Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/06—Ring systems of three rings
  • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
  • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
  • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
  • C07D219/08—Nitrogen atoms
  • C07D219/10—Nitrogen atoms attached in position 9
  • C07D219/12—Amino-alkylamino radicals attached in position 9
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

• the present invention relates to a novel use of compounds, as such or in the form of pharmaceutical compositions, as antiretroviral therapeutics (also for prophylaxis) inhibiting the interaction of transcriptional regulators with retroviral response elements, to processes for the manufacture of pharmaceutical compositions for the novel intended use, to pharmaceutical compositions comprising the compounds and to novel intermediates and/or to a method of treatment comprising administering such a compound; the invention also relates to novel compounds of that type, to those novel compounds for use in a method for the diagnostic or therapeutic treatment of the human or animal body, and to processes for the preparation of these compounds.
• retroviruses A large number of retroviruses have been identified and characterized in recent efforts to understand causes for certain diseases.
• viruses affecting e.g., cats, such as FIV, apes, such as SIV, and humans, such as HTLV-I or HIV, especially HIV-1 or HIV-2.
• a characteristic of these retroviruses is that the transcription of their RNA is controlled by regulatory proteins which bind to hairpin stem-loop RNA conformations present on mRNA's of the retrovirus.
• HIV is a virus which is regarded as causative agent for the complex disease process leading to AIDS.
• the genome of this virus encodes (inter alia) two regu ⁇ latory proteins, Tat and Rev, which act through regulatory pathways that were identified recently and 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 indu- ces the efficient export of viral RNA species that are otherwise excluded from the cell cyto ⁇ plasm.
• TAR for trans-activation response region
• 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.
• the RE corresponds to a predicted RNA secondary structure of great stability
• 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, 1 167-1171 (1991 ) and Tiley, LS., et al., Proc. Natl. Acad Sci. USA 89, 758- 62 (1992)).
• re ⁇ gion Towards the carboxyl terminus of Tat a highly basic re ⁇ gion (residues 48 - 57) is present which appears to be involved in RNA binding, it is of high therapeutic interest to identify new chemical entities with the ability to bind HIV RNA at sites of specific regulatory elements (TAR and RRE), and compete in this process with the viral Tat and Rev proteins. Disruptions of Tat/TAR and Rev/RRE complexes corrupt the re ⁇ gulatory systems essential for viral replication and provide a powerful basis for therapeutic intervention in AIDS patients. Different strains of HIV produce different forms of Tat; how ⁇ ever, the the N-terminal ammo acid sequence of 72 ammo acids is common to all forms.
• Tat(1-86) herein The principle form of Tat (designated as Tat(1-86) herein) consists of 86 am o acids in known linear sequence (see Ratner et al., Nature 313, 277 (1985), which is incorporated by reference herein). Three domains in the protein have been shown to exist by structure/func ⁇ tion analysis, including a proline-rich region spanning residues 1 -18, a cysteine- ⁇ ch 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)-Arg57, the latter basic region being designated as "basic domain" of the HIV Tat protein.
• the binding sites for Tat and Rev on the respective mRNA comprises sites with hairpin stem-loop conformations with so-called bulged residues.
• Tat is introduced to the transcription machinery following direct binding to an RNA stem-loop structure transcribed from the trans-activation responsive region (TAR). Tat recognizes a U- rich bulge sequence located six residues below the apex of the TAR RNA stem-loop.
• the compounds of formula I can be used in the as treatment of a retro ⁇ viral disease in a warm-blooded animal which disease is responsive to the inhibition of the interaction of a transcriptional regulator with a retroviral response element, that is as antire- troviral compounds and therapeutics inhibiting the interaction of transcriptional regulators with retroviral response elements, for example the interaction between HIV-1 Tat and TAR and/or the interaction between HIV-1 Rev and RRE.
• the use of the compounds of the present invention is of particularly high value for the treatment of various retroviral infections, e.g. against variants of HIV, especially such variants that have become resistant to other kinds of treatment.
• a co ⁇ tDOund to be used according to the invention is a compound of the formula I, wherein
• R t and R 2 are, independently of each other, a basic group selected from amino, N- alkylamino, N,N-dialkylamino, cycloalkylamino, amidino, N-lower alkylamidino, N,N-di-lower alkylamidino, guanidino, N-lower alkylguanidino, N,N-di-lower alkylguanidino and a group of
• Z is, independently of X and Y, -(CH 2 ) b - or is a bivalent radical of the formula
• R is hydrogen or lower alkyl, said bivalent radical being bound via its -(CH 2 ) ⁇ - or -(CH 2 ) r to the nitrogen and via its -NH- or -N(R)- to Q in formula I,
• Q is selected from aryl, arylcarbonyl, arylaminocarbonyl, heterocyclyl, heterocyclylcarbonyl or heterocyclylaminocarbonyl, aryl or heterocyclyl whenever mentioned containing 2 or more annelated rings,
• a is 2 to 4
• b is 2 to 7
• c is 1 to 3
• d is 1 to 3
• g and h is 0 to 3
• i is 2 to 7 and k is 1 to 3
• Q is arylcarbonyl, arylaminocarbonyl, heterocyclylcarbonyl or heterocyclylaminocarbonyl only if Z is a bivalent radical of the formula
• the compounds of formula I 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 enantio ⁇ mers, depending on the number of asymmetric carbon atoms and on whether isomers or isomeric mixtures are present. Preferred are pure isomers (enantiomers or diastereomers).
• lower defines a moiety with up to and including maximally 7, especially up to and
• 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.
• alkyl preferably has up to 12 carbon atoms and is linear or branched one or more times; preferred is lower alkyl, especially C C ⁇ AIkyl.
• Cycloalkyl preferably has 3 to 10, especially 3 to 8 carbon atoms, for example in cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• lower alkyl is most preferably methyl or ethyl.
• lower alkyl is most preferably methyl or ethyl.
• Cycloalkylene is a bivalent radical which preferably has 3 to 10, more preferably 3 to 8,
• Aryl comprising 2 or more annelated rings has preferably from 9 to 16 ring carbon atoms, such as in indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and may be unsubstituted or substituted by one or more substitutens, especially unsubstituted or mono- to tri-substituted preferably by lower alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl, oxo, 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 alkyla
• aryl is preferably as defined above for aryl.
• aryl is preferably as defined above for aryl.
• Heterocyclyl comprising 2 or more annelated rings is preferably a double or triple ring sy ⁇ stem having from 8 to 16 ring atoms, is bonded preferably via a carbon atom or (if a nitro ⁇ gen atom is present) via a nitrogen atom (preferably so that only tertiary nitrogen is the bin ⁇ ding group in the respective compound of formula I, that is, a hydrogen atom of a corres-
• SUBST ⁇ UTE SHEET (RULE 26) ponding compound Q-H with H bound to the nitrogen is replaced with the moiety Z binding to the rest of the molecule in formula I) and contains up to 4 hetero atoms selected from oxygen, nitrogen, sulfur, and sulfur linked to 1 or 2 oxygen atoms; which ring system in addition may also be fused to 1 or 2 phenyl rings; and which ring system may be unsaturated (preferred) or partially or fully saturated, more preferably a heterocyclic ring selected from indolyl, isoindolyl, 4,5,6,7-tetrahydro in ⁇ dolyl, indolizinyl, 3H-indolyl, indazolyl, benzo-2-oxy-1 ,3-diazolyl, purinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroquinolyl or 1 ,2,3,
• heterocyclyl comprising 2 or more annelated rings is selected from purinyl, such as purin-6-yl, acridinyl (dibenzo(b,e]pyridyl), such as acridin-4-yl or acridin-9-yl, 1 ,8- naphthalimidyl (1 ,3-dioxo-2,3-dihydro-2-azaphenalenyl), such as 1 ,8-naphthalimido, or benzo-2-oxy-1 ,3-diazolyl, such as benzo-2-oxy-1 ,3-diazol-4-yl, each of which is unsubsti ⁇ tuted or substituted with one or more, preferably 1 to 3, most preferably 1 or 2 substituents selected preferably from hydroxy, lower alkoxy, such as methoxy, halogen, such as chloro, - 8 -
• heterocyclyl is especially selected from 2-chloro-purin-6-yl, acridin-4-yl, acridin-9- yl, 6-chloro-2-methoxy-acridin-9-yl, 1 ,8-naphthalimido, 3-hydroxy-1 ,8-naphthalimido, 4- chloro-1 ,8-naphthalimido and 7-nitro-benzo-2-oxa-1 ,3-diazol-4-yl.
• R a carbon atom in Z (if Z is -(CH 2 ) -) , it is preferably a nitrogen-containing ring system that is bound via a ring nitrogen atom (preferably so that only tertiary nitrogen is the binding group in the respective compound of formula I).
• heterocyclylcarbonyl is preferably as defined above for heterocyclyl, espe ⁇ cially as one of the preferred heterocyclyl moieties, and is bound preferably via a ring carbon atom. More preferably, heterocyclylcarbonyl is selected from acridinylcarbonyl, such as acridin-4-yl-carbonyl or acridin-9-ylcarbonyl.
• heterocyclyl is preferably as defined above for heterocyclyl and is bound preferably via a ring carbon.
• a is preferably 2 or 3
• b is preferably 2, 3, 4, 5 or 6 in the radicals X and Y or 2, 3 or 4 in the radical Z
• c is preferably 1
• d is preferably 1
• e is preferably 1
• f is preferably 1
• g is preferably 1
• h is preferably 1
• i is preferably 2 to 4
• k is preferably 1.
• the presence and possible conditions for the existence of these tautomers or further tautomers are known to the person having skill in the art
• 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 la, 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 alkyl ⁇ amines, or with quaternary ammonium compounds, for example with N-methyl-N-ethyl- amine, diethylamine, triethylamine, mono-
• 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, sutfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, suc ⁇ cinic acid, maleic acid, hydroxymaleic acid, methyl maleic acid, fumaric acid, malic acid, tar- taric acid, gluconic acid, gluca ⁇ c acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-am ⁇ nosal ⁇ cylic acid, 2-phenoxybenzo ⁇ c acid, 2-acet- oxybenzoic acid, embonic acid, nicotinic acid or isonicotmic acid, as well as with amino acids, for example
• the compounds of formula I have useful, in particular pharmacologically useful, properties. Surprisingly, it has been found that the compounds of formula I are able to inhibit the propa ⁇ gation 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 compe ⁇ tition 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 auto ⁇ radiography as a decreased intensity of the retarded band.
• the unincorporated [ ⁇ - ⁇ PJATP 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 ml contains approximately 10,000 cpm of the labelled duplex TAR-RNA and 20 nM recombinant Tat protein in TK buffer (Tris.HCI 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.HCI 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).
• ICso value is deter ⁇ mined as the concentration of a compound of the formula I giving a 50 % decrease in the intensity of the retarded band (Tat-TAR complex). It is possible to show that similar binding affinity can be found when wild-type unlabelled TAR-RNA is used as competitor, thus sug ⁇ gesting that the compounds of the present invention have affinities comparable to that of the high molecular weight full-length Tat protein in vitro.
• the IC ⁇ o-values that are obtained are preferably in the range of from 1 x 10" 9 to 1 x 10' 6 M. It is necessary to mention that the test data may show variations from assay to assay due to variations in the biological materials; however, relative values determined in one assay and overlap in at least some tested compounds in different assays allow for the comparability of the effectiveness of compounds in different assays.
• Rev-RRE in vitro inhibition of the interaction between Rev and RRE
• MRC Medical Research Council
• RNA synthetic RRE duplex, Genset, Paris, France; the sequence can be found in Iwai et al., Nucl. Acids Res. 20, 6465-72 (1992)), 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, 11 1- 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 auto ⁇ radiography as a decreased intensity of the retarded band.
• compounds of the formula I are tested as follows:
• the unincorporated [ ⁇ - 32 P]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 15-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 ml contains approximately 10,000 cpm of the labelled duplex RRE-RNA and 20 nM recombinant Rev protein in TK buffer (Tris.HCI 20 mM pH 8.0, KCl 50 mM) with 10 mM DTT, 0.1 % Triton X- 100 ((Alkylphenylpoiyethylenglykol, Rohm & Haas, Darmstadt, Germany) in the absence or presence of varying concentrations of inhibitor.
• TK buffer Tris.HCI 20 mM pH 8.0, KCl 50 mM
• Triton X- 100 ((Alkylphenylpoiyethylenglykol, 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).
• IC 50 value is deter ⁇ mined as the concentration of a compound of the formula I giving a 50 % decrease in the intensity of the retarded band (Rev-RRE complex). It is possible to show that similar binding affinity can be found when wild-type unlabelled TAR-RNA is used as competitor, thus sug ⁇ gesting that the compounds of the present invention have affinities comparable to that of the high molecular weight full-length Rev protein in vitro.
• the ICso-values that are obtained are preferably in the range of from 1 x 10" 9 to 1 x 10 " ® M.
• PBLs Peripheral Blood Mononuclear Lymphocytes
• Cells (1 x 10 6 /ml) are cultured for 2 days in RPMI-1640 (Gibco), supple ⁇ mented with 10 % heat-inactivated fetal calf serum (Gibco), 50 mg/ml streptomycin, 50 U/ml penicillin (Amimed), 2 nM glutamine and 10 mM hepes buffer (Gibco).
• Stimulated lympho ⁇ cytes are obtained by culturing in the presence of PHA (0.25 mg/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 50mM of t ⁇ s- ( ⁇ , ⁇ , ⁇ -tr ⁇ s(hydroxymethyt)methylam ⁇ e, ultra pure, Merck, Federal Republic of Germany) pH 7.8; 75mM of KCl, 2mM of dithiothreitol, 5mM of MgCI 2 ; 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 dried filters are washed three times for 5 minutes with 300 mM of NaCI/25mM of tnsodium citrate and once with 95% ethanol and again air-dried Evaluation is effected in a Matrix Packard 96-well counter (Packard, Downers Grove, IL, USA).
• the RT activity is a measure of the reproduction of HIV-1.
• the compounds of formula I 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 uM 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) It can be shown that inhibition by a compound of formula I is mainly due to its ability to per ⁇ meate into cells, a fact that can be demonstrated by a Fusion Induced Gene Stimulation Assay (FIGS-assay) that excludes cell surface effects as the underlying mechanism of action.
• FIGS-assay Fusion Induced Gene Stimulation Assay
• Cellular toxicity experiments are conducted on two cell lines, lymphomic CEM-SS and epi- theloid Hela cells (obtainable through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, catalogue No. 776 and 153, respectively).
• Cells are propa ⁇ gated as monolayer cultures in DMEM-medium, 10% heat inactivated fetal bovine serum (FBS) (both from Gibco, Paisley, UK), supplemented with 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM L-glutamine (all from Amimed, Muttenz, CH).
• FBS heat inactivated fetal bovine serum
• Compounds are added to the medium on day 1 and 4, cells are harvested and living cells are counted on day 3 and day 6. With most of the compounds toxicity (> 50 % dead cells) is observed only at a final concentration exceeding 30 ⁇ M.
• a compound of formula I can be dissolved e.g. in dimethyl sulfoxide (DMSO) in a concentration of 240 mg/ml.
• DMSO dimethyl sulfoxide
• the resulting solutions are diluted 1 :20 (v/v) with 20 % (w/v) aqueous hydroxypropyl- ⁇ -cyclodextrin solution in order to obtain a concentration of the test compound in question of 12 mg/ml.
• the resulting solution is treated briefly with ultrasound and administered orally to female BALB/c mice (Bomholt- garden, Copenhagen, Denmark) by artificial tube feeding at a dose of 120 mg/kg.
• mice are sacrificed and the plasma stored in heparinised test tubes.
• the blood is centrifuged (12 000 x g, 5 min) and the plasma removed.
• the plasma is deproteinised by the addition of an equal volume of acetonitrile.
• the mixture is mixed using a vortex mixer and and left to stand at room temperature for 20 to 30 minutes.
• the precipitate is pelleted by centrifugation (12 000 x g, 5 min), and the concentration of the test compound is determined by reversed phase high performance liquid chromatography (HPLC).
• HPLC reversed phase high performance liquid chromatography
• HPLC analysis of the samples obtained in accordance with the method described above is, for example, carried out on a 125 x 4.6 mm Nucleosil* C 18 -column (reversed- phase material supplied by Macherey & Nagel, D ⁇ ren, Germany, based on silica gel denvatised with carbon radicals having 18 carbon atoms), using a 2 cm long preliminary column of the same column material.
• the test is carried out with the following linear acetonitnle/water gradient (in each case in the presence of 0.05 % trifluoroacetic acid): 20 % acetonitrile to 100 % acetonitrile for 20 m ; then 5 m 100% acetonitrile; then returning to the initial conditions for 1 m and 4 mm reequilibration.
• the flow rate is 1 ml/min.
• the test compound is detected by UV absorption measurement at 255 nm Peaks are identified by the retention time and the UV spectrum between 205 and 400 nm.
• the concentrations are determined by the external standard method; the peak heights are obtained for determining the concentrations by comparison with standard curves.
• the standard curves are obtained by analogous HPLC analysis of mouse plasma that contains known concentrations of the test compound in question and that has been worked up in accordance with the method described above.
• the compounds of formula I can thus be used in the treatment of retroviral diseases in warm-blooded animals which diseases are responsive to the inhibition of the interaction of transcriptional regulators with retroviral response elements, preferably HIV-, such as HIV-1 -, infections which are responsive to the inhibition of the interaction between Tat and TAR and/or Rev and RRE; and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in humans by inhibition of the interaction between Tat and TAR and/or Rev and RRE of HIV-1.
• 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 formula I can also be used in the treatment of commercially valuable ceil (such as lymphocyte) cultures against retroviral infections, especially against HIV, such as HIV-1 , infections
• the present invention relates also to the use of a compound of formula I in the inhibition of the interaction of transcriptional regulators with retroviral response elements, especially as mentioned above.
• the compounds of the invention may be used either on their own or in combination with other pharmacologically active substances, for example together with inhibitors of reverse transcriptase, inhibitors of retroviral aspartate protease inhibitors or other antiretrovirally active substances and preparations.
• the invention preferably relates to a use (in the processes, methods and/or pharmaceutical preparations or their preparation as defined above and below) of a compound of formula I wherein
• Ri and R 2 are, independently of each other, a basic group selected from amino, N-alkyl- amino, N,N-dialkylamino, cycloalkylamino, amidino, N-lower alkylamidino, N,N-di-lower alkyl ⁇ amidino, guanidino, N-lower alkylguanidino and N,N-di-lower alkylguanidino,
• X and Y are independently a bivalent radical of the formula -(CH 2 ) b -
• Z is a bivalent radical of the formula or
• R is hydrogen or lower alkyl, said bivalent radical being bound via its -(CH 2 ) ⁇ - or -(CH 2 ) r to the nitrogen and via its -NH- or -N(R)- to Q in formula I,
• Q is selected from aryl, arylcarbonyl, arylaminocarbonyl, heterocyclyl, heterocyclylcarbonyl or heterocyclylaminocarbonyl, especially from heterocyclyl and heterocyclylcarbonyl; aryl or heterocyclyl whenever mentioned containing 2 or more annelated rings,
• aryl comprising 2 or more annelated rings in the definitions of Q being selected preferably from indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl, which are unsubstituted or substituted by one or more (preferably 1 or 2) substitutents selected from lower alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl, oxo, 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 alkanoylamino, halogen, for example fluor
• heterocyclyl comprising 2 or more annelated rings being selected preferably from indolyl, isoindolyl, 4,5,6,7-tetrahydro indolyl, indolizinyl, 3/-/-indolyl, indazolyl, benzo-2-oxy- 1 ,3-diazolyl, purinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroquinolyl or 1 ,2,3,4-tetrahydroisoquinolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, chromenyl, chromanyl, isochromanyl, cyclohexa[b]pyrrolyl, cyclohexa[b]pyri
• b is 2 to 7, preferably 2 to 6, e and f is 1 to 3, respectively, i is 2 to 7, preferably 2 to 4, and k is 1 , with the proviso that Q is arylcarbonyl, arylaminocarbonyl, heterocyclylcarbonyl or heterocyclylaminocarbonyl only if Z is a bivalent radical of the formula
• X and Y are independently a bivalent radical of the formula -(CH 2 ) -
• Z is, independently of X and Y, one of the residues mentioned in the definition of X and Y or
• Q is selected from purinyl, such as purin-6-yl, acridinyl (dibenzo[b,e]pyridyl), such as acridin- 4-yl or acridin-9-yl, 1 ,8-naphthalimidyl (1 ,3-dioxo-2,3-dihydro-2-azaphenaienyl), such as 1 ,8- naphthalimido (bound via its nitrogen atom), and benzo-2-oxy-1 ,3-diazolyl, such as benzo- 2-oxy-1 ,3-diazol-4-yl, each of which is unsubstituted or substituted with one or more, pre ⁇ ferably 1 to 3, most preferably 1 or 2 substituents selected from hydroxy, lower alkoxy, such as methoxy, halogen, such as chloro, and nitro; especially selected from 2-chloro-purin-6-yl, acridin-4-yl, acridin-9-
• Q is acridinylcarbonyl, such as acridin-4-yl-carbonyl or acridin-9- ylcarbonyl;
• b is 2 to 7, preferably 2 to 6, e and f is 1 , respectively, i is 2 to 7, preferably 2 to 4, and k is 1 ,
• X and Y are independently a bivalent radical of the formula -(CH 2 ) b -,
• ICHJ, ⁇ Z is a bivalent radical of the formula N , wherein R is hydrogen, said bi-
• R valent radical being bound via its -(CH 2 ) r to the nitrogen and via its -N(R)- to Q in formula I,
• Q is selected from 6-chloro-2-methoxy-acridin-9-yl and acridinylcarbonyl, such as acridin-9- yl-carbonyl or (preferably) acrid in-4-ylcarbonyl;
• b is 2 to 7, preferably 2 to 6, more preferably 2 to 4, i is 2 to 4, preferably 3 to 4, and k is 1.
• the invention relates also to novel compounds of formula I and their salts and to the use thereof in the processes, methods and pharmaceutical compositions mentioned herein ⁇ before and hereinafter, and to pharmaceutical compositions comprising those compounds, especially the compounds mentioned below:
• R, and R 2 are, independently of each other, a basic group selected from amino, N-alkyl- amino, N,N-dialkylamino, cycloalkylamino, amidino, N-lower alkylamidino, N,N-di-lower alkyl ⁇ amidino, guanidino, N-lower alkylguanidino and N,N-di-lower alkylguanidino;
• X and Y are independently a bivalent radical of the formula -(CH 2 ) -,
• Z is, independently of X and Y, one of the residues mentioned in the definition of X and Y or
• Q is selected from heterocyclyl and heterocyclylcarbonyl, heterocyclyl in both cases being selected from indolyl, isoindolyl, 4,5,6,7-tetrahydro indolyl, indolizinyl, 3H-indolyl, indazolyl, benzo-2-oxy-1 ,3-diazolyl, purinyl, benzimidazolyl, benzofuranyl, isobenzof uranyl, isoquino ⁇ lyl, 1 ,2,3,4-tetrahydroquinolyl or 1 ,2,3,4-tetrahydroisoquinolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, chromenyl, chromanyi, isochromanyl, cyclohexa[b]pyrrolyl, cyclohexa[b
• b is 2 to 7, preferably 2 to 6, e and f is 1 to 3, respectively, i is 2 to 7, preferably 2 to 4, and k is 1 ,
• Q is heterocyclylcarbonyl only if Z is a bivalent radical of the formula
• R is hydrogen or lower alkyl
• X and Y are -(CH 2 ) b - and Q is
• k is 1 and R is hydrogen, and Q is 6-chloro-2-methoxy-acridin-9-yl is excluded;
• I R is 2, k is 1 and R is hydrogen, and Q is acridin-9-ylcarbonyl is excluded;
• Ri and R 2 are, independently of each other, a basic group selected from amino, N- alkylamino, N,N-dialkylamino, cycloalkylamino, amidino, N-lower alkylamidino, N,N-di-lower alkylamidino, guanidino, N-lower alkylguanidino and N,N-di-lower alkylguanidino
• X and Y independently are a group of the formula -(CH 2 ) b - ,
• Z is, independently of X and Y, one of the residues mentioned in the definition of X and Y or
• Q is selected from purinyl, such as purin-6-yi, acridinyl (dibenzo[b,e]pyridyl), such as acridin- 4-yl or acridin-9-yl, 1 ,8-naphthalimidyl (1 ,3-dioxo-2,3-dihydro-2-azaphenalenyl), such as 1 ,8- naphthalimido, and benzo-2-oxy-1 ,3-diazolyl, such as benzo-2-oxy-1 ,3-diazol-4-yl; prefer ⁇ ably from purinyl, such as purin-6-yl, acridinyl (dibenzo[b,e]pyridyl), such as acridin-4-yl or acridin-9-yl, 1 ,8-naphthalimidyl (1 ,3-dioxo-2,3-dihydro-2-azaphenalenyl), except for
• N and 1 ,8-naphthalimido being bound to -(CH 2 ) b - as Z;
• each of which is unsubstituted or substituted with one or more, preferably 1 to 3, most preferably 1 or 2 substituents selected from hydroxy, lower alkoxy, such as meihoxy, halogen, such as chloro, and nitro; especially selected from 2-chloro-purin-6-yl, acridin-4-yl, acridin-9-yl, 6-chloro-2-methoxy-acridin-9-yl, 1 ,8-naphthalimido, 3-hydroxy-1 ,8-naphthal- imido, 4-chloro-1 ,8-naphthalimido and 7-nitro-benzo-2-oxa-1 ,3-diazol-4-yl;
• acridinylcarbonyl such as acridin-4-yl-carbonyl or acridin-9-ylcarbonyl
• b is 2 to 6, e and f is 1 , respectively, i is 2 to 4 and k is l ,
• R is hydrogen
• X and Y are -(CH 2 ) b - and Q is acridin-9- ylcarbonyl or 6-chloro-2-methoxy-acridin-9-yl, then at least in one of the residues X and Y b is 3 or larger;
• k is 1 and R is hydrogen, and Q is 6-chloro-2-methoxy-acridin-9-yl is excluded;
• X and Y independently are a group -(CH 2 ) b -,
• Z is, independently of X and Y, -(CH 2 ) b -,
• Q is selected from 1 ,8-naphthalimido which is unsubstituted or substituted with one or more, preferably 1 to 3, most preferably 1 or 2 substituents selected from hydroxy, lower alkoxy, such as methoxy, halogen, such as chloro, and nitro; most preferably selected from 1 ,8- naphthalimido, 3-hydroxy-1 ,8-naphthalimido and 4-chloro-1 ,8-naphthalimido; b is 2 to 6, and e and f is 1 , respectively,
• X and Y are independently a group -(CH 2 ) b -,
• Z is a bivalent radical of the formula , wherein R is hydrogen, said bi- valent radical being bound via its -(CH 2 ) r to the nitrogen and via its -N(R)- to Q in formula I,
• Q is selected from purinyl, such as purin-6-yl, and benzo-2-oxy-1,3-diazolyl, such as benzo- 2-oxy-1 ,3-diazol-4-yl, each of which is unsubstituted or substituted with one or more, preferably 1 to 3, most preferably 1 or 2 substituents selected from hydroxy, lower alkoxy, such as methoxy, halogen, such as chloro, and nitro,
• acridinyl dibenzo ⁇ ejpyridyl
• acridin-4-yl or acridin-9-yl acridin-4-yl or acridin-9-yl
• b is 2 to 6, e and f is 1 , respectively, i is 2 to 4 and k is 1 ,
• k is 1 and R is hydrogen, and Q is acridin-9-ylcarbonyl is excluded;
• X and Y are independently a group -(CH 2 ) b -,
• ⁇ Z is a bivalent radical of the formula N , wherein R is hydrogen, said bi-
• R valent radical being bound via its -(CH 2 ) r to the nitrogen and via its -N(R)- to Q in formula I,
• Q is acridinyl (dibenzo[b,e]pyridyl), such as acridin-4-yl or acridin-9-yl; which is unsubstituted or substituted with one or more, preferably 1 to 3, most preferably 1 or 2 substituents selected from hydroxy, lower alkoxy, such as methoxy, halogen, such as chloro, and nitro, or is acridinylcarbonyl, such as acridin-9-yl-carbonyl,
• b is 3 to 6, e and f is 1 , respectively, i is 2 to 4 and k is 1 ,
• k is 1 and R is hydrogen, and Q is acridin-9-ylcarbonyl is excluded;
• R and R 2 are, independently of each other, a basic group selected from ammo (especially prefered), N-alkylamino, N,N-dialkylam ⁇ no, cycloalkylamino, amidino, N-lower alkylamidino,
• Z is a bivalent radical of the formula , said bivalent radical being bound via its -(CH 2 ) ⁇ - to the nitrogen and via its -NH- to Q in formula I,
• Q is selected from heterocyclyl and heterocyclylcarbonyl, heterocyclyl being bound via a ring carbon atom and being selected from indolyl, isomdolyl, 4,5,6,7-tetrahydro indolyl, indo zinyl, 3H-indolyl, indazolyl, benzo-2-oxy-1 ,3-diazolyl, purinyl, benzimidazolyl, benzo ⁇ furanyl, isobenzofuranyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroqu ⁇ nolyl or 1 ,2,3,4-tetra- hydroisoquinolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridmyl, chromenyl, chromanyl, isochromanyl, cyclohexa[
• b is 2 to 7, preferably 2 to 6, c, d, e and f are 1 to 3, respectively, and g and h are 0 to 3, respectively,
• a compound of the formula I named 5-(5- ⁇ 6-chioro-2-methoxy-acridin-9-yl ⁇ -aminopentyl)-1 ,5,10-triazadecane or 6-(4- ⁇ 6-chloro-2-methoxy-acridin-9-yl)-aminopentyl)-1 ,6,11 -triazaundecane, or a pharmaceutically acceptable salt thereof, respectively.
• the compounds of the formula I can be synthesized according to procedures that are known perse, but not with regard to the new compounds of formula I mentioned above and below, especially by a process comprising
• R ⁇ R 2 , X and Y are defined as for compounds of formula I, with a compound of formula III,
• Z and Q are as defined for compounds of formula i and
• A is a nucleofugal leaving group, the starting materials where necessary being present in protected form, and removing any protecting groups being present;
• Z is a bivalent moiety of the formula or of the
• Q is aryl, arylcarbonyl, heterocyclyl that is not bound via a ring nitrogen atom or heterocyclylcarbonyl and e, f, i, k, Ri, R 2 , X and Y are as defined for compounds of formula I, reacting an amino compound of the formula IV,
• Q is aryl, arylcarbonyl, heterocyclyl that is not bound via a ring nitrogen atom or heterocyclylcarbonyl and
• L is a leaving group, the starting materials where necessary being present in protected form, and removing any protecting groups being present; or
• Z is -(CH 2 ) b -, wherein b is as defined for a compound of formula I,
• Q is unsubstituted or substituted 1 ,8-naphthalimido
• R L R 2 , X, Y and b are as defined for a compound of formula I,
• T is -(CH 2 ) b -
• R , R 2> X and Y are as defined for a compound of formula I,
• R- , R2, X, Y, Z, Q, a, b, c, d, e, f, g, h, i and k have the meanings given for compounds of the formula I, if not mentioned otherwise. All starting materials can also be used in the form of salts where salt-forming groups are present and where the presence of the salts does not lead to undesired side reactions.
• protective groups for functional groups in starting materials whose reaction is to be avoided include, in particular, those protective groups (conventional protecting groups) which are customarily used in the synthesis of pep ⁇ tide compounds or else of cephalosporins and penicillins, and also nucleic acid derivatives and sugars.
• protective groups can already be present in the precursors and are in ⁇ tended to protect the functional groups concerned against unwanted side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis, etc.
• the protective groups can, in addition to this, have the effect of making the course of reactions selective, for example stereoselective. It is characteristic of protective groups that they are easily detachable, i.e. without undesirable side reactions, for example solvolytically, reduc- tively, photolytically or else enzymically, for example under ohysiological conditions as well, and that they are not present in the end products.
• a carboxyl group is, for example, protected as an ester group which can be selectively clea ⁇ ved under mild conditions.
• a carboxyl group which is protected in esterified form is primarily esterified with a lower alkyl group which is preferably branched in the 1 position of the lower alkyl group or is substituted by suitable substituents in the 1 or 2 position of the lower alkyl group.
• a protected carboxyl group which is esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.
• a protected carboxyl group which is esterified with a lower alkyl group which is branched in the 1 position of the lower alkyl group is, for example, tert-lower-alkoxycarbonyl, for exam ⁇ ple tert-butoxycarbonyl.
• a protected carboxyl group which is esterified with a lower alkyl group which is substituted in the 1 or 2 position of the lower alkyl group by suitable substituents is, for example, 1 -aryl- lower-alkoxycarbonyl, such as arylmethoxycarbonyl, having one or two aryl radicals, in which aryl is phenyl which is unsubstituted or is substituted once, twice or three times by, for example, lower alkyl, for example tert-lower-alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxyl, halogen, for example chlorine, and/or nitro, for example benzyl ⁇ oxycarbonyl, benzyloxycarbonyl which is substituted by the said substituents, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or di- phenylmethoxycarbonyl which is
• a carboxyl group can also be protected as an organic silyloxycarbonyl group.
• An organic silyioxycarbonyl group is, for example, a tri-lower-alkylsilyloxycarbonyi group, for example trimethylsilyloxycarbonyl.
• the silicon atom of the silyloxycarbonyl group can also be sub ⁇ stituted by two lower alkyl, for example methyl, groups, and an amino or carboxyl group of a second molecule of the formula I.
• Compounds possessing such protective groups can be prepared, for example, using corresponding tri-lower-alkylhalosilanes, such as tert-butyl- dimethylchlorosilane, as silylating agents.
• a carboxyl group is also protected in the form of an internal ester with a hydroxyl group which is present in the molecule at a suitable distance, for example in the g position with regard to the carboxyl group, i.e. in the form of a lactone, preferably a g-lactone.
• a protected carboxyl group is preferably tert-iower-alkoxycarbonyl, for example tert-butoxy- carbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a protected carboxyl group in the form of a lactone, in par ⁇ ticular a g-lactone.
• a protected amino group is protected by an amino protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-alk-1-enylamino or silylamino group, or as an azido group.
• an amino protecting group for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower-alk-1-enylamino or silylamino group, or as an azido group.
• acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular of a lower-alkanecarboxylic acid which is unsubstituted or substituted, for example, by halogen or aryl, or of benzoic acid which is unsubstituted or substituted, for example, by halogen, lower alkoxy or nitro, or, preferably, of a carbonic acid semiester.
• Such acyl groups are, preferably, lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower-alkanoyl, for example 2-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl which is unsubstituted or substituted, for example, by halogen, lower alkoxy or nitro, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower-alkoxycarbonyl, lower- alkoxycarbonyl which is preferably branched in the 1 position of the lower-aikyl radical or is suitably substituted in the 1 or 2 position, for example tert-lower-alkoxycarbonyl, such as tert- butoxycarbonyl, 1 -aryl-low
• aryl radicals are, in particular, phenyl radicals which are unsubstituted or sub ⁇ stituted.
• aryl radicals are benzyl-, diphenylmethyl- or, in particular, trityl-amino.
• the mercapto group is primarily present as substi ⁇ tuted arylthio or aryl-lower-alkylthio in which aryl is, for example, phenyl which is unsubstitu ⁇ ted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, for example 4-nitrophenylthio.
• aryl is, for example, phenyl which is unsubstitu ⁇ ted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, for example 4-nitrophenylthio.
• acyl is, for example, the corresponding radical of a lower-alkanecarboxylic acid, of a benzoic acid which 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 nitro, or, in parti ⁇ cular, of a carbonic acid semiester, such as a carbonic acid lower-alky! semiester.
• Corres ⁇ ponding protective groups are, primarily, 1-lower-alkanoyl-lower-alk-1-en-2-yl, for example 1 -lower-alkanoyl-prop-1 -en-2-yl, such as 1 -acetyl-prop-1-en-2-yl, or lower-alkoxycarbonyl- lower-alk-1-en-2-yl, for example lower-alkoxycarbonyl-prop-1-en-2-yl, such as 1-ethoxy- carbonyi-prop-1 -en-2-yl.
• 1-lower-alkanoyl-lower-alk-1-en-2-yl for example 1 -lower-alkanoyl-prop-1 -en-2-yl, such as 1 -acetyl-prop-1-en-2-yl, or lower-alkoxycarbonyl- lower-alk-1-en-2-yl, for example lower-alkoxycarbonyl-prop-1-en-2-yl, such as
• a silylamino group is, for example, a tri-lower-alkylsilylamino group, for example trimethyl- silylamino or tert-butyldimethylsilylamino.
• the silicon atom of the silylamino group can also only be substituted by two lower alkyl groups, for example methyl groups, and the amino group or carboxyl group of a second molecule of the formula I.
• Compounds having such protective groups can be prepared, for example, using the corresponding chlorosilanes, such as tert-butyldimethylchlorosilane, as silating agents.
• cor ⁇ responding anions are primarily those of strong inorganic acids, such as of sulfuric acid, phosphoric acid or hydrohalic acids, for example the chlorine or bromine anion, or of orga ⁇ nic sulfonic acids, such as p-toluenesulfonic acid.
• Preferred amino protective groups are lower-alkoxycarbonyl, phenyl-lower-alkoxycarbonyl, fluorenyl-lower-alkoxycarbonyl, 2-lower-alkanoyl-lower-alk-1 -en-2-yl or lower-alkoxycar- bonyl-lower-alk-1-en-2-yl, especially tert-butoxycarbonyl or benzyloxycarbonyl.
• a hydroxyl group can, for example, be protected by an acyl group, for example lower alka ⁇ noyl which is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichtoroacetyl, or, in particular, by an acyl radical, which is specified for protected amino groups, of a carbonic acid semiester.
• halogen such as chlorine
• acetyl or 2,2-dichtoroacetyl or, in particular, by an acyl radical, which is specified for protected amino groups, of a carbonic acid semiester.
• a hydroxyl group can also be protected by tri-lower- alkylsilyl, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, a readily detach ⁇ able etherifying group, for example an alkyl group, such as tert-lower-alkyl, for example tert- butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, in particular 2-oxa- or 2-thia-aliphatic or - cycloaliphatic, hydrocarbon radical, for example 1 -lower-alkoxy-lower-alkyl or 1-lower-alkyl- thio-lower-alkyl, such as methoxymethyl, 1 -methoxymethyl, 1-ethoxymethyl, methylthio- methyl, 1 -methylthioethyl or 1 -ethylthioethyl, or 2-oxa- or 2-thi
• a preferred hydroxyl protective group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenyl- methoxycarbonyl, benzyl or trityl.
• Two hydroxyl groups, in particular adjacent hydroxyl groups, which are present in a mole ⁇ cule, or an adjacent hydroxyl group and amino group, can, for example, be protected by bivalent protective groups, such as a methylene group which is preferably substituted, for example by one or two lower alkyl radicals or oxo, for example by unsubstituted or substi ⁇ tuted alkylidene, for example lower alkylidene, such as isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzylidene.
• a hydroxyl group which is located adjacent to a carboxyl group can be protected by the formation of an internal ester (lactone), in particular of a g-lactone.
• lactone an internal ester
• a protected hydroxyl group is protected by tri-lower-alkylsilyl or as a lactone, in particular by tert-butyldimethylsilyl or as a g-lactone.
• a polymeric support as is suitable, for example, for the Merrifield synthesis, and which is bound in an easily detachable manner to the functiono ⁇ nal group to be protected, for example a carboxyl group, is also expressly understood to be a protective group, for example a carboxyl protective group.
• a suitable polymeric support of this nature is, in particular, a polystyrene resin which is weakly cross-connected by copoly ⁇ merization with divinylbenzene and which carries suitable bridge members for the reversible binding.
• the nucleofugal leaving group A is preferably a nucleofugal group, preferably arylsulfonyloxy, such as toluene- sulfonyloxy, lower alkanesulfonyloxy, such as methanesulfonyloxy, or especially halogen, such as chlorine, bromine or iodine, most especially chlorine.
• arylsulfonyloxy such as toluene- sulfonyloxy
• lower alkanesulfonyloxy such as methanesulfonyloxy
• halogen such as chlorine, bromine or iodine
• the reaction is preferably carried out without bases or in the presence of relatively weak bases, such as especially metal hydroxides or carbonates, such as especially alkali metal hydroxides, for example sodium or potassium hydroxide, or in the presence of alkaline earth metal carbonates or alkali metal carbonates, for example sodium or potassium carbonate, preferably in the last-mentioned solvents, especially in halogenated hydrocarbons, such as dichloromethane or chloroform, or in carboxylic acid amides, such as dimethylformamide or dimethylacetamide, or in hydroxyaromates, such as phenol, and preferably at the tempe- ratures indicated below; or further in the presence of a strong base, such as an alkali metal hydride, for example sodium hydride or potassium hydride, or also an alkali metal amide, such as sodium amide, or an alkali metal di-lower alkylamide, such as lithium diisopropyl ⁇ amide, especially in the presence of sodium hydride or potassium hydride
• Detachment of the protective groups which are not components of the desired end product of the formula I, for example the carboxyl, amino and/or hydroxy protective groups, is effec ⁇ ted in a manner known per se, for example using solvolysis, in particular hydrolysis, alcoho- lysis or acidolysis, or by means of reduction, in particular hydrogenoiysis, or by means of other reducing agents, and also photolysis, as desired stepwise or simultaneously, with it also being possible to use enzymatic methods.
• Detachment of the protective groups is described, for example, in the standard works which are mentioned above in the section on protective groups.
• a protected carboxyl for example, for example lower-alkoxycarbonyl (which is prefer ⁇ ably branched in the 1 position), such as tert-lower-alkoxycarbonyl, lower-alkoxycarbonyl which is substituted in the 2 position by a tri-substituted silyl group or in the 1 position by lower alkoxy or lower-alkylthio, or diphenylmethoxycarbonyl which is unsubstituted or sub- stituted, can be converted into free carboxyl by treatment with a suitable acid, such as formic acid, acetic acid, oxalix acid, hydrochloric acid or trifluoroacetic acid, if desired while adding a nucleophilic compound, such as phenol or anisole.
• a suitable acid such as formic acid, acetic acid, oxalix acid, hydrochloric acid or trifluoroacetic acid, if desired while adding a nucleophilic compound, such as phenol or anisole
• Benzyloxycarbonyl which is unsubstituted or substituted can, for example, be set free by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst.
• suitably substituted benzyloxycarbonyl such as 4-nitroben- zyloxycarbonyl
• 2-halo-lower-alkoxycarbonyl if desired after converting a 2-bromo-lo- was-alkoxycarbonyl group into a corresponding 2-iodo-lower-alkoxycarbonyl group
• aroyl- methoxycarbonyl can also be converted into free carboxyl.
• Aroyimethoxycarbonyl can be cleaved by treating with a nucleophilic, preferably salt-forming reagent, such as sodium thio- phenoxide or sodium iodide.
• the carboxyl group can also be set free from 1 -aryl-lower- alkoxycarbonyl, for example arylmethoxycarbonyl, such as benzyloxycarbonyl, by hydro- lysing in the presence of a base such as an alkali metal hydroxide, for example sodium or potassium hydroxide.
• a base such as an alkali metal hydroxide, for example sodium or potassium hydroxide.
• 2- (Tri-substituted silyl)-lower-alkoxycarbonyl can also be converted into free carboxyl by treating with a salt of hydrofluoric acid which provides the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, in the absence or presence of a macrocyclic poly ⁇ ether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower- alkylammonium fluoride or tri-lower-alkylaryl-lower-alkylammonium fluoride, for example te- traethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide, N,N-dimethylformamide or N,N-di
• aprotic, polar solvent such as dimethyl sulfoxide, N,N-di
• Carboxyl which is protected as organic silyloxycarbonyl, such as tri-lower-alkylsilyl- oxycarbonyl, for example trimethylsilyloxycarbonyl, can be released solvolytically in a custo ⁇ mary manner, for example by treating with water, an alcohol or acid, or, in addition, fluoride, as described above.
• Esterified carboxyl can also be set free enzymically, for example using esterases or suitable peptidases, for example esterified arginine or lysine, such as lysine methyl ester, using trypsin.
• Carboxyl which is protected as an internal ester such as a g- lactone
• a hydroxide-containing base such as an alkaline earth metal hydroxide or, in particular, an alkali metal hy ⁇ roxi ⁇ e, for example NaOH, KOH or LiOH, in particular LiOH, with the corresponding protected hydroxyl group being set free simultaneously.
• a protected amino group is set free in a manner which is known per se and which differs depending on the nature of the protective groups, preferably using solvolysis or reduction.
• Lower-alkoxycarbonylamino such as tert-butoxycarbonylamino
• acids for example mineral acids, for example hydrohalic acid, such as hydro ⁇ chloric acid or hydrobromic acid, in particular hydrobromic acid, or of sulfuric acid or phos ⁇ phoric acid, preferably of hydrochloric acid, or of relatively strong organic acids, such as for ⁇ mic acid, oxalic acid, trichloroacetic acid or trifluoroacetic acid, in polar solvents, for examp ⁇ le water or a carboxylic acid, such as acetic acid or formic acid, esters, such as lower alkyl lower alkanoates, e.g.
• halohydrocarbons such as chlorinated lower-alkanes, for example dichloromethane or chloroform
• ethers preferably cyclic ethers, such as dioxane, or in organic carboxylic acids which are liquid at the reaction temperature, without solvent, for example in formic acid.
• 2-Halo-lower-alkoxycarbonylam ⁇ no (if desired, after converting a 2-bromo-lower-alkoxycarbonylamino group into a 2-iodo-lower-alkoxycarbonyl- amino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylammo can, for example, be cleaved by treating with a suitable reducing agent, such as zinc in the pre ⁇ sence of a suitable carboxylic acid, such as aqueous acetic acid.
• a suitable reducing agent such as zinc in the pre ⁇ sence of a suitable carboxylic acid, such as aqueous acetic acid.
• Aroylmethoxycarbonyl ⁇ amino can also be cleaved by treating with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenoxide, and 4-nitrobenzyloxycarbonylam ⁇ no also by treating with an alkali metal dithionite, for example sodium dithionite.
• a nucleophilic, preferably salt-forming, reagent such as sodium thiophenoxide, and 4-nitrobenzyloxycarbonylam ⁇ no
• an alkali metal dithionite for example sodium dithionite.
• Substituted or unsubstituted diphenyl- methoxycarbonylamino, tert-lower-alkoxycarbonylammo or 2-(tr ⁇ subst ⁇ tuted silyl)-lower-al- koxycarbonylamino, such as 2-tri-lower-alkylsilyl-lower-alkoxycarbonylam ⁇ no, can be cleaved by treating with a suitable acid, for example formic or trifluoroacetic acid, for example in a halogenated hydrocarbon, such as methylene chloride or chloroform (in particular, if hydroxyl which is simultaneously protected with benzyl is not to be set free),
• 1- aryl-iower-alkoxycarbonylamino such as substituted or unsubstituted benzyloxycarbonyl- ammo, can, for example, be cleaved by means of hydrogenolysis, i.e.
• a suitable hydrogenauon catalyst such as a palladium catalyst
• a support material such as carbon
• polar solvents such as di-lower-alkyl-lower-alkanoylamides, for example dimethylformamide
• ethers such as cyclic ethers, for example dioxane
• esters such as lower-alkyl lower-alkanoates, for example ethyl acetate
• alcohols such as methanol, ethanol or propanol, with methanol being particularly preferred, preferably, for example, at room temperature
• substituted or unsubstituted triarylmethylamino or formylamino can be cleaved, for example, by treating with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, if desired in the presence of water, and tri- phenylaminomethyl
• An amino group which is protected by 2-haloacetyl for example 2-chloroacetyl, can be set free by treating with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of the thiourea, and subsequent sol- volysis, such as alcoholysis or hydrolysis, of the resulting substitution product.
• a thiolate salt such as an alkali metal thiolate of the thiourea
• sol- volysis such as alcoholysis or hydrolysis
• An amino group which is protected by 2- (trisubstituted silyl)-lower-alkoxycarbonyl can also be converted into the free amino group by treating with a fluoride anion-providing salt of the hydrofluoric acid, as indicated above in connection with the release of a correspondingly protected carboxyl group.
• Silyl such as trimethylsilyl ortert-butyldimethylsilyl, which is bonded directly to a heteroatom, such as nitrogen, can likewise be detached with fluoride ions, preferably using a fluoride of an organic, quaternary nitrogen base, such as tetra-lower-alkylammonium fluoride or tri-lower-alkylaryl-lower-alkyl- ammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluo ⁇ ride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-di- methylacetamide, or, in particular, of an ether, such as tetrahydrofuran, at temperatures between 0 and 50°C, in particular, for example, at room temperature.
• aprotic, polar solvent such as dimethyl sulfoxide or N,N-di- methylace
• Amino which is protected in the form of an azido group is converted into free amino, for example, by means of reduction for example by means of catalytic hydrogenation with hy ⁇ drogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by means of reduction with mercapto compounds, such as dithiothreitol or mercaptoethanol, or by treating with zinc in the presence of an acid, such as acetic acid.
• a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel
• mercapto compounds such as dithiothreitol or mercaptoethanol
• the catalytic hydrogenation is preferably carried out in an inert solvent, such as a haloge ⁇ nated hydrocarbon, for example methylene chloride, or else in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at from approximately 20°C to 25°C, or else while cooling or heating.
• an inert solvent such as a haloge ⁇ nated hydrocarbon, for example methylene chloride
• an organic solvent such as an alcohol or dioxane
• a hydroxyl group which is protected by a suitable acyl group, a tri-lower-alkylsilyl group or by substituted or unsubstituted 1 -ary I (such as 1 -phenyl)-lower-alkyl is set free in an analo ⁇ gous manner to a correspondingly protected amino group.
• a hydroxyl group or mercapto group which is protected by 2,2-dichloroacetyl is set free, for example, by basic hydrolysis, while a hydroxyl group which is protected by tert-lower-alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is set free by acidolysis, for example by treating with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
• a hydroxyl group which is protected by benzyloxy is set free, for example, by means of hydrogenolysis, i.e.
• a suitable hydrogenation catalyst such as a pal ⁇ ladium catalyst, for example bound to a support material, such as charcoal, preferably in po ⁇ lar solvents, such as di-lower-alkyl-lower-alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower-alky laikanoates, for example ethyl acetate, chlorinated hydrocarbons, such as dichloromethane, or alcohols, such as methanol, ethanol or propanol, with methanol being particularly preferred, or mix ⁇ tures of two or more of these solvents, preferably, for example, at room temperature.
• a suitable hydrogenation catalyst such as a pal ⁇ ladium catalyst
• a support material such as charcoal
• po ⁇ lar solvents such as di-lower-alkyl-lower-alkanoylamides, for example dimethylformamide
• ethers such as cyclic ether
• Two hydroxyl groups, or an adjacent amino group and hydroxyl group, which are together pro ⁇ tected by means of a bivalent protective group preferably, for example, a methylene group which is substituted once or twice by lower alkyl, such as by lower alkylidene, for example isopropyl idene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be set free by acidic solvolysis, particularly in the presence of a mineral acid or a strong organic acid.
• a tri-lower-alkylsilyl group is likewise detached by means of acidolysis, for example by mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.
• Hydroxyl can also preferably be set free from tri-lower-alkylsilyloxy by treating with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, for example sodium or potassium fluoride, in the absence or presence of a macrocyclic polyether ("crown ether" ⁇ , or with a fluoride of an organic quaternary base, such as tetra-lower-alkylammonium fluoride or tri- iower-alkylaryl-lower-alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide.
• a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, for example sodium or potassium fluoride
• 2-Halo-lower-alkoxycarbonyl is removed by the above ⁇ mentioned reducing agents, for example reducing metal, such as zinc, reducing metal salts, such as chromium(ll) salts, or by sulfur compounds, for example sodium dithionite or, pre ⁇ ferably, sodium sulfide and carbon disulfide.
• reducing metal such as zinc
• reducing metal salts such as chromium(ll) salts
• sulfur compounds for example sodium dithionite or, pre ⁇ ferably, sodium sulfide and carbon disulfide.
• Esterified hydroxyl groups for example lower- alkanoyloxy, such as acetyloxy, can also be set free with esterases, while acylated amino can, for example, be set free using suitable peptidases.
• the temperatures for the release of the protected functional groups are preferably between -80°C and the boiling temperature of the reaction mixture, in particular between -80 and 110°C; particularly preferably between -20 and 50°C, for example between 10 and 35°C, such as, for example, at room temperature, or at from 50°C up to the boiling temperature of the reaction mixture concerned, for example at approximately 65°C.
• the leaving group L is preferably arylsulfonytoxy, such as toluenesulfonyloxy, lower alkane- suifonyloxy, such as methanesulfonyloxy, or especially halogen, such as chlorine, bromine or iodine, most especially chlorine, or, especially in the case where Q is arylcarbonyl or heterocyclylcarbonyl, is formed in situ, for example from a hydroxy group.
• arylsulfonytoxy such as toluenesulfonyloxy, lower alkane- suifonyloxy, such as methanesulfonyloxy
• halogen such as chlorine, bromine or iodine, most especially chlorine, or, especially in the case where Q is arylcarbonyl or heterocyclylcarbonyl, is formed in situ, for example from a hydroxy group.
• the reaction is preferably carried out without bases or in the presence of relatively weak bases, such as especially metal hydroxides or carbonates, such as especially alkali metal hydroxides, for example sodium or potassium hydroxide, or in the presence of alkaline earth metal carbonates or alkali metal carbonates, for example sodium or potassium carbonate, preferably in the last-mentioned solvents, especially in halogenated hydrocarbons, such as dichloromethane or chloroform, or in carboxylic acid amides, such as dimethylformamide or dimethylacetamide, or in hydroxyaromates, such as phenol, and preferably at the tempe ⁇ ratures indicated below; or further in the presence of a strong base, such as an alkali metal hydride, for example sodium hydride or potassium hydride, or also an alkali metal amide, such as sodium amide, or an alkali metal di-lower alkylamide, such as lithium diisopropyl ⁇ amide, especially in the presence of sodium hydride or potassium hydride
• customary condensing agents are carbodiimides, for example diethyl-, dipropyl-, N-ethyl-N , -(3-dimethylamino- propyl)carbodiimide or, in particular, dicyclohexylcarbodiimide, and, in addition, suitable carbonyl compounds, for example carbonylimidazole, 1 ,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1 ,2-oxazolium-3'-suifonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1 -ethoxycarbonyl-1 ,2- dihydr
• an organic base is added, preferably a tri-substituted nitrogen base, for example a tri-lower-alkylamine, for example with bulky radicals, for example ethyl diiso ⁇ propylamine, or with unbranched radicals, such as, in particular, triethylamine, and/or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or, preferably N-methyl ⁇ morpholine.
• Racemization-lowering reagents such as N-hydroxybenzotriazole, can also be added, possibly also in combination with organic bases, as defined immediately above.
• reaction conditions are analogous to those mentioned in the detailed description of process a).
• Reactive derivatives of unsubstituted or substituted naphthalene-1 ,8-dicarbonic acids are preferably reactive esters or especially reactive anhydrides. Reactive carbonic acid derivatives can also be formed in situ.
• Reactive esters are, for example, the hydroxybenzotriazole (HOBT), pentafluorophenyl, 4- nitrophenyl or N-hydroxysuccinimide ester of an unsubstituted or substituted naphthalene- 1 ,8-dicarbonic acid.
• HOBT hydroxybenzotriazole
• pentafluorophenyl pentafluorophenyl
• 4- nitrophenyl or N-hydroxysuccinimide ester of an unsubstituted or substituted naphthalene- 1 ,8-dicarbonic acid hydroxybenzotriazole
• anhydride and as reactive derivative is an unsubstituted or substituted naphthalene- 1 ,8-dicarbonic acid anhydride (internal anhydride).
• the reaction steps required for the synthesis of the resulting imide bond usually depend on the type of activation of the carboxylic groups participating in the reaction.
• 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.
• chaotropic agents such as LiF in NB-methylpyrrolidone.
• 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.
• the reaction preferably takes place in an appropriate solvent, such as an alkohol, for example methanol, ethanol or especially n-propanol or isopropanol, at the temperatures mentioned above.
• an alkohol for example methanol, ethanol or especially n-propanol or isopropanol
• Condensation may also proceed with the free unsubstituted or substituted naphthalene-1 ,8- dicarbonic acid by in situ formation of a reactive derivative, (i) directly with a carbodiimide, e.g. dicyclohexylcarbodiimide (DCC), N-ethyl-N'-(3-di methylaminopropy -carbodiimide, N.N'-diethylcarbodiimide or N.N'-diisopropylcarbo diimide (DICD); with a carbonyl compound such as carbonyldiimidazole; with 1 ,2-ox azolium compounds such as 2-ethyl-5-phenyl-1 ,2-oxazolium-3'-sulfonate and 2-tert- butyl-5- m ⁇ thyiisoxazolium perchlorate; with acylamino compounds such as 2-ethoxy- 1- ethoxycarbonyl
• 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.
• reaction conditions are analogous to those mentioned in the detailed description of process a).
• the conversion of a salt of a compound of formula I into a different salt is carried out, for example, in solvents, especially in organic solvents, more especially in polar organic sol ⁇ vents, very especially in esters, for example lower alkanoyl-lower alkyl esters, such as ethyl acetate, in amides, for example N.N-di-lower alkyl-lower alkanoylamides, such as dimethyl ⁇ formamide, in alcohols, for example hydroxy-lower alkanes, such as methanol, ethanol, ethylene glycol or glycerol, or aryl alcohols, such as phenols, for example phenol, or in di ⁇ methyl sulfoxide, in the absence or presence of water, preferably in the presence of water, or in water itself. Special preference is given to reaction in alcohols, such as the last-men ⁇ tioned hydroxy-lower alkanes, in mixtures of such alcohols and water, or in water itself.
• reaction is carried out, for example, in free solution, but it may also be effected over chromatographic columns, for example by gel filtration.
• the reaction is carried out at temperatures from immediately above the freezing point to the boiling point of the solutions in question, preferably at from 0 to 50°C, especially at from 20 to 40°C, for example at room temperature, in the presence or absence of a protecting gas, such as nitrogen or argon.
• a protecting gas such as nitrogen or argon.
• the compounds of formula I and the salt-forming base or acid are used in suitable molar ratios, or the salt forming base or acid is employed in excess.
• the individual components are used in the molar ratio that corresponds to the ratio of the mola ⁇ ty of the base of formulal and the acid in the resulting salts.
• the salts that are formed precipitate for example, by themselves, in some cases only after cooling, or they are precipitated by the addition of solvents, especially of non-polar solvents, for example ethers, such as diethyl ether, or of water, and/or are obtained by partial or complete concentration by evaporation.
• solvents especially of non-polar solvents, for example ethers, such as diethyl ether, or of water, and/or are obtained by partial or complete concentration by evaporation.
• the reaction may also be effected via the free compounds of formula I, which are prepared, for example, by converting the base or acid salt of a base of formula I, with a first base or acid, used as starting material into the free compound with the aid of an acid or base, for example a hydroxy base, such as an alkali metal hydroxide, for example NaOH or KOH, or with an OH -charged ion exchanger in aqueous solution in the presence or absence of an organic solvent, as defined above; the subsequent conversion of the free compound may be carried out, for example, as described above.
• a hydroxy base such as an alkali metal hydroxide, for example NaOH or KOH
• an OH -charged ion exchanger in aqueous solution in the presence or absence of an organic solvent, as defined above
• the free compounds of formula I are preferably prepared as just described, also by chromatography, for example by gel filtration, or over ion exchangers.
• 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 mate ⁇ als.
• 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 preferred.
• conditions and reactants analogous to those described in the Examples are especially preferred.
• An imino compound of the formula II is, for example, either known (see, e.g., WO 89/98998) or accessible, e.g., by reacting a compound of formula Vll,
• R T and X are defined as for formula I and B is a leaving group, especially aryl- sulfonyloxy, such as toluenesulfonyloxy, lower alkanesulfonyloxy, such as methanesulfonyl- oxy, or more especially halogen, such as chlorine, bromine or iodine, with an alkali metal phthalimide salt, such as the potassium salt of phthalimide, cleavage of the resulting phthalimide compound, e.g. by hydrazinolysis, resulting in a compound of the formula IX,
• Ri and X are as defined for formula I, if necessary, formation of the respective sulfonamide, e.g. by reaction with p-toluolsulfonylchloride, and reaction with a compound of the formula IX, R 2 -Y-B (IX)
• R 2 and Y are as defined for formula I and B is a leaving group, independently as defined for B in formula Vll.
• An amidino, N-lower alkyl- or N,N-di-lower alkylamidino compound of formula Vll can be prepared, for example, by reaction of a compound of the formula X,
• X is as defined for formula I, followed by introduction of the leaving group B, e.g. by reaction with an arylsulfonylhalogenide or a lower alkanesulfonylhalogenide and, if desired, replacement of the resulting arylsulfonyloxy group or lower alkanesulfonyloxy group with a halogenide; or
• a compound of formula Vll wherein guanidino, N-lower alkylguanidino or N,N-di-lower alkylguanidino is present as Ri can be prepared, for example, by reaction of a compound of formula X, as defined above, with guanidine, N-Alkylguanidine or N,N-di-lower alkylguanidine (or a salt thereof) and subsequent introduction of the leaving group B, e.g.
• NH can be prepared, for example, by reacting am imidoester compound of the formula VII*,
• Alk is an alkyl, for example a lower alkyl, group and B* is a protected hydroxy group, with a compound of the formula H 2 N-(CH 2 ) a -NH 2 , for example by heating in an inert solvent, such as xylene, preferably under reflux, subsequently removing the hydroxy protecting group and replacing the resulting hydroxy by a leaving group B, as defined for compounds of formula Vll, under customary conditions.
• a compound of the formula VII* can be obtained from the respective nitrile compound B*-X-CN by reaction with an alcohol HO-Alk in the presence of a strong acid, for example HCI. Also by reaction of appropriate acid halogenides of the formula B-X-CO-Hal with a compound of the formula
• a compound of formula III is known or commercially available, or it can be synthesized according to one of the following procedures:
• Z* is equal to Z', except that the final amino hydrogen is missing and replaced by the bond to Q, and Q is defined as for a compond of formula IV and V, respectively; introduction of a nucleofugal leaving group A, e.g. by reaction of the hydroxy group with an arylsulfonylhalogenide or a lower alkanesulfonylhalogenide and, if desired, replacement of the resulting arylsulfonyloxy group or lower alkanesulfonyloxy group with a halogenide, leads then to a compound of formula III wherein Z is Z'.
• Q*-H (XV) wherein Q* is nitrogen-containing heterocyclyl containing 2 or more annelated rings that is bound to the hydrogen via a ring nitrogen atom with a compound of the formula
• Z" is a moiety of the formula -(CH 2 ) b - and G is a nucleofugal leaving group, especially arylsulfonyloxy, such as toluenesulfonyloxy, lower alkanesulfonyloxy, such as methanesulfonyloxy, or more especially halogen, such as chlorine, bromine or iodine, leads to a compond of the formula XVII,
• nucleofugal leaving group A e.g. by reaction of the hydroxy group with an arylsulfonylhalogenide or a lower alkanesulfonylhalogenide and, if desired, replacement of the resulting arylsulfonyloxy group or lower alkanesulfonyloxy group with a halogenide, leads then to a compound of formula III wherein Z is Z" and Q is Q*. as defined in the last paragraph.
• a compound of formula IV may, for example, be prepared by nucleophilic reaction of a compound of the formula II, as defined under process a), with a compound of the formula XVIII,
• Z** is as defined for Z' for a compound of formula IV, except that the bond to the nirtogen in formula IV is missing, and K is a nucleofugal leaving group, especially aryl ⁇ sulfonyloxy, such as toluenesulfonyloxy, lower alkanesulfonyloxy, such as methanesulfonyl ⁇ oxy, or more especially halogen, such as chlorine, bromine or iodine.
• aryl ⁇ sulfonyloxy such as toluenesulfonyloxy
• lower alkanesulfonyloxy such as methanesulfonyl ⁇ oxy
• halogen such as chlorine, bromine or iodine
• a compound of the formula VI is known in the art or commercially available, and/or it can be synthesized according to the following proceedure:
• M is a nucleofugal leaving group, especially arylsulfonyloxy, such as toluene ⁇ sulfonyloxy, lower alkanesulfonyloxy, such as methanesulfonyloxy, or more especially halogen, such as chlorine (most preferred), bromine or iodine, and b is as defined for a compound of formula I, leads to a compound of the formula XX,
• R 1t X, Y, R 2 and b are as defined under a compound of formula I, which can then be reduced to an amino compound of the formula VI, e.g. with hydrogen in the presence of a catalyst, such as Raney-Nickel, or with a complex hydride, such as lithium aluminium hydride (LiAIH 4 ).
• a catalyst such as Raney-Nickel
• a complex hydride such as lithium aluminium hydride (LiAIH 4 ).
• Unsubstituted or substituted 1 ,8-naphthalene-dicarboxylic acids are known in the art or commercially available, or they can be prepared according to procedures that are known in the art (see, for example, DE-OS 28 23 987, DE-OS 23 23 555 and US 4,146,720.
• 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 stereo selectively.
• 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 trifluoro acetic 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 corresponding intermediates 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, conden ⁇ sation agents or neutralising agents, for example ion exchangers, such as cation exchan ⁇ gers, 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, or phenols, such as phenol, 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
• 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 carried 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 m situ.
• a starting material which result in the compounds of formulal described at the beginning as being especially valuable.
• reaction conditions and processes of manufacture that are analogous to those mentioned in the Examples.
• the remaining starting materials required for the synthesis of compounds of the formulae I, II, III, IV, V and VI and the other compounds mentioned can be synthesized according to methods that are known in the art, or they are known and/or commercially available.
• compositions for the preparation thereof, and the use according to the invention of a compound of formula I and compositions comprising compounds of formula I as active ingredient
• compositions that comprise (preferably a novel) compound of formula I, a tautomer or a salt thereof, as active ingredient and that can be used especially in the treatment of a disease mentioned at the beginning.
• Special preference is given to compositions for enteral, such as nasal, buccal, rectal or, especially, oral, and parenteral, such as intravenous, intramuscular or subcutaneous, administration to warm-blooded animals, especially humans.
• the compositions comprise the active ingredient on its own or, preferably, together with a pharmaceutically acceptable carrier.
• the dose of active ingredient depends on the disease to be treated, and on the species, its age, weight and individual condition, on individual pharmacokinetic conditions, and on the mode of administration.
• the invention relates also to pharmaceutical compositions comprising (preferably a novel) compound of formula I, a tautomer or a pharmaceutically acceptable salt thereof, for use in a method for the prophylactic or, especially, therapeutic treatment of the human or animal body, to a process for the preparation thereof, especially as compositions for the treatment of a retroviral infection in a warm-blooded animal that is responsive to the inhibition of the interaction of a transcriptional regulator with a retroviral response element, preferably a HIV- , such as HIV-1-, infection which is responsive to the inhibition of the interaction between Tat and TAR and/or Rev and RRE; and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in ahuman), and to a method of treating the diseases mentioned above.
• a retroviral infection in a warm-blooded animal that is responsive to the inhibition of the interaction of a transcriptional regulator with a retroviral response element, preferably a HIV- , such as HIV-1-, infection which is responsive to the inhibition of
• the invention relates also to processes for, and to the use of (preferably the novel) compounds of formula I in the preparation of pharmaceutical compositions that comprise compounds of formula I as active component (active ingredient).
• active ingredient is always a novel compound of formula I, as defined above.
• 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.
• a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human or a (e.g. commercially usable) mammal, suffe ⁇ ring from a retroviral disease that is responsive to the inhibition of the interaction of a trans ⁇ criptional regulator with a retroviral response element; preferably a HIV-infection, such as a HIV-1 -infection, which is responsive to the inhibition of the interaction between Tat and TAR and/or Rev and RRE, and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in a human; which composition comprises a compound of formula I, or a salt thereof where salt-forming groups are present, in an amount that is effective in inhibiting the interaction of transcriptional regulators with retroviral response elements, preferably of the interaction between Tat and TAR and/or Rev and RRE; together with at least one pharma ⁇ ceutically acceptable carrier.
• a pharmaceutical composition for the prophylactic or, especially, therapeutic treatment of a retroviral infection in a warm-blooded animal that is responsive to the inhibition of the interaction of a transcriptional regulator with a retroviral response ele ⁇ ment, preferably a HIV-infection, such as a H IV- 1 -infection, which is responsive to the inhi ⁇ bition of the interaction between Tat and TAR and/or Rev and RRE; and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in a warm-blooded animal, especially a human or a (e.g.
• composition comprises as active ingredient a novel compound of formula I, or a pharma ceutically acceptable salt thereof, in an amount that is prophylactically or, especially, therapeutically effective against the mentioned diseases.
• the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, dosage forms that are in single dose form preferably comprising from approximately 20% to approximately 90% active ingredient, and dosage forms that are not in single dose form preferably comprising from approximately 5% to approximately 20% active ingredient.
• Unit dose forms are, for example, dragees, tablets, ampoules, vials, sup ⁇ positories or capsules.
• Other dosage forms are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
• Examples are capsules com ⁇ prising from approximately 0.05g to approximately 1.Og of the active ingredient.
• compositions of the present invention are prepared in a manner known ⁇ er se, for example by means of conventional mixing, granulating, confectioning, dissol ving or lyophilising processes.
• solutions of the active ingredient additionally also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, which, for example in the case of lyophilised compositions comprising the active ingredient on its own or together with a carrier, e.g. mannitol, may be prepared before use.
• the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known ⁇ er se, for example by means of conventional dissolving or lyophilising processes.
• the said solutions or suspen ⁇ sions may comprise viscosityincreasing substances, such as sodium carboxymethylcellu- lose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or also solubilisers, for example Tween 80 [polyoxyethylene(20) sorbitan monooleate; trademark of ICI Americas, Inc, USA].
• viscosityincreasing substances such as sodium carboxymethylcellu- lose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin, or also solubilisers, for example Tween 80 [polyoxyethylene(20) sorbitan monooleate; trademark of ICI Americas, Inc, USA].
• Suspensions in oil comprise as the oil component the vegetable, synthetic or semisynthetic oils customarily used for injection purposes.
• liquid fatty acid esters which contain as acid component a long-chain 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 corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, where appropriate with the addition of antioxidants, for example vitamin E, b-carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
• the alcohol component of those fatty acid esters has not more than 6 carbon atoms and is a mono- or poly-valent, for example mono-, di- or tri-valent, alcohol, for example methanol, ethanol, propanol, butanol or pen- tanol or their isomers, but especially glycol and glycerol.
• fatty acid esters ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M2375” (polyoxyethylene glycerol trioleate from Gattefosse, Paris), "Labrafil M1944 CS” (unsaturated polyglycolised glycerides prepared by alcoholysis of apricot kernel oil and composed of glycerides and polyethylene glycol esters; Gattefosse, France), "Labrasol” (sa ⁇ turated polyglycolised glycerides prepared by alcoholysis of TCM and composed of glyceri ⁇ des and polyethylene glycol esters; Gattefosse, France) and/or "Miglyol812" (triglyceride of saturated fatty acids having a chain length of from CQ to C- ) 2 from H ⁇ ls AG, Germany), but especially vegetable oils, such as cottons
• the preparation of the injection compositions is carried out in customary manner under sterile conditions, as well as the introduction, for example, into ampoules or vials and the sealing of the containers.
• compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, granulating a resulting mixture, where appropriate, and processing the mixture or granules, if desired, where appropriate with the addition of additional excipients, to form tablets or dragee cores.
• Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri calcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegra ⁇ tors, such as the above-mentioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, or alginic acid or a salt thereof, such as sodium alginate.
• Additional 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, or derivatives thereof.
• Dragee cores can be provided with suitable, where appropriate enteric coatings, there being used inter alia concentrated sugar solutions, which may comprise gum arabic, talc, poly ⁇ vinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
• enteric coatings there being used inter alia concentrated sugar solutions, which may comprise gum arabic, talc, poly ⁇ vinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Colourings or
• compositions for oral administration are also hard gelatin capsules, and soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
• the hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magne ⁇ sium stearate, and, where appropriate, stabilisers.
• the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilisers and detergents, for example of the polyoxy ⁇ ethylene sorbitan fatty acid ester type.
• suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it likewise being possible to add stabilisers and detergents, for example of the polyoxy ⁇ ethylene sorbitan fatty acid ester type.
• oral dosage forms are, for example, syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of approximately from 5% to 20%, preferably approximately 10% or in a similar concentration that provides a suitable single dose when administered, for example, in a measure of 5 or 10ml.
• syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of approximately from 5% to 20%, preferably approximately 10% or in a similar concentration that provides a suitable single dose when administered, for example, in a measure of 5 or 10ml.
• powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packed in single dose quantities.
• Suitable rectally administrable pharmaceutical compositions are, for example, supposi tories that consist of a combination of the active ingredient with a suppository base.
• Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
• aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers.
• the active ingre ⁇ histone, where appropriate together with excipients, can also be in the form of a lyophilisate and be made into a solution prior to parenteral administration by the addition of suitable solvents.
• Solutions used, for example, for parenteral administration can also be used as infusion solutions.
• Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or micro bicides, such as sorbic acid or benzoic acid.
• Ointments are oil-in-water emulsions that comprise up to 70%, but preferably from 20 to 50%, water or aqueous phase.
• fatty phase especially hydro carbons, for example paraffin oil or hard paraffins, which, in order to improve the water- binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax.
• Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters, for example sorbitan oleate and/or sorbitan isostearate.
• Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and perfumes.
• humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and perfumes.
• Fatty ointments are anhydrous and comprise as base especially hydrocarbons, for example paraffin or paraffin oil, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil or castor oil, also fatty acid partial esters of glycerol, for example glycerol mono- and/or di-stearate, and also, for example, the fatty alcohols increasing water absorption, emulsifiers and/or additives mentioned in connection with the ointments.
• hydrocarbons for example paraffin or paraffin oil, also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil or castor oil, also fatty acid partial esters of glycerol, for example glycerol mono- and/or di-stearate, and also, for example, the fatty alcohols increasing water absorption, emulsifiers and/or additives mentioned in
• Creams are oil-in-water emulsions that comprise more than 50% water.
• oily base there are used especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example Vaseline (petrolatum) or paraffin oil.
• Suitable emulsifiers are surface-active substances having predominantly hydrophilic proper ⁇ ties, such as non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty acid esters, and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or cor- responding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol.
• non-ionic emulsifiers for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty acid
• Additives to the aqueous phase are inter alia agents that reduce the drying out of the creams, for exam ⁇ ple polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, also preservatives and perfumes.
• Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, also talc and/or aluminium silicates, the purpose of which is to bind any moisture or secretions present.
• metal oxides for example titanium oxide or zinc oxide
• talc and/or aluminium silicates the purpose of which is to bind any moisture or secretions present.
• Foams are administered from pressurised containers and are liquid oil-in-water emulsions in aerosol form, there being used as propellants halogenated hydrocarbons, such as chloro- fluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N2O or carbon dioxide.
• halogenated hydrocarbons such as chloro- fluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, or preferably non-halogenated gaseous hydrocarbons, air, N2O or carbon dioxide.
• oil phase there are used inter alia the oil phases used above under ointments and creams, likewise the additives mentioned therein.
• Tinctures and solutions generally have an aqueous-ethanolic base to which there are added inter alia polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other excipients and additives.
• polyalcohols for example glycerol, glycols and/or polyethylene glycol
• humectants for reducing evaporation for example glycerol, glycols and/or polyethylene glycol
• fat-restoring substances such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances
• the invention relates also to a process or a method for the treatment of a pathological condition mentioned above, especially a retroviral disease which is responsive to inhibition of the interaction of a transcriptional regulator with a retroviral response element, preferably a HIV-infection, such as a HIV-1 -infection, which is responsive to the inhibition of the inter ⁇ action between Tat and TAR and/or Rev and RRE; and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in a human.
• a retroviral disease which is responsive to inhibition of the interaction of a transcriptional regulator with a retroviral response element, preferably a HIV-infection, such as a HIV-1 -infection, which is responsive to the inhibition of the inter ⁇ action between Tat and TAR and/or Rev and RRE; and more specifically for the treatment of AIDS and its initial stages, such as ARDS, in a human.
• the compounds of formula I may be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount that is effective against the mentioned diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds being used especially in the form of pharmaceutical compositions.
• a daily dose of from approximately 0.1 g to approximately 5g, preferably from approximately 0.5g to approximately 2g, of a compound of the present invention is administered.
• a pharmaceutical composition that is suitable for administra tion to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, e.g. lymphocytes), for the treatment
• 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 pharma ⁇ ceutically 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 (also for prophylaxis) a retroviral infection by inhibiting the interaction of a transcriptional regulator with a retroviral response element, 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 at least one of the mentioned diseases, especially an HIV-infection, including AIDS, requires such treatment.
• a transcriptional regulator for example HIV infection, including AIDS
• the dose to be administered to warm-blooded animals 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.
• Pharma ⁇ ceutical 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 perse, 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 carrier, 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 perse, for example by means of conventional dissolving or lyophilising processes.
• the said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxy- methylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
• Suspensions in oil comprise as the oil component the vegetable, synthetic or semi ⁇ synthetic oils customary for injection purposes.
• 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 corresponding 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, b-carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
• anti oxidants for example vitamin E, b-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 Cg 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 process ⁇ ing 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 incorporated into plastics carriers 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 pyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxy ⁇ methyl starch, crossiinked polyvinylpyrrolidone, 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
• 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, polyvinylpyrrolidone, 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, in soft capsules 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. Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification purposes or to indicate different doses of active ingredient.
• Described compounds can be synthesized according to methods outlined within this specification, especially in analogy to the methods decribed in Examples 1 , 2 and 8.
• Silica gel (mean diameter 40-63 mm from E. Merck, Darmstadt, FRG is used for flash chromatography.
• ratios of the components are given with reference to volumes (v/v).
• the precipitating product is filtered off and recrystallized from methanol/ethyl acetate giving yellow crystals (m.p. 242 °C).
• the starting materials are prepared as follows:
• Example 2 5-(2- ⁇ 4-Acridinoyll-aminoethyl)-1.5.10-triazadecane 1.13 g (1.9 mmol) of 5-(2- ⁇ 4-acridinoyl ⁇ -aminoethyl)-1 ,10-di-(tert-butoxycarbonyl)-1 ,5,10- triazadecane and 971 mg (7.7 mmol) of oxalic acid (dihydrate) are refluxed in 30 ml of 50% aqueous methanol for 23 hours. The solvent is evaporated under vacuum and the crude product is recrystallized from water/methanol. The solid is dried at 100 °C under vacuum giving the title compound in the form of crystals (m.p. 126-132°C).
• the starting materials are prepared as follows:
• the precipitated dicyclohexyl urea is filtered off, and the filtrate is concentrated under reduced pressure, taken up in ethyl acetate, washed two times with NaHCO3-solution and dried over Na2SU4 ; then the solvent is removed under reduced pressure.
• the title compound is synthesized starting from 2-[(o-carboxyphenyl)amino]-benzaldehyde according to the procedure of G.J. Atwell et al. (see J. Med. Chem. 30, 664-9 (1987)); m.p. 192-3 °C; light brown crystals.
• Example 3 N-(3-f1.5.10-Triazadecan-5-yl)-propyl)-3-nitro-1 ,8-naphthalimide trihydrochloride
• the title compound is prepared in analogy to that of Example 8, starting from 1 ,8-naphthalic anhydride (Fluka, Buchs, Switzerland) and 5-(3-aminopropyl)-1 ,10-di-(tert-butoxycarbonyl)- 1 ,5,10-triazadecane (Example 1a).
• Example 6 N-(2-[1.5.10-Triazadecan-5-yll-ethyl)-1.8-naphthalimide trihvdrochloride
• Example 7 N-(3-[1.5.10-Triazadecan-5-yl]-propyl)-1.8-naphthalimide trihvdrochloride
• the starting material is prepared as follows:
• Example 9 N-(3-[1.5.10-Triazadecan-5-v ⁇ -propyl)-4-chloro-1.8-naphthalimide trihvdro ⁇ chloride
• Example 12 5-(2-(Acridin-9-ylcarbonyl>-aminoethyl)-1.5.10-triazadecane tetrahvdrochloride
• Example 13 5-(3--f2-Chloro-purin-6-yl aminopropyl)-1.5.10-triazadecane tetrahvdrochloride
• the starting materials are prepared as follows:
• Example 18 4-(2- ⁇ Acridin-9-ylcarbonylV-aminoethyl)-1.4.7-triazaheptane tri hydrochloride
• the starting material is prepared as follows:
• Example 2 The title compound is prepared in analogy to that of Example 1 starting from 6,9-dichloro-2- methoxyacridine (Aldrich, Buchs, Switzerland) and. 6- ⁇ 2-aminoethyl)-1 ,11 -di-(tert-butoxy- carbonyl)-1 ,6,1 1 -triazaundecane (synthesized from 1 ,11 -di-(tert-butoxycarbonyl)-1 ,6,11 - triazaundecane (see Bergeron et al., Synthesis 9, 732-3 (1981)) and 2-chloroacetonitrile in analogy to Example 2b) and 2c): m.p.
• Example 2 The title compound is prepared in analogy to that of Example 1 starting from 6,9-dichloro-2- methoxyacridine (Aldrich, Buchs, Switzerland) and 8-(2-aminopropyl)-1 ,15-di-(tert-butoxy- carbonyl)-1 ,8,15-triazapentadecane (prepared from bis-(6-aminohexyl)amine (Aldrich,
• the starting material is prepared as follows:
• the starting material is prepared as follows:
• the starting material is prepared as follows:
• Example 26 6-(4-(6-Chloro-2-methoxy-acridin-9-yl)-aminopentyl)-1.6.11 -triazaundecane tetrahvdrochloride
• the starting material is prepared 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.Oml of solution has the following composition:
• Example 27 Sterile dry substance for injection:
• 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 30min 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.

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• 1996
  • 1996-01-26 GB GBGB9601651.4A patent/GB9601651D0/en active Pending
• 1997
  • 1997-01-14 AU AU15921/97A patent/AU1592197A/en not_active Abandoned
  • 1997-01-14 WO PCT/EP1997/000139 patent/WO1997027179A2/en active Application Filing

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