(l-86) The principle form of Tat (designated as Tat(l-86) herein) consists of 86 amino acids in known linear sequence (see Ratner et al., Nature 313, 277 (1985), which is inco ⁇ orated by reference herein).
  • Three domains in the protein have been shown to exist by structure/function analysis, including a proline-rich region spanning residues 1-18, a cysteine-rich region spanning residues 22-37, and a basic region of nine amino acid spanning residues 49-57 with the sequence 49 (L)-Arg-(L)-Lys-(L)-Lys-(L)-Arg-(L)-Arg-(L)-Gln-(L)-Arg-(L) -Arg-(L)-Arg 57 ,
  • basic region of the HIV Tat protein hereinafter.
  • the compounds of the present invention show very favourable and valuable pharmaceutical characteristics, especially with regard to the therapeutic and/or diagnostic treatment of retroviral infections, particularly AIDS.
  • the compounds of the invention comprising a peptoid structure provide synthetic structures with a comparatively low molecular weight which are effective in the treatment of HIV infection, especially HIV-1 infection, acting preferably on the basis of the mechanism described above.
  • the compounds of the invention comprising a peptoid structure represent a class of molecules with the ability to interfere with the Tat/TAR and Rev/RRE complex formations, inter alia with the following distinct advantageous characteristics:
  • the compounds of the invention act through a mechanism that provides them with an incomparable therapeutic potential to complement or replace existing, specific or less specific antiviral treatments, with particular value for the treatment against variants of HIV, especially such variants that have become resistant to other kinds of treatment.
  • An antiretroviral compound of the invention comprising a peptoid structure is preferably a peptoid compound of the formula I,
  • k 0 to 20
  • m 3 to 10
  • n 1 to 10
  • R ] represents hydrogen, acyl or an amino-substituent other than acyl
  • R 2 represents an OH group, a C-terminal protecting group or a primary, secondary or tertiary amino group
  • any A independently of the others being present represents a bivalent radical of an ⁇ -amino acid
  • any X independently of the others being present represents a bivalent radical of the partial formula II
  • each of R 3 , R 4 and R 5 independently of the others, represents hydrogen or a side chain of an ⁇ -amino acid other than glycine, or R 3 and R 4 together form an alkylene bridge and R 5 is hydrogen, or R 4 and R 5 together form an alkylene bridge and R 3 is hydrogen;
  • bivalent radicals X together form a TAR-binding, transactivation-deficient oligopeptide analogue of the basic domain of the HIV Tat protein, and
  • any B independently of the others being present represents a bivalent radical of an ⁇ -amino acid
  • the compounds of the present invention can exist as isomers or mixtures of isomers; for example, if one or more asymmetric carbon atoms are present, these carbon atoms can be in the (R)-, (S)- or (R,S)-configuration, independent of one another. It is thus possible to obtain isomeric mixtures, such as racemates or diastereomeric mixtures, or pure diastereomers or entantiomers, depending on the number of asymmetric carbon atoms and on whether isomers or isomeric mixtures are present. Preferred are pure isomers (enantiomers or diastereomers).
  • k is 0 to 20, preferably 0 to 12, most preferably 0 or 12; m is 3 to 10, preferably 4 to 6, most preferably 5; and n is 1 to 10, preferably 1 to 4.
  • lower defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched or straight-chained.
  • Lower alkyl for example, is methyl, ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl.
  • Acyl has, for example, up to 25, preferably up to 19, carbon atoms and is especially the acyl group of a carboxylic acid or of a semiester of carbonic acid.
  • acyl groups of a carboxylic acid are unsubstituted or substituted alkanoyl having up to 19 carbon atoms, for example n-decanoyl, or preferably
  • lower alkanoyl such as formyl, acetyl, propionyl, butyryl or pivaloyl
  • substituted lower alkanoyl wherein preferably up to four, especially (except in the case of halogen which may be present up to three times as a substituent) up to two, substituents may be present, especially one substituent (except in the case of halogen which may be present up to three times as a substituent), the substituents being independently selected especially from
  • cycloalkyi with from 3 to 7 carbon atoms, especially in cycloalkyl-lower alkanoyl wherein lower alkanoyl is as defined above, for example cycloalkylcarbonyl, such as cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl-carbonyl, or 2-cyclohexyl- or 2-cyclopentyl-acetyl,
  • aryl which has preferably from 6 to 14 ring carbon atoms, such as in phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and may be unsubsti ⁇ tuted or mono- to tri-substituted especially by lower alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl- lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoyl amino, halogen, for example fluorine, chlorine or bromine, carb
  • heterocyclyl which is preferably a single or double ring system having from 3 to 10 ring atoms, is bonded via a carbon atom or, especially, via a nitrogen atom and contains up to 3 further hetero atoms selected from oxygen, nitrogen, sulfur, and sulfur linked to 1 or 2 oxygen atoms; which in addition may also be fused with 1 or 2 phenyl radicals or with 1 or 2 cycloalkyi radicals, cycloalkyi preferably having from 5 to 7 ring atoms; and which may be unsaturated or partially or fully saturated, for example thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, 3,1-benzofuranyl,
  • lower alkoxy especially in lower alkoxy-lower alkanoyl, for example lower alkoxy- acetyl or lower alkoxypropionyl, such as methoxyacetyl, ethoxyacetyl or 3-methoxypropionyl,
  • halo-lower alkanoyl containing up to 3 halogen atoms for example ⁇ -haloacetyl, such as ⁇ -fluoro-, ⁇ -chloro-, ⁇ -bromo-, ⁇ -iodo-, ⁇ , ⁇ , ⁇ -trifluoro- or ⁇ , ⁇ , ⁇ -trichloro-acetyl, or halopropionyl, such as ⁇ -chloro- or ⁇ - bromo-propionyl, and
  • aryl cycloalkyi
  • heterocyclyl are not restricted to the substitutents of lower alkanoyl, but are generally valid where these terms appear in the present specification, subject to the specific definitions of those moieties that, in each case, are characterized as being preferred.
  • a preferred acyl group of a semiester of carbonic acid has up to 19 carbon atoms and is selected preferably from the group comprising
  • lower alkoxycarbonyl for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, isobutoxy- or tert-lower alkoxy-carbonyl, or also or especially n-propoxycarbonyl, such as tert-butoxycarbonyl or isobutoxycarbonyl,
  • 2-halo-lower alkoxycarbonyl such as 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-trichloro- ethoxycarbonyl, aryl-lower alkoxycarbonyl, for example arylmethoxy-carbonyl, wherein aryl has from 6 to 14 carbon atoms and is, for example, phenyl, 1- or 2-naphthyl, fluorenyl, especially 9-fluorenyl, or phenyl mono- or poly-substituted by lower alkyl, for example methyl or tert-butyl, phenyl, hydroxy, lower alkoxy, for example methoxy, ethoxy or tert-butoxy, halogen, for example chlorine or bromine, and/or by nitro, for example phenyl-lower alkoxycarbonyl, such as benzyloxy carbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbon
  • heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is preferably a single or double ring system having from 3 to 10 ring atoms, is bonded via a carbon atom or, especially, via a nitrogen atom and contains up to 3 further hetero atoms selected from oxygen, nitrogen, sulfur, and sulfur linked to 1 or 2 oxygen atoms; which in addition may also be fused with 1 or 2 phenyl radicals or with 1 or 2 cycloalkyi radicals, cycloalkyi preferably having from 5 to 7 ring atoms; and which may be unsaturated or partially or fully saturated, for example thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolyl, is
  • lower alkenyloxycarbonyl wherein preferably the lower alkenyl radical is bonded to the bonding oxygen atom via a saturated carbon atom, such as allyloxycarbonyl,
  • lower alkoxy-lower alkoxycarbonyl such as 2-methoxyethoxycarbonyl
  • (lower alkoxy-lower alkoxy )-lower alkoxycarbonyl such as 2-(2-methoxyethoxy)- ethoxycarbonyl
  • amino-substituent other than acyl is preferably an arylmethyl, etherified mercapto, 2-acyl-lower alk-1-enyl, a silyl group or an organic sulfonyl group.
  • each aryl radical has preferably from 6 to 14 ring carbon atoms, such as in phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and may be unsubstituted or mono- to tri-substituted especially by lower alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkyl ⁇ amino,
  • acyl is, preferably, the corresponding radical of a lower alkanoic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • lower alkyl such as methyl or tert-butyl
  • lower alkoxy such as methoxy
  • halogen such as chlorine
  • nitro or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • Corresponding groups are especially 1-lower alkanoyl-lower alk-l-en-2-yl, for example 1-lower alkanoylprop-l-en-2-yl, such as 1-acetyl- prop-l-en-2-yl, or lower alkoxycarbonyl-lower alk-l-en-2-yl, for example lower alkoxycarbonylprop-l-en-2-yl, such as l-ethoxycarbonylprop-l-en-2-yl.
  • a siiyl group is, for example, a tri-lower alkylsilyl group, for example trimethylsilyl or tert-butyl-dimethylsilyl.
  • a C-terminal protecting group is preferably an esterifying group, thus leading to an esterified C-terminal carboxy group. More preferred is a lower alkoxy group that is preferably branched in the 1 -position of the lower alkoxy group or substituted in the 1- or 2-position of the lower alkoxy group by suitable substituents.
  • a lower alkoxy group that is branched in the 1 -position of the lower alkoxy group is, for example, tert-lower alkoxy, for example tert-butoxy.
  • a lower alkoxy group that is substituted in the 1- or 2-position of the lower alkoxy group by suitable substituents is, for example, arylmethoxy having one or two aryl radicals, wherein aryl is preferably phenyl that is unsubstituted or mono-, di- or tri-substituted, for example, by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxy, benzyloxy substituted by the mentioned substituents, for example 4-nitro- benzyloxy or 4-methoxybenzyloxy, diphenylmethoxy or diphenylmethoxy substituted by the mentioned substituents, for example di(4-methoxyphenyl)methoxy; 1-lower alkoxy- lower alkoxy, for example methoxymethoxy, 1 -methoxy
  • a C-terminal protecting group can furthermore be an organic silyloxy group.
  • An organic silyloxy group is, for example, a tri-lower alkylsilyloxy group, for example trimethylsilyloxy.
  • the silicon atom of the silyloxy group can also be substituted by two lower alkyl groups, for example methyl groups.
  • a C-terminal protecting group is preferably tert-lower alkoxy, for example tert-butyloxy, benzyloxy, 4-nitrobenzyloxy, 9-fluorenylmethoxy or diphenylmethoxy.
  • a primary, secondary or tertiary amino group is preferably a free amino group, a mono- or disubstituted amino group the substituents of which are preferably selected from the group comprising lower alkyl, e.g. methyl or ethyl, aryl-lower alkyl, such as phenyl-lower alkyl, e.g. benzyl, or heterocyclyl-lower alkyl, such as pyrrolidinyl-lower alkyl, e.g. 2-(l-pyrrolidinyl)-ethyl, pyridyl-lower alkyl, e.g.
  • a disubstituted amino group may also be N-containing heterocyclyl bonded via its nitrogen atom, such as e.g. 1-pyrrolidinyl or 4-mo ⁇ holinyl.
  • a bivalent radical of an ⁇ -amino acid is preferably bonded N-terminally by way of its ⁇ -amino group and C-terminally by way of its carboxy group and is preferably selected from the group comprising a bivalent radical of a natural ⁇ -amino acid having the L-conf ⁇ guration, such as those normally occurring in proteins, or an epimer of such an amino acid, that is to say having the unnatural D-configuration, or a D,L-isomeric mixture thereof; or a homologue of such an amino acid, for example wherein the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms, such as an ⁇ -amino alkanoic acid with 5 up to and including 10 carbon atoms in a linear chain, a substituted aromatic ( ⁇ -aryl or ⁇ -aryl lower alkyl) amino acid wherein the aryl radical has from 6 to 14 carbon atoms, for example a substituted phenylalanine or phen
  • the bivalent radical bonded via its ⁇ -amino and its ⁇ -carbonyl group, of an amino acid selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline ( ⁇ -aminovaleric acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine ( ⁇ -aminohexanoic acid, H-Nle-OH), ⁇ -amino-n-decanoic acid, serine (H-Ser-OH), homoserine ( ⁇ -amino- ⁇ -hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH),
  • each of the mentioned amino acids (with the exception of glycine) to be in the D-, L- or (D,L)-form, preferably in the L- or in the D-form.
  • a side chain of an ⁇ -amino acid other than glycine and proline is the group other than the amino and the carboxy group bound to the ⁇ -carbon of the respective amino acid, that is a group R 6 that is bound to an amino acid structure of the formula III
  • R 6 is a side chain selected so as to give an ⁇ -amino acid (except for glycine where the residue corresponding to R 6 would be H and except for proline), more specifically one of the ⁇ -amino acids as defined above; more preferably, R 5 is a residue from the group comprising lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, or substituted lower alkyl, such as aryl-lower alkyl wherein the aryl is preferably phenyl that may be mono- or poly-substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example ace
  • alkyl preferably means lower alkyl, especially C r C 4 -alkyl, such a methyl or ethyl.
  • the term "comprising a peptoid structure” means that the compounds of formula I are oligoamidic compounds with at least one residue X of formula II in formula I wherein R 3 is not hydrogen, but a side chain of an amino acid other than glycine and proline.
  • TAR-binding perferably means binding as measured in the Tat-TAR gel-shift assay described below.
  • m is 4 to 9, preferably 4 to 6; and the basic side chains R 3 , R 4 and/or R 5 mentioned in the last paragraph above are preferred, with the exception of the X at position 4 of the residue -(X) m - (counted from the N-terminus, that is the underlined moiety in the following representation of the residue -(X) m -, namely -X-X-X-X- ...) where any of the side chains mentioned above, especially in the last paragraph, is possible; and more preferably
  • each X is a bivalent radical of the partial formula II
  • R 3 represents a side chain selected from the group comprising lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, or substituted lower alkyl, such as aryl-lower alkyl wherein the aryl is preferably phenyl that may be mono- or poly-substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example acetylamino or pivaloylamino, lower alkoxycarbonylamino, for example tert-butoxycarbonylamino, arylmethoxycarbonylamino wherein aryl preferably has from 6 to 14 carbon
  • each of R 4 and R 5 represents hydrogen.
  • a bivalent radical of an ⁇ -amino acid is preferably a bivalent radical of an amino acid selected from glycine, alanine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine and lysine, which are present preferably in the L-form (where an asymmetric ⁇ -carbon atom is present).
  • a bivalent radical of an ⁇ -amino acid is preferably a bivalent radical of an amino acid selected from lysine, arginine and proline, each of which is present preferably in the D-form.
  • a and B are selected so as not to interfere with the binding of the respective compound of formula I to the TAR target.
  • Most preferred are sequences that are analogous (with small deviations, such as conservative substitutions of amino acids, e.g. up to three such substitutions ) or identical to those in the corresponding Tat (1-86).
  • Salts of compounds of formula I are especially acid addition salts, salts with bases or, where several salt-forming groups are present, can also be mixed salts or internal salts.
  • Salts are especially pharmaceutically acceptable salts of compounds of formula I.
  • Such salts are formed, for example, from compounds of formula I having an acid group, for example a carboxy group, a sulfo group, or a phosphoryl group substituted by one or two hydroxy groups, and are, for example, salts thereof with suitable bases, such as non-toxic metal salts derived from metals of groups Ia, lb, Ila and lib of the Periodic Table of the Elements, especially suitable alkali metal salts, for example lithium, sodium or potassium salts, or alkaline earth metal salts, for example magnesium or calcium salts, also zinc salts or ammonium salts, as well as salts formed with organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di- or tri-lower alkylamines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis-
  • the compounds of formula I having a basic group, for example an amino group can form acid addition salts, for example with inorganic acids, for example hydrohalic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methyl- maleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosali- cylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, as well as with amino acids, for example the ⁇ -amino
  • the compounds of the invention have useful, in particular pharmacologically useful, properties.
  • the compounds of formula I are able to inhibit the propagation of HIV, especially HIV-1, in infected human lymphocytes and show a particularly potent, specific inhibition on the binding of the Tat protein to TAR, mainly by binding to TAR. They thus represent a totally new class of inhibitors and therapeutics.
  • the in vitro inhibition of the interaction between Tat and TAR can be shown by a competition Tat-TAR gel-shift assay.
  • the sequence of recombinant Tat can be found in Churcher et al., J. Mol. Biol. 230, 90-110 (1993) to the RNA (synthetic TAR duplex, Genset, Paris, France; the sequence can be found in Hamy et al., J. Mol. Biol. 230, 111-123 (1993)), the overall size and the charge/weight ratio of the formed duplex are changed, so that electrophoretic migration through a native polyacrylamide gel is affected.
  • RNA and complexes can be discriminated based on their relative positions in the gel (Hamy et al., J. Mol. Biol. 230, 111-123 (1993)). If the binding reaction with a substance able to prevent the protein binding to the radiolabelled RNA, this competition for binding can be visualized on the autoradiography as a decreased intensity of the retarded band.
  • compounds of the formula I are tested as follows:
  • the uninco ⁇ orated [ ⁇ -32P]ATP is removed by chromatography through a sephadex NAP- 10 column (Pharmacia, Uppsala, Sweden) equilibrated with water.
  • the labelled 14-mer is annealed to 1.5 equivalents of unlabelled 17-mer by heating to 90 °C for 3 min, followed by slow cooling down to 0 °C.
  • the binding reaction for protein and RNA which takes place in a volume of 25 ⁇ l contains approximately 10,000 cpm of the labelled duplex TAR-RNA and 20 nM recombinant Tat protein in TK buffer (Tris-HCl 20 mM pH 8.0, KCl 50 mM) with 10 mM DTT, 0.1 % Triton X-100 ((Alkylphenylpolyethylenglykol, Rohm & Haas, Darmstadt, Germany) in the absence or presence of varying concentrations of inhibitor.
  • TK buffer Tris-HCl 20 mM pH 8.0, KCl 50 mM
  • Triton X-100 (Alkylphenylpolyethylenglykol, Rohm & Haas, Darmstadt, Germany) in the absence or presence of varying concentrations of inhibitor.
  • the autoradiographies are quantified by Phosphorimager (Molecular Dynamics/Bucher, Basle, Switzerland).
  • a CD50 value is determined as the concentration of a compound of the formula I giving a 50 % decrease in the intensity of the retarded band (Tat-TAR complex).
  • the CD50-values that are obtained are preferably in the range of from 1 x 10" 9 to 1 x 10" 6 M. It is possible to show that similar binding affinity can be found when wild-type unlabelled TAR-RNA is used as competitor, thus suggesting that the compounds of the present invention have affinities comparable to that of the high molecular weight full-length Tat protein in vitro.
  • the compounds of the present invention can also be shown to inhibit Rev/RRE interaction in a competition Rev-RRE gel-shift assay (see Kjems, J., et al., EMBO J. 11, 1119-1129 (1992) and Tan, R., et al., Cell 73, 1031-40 (1993).
  • PBLs Peripheral Blood Mononuclear Lymphocytes
  • Cells (1 x 10 6 /ml) are cultured for 2 days in RPMI-1640 (Gibco), supplemented with 10 % heat-inactivated fetal calf serum (Gibco), 50 ⁇ g ml streptomycin, 50 U/ml penicillin (Amimed), 2 nM glutamine and 10 mM hepes buffer (Gibco).
  • Stimulated lymphocytes are obtained by culturing in the presence of PHA (0.25 ⁇ g/ml; Wellcome diagnostics, Templehill, Dartford, England). PHA-lymphocyte stimulation is confirmed by the increase in cell size (Scattergram, FACS analysis).
  • RT determination is possible as follows: The RT activity is determined in 50 mM of tris ( ⁇ , ⁇ , ⁇ -tris(hydroxymethyl)methylamine, ultra pure, Merck, Federal Republic of Germany) pH 7.8; 75 mM of KCl, 2 mM of dithiothreitol, 5 mM of MgCl2; 0.05 % Nonidet P-40 (detergent; Sigma, Switzerland); 50 ⁇ g/ml of polyadenylic acid (Pharmacia, Sweden); 1.6 ⁇ g/ml of dT(12-18) (Sigma, Switzerland). The mixture is filtered through an Acrodisc filter (0.45 ⁇ : Gellman Science Inc, Ann Arbor) and stored at -20°C.
  • Acrodisc filter (0.45 ⁇ : Gellman Science Inc, Ann Arbor
  • the RT activity is a measure of the reproduction of HIV-1.
  • the compounds of formula I according to the invention inhibit virus reproduction when administered in the micromolar range, for example during 18 days after infection practically no increase in RT activity can be determined in the presence of preferably 5 to 50 ⁇ M concentrations of an inhibitor of the present invention (for example 0 to 100 counts per minute), while in the control high increase of RT activity can be found (for example more than 2000 counts per minute on day 18).
  • the compounds of the present invention can thus be used in the treatment of retroviral infections in warm-blooded animals, especially HIV, such as HTV-l, infections, and more specifically for the treatment of AIDS in humans.
  • treatment of infected cells, e.g. lymphocytes, outside the body is possible in order to reintroduce healthy cells by transplantantion or injection, for example in order to improve the lymphocyte titer in patients with advanced AIDS.
  • the compounds of the present invention can also be used in the treatment of commercially valuable cell, such as lymphocyte, cultures against retroviral infections, especially against HIV, such as HTV-l, infections.
  • k is 0 to 20, preferably 0 to 12, most preferably 0 or 12, m is 3 to 10, preferably 4 to 6, most preferably 5, n is 1 to 10, preferably 1 to 4;
  • substituted lower alkanoyl wherein the substituents are independently selected from - cycloalkyi with from 3 to 7 carbon atoms; - aryl selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, each of which is unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy, N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, nap
  • heterocyclyl selected from thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, 3,1-benzofuranyl, chromanyl, cyclohexa[b]pyrrolyl, cyclohexa- [bjpyridyl, cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, piperidyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, S,S-dioxo-thiomo ⁇ holinyl
  • aryl-lower alkoxycarbonyl wherein aryl is phenyl, 1- or 2-naphthyl, fluorenyl or phenyl mono- or poly-substituted by lower alkyl, phenyl, hydroxy, lower alkoxy, halogen or nitro,
  • heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, pyridyl, - pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, quinolyl, iso- quinolyl, 3,1-benzofuranyl, cyclohexa[b]pynolyl, cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, piperidyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, S,S- dio
  • aryl-lower alkyl with up to three aryl groups, wherein each aryl is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl which are unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy, N,N-di- lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl
  • arylthio or aryl-lower alkylthio, wherein aryl is phenyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or nitro,
  • arylsulfonyl wherein aryl is phenyl that is unsubstituted or substituted by one to five lower alkyl or lower alkoxy groups,
  • arylmethoxy having one or two aryl radicals, wherein aryl is phenyl that is unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy, halogen or nitro,
  • a mono- or disubstituted amino group the substituents of which are selected independently from the group comprising lower alkyl, phenyl-lower alkyl, pyrrolidinyl-lower alkyl, pyridyl-lower alkyl, furyl-lower alkyl, mo ⁇ holinyl-lower alkyl and indolyl-lower alkyl, or a disubstituted amino group selected from 1-pyrrolidinyl an 4-mo ⁇ holinyl;
  • any A being present and any B being present are independently selected from the group comprising a bivalent radical, bonded via its ⁇ -amino and its ⁇ -carbonyl group, of an amino acid selected from glycine alanine, valine, norvaline, leucine, isoleucine, norleucine, ⁇ -amino-n-decanoic acid, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-amino- phenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenyl- alanine, ⁇ -phenylserine,phenylglycine, ⁇ -naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic
  • each of the mentioned amino acids (with the exception of glycine) to be in the D-, L- or (D,L)-form, preferably in the L-form (more preferred in the case of the radical A) or in the D-form (more preferred in the case of the radical B);
  • the moiety A being a bivalent radical of an ⁇ -amino acid selected from glycine, alanine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine and lysine, which are present preferably in the L-form (where an asymmetric ⁇ -carbon atom is present), the moiety B being a bivalent radical of an ⁇ -amino acid selected from lysine, arginine and proline, each of which is present preferably in the D-form;
  • each X being present is a bivalent radical of the partial formula II,
  • R 3 represents a side chain selected from the group comprising lower alkyl or substituted lower alkyl selected from
  • - amino-lower alkyl such as 4-aminobutyl or 6-aminohexyl
  • N-lower alkylamino- such as N-methylamino-, N,N-di-lower alkylamino-, N-(phenyl-lower alkyl)-N-(lower alkyl)-amino-, such as N-benzyl-N-methylamino-, N,N-di(phenyl-lower alkyl)-amino-, such as N,N-dibenzylamino-, or guanidino-lower alkyl, such as 3-guanidinopropyl (lower alkyl preferably being methyl, ethyl or propyl),
  • - pyridyl-lower alkyl for example (2-pyridyl)-lower alkyl, such as 2-(2- ⁇ yridyl)ethyl,
  • - pyrrolidinyl-lower alkyl for example (l-pyrrolidinyl)-lower alkyl, such as 2-(l-pynolidinyl)ethyl,
  • - mo ⁇ holinyl-lower alkyl for example (4-mo ⁇ holinyl)-lower alkyl, such as 2-(4-mo ⁇ holinyl)ethyl,
  • residue X which is in position 4 of the bivalent residue -(X) m - when counted from the N-terminus may in addition be a side chain selected from
  • aryl is phenyl that is unsubstituted or mono- or poly-substituted by lower alkyl, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, arylmethoxycarbonylamino wherein aryl has from 6 to 14 carbon atoms, halogen, carboxy or nitro;
  • - furyl-lower alkyl for example (2-furyl)-lower alkyl, such as (2-furyl)methyl, and
  • indolyl-lower alkyl for example (3-indolyl)-lower alkyl, such as 2-(3-indolyl)-ethyl;
  • R 4 and R 5 each represent hydrogen
  • k is 0 to 12, more preferably 0 or 12, most preferably 0, m is 4 to 6, most preferably 5, n is 1 to 4;
  • R 2 is amino, or further
  • a mono- or disubstituted amino group the substituents of which are selected independently from the group comprising lower alkyl, phenyl-lower alkyl, pyrrolidinyl-lower alkyl, pyridyl-lower alkyl, furyl-lower alkyl, mo ⁇ holinyl-lower alkyl and indolyl-lower alkyl, or a disubstituted amino group selected from 1-pyrrolidinyl an 4-mo ⁇ holinyl;
  • any A being present is a bivalent radical of an ⁇ -amino acid bound at its N-terminus via its ⁇ -amino group and at its C-terminus via its ⁇ -carbonyl group selected from glycine, alanine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine and lysine, which are present in the D- or preferably in the L-form (where an asymmetric ⁇ -carbon atom is present);
  • any B being present is a bivalent radical of an ⁇ -amino acid bound at its N-terminus via its ⁇ -amino group and at its C-terminus via its ⁇ -carbonyl group selected from lysine, arginine and proline, each of which is present preferably in the D-form;
  • R 3 represents a side chain selected from the group comprising lower alkyl or substituted lower alkyl selected from
  • - amino-lower alkyl such as 4-aminobutyl or 6-aminohexyl
  • N-lower alkylamino- such as N-methylamino-, N,N-di-lower alkylamino-, N-(phenyl-lower alkyl)-N-(lower alkyl)-amino-, such as N-benzyl-N-methylamino-, N,N-di(phenyl-lower alkyl)-amino-, such as N,N-dibenzylamino-, or guanidino-lower alkyl, such as 3-guanidinopropyl (lower alkyl preferably being methyl, ethyl or propyl),
  • - pyridyl-lower alkyl for example (2-pyridyl)-lower alkyl, such as 2-(2-pyridyl)ethyl,
  • - pyrrolidinyl-lower alkyl for example (l-pyrrolidinyl)-lower alkyl, such as 2-(l-pyrrolidinyl)ethyl, and
  • - mo ⁇ holinyl-lower alkyl for example (4-mo ⁇ holinyl)-lower alkyl, such as 2-(4-mo ⁇ holinyl)ethyl, or, in the case of the residue X which is in position 4 of the bivalent residue -(X) m - when counted from the N-terminus (that is the underlined moiety in the following representation of the bivalent radical -(X) m -, namely -X-X-X-X- 7), may in addition be a side chain selected from
  • aryl is phenyl that is unsubstituted or mono- or poly-substituted by lower alkyl, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, arylmethoxycarbonylamino wherein aryl has from 6 to 14 carbon atoms, halogen, carboxy or nitro;
  • - furyl-lower alkyl for example (2-furyl)-lower alkyl, such as (2-furyl)methyl, and
  • indolyl-lower alkyl for example (3-indolyl)-lower alkyl, such as 2-(3-indolyl)-ethyl;
  • - amino-lower alkyl such as 4-aminobutyl or 6-aminohexyl, or
  • aryl is phenyl that is unsubstituted or mono- or poly-substituted by lower alkyl, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, aryl ⁇ methoxycarbonylamino wherein aryl has from 6 to 14 carbon atoms, halogen, carboxy or nitro; phenyl-lower alkyl, especially benzyl, being most preferred in that position;
  • R 4 and R 5 each represent hydrogen
  • k is 0 or 12, most preferably 0, m is 4 to 6, most preferably 5, n is 1 to 4;
  • R is ammo
  • any A being present is a bivalent radical of an ⁇ -amino acid bound at its N-terminus via its ⁇ -amino group and at its C-terminus via its ⁇ -carbonyl group selected from glycine, alanine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine and lysine, which are present in the D- or preferably in the L-form (where an asymmetric ⁇ -carbon atom is present);
  • any B being present is a bivalent radical of an ⁇ -amino acid bound at its N-terminus via its ⁇ -amino group and at its C-terminus via its ⁇ -carbonyl group selected from lysine, arginine and proline, each of which is present preferably in the D-form;
  • R 3 represents a side chain selected from the group comprising
  • - amino-lower alkyl such as 4-aminobutyl or 6-aminohexyl
  • guanidino-lower alkyl such as 3-guanidinopropyl
  • residue X which is in position 4 of the bivalent residue -(X) m - when counted from the N-terminus that is the underlined moiety in the following representation of the bivalent radical -(X) m -, namely -X-X-X-X- ...), may in addition be a phenyl-lower alkyl side chain, such as benzyl;
  • R and R 5 each represent hydrogen
  • the compounds of the present invention can be synthesized according to known procedures, especially by a process comprising
  • R 3 is a residue from the group comprising lower alkyl or substituted lower alkyl (preferably as defined above for R 6 in formula III), while R 2 , R 4 , R 5 , A, B, X, m and n have the meanings given for compounds of the formula I,
  • R 2 ' has the same meaning as R 2 in compounds of formula I or is a resin for solid phase synthesis and R 4 , R 5 , X, B, m and n have the meanings given for compounds of formula I, under nucleophilic substitution, in the mentioned starting materials free functional groups with the exception of those that participate in the reaction if required being present in protected form; and removing any protecting groups and cleaving from any resin for solid phase synthesis being present;
  • R j , R 2 , R 3 , R 4 , R 5 , A, B, X, k, m and n have the meanings given for compounds of the formula I, if not mentioned otherwise.
  • the compounds of the present invention preferably can be readily prepared according to well-established, standard liquid or. preferably, solid-phase peptide synthesis methods, general descriptions of which are broadly availabe, for example in J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Company, Rockford, Illinois (1984), in M. Bodanzsky and A. Bodanzsky, The Practice of Peptide Synthesis, Springer Verlag, New York (1984); and Applied Biosystems 430A Users Manual, ABI Inc., Foster City, California, but may also be prepared in solution or by a combination of solid-phase and solution chemistry.
  • a fragment with a free carboxy group can be an amino acid (if required, in suitably protected form) or a di-, tri- or other oligopeptide (the term "peptide” here also comprising peptoid structures) or also, e.g. in the case of the synthesis of derivatives of formula I with acylated terminal amino group, the acylating carbonic acid, especially acetic acid.
  • a fragment that has an amino group with at least one free hydrogen atom can also be a single amino acid, a di-, tri- or oligopeptide or, in the case of preparation of peptamides, ammonia or mono- or disubstituted ammonia.
  • Reactive derivatives of carbonic acids are preferably reactive esters or reactive anhydrides, or reactive cyclic amides. Reactive carbonic acid derivatives can also be formed in situ.
  • a reactive derivative of an "amino group with at least one free hydrogen” is preferably derivatized by the reaction with a phosphite, such as diethyl-chlorophosphite, 1,2-phenylene-chlorophosphite, ethyl-dichlorophosphite, ethylene-chlorophosphite or tetraethyl-pyrophosphite; or is present in the form of a carbamic acid chloride wherein the amino group participating in the reaction is subtituted by halocarbonyl, such as chlorocarbonyl.
  • a phosphite such as diethyl-chlorophosphite, 1,2-phenylene-chlorophosphite, ethyl-dichlorophosphite, ethylene-chlorophosphite or tetraethyl-pyrophosphite
  • a phosphite
  • the reactions normally run in the presence of a condensing agent or, when activating the carboxylic acids in the form of anhydrides, of an agent that binds the carboxylic acid formed. In some cases it is also possible to add chaotropic agents such as LiF in NB-methylpynolidone.
  • the reactions are especially carried out in a temperature range from -30 to +150 °C, preferably from +10 to +70 °C, and, most preferably, from +20 to +50 °C, if appropriate, in an inert gas atmosphere, e.g. under nitrogen or argon.
  • unreacted amino groups can be acylated after a reaction cycle, e.g. by acetylation of unreacted amino groups with 10 ml acetic anhydride/pyridine/DMA (1:1:8), thus facilitating later purification of the final product.
  • a suitably protected amino acid an ⁇ -amino acid or (for the introduction of peptoid structures) an amino acid of formula lib
  • R 3 , R 4 and R 5 have the meaning given under formula II above, R 3 not being hydrogen] as a ligand is attached via its carboxyl group (-COOH) to a derivatized, insoluble polymeric support, e.g. a cross-linked styrene or polyamide resin, such as a 4-(2',4'-dimethoxyphenyl-[hydroxy- or amino-]methyl)-phenyoxymethyl-polystyrene resin by a condensation reaction.
  • "Suitably protected” refers to the presence of protecting groups on the ⁇ -amino group ( ⁇ -NH 2 or ⁇ -NHR 3 ) and any side-chain functional group (if present) of the amino acid. Di-, tri- or other oligopeptides can be used instead of the amino acids as building blocks (fragments).
  • Synthesis proceeds in a stepwise, cyclical fashion by successively removing the ⁇ -NH or ⁇ -NHR 3 protecting group and then coupling an activated fragment (e.g. an amino acid, di-, tri- or oligopeptide) to the deprotected ⁇ -NH 2 or ⁇ -NHR 3 .
  • an activated fragment e.g. an amino acid, di-, tri- or oligopeptide
  • activation of the ⁇ -COOH group of the amino acid to be attached by the condensation reaction is effected (i) directly with a carbodiimide, e.g.
  • DCC dicyclohexylcarbodiimide
  • a carbonyl compound such as carbonyldiimidazole
  • 1,2-ox- azolium compounds such as 2-ethyl-5-phenyl-l,2-oxazolium-3 '-sulfonate and 2-tert- butyl-5-methylisoxazolium perchlorate
  • acylamino compounds such as 2-ethoxy- l-ethoxycarbonyl-l,2-dihydroquinoline
  • an uronium compound such as 2-(lH-benzo- triazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU
  • an "active ester” e.g. a hydroxybenzotriazole (HOBT), pentafluorophenyl, 4-nitrophenyl or N-hydroxysuccinimide ester.
  • Useful acid binding agents that can be employed in the condensation reactions are, for example, alkaline metals, carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (if appropriate, together with a sulfate), or organic bases such as sterically hindered organic nitrogen bases, for example tri-lower alkylamines, such as N,N-diisopropyl-N-ethylamine,
  • Reactive groups in the monomers of ligands or in the resin-bound or free intermediates resulting from one or more coupling steps can be protected by third groups as protecting groups that are customarily used in peptide synthesis.
  • third groups protecting groups that are customarily used in peptide synthesis. Examples of protecting groups, their introduction and their removal are, for example, described in standard works such as "Protective groups in Organic Chemistry", Plenum Press, London, New York 1973; “Methoden der organischen Chemie”, Houben-Weyl, 4. edition, Vol. 15/1, Georg-Thieme Verlag, Stuttgart 1974; Th. W.
  • protecting groups comprises also resins used for solid phase synthesis, preferably those specifically mentioned above and below.
  • hydroxy protecting groups are acyl radicals, such as tert-lower alkoxycarbonyl radicals, for example tert-butoxycarbonyl, etherifying groups, such as tert-lower alkyl groups, for example t-butyl, or silyl- or tin radicals, such as tert-butyl-dimethylsilyl or the tri-n-butyltin radical.
  • acyl radicals such as tert-lower alkoxycarbonyl radicals, for example tert-butoxycarbonyl
  • etherifying groups such as tert-lower alkyl groups, for example t-butyl
  • silyl- or tin radicals such as tert-butyl-dimethylsilyl or the tri-n-butyltin radical.
  • Carboxy groups can be protected by groups as defined above for the C-terminal protecting groups R 2 , preferably by esterifying groups selected from those of the tert-butyl type, from benzyl, from trimethylsilylethyl and from 2-triphenylsilyl groups .
  • Amino or guanidino groups can be protected by removable acyl groups or by arylmethyl, etherified mercapto, 2-acyl-lower alk-1-enyl, a silyl group or an organic sulfonyl group (preferably as defined above for an "amino substituent other than acyl" R j ) or tin amino protecting groups; tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, 4-nitro- benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl (especially the tyrosine OH group), diphenylmethoxycarbonyl, nitrophenylsulfenyl, 2,2,2-trichloro- ethoxycarbonyl, 2,2,5,7,8-pentamefhylchroman-6-sulfonyl (PMC), 2,2,4,6,7-pentamethyl- dihydrobenz
  • Imino groups (e.g. in imidazole) can be protected by 2,4-dinitrophenyl or p-toluene- sulfonyl, or (e.g. in indole) by formyl.
  • Mercapto groups can be protected, e.g., by acetamidomethyl, by trityl or by p-methylbenzyl.
  • protective groups are usually removed after the complete synthesis of the resin-bound molecule by conventional methods of peptide chemistry, conveniently by treatment with 95 % trifluoroacetic acid.
  • strong nucleophiles such as 1,2-ethanedithiol, may be additionally added to capture the generated compounds resulting from the protecting groups.
  • Groups of the ⁇ -elimination type are typically protective groups of the fluorenylmethyl type.
  • the two prefe ⁇ ed methods of solid phase peptide synthesis are the Boc and the Fmoc methods, which are named with reference to their use of the tert-butoxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc) group, respectively, to protect the ⁇ -NH 2 or ⁇ -NHR 3 of the amino acid residue to be coupled.
  • TFA trifluoroacetic acid
  • Prefe ⁇ ed third groups as protecting groups (for functional groups in side chains) are relatively stable in weak acid, e.g. TFA. Most can be cleaved by strong acids such as hydrofluric acid (HF) or trifluoromethanesulfonic acid.
  • HF hydrofluric acid
  • a small number of side chain groups e.g. 2,4-dinitrophenyl protected imino in the histidyl side chain, may require a separate deprotection step, e.g. treatment with thiophenol or ammonolysis.
  • the product is typically cleaved from the resin and simultaneously deprotected by HF treatment at low temperature (e.g. around 0 °C).
  • the Fmoc-group can be cleaved off preferably in the presence of a mild nitrogen base, preferably piperidine, in an inert solvent, preferably dimethyl acetamide, thereby allowing the use of side-chain protecting groups which are labile to milder treatment, e.g. TFA.
  • a mild nitrogen base preferably piperidine
  • an inert solvent preferably dimethyl acetamide
  • An acid labile ether resin such as HMP-resin (p-hydroxymethylphenoxymethyl poly ⁇ styrene), 4-(2',4'-dimethoxyphenyl-hydroxymethyl)-phenoxymethyl-polystyrene or preferably a resin with a benzyloxy- or alkyloxy linker (see Wang, J. Amer. Chem. Soc. 95, 1328 (1973); or, for the synthesis of compounds with a C-terminal amino group R 2 (in amide bond) which are prefe ⁇ ed, 4-(2',4'-dimethoxyphenyl-aminomethyl)-phenoxy- methyl-polystyrene (Rink et al., Tetrahedr. Lett. 28(33), 3787-90 (1987) is used as the solid support, permitting simultaneous cleavage/deprotection in TFA.
  • HMP-resin p-hydroxymethylphenoxymethyl poly ⁇ styrene
  • Z is preferably a nucleofugal group, preferably aryl- sulfonyloxy, such as toluenesulfonyloxy, lower alkanesulfonyloxy, such as methane- sulfonyloxy, or especially halogen, such as chlorine, bromine or iodine, more especially chlorine or iodine and most especially bromine.
  • aryl- sulfonyloxy such as toluenesulfonyloxy
  • lower alkanesulfonyloxy such as methane- sulfonyloxy
  • halogen such as chlorine, bromine or iodine, more especially chlorine or iodine and most especially bromine.
  • aprotic solvents such as ketones, for example a di-lower alkyl ketone, such as acetone, nitriles, for example a lower alkylnitrile, such as acetonitrile, carboxylic acid amides, for example a di-lower alkyl-lower alkanoylamide, such as dimethylformamide or dimethylacetamide, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, hexamethyl- phosphoric acid triamide or ethers, such as di-lower alkyl ethers, for example diethyl ether, or cyclic ethers, such as tetrahydrofuran or dioxane, or also in protic solvents, such as alcohols, especially lower alkanols, for example methanol or ethanol, or mixtures of two or more of the mentioned
  • aprotic solvents such as ketones, for example a di-lower alkyl ket
  • the protecting groups, their introduction, their removal, the resins used for solid phase synthesis and methods of cleavage from them are preferably analogous to those described under process b).
  • Salts of compounds of formula I having at least one salt-forming group may be prepared in a manner known er se.
  • salts of compounds of formula I having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethyl- hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the co ⁇ esponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with co ⁇ esponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethyl- hexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the co ⁇ espond
  • Acid addition salts of compounds of formula I are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of formula I containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromato ⁇ graphic separation, for example over silica gel, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • the present invention relates also to novel starting materials and/or intermediates and to processes for their preparation.
  • the starting materials used and the reaction conditions selected are preferably those that result in the compounds described as being prefe ⁇ ed.
  • starting materials are known, can be prepared according to processes known per se and/or are available commercially.
  • D-, D,L- or L- amino acids, di-, tri- or oligopeptides, derivatized and/or preloaded resins the ancillary reagents and solvents required for either Boc or Fmoc peptide synthesis are commercially available from various suppliers or can be prepared readily according to standard procedures.
  • di-, tri- or oligopeptoids can be prepared readily according to standard procedures.
  • automated peptide synthesizers with optimized, preprogrammed Boc and Fmoc synthesis cycles are available from numerous sources.
  • the compounds of formula V can be prepared by condensation of a carbonic acid of the formula (VI),
  • R 2 ' has the same meaning as R 2 in compounds of formula I or is a resin for solid phase synthesis, while X, B, m and n have the meanings given in the definition of compounds of formula I. If necessary, functional groups that are not to be reacted are present in protected form. The condensation conditions, protective groups, their introduction etc. are analogous to those described for the synthesis of compounds of formula I under process a).
  • H-Nahg-Narg-Narg-Nphe-Narg-NH 2 (SEQ ID NO:2) which is very active in the above-mentioned indications, or a salt thereof.
  • protecting groups in starting materials the reaction of which is to be avoided can be protected by suitable protect ⁇ ing groups (conventional protecting groups) which are customarily used in the synthesis of peptide compounds, and also in the synthesis of cephalosporins and penicillins as well as nucleic acid derivatives and sugars.
  • protect ⁇ ing groups conventional protecting groups
  • These protecting groups may already be present in the precursors and are intended to protect the functional groups in question against undesired secondary reactions, such as acylation, etherification, esterification, oxidation, solvolysis, etc.
  • the protecting groups can additionally cause the reactions to proceed selectively, for example stereoselectively.
  • protecting groups that they can be removed easily, i.e. without undesired secondary reactions taking place, for example by solvolysis, reduction, photolysis, and also enzymatically, for example also under physiological conditions, and, especially, that they are not present in the end products.
  • the protecting groups can be so selected that more than one such group can be removed simultaneously, for example by acidolysis, such as by treatment with trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium-on-carbon catalyst.
  • the groups can also be so selected that they cannot all be removed simultaneously, but rather in a desired sequence, the co ⁇ esponding inte ⁇ nediates being obtained.
  • any reference hereinbefore and hereinafter to a free compound or a salt thereof is to be understood as meaning also the corresponding salt or free compound, respectively, where appropriate and expedient.
  • All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents or neutralising agents, for example ion exchangers, such as cation exchangers, e.g.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mix ⁇ tures of isomers, for example racemates or mixtures of diastereoisomers, for example ana ⁇ logously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as aceto ⁇ nitrile, halogenated hydrocarbons, such as methylene chloride, acid amides, such as dimethylformamide, bases, such as heterocyclic nitrogen bases, for example pyridine, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or iso
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallisation.
  • protected starting materials may be used in all process steps and the protecting groups may be removed at suitable stages of the reaction.
  • the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are ca ⁇ ied out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • reaction conditions that are analogous to those mentioned in the Examples.
  • the invention relates also to pharmaceutical compositions comprising compounds of formula I.
  • the pharmacologically acceptable compounds of the present invention may be used, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.
  • compositions according to the invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals), that comprise an effective dose of the pharmacological active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • the invention relates also to a method of treating diseases caused by viruses, especially by retroviral infections, for example HIV infection, including AIDS, which comprises administering a prophylactically or especially therapeutically effective amount of a compound of formula I according to the invention, especially to a warm-blooded animal, for example a human, who on account of one of the mentioned diseases, especially HTV-infection, including AIDS, requires such treatment.
  • the dose to be administered to warm-blooded animals for example humans of approximately 70 kg body weight, is from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1.5 g, for example approximately from 100 mg to 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
  • compositions comprise from approximately 1 % to approximately 95 %, preferably from approximately 20 % to approximately 90 %, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilising, mixing, granulating or confectioning processes.
  • Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions are preferably used, it being possible, for example in the case of lyophilised compositions that comprise the active ingredient alone or together with a ca ⁇ ier, for example mannitol, for such solutions or suspensions to be produced prior to use.
  • the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting and/or emulsifying agents, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes.
  • the said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpy ⁇ olidone or gelatin.
  • Suspensions in oil comprise as the oil component the vegetable, synthetic or semi- synthetic oils customary for injection pu ⁇ oses.
  • liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or co ⁇ esponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of anti ⁇ oxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • anti ⁇ oxidants for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812” (triglyceride of saturated fatty acids with a chain length of C 8 to C ]2 , H ⁇ ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • the injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be inco ⁇ orated into plastics ca ⁇ iers that allow the active ingredients to diffuse or be released in measured amounts.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl ⁇ py ⁇ olidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpy ⁇ olidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphat
  • Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpy ⁇ olidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Capsules are dry-filled capsules made of gelatin and soft sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers and/or antibacterial agents to be added.
  • suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers and/or antibacterial agents to be added.
  • Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification pu ⁇ oses or to
  • Analytical HPLC is performed on a Shimadzu system (Kyoto, Japan) with product monitoring at 215 n by a Bischoff Lambda 1000 UV-detector from Metrohm (Wallisellen, Switzerland).
  • a C 18 reversed phase column 250 x 4.6 mm, Nucleosil C 18 , 5 ⁇ m; Macherey & Nagel, Duren, Germany) is used. The flow rate is 1 ml/min.
  • the linear gradient is from 10 % B/90 % A to 90 % B/10 % A in 30 min.
  • the analytical data are presented as retention times t R .
  • Matrix-assisted laser deso ⁇ tion ionization (MALDI) mass spectrometry is carried out on a Linear Scientific LDI 1700 (Reno, NV, USA): the sample and 1,5-dihydroxybenzoic acid are co-crystallized, i ⁇ adiated with laser light (337 nm), and the masses of the ions produced are measured in a time-of-flight detection system.
  • MALDI Matrix-assisted laser deso ⁇ tion ionization
  • the Examples 1 to 6 are obtained as trifluoroacetate salts.
  • Example 1 H-Nahg-Narg-Narg-Nphe-Narg-(D-Lvs -(D-LvsV(D-ArgV(D-ProVNH
  • Resin 2 (see example lb)) is washed with ethylene chloride (3 x) and treated with 5 ml 95 % TFA/EDT (8:2) for 15 min. The treatment is repeated twice, while all filtrates are collected and pooled. The resin is washed with DCM (2 x) and TFE (2 x) and the filtrates are added to the pool, which is concentrated to a 5 ml volume in vacuo. 60 ml PE/DIPE (1:1) are added, and the filtrate is isolated and washed with PE/DIPE (1:1). The material is treated with 95% TFA/EDT (8:2) for 120 min, then precipitated again and washed with PE/DIPE (1:1).
  • the material eluted at the main peak is collected, lyophilized and obtained as a white powder.
  • the starting material is prepared as follows: l a) Fmoc-Narg( ' PmcVNarg(Pmc)-Nphe-Narg(Pmc)-D-Lvs(BocVD-Arg(PmcVD-Pro- amide of 4-(2 , ,4'-dimethoxyphenyl-aminomethyl)-phenoxymethyl-polvstyrene resin (Resin 1)
  • the resin is washed 5 times with isopropanol and dried under vacuum.
  • Example 7 (SEQ ID NO:7) Nahg-Narg-Narg-Npeg-Narg-(D-Lys)-NH ? :
  • Resin 1' is washed with ethylene chloride (3x) and treated with 5 ml 95% TFA/EDT (8:2) for 15 min. The treatment is repeated twice, while all filtrates are collected and pooled. The resin is washed with DCM (2x) and TFE (2x) and the filtrates are added to the pool, which is concentrated to a 5 ml volume in vacuo. 60 ml PE/DIPE (1:1) are added and the precipitate is isolated and washed with PE/DIPE (1:1). The material is treated with 95% TFA/EDT (8:2) for 120 min, then again precipitated ans washed with PE/DIPE (1:1). This procedure is repeated with a diminished reaction time of 60 min.
  • the last precipitate is isolated, washed with PE/DIPE (1:1), dissolved in water and lyophilized.
  • the product (title compound) is characterized by analytical HPLC with an analogous chromatography, using a Nucleosil 7C18 (5 ⁇ m) reversed phase column (4.6 x 250 mm, Macherey & Nagel, Duren, FRG), linear gradient 1% B to 90 % B in 30 min; flow 1 ml/min; detection at 215 nm; as well as by mass spectrometry (MALDI on an instrument from Linear Scientific, Reno, NV: model LDI 1700). HPLC-retention time: 11.3 min; MALDI-MS: molecule peak 934 (co ⁇ esponds to theory).
  • the starting material is prepared as follows:
  • MALDI-MS molecule peak 954 (co ⁇ esponds to theory);
  • MALDI-MS molecule peak 992 (corresponds to theory);
  • the starting material is prepared as follows:
  • Boc-protected 2-(4-(2-aminoethyl)phenoxy)ethylbromide is obtained by simple reaction of dibromoethane with Boc-protected 4-(2-aminoethyl)phenol which is obtained easily by Boc-protection of 4-(2-aminoethyl)phenol (Aldrich, Buchs, Switzerland) are reacted with 18.5 g sodium azide at 100 °C during 1 h.
  • the reaction mixture is passed onto alkaline ice water.
  • the suspension is extracted with ether/petrol ether (2 x), and the organic phases are washed with water. Evaporation leads to the title compound, melting point 56-65 °C.
  • MALDI-MS molecule peak 948 (corresponds to theory);
  • the starting material is prepared as follows:
  • the title compound is obtained by catalytic hydrogenation of Boc-protected 2-(amino)-2-(phenyl)-acetonitrile (obtainable by first reacting benzaldehyde cyanhydrin (Aldrich, Buchs, Switzerland) in ethanol with 5 M ammonia at room temperature for 8 days, then evaporation, take up residue in ether, extract with diluted HCl, neutralisation of the extract with NaOH-solution which leads to precipitation, take up product again in ehter and repeat the extraction/precipitation which leads to crystalline 2-(amino)-2-(phenyl)acetonitrile, which is then protected by reaction with Boc-anhydride in tetrahydrofurane) at 105 °C/70 bar in tetrahydrofurane/triethylamine (30:1): melting point 89-92 °C.
  • MALDI-MS molecule peak 1048 (corresponds to theory);
  • the starting material is preapared as follows
  • a sterile-filtered aqueous solution, with 20 % cyclodextrins as solubilisers, of one of the compounds of formula I mentioned in the preceding Examples (e.g. Example 1) as active ingredient, is so mixed under aseptic conditions, with heating, with a sterile gelatine solution containing phenol as preservative, that 1.0 ml of solution has the following composition:
  • Example 13 Sterile dry substance for injection:
  • 500 mg of finely ground ( ⁇ 5.0 ⁇ m) powder of one of the compounds of formula I men ⁇ tioned in the preceding Examples is suspended as active ingredient in a mixture of 3.5 ml of Myglyol 812® and 0.08 g of benzyl alcohol.
  • the suspension is introduced into a container having a metering valve.
  • 5.0 g of Freon 12® are introduced under pressure into the container through the valve.
  • the "Freon” is dissolved in the Myglyol/benzyl alcohol mixture by shaking.
  • the spray container contains approximately 100 single doses which can be administered individually.
  • active ingredient 1000 g corn starch 680 g colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis
  • a mixture of one of the compounds of formula I mentioned in the preceding Examples (e.g. Example 1) as active ingredient, 50 g of corn starch and the colloidal silica is processed with a starch paste, made from 250 g of corn starch and 2.2 kg of demineralised water, to form a moist mass. This is forced through a sieve having a mesh size of 3 mm and dried at 45° for 30 min in a fluidised bed drier.
  • the dry granules are pressed through a sieve having a mesh size of 1 mm, mixed with a pre-sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and compressed to form slightly biconvex tablets.
  • Xaa Phe Thr Thr Lys Ala Leu Glv lie Ser Tyr Gly Xaa Xaa XaaXaa

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EP96917496A 1995-06-07 1996-06-04 Antivirale peptoid-verbindungen Withdrawn EP0832110A1 (de)

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GB9511474 1995-06-07
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US5843995A (en) * 1997-07-07 1998-12-01 University Of Medicine And Dentistry Of New Jersey Inhibition of HIV-1 replication using oligocarbamate derivatives
WO1999025327A2 (en) * 1997-11-14 1999-05-27 Warner-Lambert Company Small molecule intervention in hiv-1 replication
EP2401264A4 (de) * 2009-02-24 2013-08-07 Univ New York Peptoid-oligomere, pharmazeutische zusammensetzungen daraus und verfahren zu deren verwendung
IT1397569B1 (it) 2009-12-10 2013-01-16 Icgeb Peptidi e loro derivati che inibiscono il rilascio extracellulare della proteina tat di hiv-1 e la replicazione di hiv-1.
MX365465B (es) 2013-03-21 2019-06-04 Sanofi Aventis Deutschland Sintesis de productos peptidicos que contienen imida ciclica.
MX363522B (es) 2013-03-21 2019-03-26 Sanofi Aventis Deutschland Síntesis de productos peptídicos que contienen hidantoína.
JP7745323B2 (ja) * 2019-04-30 2025-09-29 マックスウェル バイオサイエンシーズ，インコーポレイテツド ハロゲン化抗菌ペプトイド

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US5654398A (en) * 1993-06-03 1997-08-05 The Regents Of The University Of California Compositions and methods for inhibiting replication of human immunodeficiency virus-1

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