EP0763041A1 - Derives d'indolocarbazole destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux antitumoraux - Google Patents

Derives d'indolocarbazole destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux antitumoraux

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Publication number
EP0763041A1
EP0763041A1 EP95920067A EP95920067A EP0763041A1 EP 0763041 A1 EP0763041 A1 EP 0763041A1 EP 95920067 A EP95920067 A EP 95920067A EP 95920067 A EP95920067 A EP 95920067A EP 0763041 A1 EP0763041 A1 EP 0763041A1
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EP
European Patent Office
Prior art keywords
formula
compound
staurosporin
salt
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP95920067A
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German (de)
English (en)
Inventor
Urs Regenass
Giorgio Caravatti
Andreas Fredenhagen
Oskar Wacker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Erfindungen Verwaltungs GmbH
Ciba Geigy AG
Novartis AG
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Application filed by Novartis Erfindungen Verwaltungs GmbH, Ciba Geigy AG, Novartis AG filed Critical Novartis Erfindungen Verwaltungs GmbH
Publication of EP0763041A1 publication Critical patent/EP0763041A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/044—Pyrrole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms

Definitions

  • the invention relates to staurosporin derivatives, to a process for the preparation thereof, to pharmaceutical compositions comprising such staurosporin derivatives, and to the use thereof as medicaments.
  • Staurosporin which forms the basis of the derivatives according to the invention, was isolated as early as 1977 from cultures of Streptomyces staurosporeus AWAYA, TAKA- HASHI and OMURA, sp. nov. AM 2282, see S. Omura et al, J. Antibiot. 30, 275-281 (1977). Hitherto, only the relative, but not the absolute, configuration of staurosporin was known. The absolute configuration has been published only recently by N. Funato et al., Tetrahedron Letters 35:8, 1251-1254 (1994) and corresponds to the mirror image of the structure previously used in the literature to indicate the relative configuration of staurosporin.
  • Staurosporin and most of the staurosporin derivatives known hitherto show a strong inhibitory action on protein kinase C.
  • Protein kinase C which is dependent upon phospho- lipids and calcium, occurs within the cell in several forms and participates in various fundamental processes, such as signal transmission, proliferation and differentiation and also secretion of hormones and neurotransmitters. Activation of that enzyme is brought about either by receptor-mediated hydrolysis of phospholipids of the cell membrane or by direct interaction with certain tumour-promoting active agents.
  • the sensitivity of the cell towards receptor-mediated signal transmission can be significantly influenced by modifying the activity of protein kinase C (as the signal transmitter).
  • Compounds that are capable of influencing the activity of protein kinase C may be used as tumour-inhibiting, anti-inflammatory, immuno-modulating and antibacterial active ingredients and may even be of interest as agents against atherosclerosis and disorders of the cardiovascular system and the central nervous system.
  • the inhibitory action on protein kinase C is weakened by a factor of from approximately 20 to over 1000 if the lactam nitrogen of staurosporin carries instead of hydrogen another substituent, that is to say, if the substituent Rj in formula I shown hereinafter is other than hydrogen.
  • the substituent Rj in formula I shown hereinafter is other than hydrogen.
  • the anti-tumour activity also decreases markedly.
  • the appearance of resistance to classical cytostatic agents is a great problem in cancer chemotherapy.
  • the resistance is in many cases accompanied by a reduction in the intra ⁇ cellular concentration of active ingredient. That reduction is often associated with the appearance of a membrane-bound 170 kilodalton glycoprotein (Pgp).
  • That protein acts as a pump having a broad specificity and is capable of transporting frequently used anti- tumour agents, such as the Vinca alkaloids, anthracyclins, podophyllotoxins and actino- mycin D, out of the cell.
  • staurosporin derivatives of formula I shown hereinbelow are capable of fully re-sensitising multidrug-resistant cells to the action of anti-tumour agents, such as cytostatics, as can be demonstrated inter alia by the example of resistant human KB-8511 cells.
  • anti-tumour agents such as cytostatics
  • all derivatives show a greatly weakened inhibitory action or no inhibitory action at all on protein kinase C and the anti-tumour activity is also markedly reduced.
  • the staurosporin derivatives of formula I are roughly equivalent to the analogous derivatives wherein R j is hydrogen.
  • a combination of a conventional cytostatic agent with a staurosporin derivative of formula I shown hereinbelow has the advantage that the side-effects associated with the protein kinase C inhibitory action do not occur or occur only in a very much weaker form.
  • the administra ⁇ tion of protein kinase C inhibiting staurosporin derivatives results, for example in dogs, in nausea to the point of vomiting.
  • the latter is understandably disadvantageous, especially for an orally administered anti-tumour agent, since active ingredient may also be vomited, with the result that the dose of active ingredient effectively taken may be different from the intended and administered dose.
  • the invention relates to staurosporin derivatives of formula I
  • Rj is an acyl radical having from 2 to 30 carbon atoms, an aliphatic hydrocarbon radical having up to 29 carbon atoms that is substituted by acyclic substituents, a cyclo- aliphatic or cycloaliphatic-aliphatic radical each having up to 29 carbon atoms, or a heterocyclic, heterocyclic-aliphatic or heteroaliphatic radical each having up to 20 carbon atoms and up to 9 hetero atoms,
  • R 2 is hydrogen, an aliphatic, carbocyclic or carbocyclic-aliphatic radical each having up to 29 carbon atoms, a heterocyclic or heterocyclic-aliphatic radical each having up to 20 carbon atoms and up to 9 hetero atoms, or an acyl radical having up to 30 carbon atoms, and
  • R 3 is hydrogen, hydroxy, lower alkoxy or oxo, and salts of such compounds of formula I having at least one salt-forming group, with the exception of the compound of formula I wherein Rj is methoxycarbonylmethyl,
  • R 2 is benzoyi and R 3 is hydrogen.
  • An acyl radical Rj having from 2 to 30 carbon atoms is derived from an optionally functionally modified carboxylic acid, an organic sulfonic acid or a free or esterified phosphoric acid, such as pyro- or ortho-phosphoric acid.
  • the hydrocarbyl (hydrocarbon radical) R° is an acyclic (aliphatic), carbocyclic or carbo- cyclic-acyclic hydrocarbon radical having up to 29 carbon atoms, especially up to 18, and preferably up to 12, carbon atoms and is saturated or unsaturated and unsubstituted or substituted. It may also contain in place of one, two or more carbon atoms identical or different hetero atoms, such as especially oxygen, sulfur and nitrogen, in the acyclic and or cyclic moiety; in the latter case, it is referred to as a heterocyclic radical (hetero- cyclyl radical) or a heterocyclic-acyclic radical.
  • Unsaturated radicals are those which contain one or more, especially conjugated and/or isolated, multiple bonds (double and/or triple bonds).
  • cyclic radicals also includes aromatic radicals, for example those wherein at least one 6-membered carbo ⁇ cyclic or one 5- to 8-membered heterocyclic ring contains the maximum number of non-cumulated double bonds.
  • Carbocyclic radicals wherein at least one ring is in the form of a 6-membered aromatic ring i.e. a benzene ring
  • aryl radicals are referred to as aryl radicals.
  • organic radicals referred to as "lower” contain not more than 7, preferably not more than 4, carbon atoms.
  • An acyclic unsubstituted hydrocarbon radical is especially a straight-chain or branched lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl radical.
  • Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or also n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl;
  • lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl or 2- or 3-butenyl;
  • lower alkadienyl is, for example, l-penta-2,4-dienyl;
  • lower alkynyl is, for example, propargyl or 2-butynyl.
  • the double bond
  • a carbocyclic hydrocarbon radical is especially a mono-, bi- or poly-cyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical.
  • radicals having a maximum of 14, especially 12, ring carbon atoms and 3- to 8-, preferably 5- to 7- and especially 6-membered rings it also being possible for them to carry one or more, for example two, acyclic radicals, for example those mentioned above, and especially the lower alkyl radicals, or further carbocyclic radicals.
  • Carbocyclic- acyclic radicals are those in which an acyclic radical, especially one having a maximum of 7, preferably a maximum of 4, carbon atoms, such as especially methyl, ethyl and vinyl, carries one or more carbocyclic, if desired aromatic, radicals as defined above.
  • an acyclic radical especially one having a maximum of 7, preferably a maximum of 4, carbon atoms, such as especially methyl, ethyl and vinyl
  • cycloalkyl-lower alkyl and aryl-lower alkyl radicals and the analogues thereof that are unsaturated in the ring and/or chain and that carry the ring at the terminal carbon atom of the chain.
  • Cycloalkyl has especially from 3 up to and including 10 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and also bicyclo[2,2,2]octyl, 2-bicyclo[2,2,l]heptyl and adamantyl, each of which may also be substituted by 1, 2 or more, for example lower, alkyl radicals, especially methyl radicals; cycloalkenyl is, for example, one of the monocyclic cycloalkyl radicals already mentioned that has a double bond in the 1-, 2- or 3-position.
  • Cycloalkyl-lower alkyl or -lower alkenyl is, for example, methyl, 1- or 2-ethyl, 1- or 2- vinyl, 1-, 2- or 3-propyl or allyl substituted by one of the above-mentioned cycloalkyl radicals, those substituted at the end of the linear chain being preferred.
  • An aryl radical is especially phenyl, but also naphthyl, such as 1- or 2-naphthyl, biphenyl- yl, such as especially 4-biphenylyl, or also anthryl, fluorenyl or azulenyl, or an aromatic analogue thereof having one or more saturated rings.
  • Preferred aryl-lower alkyl and aryl- lower alkenyl radicals are, for example, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, for example benzyl, phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, and also 1- or 2-naphthylmethyl.
  • aryl radicals that carry acyclic radicals, such as lower alkyl there are to be mentioned, in particular, o-, m- and p-tolyl and xylyl radicals having methyl radicals situated in different positions.
  • Heterocyclic radicals including heterocyclic-acyclic radicals, are especially monocyclic, but also bi- or poly-cyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza or tetraza-cyclic radicals of aromatic character, and corresponding partially saturated or, especially, completely saturated heterocyclic radicals of that kind, it being possible for such radicals, where appropriate, for example like the above-mentioned carbocyclic or aryl radicals, to carry further acyclic, carbocyclic or heterocyclic radicals and or to be mono-, di- or poly- substituted by functional groups.
  • heterocyclic-acyclic radicals is, for example, as defined in the case of the corresponding carbocyclic-acyclic radicals.
  • Such radicals are, especially, unsubstituted or substituted monocyclic radicals having one nitrogen, oxygen or sulfur atom, such as 2-aziridinyl, and especially aromatic radicals of that kind, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3- or 4-pyridyl, or also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl;
  • analogous bicyclic radicals having one nitrogen, oxygen or sulfur atom are, for example, indolyl, such as 2- or 3-indolyl, quinolyl, such as 2- or 4-quinolyl, isoquinolyl, such as 3- or 5-isoquinolyl, benzofuranyl, such as 2-benzofuranyl, chromenyl, such as 3-chromenyl, or
  • radicals Corresponding partially saturated or, especially, completely saturated analogous radicals also come into consideration, such as 2-tetrahydrofuryl, 4-tetrahydro- furyl, 2- or 3-pyrrolidyl, 2-, 3- or 4-piperidyl, and also 2- or 3-morpholinyl, 2- or 3-thio- morpholinyl, 2-piperazinyl and N,N'-bis-lower alkyl-2-piperazinyl radicals.
  • These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, especi ⁇ ally those mentioned above.
  • Heterocyclic-acyclic radicals are derived especially from acyclic radicals having a maximum of 7, preferably a maximum of 4, carbon atoms, for example from those mentioned above, and may carry one, two or more heterocyclic radicals, for example those mentioned above, it also being possible for the ring to be bonded to the chain by one of its nitrogen atoms.
  • a hydrocarbyl may be substi ⁇ tuted by one, two or more substituents (functional groups) of the same kind or of different kinds; the following substituents come into consideration especially: free, etherified and esterified hydroxy groups; mercapto, lower alkylthio and unsubstituted or substituted phenylthio groups; halogen atoms, such as chlorine and fluorine, but also bromine and iodine; oxo groups that are in the form of formyl (i.e.
  • aldehydo aldehydo
  • keto groups and in the form of corresponding acetals and ketals, respectively; azido and nitro groups; primary, secondary and, preferably, tertiary amino groups, primary and secondary amino groups that are protected by conventional protecting groups, acylamino groups and diacylamino groups, and free or functionally modified sulfo groups, such as sulfamoyl groups or sulfo groups in salt form. None of these functional groups should be located at the carbon atom from which the free valency extends and they are all preferably separated therefrom by 2 or even more carbon atoms.
  • the hydrocarbyl radical may also carry free and functionally modified carboxy groups, such as carboxy groups in salt form or esterified carboxy groups, or carbamoyl, ureido or guanidino groups optionally carrying one or two hydro ⁇ carbon radicals, and cyano groups.
  • An etherified hydroxy group present as a substituent in the hydrocarbyl is, for example, a lower alkoxy group, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert- butoxy group, which may also be substituted.
  • such a lower alkoxy group may be substituted, for example mono-, di- or poly-substituted, by halogen atoms, especi ⁇ ally in the 2-position, such as in the 2,2,2-trichloroethoxy, 2-chloroethoxy and 2-iodo- ethoxy radical, or substituted, preferably mono-substituted, by hydroxy or by lower alkoxy radicals, especially in the 2-position, such as in the 2-methoxyethoxy radical.
  • Such etherified hydroxy groups are also unsubstituted or substituted phenoxy radicals and phenyl-lower alkoxy radicals, such as especially benzyloxy, benz- hydryloxy and triphenylmethoxy (trityloxy), and heterocyclyloxy radicals, such as especi ⁇ ally 2-tetrahydropyranyloxy.
  • the groupings methylenedioxy and ethylenedioxy may be regarded as special etherified hydroxy groups; the former as a rule bridges 2 adjacent carbon atoms, especially in aryl radicals, and the latter is bonded to one and the same carbon atom and may be regarded as a protecting group for oxo.
  • etherified hydroxy groups is also to be understood in this context as including silylated hydroxy groups, as occur, for example, in tri-lower alkylsilyloxy, such as trimethylsilyloxy and dimethyl-tert-butylsilyloxy, or phenyl-di-lower alkylsilyloxy or lower alkyl-diphenylsilyloxy.
  • An esterified hydroxy group present as a substituent in the hydrocarbyl is, for example, lower alkanoyloxy.
  • An esterified carboxy group present as a substituent in the hydrocarbyl is one in which the hydrogen atom has been replaced by one of the hydrocarbon radicals characterised above, preferably a lower alkyl or phenyl-lower alkyl radical; there may be mentioned as examples of an esterified carboxy group lower alkoxycarbonyl or phenyl-lower alkoxy ⁇ carbonyl that is unsubstituted or substituted in the phenyl moiety, especially the methoxy-, ethoxy-, tert-butoxy- or benzyloxy-carbonyl group, and also a lactonised carboxy group.
  • a primary amino group -NH 2 as a substituent of the hydrocarbyl may also be in protected form.
  • a secondary amino group carries, in place of one of the two hydrogen atoms, a hydrocarbyl radical, preferably an unsubstituted hydrocarbyl radical, such as one of those mentioned above, especially lower alkyl, and may also be in protected form.
  • a tertiary amino group occurring as a substituent in the hydrocarbyl carries 2 different or, preferably, identical hydrocarbyl radicals (including the heterocyclic radicals), such as the unsubstituted hydrocarbyl radicals characterised above, especially lower alkyl.
  • a preferred amino group is one of the formula R 4 (R 5 )N-, wherein R 4 and R 5 are each independently of the other hydrogen, unsubstituted acyclic C r C 7 hydrocarbyl (such as, especially, a C j -C 4 alkyl or C -C 4 alkenyl) or monocyclic aryl, aralkyl or aralkenyl that has a maximum of 10 carbon atoms and that is unsubstituted or substituted by C r C 4 alkyl, C j -C 4 alkoxy, halogen and/or by nitro, it being possible for the carbon-containing radicals to be bonded to one another by a carbon-carbon bond or by an oxygen atom, by a sulfur atom, or by a nitrogen atom that is unsubstituted or substituted by hydrocarbyl.
  • R 4 and R 5 are each independently of the other hydrogen, unsubstituted acyclic C r C 7 hydrocarbyl (such
  • di-lower alkylamino such as dimethylamino, diethylamino, pyrrol- idino, piperidino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, or diphenylamino and dibenzylamino each unsubstituted or substituted, especially in the phenyl moiety, for example by lower alkyl, lower alkoxy, halogen and/or by nitro; and, of the protected amino groups, especially lower alkoxycarbonylamino, such as tert-butoxy- carbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxy- carbonylamino, and 9-fluorenylmethoxycarbonylamino.
  • di-lower alkylamino such as dimethylamino, diethylamino, pyrrol- idino, piperidino, morpholino, thiomorpholin
  • aromatic carbocyclic and hetero ⁇ cyclic hydrocarbyl radicals may be mono- or poly-substituted, such as di- or tri- substituted, especially by C r C 4 alkyl, C r C 4 alkoxy, halogen, nitro, trifluoromethyl, also carboxy, C r C 4 alkoxycarbonyl, methylenedioxy and or by cyano.
  • Substituents mentioned specifically hereinbefore and hereinafter are to be regarded as preferences.
  • Preferred compounds of formula I according to the invention are, for example, those wherein hydrocarbyl R° has the following preferred meanings of an acyclic hydrocarbyl: a C r C 20 alkyl, a C 2 -C 20 hydroxyalkyl the hydroxy group of which is located in any position apart from the 1-position, preferably in the 2-position, a cyano-[C r C 20 ]alkyl the cyano group of which is preferably located in the 1- or co-position, or a carboxy- [C r C 20 ] alkyl the carboxy group of which is preferably located in the 1- or co-position and may, where appropriate, also be in salt form or in the form of a C r C 4 alkyl ester (C r C 4 alkoxy- carbonyl) or a benzyl ester (benzyloxycarbonyl), and a C 3 -C 2 oalkenyl the free valency of which is not located at the same carbon atom as is the double
  • hydrocarbyl R° has the following preferred meanings of a carbocyclic or heterocyclic, or also carbocyclic-acyclic or heterocyclic-acyclic, hydrocarbyl: a bicyclic or, preferably, monocyclic aryl, especially phenyl, or also naphthyl, that may carry one or more of the following substituents: halogen atoms, especially fluorine, chlorine and bromine, C r C 4 - alkyl radicals, especially methyl, C r C 4 alkoxy groups, especially methoxy, methylene ⁇ dioxy, nitro groups and/or carboxy groups that may be free, in salt form or in the form of C j -C 4 alkyl esters, especially methoxycarbonyl or ethoxy carbonyl.
  • hydrocarbyl R° has the following preferred meanings of a carbocyclic or heterocyclic, or also carbocyclic-acyclic or heterocyclic-acyclic, hydrocarbyl: a bicyclic
  • the aryl radicals carry not more than 2 substituents, especially those of the same kind, or carry only a single substituent; most especially, they are unsubstituted.
  • a preferred heterocyclic hydrocarbyl is, for example, one that is analogous to the aryl radicals given prominence above and that contains, instead of one or two carbon atoms, in each case a hetero atom, especially nitrogen, such as a pyridyl or quinolyl, or quinazolyl, respectively, wherein the free valency is located at a carbon atom and accordingly can also be substi ⁇ tuted.
  • Preferred carbocyclic-acyclic and heterocyclic-acyclic hydrocarbyl radicals are those wherein two or three, but preferably only one, of the above-defined cyclic radicals, preferably the unsubstituted cyclic radicals, is carried by a C r C 3 alkyl, all of them preferably being located at one carbon atom, preferably the terminal carbon atom; unsubstituted benzyl is most preferred.
  • Especially preferred compounds of formula I are those wherein R° is C r C 7 alkyl, especi ⁇ ally C r C 4 alkyl, hydroxy-C 2 -C 18 alkyl, especially hydroxy-C 2 -C 14 alkyl, cyano-C r C 7 alkyl, especially cyano-Cj-C 4 alkyl, carboxy-C r C 7 alkyl, especially carboxy-C r C 4 alkyl, C r C 7 - alkoxy-carbonyl-C r C 7 alkyl, especially C 1 -C 4 alkoxy-carbonyl-C 1 -C 4 alkyl, benzyloxy- carbonyl-C r C 7 alkyl, especially benzyloxycarbonyl-C r C 4 alkyl, C 3 -C 7 alkenyl, phenyl, naphthyl, pyridyl, quinolyl, or quinazolyl, or phenyl-C
  • R° is C r C 4 alkyl, such as methyl or ethyl, hydroxy-C 2 -C 14 alkyl, such as 2-hydroxy-propyl, -hexyl, -decyl or -tetradecyl, cyano-C r C 4 alkyl, such as 2-cyanoethyl, carboxy-C r C 4 alkyl, such as carboxymethyl, C r C 4 alkoxycarbonyl-C r C alkyl, such as methoxycarbonyl-methyl or -ethyl, C 3 -C 7 alkenyl, such as allyl, or phenyl, the hydroxy group in a correspondingly substituted alkyl preferably being located in the 2-position and the cyano, carboxy or alkoxycarbonyl group being located especially in the 1- or co-position.
  • R° is C r C 4 alkyl, such as methyl or ethyl, hydroxy-C 2 -C 14
  • acyl derived from an organic sulfonic acid which is designated Ac 2
  • Ac 2 is especially one of the partial formula R°-SO 2 - wherein R° is a hydrocarbyl having the general meanings given above and the meanings given prominence above, the latter meanings generally representing also in this case the preferred selection.
  • Preferred acyl radicals Ac 1 are acyl radicals of a carboxylic acid that are characterised by the partial formula R°-CO- wherein R° has one of the above-mentioned general and preferred meanings of the hydrocarbyl radical R°, and that are accordingly derived from an unsubstituted or substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic or heterocyclic-acyclic monocarboxylic acid.
  • a preferred hydrocarbyl in such an acyl is, for example, a C j -C ⁇ alkyl, especially a C r C 7 - or C r C 4 -alkyl, especially one that, in the case of more than 5 carbon atoms, has a linear chain and that may also carry the following sub ⁇ stituents: a carboxy group that may also be in salt form or in the form of a cyano group or a C j -C 4 alkyl ester (C r C 4 alkoxycarbonyl group) and that is preferably located in the ⁇ -position, an amino group of the above-defined formula R 4 (R 5 )N-, preferably one in which R 4 and R 5 are each hydrogen and that is then preferably located in the 1 -position, or one or more halogen atoms, especially fluorine or chlorine, which are preferably located vicinal to the carbonyl group.
  • a carboxy group that may also be in salt form or in the form of a
  • acyl is a bicyclic or, especially, mono ⁇ cyclic aroyl, especially benzoyi, that may also carry one or more of the following substi ⁇ tuents: halogen atoms, especially chlorine or fluorine, nitro groups, C r C 4 alkyl radicals, especially methyl, hydroxy groups and etherified hydroxy groups, especially C r C 4 alkoxy, such as methoxy, phenoxy and methylenedioxy, and carboxy groups that may also be in salt form or in the form of a cyano group or a C r C 4 alkyl ester (C r C 4 alkoxycarbonyl).
  • the aroyl radicals carry not more than 2, and especially only one, such substituent.
  • analogous heteroaroyl radicals especially those derived from pyridine, pyrrole, furan, thiophene and imidazole and from analogues thereof having a fused benzo ring (such as quinoline, isoquinoline, benzofuran and benzimidazole) and that are also unsubstituted or substituted as indicated above.
  • Preferred acyl radicals of that kind are also derived from monocyclic aryl-alkenyl, for example corresponding aryl- C 2 -C 5 alkenyl, such as benzyl and styryl (i.e.
  • acyl radicals R j that are derived from the following carboxylic acids: aliphatic monocarboxylic acids having a maximum of 20 carbon atoms, such as lower alkanecarboxylic acids, for example propionic, butyric, isobutyric, valeric, isovaleric, caproic, trimethylacetic, oenan- thic and diethylacetic acid and, especially, acetic acid, and lauric, myristic, palmitic and stearic acid, and oleic acid, elaidic acid, linoleic acid and linolenic acid, but also corres ⁇ ponding halogenated lower alkanecarboxylic acids, such as chloroacetic acid, trifluoro- or trichloro-acetic acid, bromoacetic or ⁇ -bromoisova
  • amino group is substituted by conventional, for example one of the above- mentioned, amino-protecting groups; and also dicarboxylic acids, such as oxalic acid, malonic acid, mono- or di-lower alkylmalonic acids, succinic acid, glutaric acid, adipic acid, erucic acid, maleic acid, or a phthalic, quinolinic, isoquinolinic or phenylsuccinic acid that is unsubstituted or substituted by halogen, such as fluorine, chlorine or bromine, and/or by lower alkyl, hydroxy, lower alkoxy and by nitro, and also glutamic acids and aspartic acid, the latter two acids preferably having protected amino groups.
  • dicarboxylic acids such as oxalic acid, malonic acid, mono- or di-lower alkylmalonic acids, succinic acid, glutaric acid, adipic acid, erucic acid, maleic acid, or a phthalic, quinolini
  • the second carboxy group may not only be free but may also be functionally modified, for example in the form of a C r C 4 alkyl ester or in the form of a salt, preferably in the form of a physiologically tolerable salt, with a salt-forming basic component.
  • a salt-forming basic component preferably in the form of a physiologically tolerable salt.
  • metal or ammonium salts such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines.
  • acyl Ac 1 is derived from monoesters of carbonic acid and is charac ⁇ terised by the partial formula R°-O-CO-.
  • hydrocarbyl radicals R° in these derivatives there are to be mentioned, for example, the following: acyclic hydrocarbyl, especially a C r C 20 alkyl, preferably a linear C r C 20 alkyl, that may be substi ⁇ tuted by a carboxy group, preferably in a functionally modified form, such as a salt, cyano or a C j - alkyl ester, that is preferably located in the co-position, or an analogous linear (mono- to hexa-)oxaalkyl having from 4 to 20 chain members, especially one character ⁇ ised above as being especially preferred.
  • R° are unsubstituted or substituted phenyl and benzyl radicals, for example those mentioned above as being preferred.
  • the acyl radical Ac 2 is derived from an acyclic, carbocyclic or heterocyclic, or also a carbocyclic-acyclic or heterocyclic-acyclic sulfonic acid and corresponds to the mentioned partial formula R°-SO 2 - wherein R° is hydrocarbyl having the above-mentioned general and, especially, the preferred meanings.
  • R° is hydrocarbyl having the above-mentioned general and, especially, the preferred meanings.
  • R° is a C ⁇ -C alkyl, or, especially, a bicyclic or especially a monocyclic aryl, such as especially phenyl, that may be substituted in a manner analogous to that described above for the aroyl radicals given prominence.
  • Prominence is also to be given to bicyclic and mono ⁇ cyclic aromatic heterocyclyl radicals of analogous structure, in which one or two of the carbon atoms have been replaced by hetero atoms, such as pyrimidyl, for example 2- or 4-pyrimidyl, quinolyl or isoquinolyl.
  • heterocyclyl radicals also may carry substi ⁇ tuents, especially those given prominence for aroyl (in that case, for example, a hydroxy derivative is, by virtue of tautomeric shifting of the double bond, the same as a dihydro- oxo derivative).
  • the acyl radical Ac 3 derived from a phosphoric acid is, for example, an acyl radical that is derived from pyrophosphoric acid or, especially, from orthophosphoric acid and that may also be in a functionally modified form, for example in the form of a salt, a hydrocarbyl ester or an amide.
  • R j is an acyl of the partial formula R°-CO- wherein R° is C r C 7 alkyl, especially C r C 4 alkyl, such as methyl or tert- butyl, that may also be substituted by halogen, such as fluorine or chlorine, carboxy or by C j - alkoxy-carbonyl, such as methoxycarbonyl, such as trifluoro- or trichloro-methyl, - 14 -
  • Rj is an acyl of the partial formula R°-C - wherein R° is phenyl that is unsubstituted or that jnay also be substituted by C ⁇ -C alkyl, C l -C 4 alkoxy, halogen, such as fluorine or chlorine,! nitro, trifluoromethyl, carboxy or by C j ⁇ alkoxy-carbonyl.
  • Rj is an acyl of the partial formula R°-SO 2 - wherein R° is C r C alkyl, especially i ⁇ alkyl.
  • Rj is an acyl of the partial formula R°-SO 2 - wherein R° is phenyl, or also pyridyl, furyl, thieityl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by Ci ⁇ alk l, C ] ⁇ C 4 alkoxy, halogen, nitro, trifluoromethyl, carb ⁇ xv. Cj-C 4 alkoxy- carbonyl, methylenedioxy and/or by cyano.
  • R is an acyl of the partial formula R c -SO r wherein R° is phenyl or C ⁇ -C 4 alkyl- or halo-substituted phenyl or isoquinolyl, such as 5-isoquinolyl.
  • R ⁇ is an acyl of the partial formula R°-0-CO- wherein R° is C j -Cfllky], especially C r C 4 t ⁇ kjfl.
  • Rj is an acyl of the partial formula R°-0-CO- wherein R° is phenyl, or also pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by C j -C 4 alkyl, C
  • R t is ah acyl of the partial formula R°-O-C - wherein R° is unsubstituted phenyl.
  • Rj is an ac l of the partial formula R 4 (R 5 )N-C( ⁇ W wherein W is sulfur or, especially, oxygen, R,, is hydrogen and R $ is Cj-C aJkyl, especially C 1 -C 4 alkyl, C 3 -C 7 aJkenyl or phenyl, br also pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benziniidazolyl, each of which is unsubstituted or substituted by C r C 4 alkyl, C r C 4 alkoxy, halogen, nitro, trifluoromethyl, carboxy, C r C 4 alkoxy-carbonyl, methylenedioxy and/or by cyano.
  • R j is derived from an ⁇ -amino acid, especially a naturally occurring ⁇ -amino acid of the L-series.
  • R j is derived from an ⁇ -amino acid selected from glycine, phenylglycine, alanine, phenylalanine, proline, leucine, serine, valine, tyrosine, arginine, histidine and asparagine.
  • R j is derived from an ⁇ -amino acid selected from glycine, alanine, phenylalanine, serine, arginine and histidine.
  • An aliphatic hydrocarbon radical Rj having up to 29 carbon atoms that is substituted by acyclic substituents has preferably a maximum of 18, especially a maximum of 12 and, as a rule, not more than 7, carbon atoms, can be saturated or unsaturated and is especially a linear or branched lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl radical that is substituted by acyclic substituents.
  • Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or also n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl; lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl or 2- or 3-butenyl; lower alkadienyl is, for example, l-penta-2,4-dienyl; lower alkynyl is, for example, propargyl or 2-butynyl.
  • the double bond is located especially in a position higher than the ⁇ -position with respect to the free valency.
  • Substituents are especially the acyclic radicals mentioned above as substituents of R°, preferably free or esterified carboxy, such as lower alkoxy ⁇ carbonyl, or di-lower alkylamino.
  • a cycloaliphatic radical Rj having up to 29 carbon atoms is especially a substituted or, preferably, an unsubstituted mono-, bi- or poly-cyclic cycloalkyl, cycloalkenyl or cyclo- alkadienyl radical.
  • Preferred are radicals having a maximum of 14, especially 12, ring carbon atoms and 3- to 8-, preferably 5- to 7- and especially 6-membered rings that may also carry one or more, for example two, aliphatic hydrocarbon radicals, for example those mentioned above, especially the lower alkyl radicals, or further cycloaliphatic radicals.
  • Preferred substituents are the acyclic substituents mentioned above for R°.
  • a cycloaliphatic-aliphatic radical Rj having up to 29 carbon atoms is a radical in which an acyclic radical, especially one having a maximum of 7, and preferably a maximum of 4, carbon atoms, such as especially methyl, ethyl and vinyl, carries one or more cyclo ⁇ aliphatic radicals having the meanings given above.
  • an acyclic radical especially one having a maximum of 7, and preferably a maximum of 4, carbon atoms, such as especially methyl, ethyl and vinyl, carries one or more cyclo ⁇ aliphatic radicals having the meanings given above.
  • cycloalkyl-lower alkyl radicals, and the analogues thereof that are unsaturated in the ring and/or chain but are non-aromatic and that carry the ring at the terminal carbon atom of the chain.
  • Heterocyclic radicals Rj having up to 20 carbon atoms and up to 9 hetero atoms are especially monocyclic, but also bi- or poly-cyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza- or tetraza-cyclic radicals of aromatic character and corresponding partially satur ⁇ ated or, especially, completely saturated heterocyclic radicals of that kind, it being possible, where appropriate, for such radicals to carry further acyclic, carbocyclic or heterocyclic radicals and/or to be mono-, di- or poly-substituted by functional groups, preferably those mentioned above as substituents of aliphatic hydrocarbon radicals.
  • the free valency of the heterocyclic radical Rj must extend from one of its carbon atoms. They are especially unsubstituted or substituted monocyclic radicals having one nitrogen, oxygen or sulfur atom, such as 2-aziridinyl, and especially aromatic radicals of that kind, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2-, 3- or 4-pyridyl, or thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl; analogous bicyclic radicals having one nitrogen, oxygen or sulfur atom are, for example, indolyl, such as 2- or 3-indolyl, quinolyl, such as 2- or 4-quinolyl, isoquinolyl, such as 3- or 5-isoquinolyl, benzofuranyl, such as 2-benzofuranyl, chromenyl, such as 3-chromenyl, or benzothienyl, such as 2- or 3-benzothienyl; preferred monocycl
  • radicals also come into considera ⁇ tion, such as 2-tetrahydrofuryl, 2- or 3-pyrrolidyl, 2-, 3- or 4-piperidyl, and also 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl and N,N'-bis-lower alkyl-2- piperazinyl radicals.
  • These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, especially those mentioned above.
  • Heterocyclic-aliphatic radicals R] are especially aliphatic radicals having a maximum of 7, preferably a maximum of 4, carbon atoms, for example those mentioned above, that carry one, two or more heterocyclic radicals, for example those mentioned above, it also being possible for the heterocyclic ring to be bonded to the aliphatic chain by one of its nitrogen atoms.
  • a preferred heterocyclic-aliphatic radical R j is, for example, pyrid-3-yl-methyl.
  • a heteroaliphatic radical R j having up to 20 carbon atoms and up to 10 hetero atoms is an aliphatic radical that contains, in place of one, two or more carbon atoms, identical or different hetero atoms, such as especially oxygen, sulfur and nitrogen.
  • R ⁇ are most preferred: C r C 2 alkyl substituted by lower alkoxy ⁇ carbonyl, such as especially methoxycarbonyl, by carboxy, by pyridyl, such as especially pyrid-3-yl, or by di-lower alkylamino, such as especially diethylamino; or lower alkanoyl, such as especially acetyl, benzoyi, pyridylcarbonyl, such as especially nicotinoyl or isonicotinoyl, or pyrrolylcarbonyl, such as especially 2-pyrroyl.
  • C r C 2 alkyl substituted by lower alkoxy ⁇ carbonyl such as especially methoxycarbonyl, by carboxy
  • pyridyl such as especially pyrid-3-yl, or by di-lower alkylamino, such as especially diethylamino
  • lower alkanoyl such as especially acetyl, benzoyi, pyri
  • An aliphatic radical R is, for example, one of the radicals that is mentioned above for an aliphatic hydrocarbon radical Rj, but that, in contrast to the aliphatic hydrocarbon radical Ri, may also be unsubstituted and/or may contain, in place of one or more than one carbon atom, also hetero atoms.
  • a carbocyclic or carbocyclic-aliphatic radical R 2 having up to 29 carbon atoms includes the meanings mentioned above for a cycloaliphatic or cycloaliphatic-aliphatic radical R ] and in addition, however, aromatic and aromatic-aliphatic radicals.
  • An aromatic radical (aryl radical) R 2 is especially a phenyl, but also a naphthyl, such as 1- or 2-naphthyl, a biphenylyl, such as especially 4-biphenylyl, or also an anthryl, fluorenyl or azulenyl, or an aromatic analogue thereof having one or more saturated rings.
  • Preferred aromatic- aliphatic radicals are aryl-lower alkyl and aryl-lower alkenyl radicals, for example phenyl-lower alkyl or phenyl-lower alkenyl having a terminal phenyl radical, for example benzyl, phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, or also 1- or 2-naphthylmethyl.
  • aryl-lower alkyl and aryl-lower alkenyl radicals for example phenyl-lower alkyl or phenyl-lower alkenyl having a terminal phenyl radical, for example benzyl, phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, or also 1- or 2-naphthylmethyl.
  • a heterocyclic-aliphatic radical R 2 has one of the meanings mentioned above for a hetero ⁇ cyclic-aliphatic radical Rj.
  • An acyl radical R 2 having up to 30 carbon atoms is formyl or has one of the meanings mentioned above for an acyl radical R j having from 2 to 30 carbon atoms.
  • R 2 are preferred: hydrogen, C r C 2 alkyl that is unsubstituted or substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl or tertiary butoxycarbonyl, or by carboxy; or lower alkanoyl, such as especially acetyl, 2-(tetrahydro- pyran-4-yl)-oxy-lower alkanoyl, such as especially 2-(tetrahydropyran-4-yl)-oxy- propionyl or 2-(tetrahydropyran-4-yl)-oxy-acetyl, lower alkoxycarbonyl, such as especi ⁇ ally tertiary butoxycarbonyl, or benzoyi.
  • lower alkoxycarbonyl such as especi ⁇ ally tertiary butoxycarbonyl, or benzoyi.
  • Lower alkoxy R 3 is preferably methoxy.
  • the compounds according to the invention may, provided they contain salt-forming groups, also be in the form of salts, especially pharmaceutically acceptable, i.e. physiologically tolerable, salts.
  • pharmaceutically acceptable salts especially pharmaceutically acceptable, i.e. physiologically tolerable, salts.
  • pharmaceutically unsuitable salts Only pharmaceutically acceptable salts are used therapeutically and these are preferred.
  • compounds of formula I having free acid groups may be in the form of a salt, preferably a physiologically tolerable salt, with a salt-forming basic component.
  • a salt preferably a physiologically tolerable salt
  • metal or ammonium salts such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, especially tertiary monoamines and heterocyclic bases, for example triethylamine, tri-(2-hydroxyethyl)-amine, N-ethylpiperidine or N,N'-dimethylpiperazine.
  • Compounds according to the invention of basic character may also be in the form of addition salts, especially in the form of acid addition salts with inorganic and organic acids, but also in the form of quaternary salts.
  • compounds of formula I that carry a basic group, such as an amino group, as a substituent may form acid addition salts with commonly used acids.
  • Suitable acids are, for example, hydrohalic acids, for example hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, and aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenedisulfonic, halobenzenesulfonic, toluene- sulfonic, naphthalenesulfonic acids or sulfani
  • the staurosporin derivatives of formula I are capable of fully re-sensitising multidrug- resistant cells to the action of anti-tumour agents, such as cytostatics, as is demonstrated in the Examples section of this text in the case of resistant human KB-8511 cells.
  • anti-tumour agents such as cytostatics
  • anti-tumour agents are, for example, doxorubicin, daunorubicin, vincristine, etoposide, taxol, mitomycin C, actinomycin D, mitoxantrone and, especially, vinblastine and adriamycin.
  • the staurosporin derivatives of formula I and pharmaceutically acceptable salts of such derivatives having at least one salt-forming group can therefore be used in combination with one of those anti-tumour agents for the treatment of tumour diseases.
  • the pig brain protein kinase C used according to the methodology mentioned is a mixture of different subtypes (isotypes) of protein kinase C. For that reason, nowadays, pure, recombinant isotypes of protein kinase C are mostly used instead of pig brain protein kinase C.
  • Measurement of the activity of the recombinant PKC isotypes obtained by the above method is carried out in the absence of lipid and calcium (co-factors).
  • Protamine sulfate which is phosphorylated in the absence of co-factors, is used as a substrate for this.
  • the activity of the enzymes reflects the transfer of ⁇ 2p from ⁇ -[ ⁇ P]-ATP to protamine sulfate.
  • Protamine sulfate is a mixture of polypeptides that each comprise four C-terminal arginine residues.
  • Measurement of the phosphate incorporation is carried out under the following conditions: 100 ⁇ l of the reaction mixture contain in final concentrations 20 mmol TRIS-HC1 pH 7.4, 10 mmol Mg[NO3]2, 0.5 mg/ml protamine sulfate, 10 ⁇ mol ATP (0.1 ⁇ Ci ⁇ -[ 32 P]-ATP; 10 Ci/mol; Amersham, Little Chalfont, United Kingdom), various concentrations of inhibitory substances and 0.5-2.5 U (Units; one unit is the enzyme quantity that transfers one nanomol of 32 P from the above-mentioned ⁇ -[ 32 P]-ATP to Histon HI [Sigma, type V-S] in one minute per milligram of protein) of the enzymes.
  • the reaction is initiated by adding the enzymes and transferring to 32°C. The reaction time is 20 minutes. Thereafter, the reaction is stopped by dropping aliquots of 50 ⁇ l onto P81 chromatography paper (Whatman, Maidstone, United Kingdom). After removing unbound ⁇ -[" ⁇ P]-ATP and nucleotide fractions by washing procedures as described by J.J. Witt and R. Roskoski, "Rapid protein kinase assay using phospho-cellulose-paper absorption", Anal. Biochem. 66, 253-258 (1975), the phosphorylation of the substrate is determined by scintillation measurement.
  • the compounds of formula I generally do not inhibit the various isotypes of protein kinase C (PKC) until they are at a concentration IC 50 that is greater by a factor of from about 20 to over 1000 than the IC 50 values that are found for analogous compounds wherein R j is hydrogen.
  • PLC protein kinase C
  • R j is C r C 2 alkyl that is substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl, by carboxy, by pyridyl, such as especially pyrid-3-yl, or by di-lower alkylamino, such as especially diethylamino, or is lower alkanoyl, such as especially acetyl, benzoyi, pyridylcarbonyl, such as especially nicotinoyl or isonicotinoyl, or pyrrolylcarbonyl, such as especially 2-pyrroyl, R 2 is hydrogen, C j -C 2 alkyl that is unsubstituted or substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl or tertiary butoxycarbonyl, or by carboxy, or is lower alkanoyl, such as especially acetyl, 2-(tetrahydropyran-4-yl-
  • Preferred in particular are compounds of formula I wherein R 2 is other than hydrogen, and salts of such compounds having at least one salt-forming group.
  • R j is other than lower alkanoyl, especially those compounds having virtually no significant inhibitory action on PKC, and salts of such compounds having at least one salt-forming group.
  • the compounds of formula I and salts of such compounds having at least one salt-forming group are prepared by processes known per se.
  • the process according to the invention comprises
  • Rj is as defined above, any functional groups present therein being, if necessary, in protected form, and Y is a reactive activated hydroxy group or an additional single bond the other end of which replaces a hydrogen atom in the radical R j , or with a salt of such a compound having at least one salt-forming group, and removing any protecting groups, or
  • R 2 a has the meanings of R 2 mentioned above, with the exception of hydrogen, any functional groups present in the radical R 2 a being, if necessary, in protected form, and X is a leaving group or an additional single bond the other end of which replaces a hydrogen atom in the radical R 2 a , or with a salt of such a compound having at least one salt-forming group, and removing any protecting groups,
  • the end products of formula I may contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula I.
  • protecting group denotes only a readily removable group that is not a component part of the particular desired end product of formula I.
  • Free functional groups that may be present in compounds of formulae II and HI, which are preferably protected by readily removable protecting groups, are especially free amino or carboxy groups. It may also be advantageous to protect free hydroxy. Func ⁇ tional groups that are intended to participate in the desired reaction are not, of course, protected.
  • Protecting groups and the methods by which they are introduced and removed are des ⁇ cribed, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in “Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and also in Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. It is characteristic of protecting groups that they can be removed easily, i.e. without undesir ⁇ able secondary reactions taking place, for example by solvolysis, reduction, photolysis or also under physiological conditions.
  • a protected amino group may, for example, be in the form of a readily cleavable acyl- amino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-en-yl-amino, silyl- amino or stannylamino group or in the form of an azido group.
  • acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially of an unsubstituted or substituted, for example halo- or aryl-substituted, alkanecarboxylic acid or an unsubsti ⁇ tuted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or of a carbonic acid semiester.
  • Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyi, for example benzoyi, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the 1 -position of the lower alkyl radical or suitably substituted in the 1- or 2-position, especially tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, aryl- methoxycarbonyl having one or two aryl radicals which are preferably
  • acyl radicals that are suitable as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as di-lower alkyl- phosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, for example dicyclohexylphosphoryl, unsubstituted or substituted diphenylphosphoryl, for example diphenylphosphoryl, unsub ⁇ stituted or substituted, for example nitro-substituted, di-(phenyl-lower alkyl)-phosphoryl, for example dibenzylphosphoryl or di-(4-nitrobenzyl)-phosphoryl, unsubstituted or substi ⁇ tuted phenyloxy-phenyl-phosphonyl, for example phenyloxyphenyl-phosphonyl, di-lower alkylphosphinyl, for example dieth
  • aryl radicals are, especially, unsubstituted or substituted phenyl radicals.
  • aryl radicals are, for example, benzyl-, diphenylmethyl- and, especially, trityl-amino.
  • An etherified mercapto group in an amino group protected by such a radical is especially arylthio or aryl-lower alkylthio wherein aryl is especially phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro.
  • a corresponding amino-protecting group is, for example, 4-nitrophenylthio.
  • acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • lower alkyl such as methyl or tert-butyl
  • lower alkoxy such as methoxy
  • halogen such as chlorine
  • nitro or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
  • Corresponding protecting groups are especially 1 -lower alkanoyl-prop-l-en-2-yl, for example l-acetyl-prop-l-en-2-yl, or 1 -lower alkoxycarbonyl-prop-l-en-2-yl, for example 1 -ethoxycarbonyl-prop- 1 -en-2-y 1.
  • Preferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially tert-butoxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted, for example as indicated, for example 4-nitro-benzyloxy carbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl.
  • Carboxy groups are usually protected in esterified form, such ester groupings being readily cleavable under mild conditions.
  • Carboxy groups protected in that manner contain as esterifying groups especially lower alkyl groups that are branched in the 1 -position or suitably substituted in the 1- or 2-position.
  • Preferred carboxy groups in esterified form are inter alia tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, arylmethoxy- carbonyl having one or two aryl radicals which are phenyl radicals that are unsubstituted or mono- or poly-substituted, for example, by lower alkyl, such as tert-lower alkyl, for example tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, such as benzyloxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example 4-methoxybenzyloxycarbonyl or 4-nitro- benzyloxycarbonyl, or diphenylmethoxycarbonyl that is unsubstituted or substituted, for example as mentioned above, for example diphenylmethoxycarbonyl or di-(4-methoxy- pheny
  • the organic silyl and stannyl radicals mentioned above and hereinafter contain preferably lower alkyl, especially methyl, as substituents of the silicon or tin atoms.
  • Corresponding silyl or stannyl groups are especially tri-lower alkylsilyl, especially trimethylsilyl, or dimethyl-tert-butyl-silyl, or correspondingly substituted stannyl, for example tri-n-butyl- stannyl.
  • Preferred protected carboxy groups are tert-lower alkoxycarbonyl, such as tert-butoxy ⁇ carbonyl, and especially benzyloxycarbonyl that is unsubstituted or substituted, for example, as mentioned above, such as 4-nitrobenzyloxy carbonyl, or diphenylmethoxy ⁇ carbonyl, especially 2-(trimethylsilyl)ethoxycarbonyl.
  • Hydroxy-protecting groups are, for example, acyl radicals, such as unsubstituted or substi ⁇ tuted, for example halo-substituted, lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carbonic acid semiesters, especially tert-butoxycarbonyl, unsubstituted or substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or diphenyl ⁇ methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl, or organic silyl or stannyl radicals, or readily removable etherifying groups, such as tert-lower alkyl, for example tert-butyl, 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radicals, especially 1 -lower alkoxy-
  • protecting groups that are not constituents of the desired end product of formula I for example the carboxy-, amino-, hydroxy- or carbamoyl-protecting groups
  • the protecting groups are preferably so chosen that more than one such group can be removed simultaneously.
  • a protected amino group is freed in a manner known per se and, according to the nature of the protecting groups, in various ways, preferably by solvolysis or reduction.
  • 2-Halo- lower alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroyl ⁇ methoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
  • a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
  • Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite.
  • a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate
  • 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite.
  • Unsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substituted silyl)-ethoxycarbonylamino can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, or with a saturated hydrochloric acid solution in ethyl acetate or dioxane; unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for example, by means of hydrogenolysis, i.e.
  • unsubstituted or substi ⁇ tuted triarylmethylamino or formylamino can be cleaved, for example, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water; and an amino group protected by an organic silyl group can be freed, for example, by means of hydrolysis or alcoholysis.
  • An amino group protected by 2-haloacetyl for example 2-chloroacetyl
  • 2-chloroacetyl can be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product.
  • An amino group protected by 2-substituted silylethoxycarbonyl can be converted into the free amino group also by treatment with a salt of hydrofluoric acid that yields fluoride anions.
  • Tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1 -position by lower alkoxy or by lower alkylthio, or unsub ⁇ stituted or substituted diphenylmethoxycarbonyl can be converted into free carboxy, for example, by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, where appropriate with the addition of a nucleophilic compound, such as phenol or anisole.
  • Unsubstituted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst.
  • suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl
  • 2-halo-lower alkoxycarbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxy carbonyl can also be converted into free carboxy.
  • Aroylmethoxy- carbonyl can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide.
  • Substituted 2-silylethoxycarbonyl can also be converted into free carboxy by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium or potas ⁇ sium fluoride, in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower alkyl-arylammonium fluoride, for example tetraethylammonium fluoride or tetra- butylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide.
  • a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium or potas ⁇ sium fluoride
  • a hydroxy group protected by a suitable acyl group, an organic silyl group or by unsubsti ⁇ tuted or substituted 1 -phenyl-lower alkyl is freed analogously to a correspondingly protected amino group.
  • Hydroxy protected by unsubstituted or substituted 1 -phenyl-lower alkyl, for example benzyl, is freed preferably by catalytic hydrogenation, for example in the presence of a palladium-on-carbon catalyst.
  • a hydroxy group protected by 2,2-di- chloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy group etherified by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong organic carboxylic acid, for example trifluoroacetic acid.
  • Hydroxy etherified by an organic silyl radical for example trimethylsilyl, can also be freed with a salt of hydrofluoric acid that yields fluoride anions, for example tetrabutylammonium fluoride.
  • Y is a reactive activated hydroxy group
  • Y is bonded to a saturated carbon atom or a carbonyl carbon atom in the radical Rj and is then especially a reactive esterified hydroxy group, i.e. one that is esterified by a strong inorganic acid, such as a hydrohalic acid (for example hydrochloric, hydrobromic or hydriodic acid), by an oxygen-containing mineral acid, such as phosphoric acid and, especially, sulfuric acid, or by a strong organic, such as aliphatic or aromatic, sulfonic acid (for example methane- and ethane- or benzene-, p-toluene-, p-nitrobenzene- and p-chlorobenzene-sulfonic acid), for example halogen, such as especially chlorine.
  • a strong inorganic acid such as a hydrohalic acid (for example hydrochloric, hydrobromic or hydriodic acid)
  • an oxygen-containing mineral acid
  • R j Y is, for example, an alkene, especially one in which the double bond has been additionally activated by a structural peculiarity, as in 2-methylpropene, or by substi ⁇ tution, such as especially in acrylonitrile.
  • Y is a single bond the other end of which is not bonded directly to a carbon atom in the radical R j but is bonded to a hetero atom occurring as a substituent, such as oxygen (for example in a hydroxy group) or nitrogen (in an amino group) (replacing a hydrogen atom of that group).
  • Especially preferred reagents of that kind contain the ⁇ -epoxide (oxirane) or ⁇ -imine (aziridine) grouping and serve as an advantageous source of radicals R° having a 2-hydroxyalkyl grouping or 2-aminoalkyl grouping, respectively.
  • R j is an acyl radical
  • the reagent R j Y is a reactive carboxylic acid derivative.
  • Y therein is, for example, a reactive esterified hydroxy group, such as especially halogen.
  • Such reactive carboxylic acid derivatives of formula HI are especially reactive activated esters or reactive anhydrides, or also reactive cyclic amides, it also being possible for the activation of the carboxylic acid of formula Rj-OH used as acylating agent to be per ⁇ formed in situ in the presence of the compound of formula II.
  • esters of acids are especially esters that are unsaturated at the linking carbon atom of the esterifying radical, for example of the vinyl ester type, such as vinyl esters proper (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1 ,2-oxazolium or Wood ⁇ ward method), or 1 -lower alkoxy vinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxy acetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodi
  • Anhydrides of acids may be symmetric or preferably mixed anhydrides of those acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid lower alkyl semiesters (obtain ⁇ able, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid lower alkyl esters or with a 1 -lower alkoxycarbonyl-2-lower alkoxy- 1 ,2-dihydroquinoline, for example 1 -lower alkoxycarbonyl-2-ethoxy- 1 ,
  • Suitable cyclic amides are especially amides having five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazoles, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • imidazoles for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method)
  • pyrazoles for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • N,N'-disubstituted amidino esters can be formed in situ by reacting a mixture of the starting material of formula ⁇ and the acid used as acylating agent in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N'-dicyclohexyl- carbodiimide.
  • amino or amido esters of the acids used as acylating agents in the presence of the starting material of formula II that is to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodi- imide, and of an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccin- imide, N-hydroxy-norbornane-2,3-dicarboximide or N-hydroxybenzotriazole, where appropriate in the presence of a suitable base, for example 4-dimethylaminopyridine or tetramethylguanidine.
  • an N,N'-disubstituted carbodiimide for example N,N'-dicyclohexylcarbodi- imide
  • an N-hydroxyamine or N-hydroxyamide for example N-hydroxysuccin- imide, N-hydroxy-norbornane-2,
  • Process a) is preferably carried out by first reacting the starting material of formula II in a suitable solvent, such as dimethylformamide or tetrahydrofuran, with a suitable base, such as sodium bis(trimethyl- silyl)amide in tetrahydrofuran or sodium hydride, at a temperature of preferably from -20°C to +70°C, especially from 0°C to room temperature, and then adding the compound of formula HI, for example in a suitable solvent, such as tetrahydrofuran.
  • a suitable solvent such as dimethylformamide or tetrahydrofuran
  • a suitable base such as sodium bis(trimethyl- silyl)amide in tetrahydrofuran or sodium hydride
  • Process a) is preferably carried out by reacting the starting material of formula II in a suitable solvent, such as methylene chloride, in the presence of a suitable base, such as triethylamine, with a reactive acid derivative of formula HI, which may also be formed in situ from the corresponding acid, at a tempera ⁇ ture of from 0°C to +150°C, for example under reflux.
  • a suitable solvent such as methylene chloride
  • a suitable base such as triethylamine
  • the starting material of formula ⁇ can first be reacted in a suitable solvent, such as absolute tetrahydrofuran, with a suitable base, such as sodium bis(trimethylsilyl)amide in tetrahydrofuran, at a temperature of from 0°C to room temperature, and then a reactive acid derivative of formula UI can be added.
  • a suitable solvent such as absolute tetrahydrofuran
  • a suitable base such as sodium bis(trimethylsilyl)amide in tetrahydrofuran
  • the functional groups to be protected in the reactants of formulae IV and V and the protecting groups used for that purpose correspond to those mentioned in Process a).
  • Functional groups that are intended to participate in the desired reaction such as the group -NH-CH 3 , are not, of course, protected.
  • the introduction and removal of the protecting groups is also carried out analogously to the manner described in Process a).
  • the leaving group X in a compound of formula V corresponds to the reactive activated hydroxy group Y in the compound of formula UI and the reagents of formula V are analogous to the reagents of formula HI.
  • the leaving group X is, for example, a diazonium group.
  • Process b) is preferably carried out by reacting the starting material of formula IV in a suitable solvent, such as dimethyl ⁇ formamide or a halogenated hydrocarbon, such as chloroform, in the presence of a suitable base, such as N,N-diisopropylethylamine, at a suitable temperature, such as room tempera ⁇ ture or elevated temperature up to about +150°C, with a compound of formula V, the reaction being carried out at elevated temperature, for example under pressure in a closed vessel, such as a bomb tube, especially when X is an additional single bond the other end of which replaces a hydrogen atom in the radical R 2 a , for example when the compound of formula V is an oxirane or acrylonitrile.
  • the reaction with oxiranes is preferably carried out in a lower alkanol, such as ethanol, as solvent.
  • an ester grouping can be hydrolysed to carboxy or a carbonyl group can be reduced.
  • the said hydrolysis is carried out, for example, in a manner known per se with dilute, for example 2-normal, sodium hydroxide solution in a lower alkanol, such as ethanol, at room temperature, and can also be seen as the removal of a protecting group.
  • reducing agents that come into consideration are, for example, complex metal hydrides, such as alkali metal aluminium hydrides and, especially, alkali metal borohydrides, for example lithium aluminium hydride, potassium borohydride, lithium borohydride and, especially, sodium borohydride, and derivatives thereof wherein one or more hydrogen atoms have been replaced by alkoxy radicals or by cyano, for example methoxysodium borohydride, tri-(tert-butoxy)lithium borohydride or di-(2-methoxyethoxy)-disodium lithium hydride or sodium cyanoborohydride, and also diborane.
  • complex metal hydrides such as alkali metal aluminium hydrides and, especially, alkali metal borohydrides, for example lithium aluminium hydride, potassium borohydride, lithium borohydride and, especially, sodium borohydride, and derivatives thereof wherein one or more hydrogen atoms have been replaced by alkoxy radicals or by cyano,
  • Salt-forming groups in compounds of formula II to V and salts thereof are those mentioned above for the compounds of formula I.
  • salt formation which is to be carried out if desired, or the freeing of the fundamental forms from their salts is carried out in a conventional manner that is generally known per se.
  • compounds carrying carboxy groups are converted into corresponding salts with bases, especially into alkali metal salts, by treatment with a corresponding base, especially a compound giving an alkaline reaction, such as hydroxide, carbonate or bicarbonate.
  • the salts can be converted into free carboxy compounds by acidifying, for example with inorganic acids, such as especially hydrohalic acids.
  • End products giving a basic reaction for example amines
  • Salts such as the picrates
  • Salts can also be used for the purification of the compounds obtained, by converting the free compounds into salts, separating these and recovering the free compounds from the salts again.
  • any reference to the free compounds is to be understood as including also the corresponding salts (including quaternary salts) where appropriate and expedient.
  • the starting materials corresponding to the formula IV wherein, however, R j is hydrogen are known or can be prepared by processes that are known per se.
  • the starting material corresponding to the formula IV wherein Rj and R 3 are each hydrogen, i.e. staurosporin, is commercially available and can be obtained by fermentation with the strain Streptomyces staurosporeus. That strain was deposited under number PERM P-3725 at the Fermenta ⁇ tion Research Institute, Japan, in connection with Japanese Examined Patent Publication [Kokoku] No. 57-53076 which was published on 11.11.1982, see S. Omura et al, J. Antibiot. 30, 275-281 (1977).
  • Staurosporin derivatives corresponding to formula IV wherein R 3 is other than hydrogen are, for example, described by I. Takahashi et al, J. Pharmacol. Exp. Ther. 255(3) (1990) 1218-1221 and in WO-A-8907-105-A (Applicant: Kyowa Hakko Kogyo KK, Japanese Priority No. 024571 of 4. 2. 1988).
  • Compounds of formula II wherein R 3 is oxo are obtained, for example, from the corresponding compounds of formula II wherein R 3 is hydrogen by oxidation with chromium trioxide in pyridine. From the 7-oxo compounds so obtained the corresponding 7-hydroxy compounds wherein R 3 is hydroxy are obtained by reduction with sodium borohydride.
  • the starting materials of formula V wherein R 2 a is 2-(tetrahydropyran-4-yl-oxy)-lower alkanoyl are obtained, for example, by reacting tetrahydropyran-4-ol with a corresponding chloro-lower alkanoic acid.
  • tetrahydropyran-4-ol is first reacted in a suitable inert aprotic solvent, such as an acyclic or cyclic ether, such as dioxane, with a suitable base, such as sodium hydride.
  • the suspension so obtained is added dropwise to a solution of a chloro-lower alkanoic acid in a suitable inert aprotic solvent, such as an acyclic or cyclic ether, such as dioxane.
  • a suitable inert aprotic solvent such as an acyclic or cyclic ether, such as dioxane.
  • the reaction is carried out at from O°C to 150°C, preferably from 20°C to 100°C, for example at the reflux temperature of the solvent used.
  • the compounds of formula I carrying a 2-(tetrahydropyran-4-yl-oxy)-lower alkanoyl radical are many times, for example more than 10 times, more soluble in water and other solvents than are other N-acyl-staurosporin derivatives, such as N-benzoylstaurosporin.
  • all of the processes described above, including the processes for removing protecting groups and the additional process measures, are carried out in a manner known per se, for example in the presence or absence of preferably inert solvents and diluents, if necessary in the presence of condensation agents or catalysts, at reduced or elevated temperature, for example in a temperature range of from approximately -70°C to approximately +150°C, especially from approximately -20°C to approximately +100°C, mainly from approximately 0°C to approximately +70°C, preferably from approximately 0°C to approximately +50°C, mainly at room temperature, in a suitable vessel and, if necessary, under an inert gas atmosphere, for example a nitrogen atmosphere.
  • 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 steps are carried out, or the process is discontinued at any stage or a starting material is formed under the reaction conditions or is used in the form of a reactive derivative or salt.
  • the starting materials used are preferably those which result in accordance with the process in the compounds described above as being especially valuable.
  • the present invention relates also to novel starting materials and/or intermediates and to processes for the preparation thereof.
  • the starting materials used and the reaction condi ⁇ tions chosen are preferably such that the compounds mentioned in this Application as being especially preferred are obtained.
  • the invention relates also to the use of the compounds of formula I and their pharmaceuti ⁇ cally acceptable acid addition salts, preferably in the form of pharmaceutical composi ⁇ tions, for the therapeutic treatment of the human or animal body, especially in the case of the diseases mentioned above.
  • the invention relates also to a method of removing exist ⁇ ing multidrug resistance and of preventing the development of multidrug resistance in a warm-blooded animal in need of such treatment, wherein an effective dose that removes the multi-drug resistance and avoids the development thereof of a compound of formula I, or of a pharmaceutically acceptable salt thereof, is administered enterally, for example orally, or parenterally, for example intraperitoneally or intravenously, to that warm ⁇ blooded animal.
  • the dose of the active ingredient depends inter alia upon the nature of the disease, the species to be treated and its size, the organism's state of defence and the mode of administration.
  • a daily dose of from 10 mg to 1000 mg, mainly from 50 mg to 500 mg, preferably from 70 mg to 300 mg, for example 150 mg, of a compound of formula I will be administered, for example enterally, such as orally, or parenterally, such as intravenously or intraperitoneally, to a warm-blooded animal of approximately 70 kg body weight.
  • This total daily dose may be divided into 2 or 3 doses per day.
  • compositions that comprise an effective amount, especially an amount effective for the prophylaxis or treatment of one of the diseases mentioned above, of the active ingredient together with pharmaceutically accept ⁇ able carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral, for example intravenous or intraperitoneal, administration, and may be inorganic or organic and solid or liquid.
  • tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • diluents for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol
  • lubricants for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminium silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colourings, flavourings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or infusion solutions.
  • binders for example magnesium aluminium silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone
  • disintegrators for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorb
  • Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible, for example in the case of lyophilised compositions that comprise the active ingredient on its own or together with a carrier, for example mannitol, for such solutions or suspensions to be made up prior to 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.
  • compositions in question which may, if desired, comprise other pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for example by means of conventional mixing, granulating, confec ⁇ tioning, dissolving or lyophilising processes, and comprise approximately from 0.01 % to 90 %, and in the case of lyophilised compositions up to 100 %, especially from approxi ⁇ mately 0.1 % to approximately 50 %, most especially from 1 % to 30 %, active ingred ⁇ ients), an active ingredient concentration below 1 % being especially suitable for compositions for topical administration.
  • the following Examples illustrate the invention without limiting it in any way.
  • the R f values are determined on silica gel thin-layer plates (produced by Merck, Darmstadt, Germany).
  • the ratio of the eluants to one another in the eluant mixtures used is given in parts by volume (v/v), and temperatures are given in degrees Celsius.
  • the concentration, c, of the substance in the solvent or solvent mixture is given as a percentage (weight/volume).
  • N-R 2 in the tetrahydropyran ring in formula I is designated "N".
  • N-BOC-staurosporin is a staurosporin derivative in which the radical R is BOC.
  • the nitrogen atom N-R j is designated "6", as will be apparent from the numbering given in formula I.
  • 6-methoxycarbonyl- methyl-staurosporin is a staurosporin derivative in which the radical R j is methoxy ⁇ carbonylmethyl.
  • Example 1 1.132 g (0.002 mol) of N-BOC-staurosporin are dissolved in 10 ml of dry dimethylformamide and, at room temperature under a nitrogen atmosphere, 2.2 ml of a 1 -molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran are added and stirring is carried out for one hour. There is then added to the dark-brown solution 0.4 ml (0.0022 mol) of bromoacetic acid methyl ester, the reaction mixture being decolorised again. After 3 hours at room temperature, the reaction mixture is poured onto ice and extracted with ethyl acetate.
  • the organic phase is washed with 0.1 -normal hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and concen ⁇ trated by evaporation.
  • Example 5 In a round-bottomed flask equipped with an argon balloon, 6 mg of sodium hydride (80 %) are added at 0°C to 20 mg of N-benzoyl-staurosporin in 2 ml of THF and the mixture is stirred for 15 minutes. 30 mg of diethylaminoethyl chloride hydrochloride in 800 ⁇ l of THF are then added and the reaction mixture is stirred first for one day at room temperature and then for a day at 40°C. 5 ml of 1 -normal HCl are then added thereto and extraction is carried out with methylene chloride. The organic phase is washed with water and dried with a silicone folded filter, and the solvent is removed.
  • sodium hydride 80 % are added at 0°C to 20 mg of N-benzoyl-staurosporin in 2 ml of THF and the mixture is stirred for 15 minutes. 30 mg of diethylaminoethyl chloride hydrochloride in 800 ⁇
  • Example 6 12.7 ⁇ l of triethylamine and 12.3 mg of pyrrole-2-carboxylic acid chloride (see Beilstein Vol. 12, Supplement ⁇ , page 492) are added to a solution of 10 mg of N-benzoyl-staurosporin in 0.6 ml of dry methylene chloride. The solution is stirred under reflux for 2 days. The reaction solution is partitioned between 20 ml of methylene chloride and 20 ml of saturated sodium carbonate solution, the organic phase is washed with a small amount of water and dried with a silicone folded filter and the solvent is removed in vacuo.
  • Example 7 A solution of 40 mg of N-benzoyl-staurosporin, 75 mg of isonicotinic acid chloride hydrochloride and 100 ⁇ l of triethylamine in 5 ml of dry methylene chloride is stirred under reflux for 5 hours.
  • the reaction solution is partitioned between 20 ml of methylene chloride and 20 ml of saturated sodium carbonate solution, the organic phase is washed with a small amount of water and dried with a silicone folded filter and the solvent is removed in vacuo.
  • Example 8 A solution of 50 mg of N-benzoyl-staurosporin, 100 mg of nicotinic acid chloride hydrochloride and 120 ⁇ l of triethylamine in 7 ml of dry methylene chloride is stirred under reflux for 5 hours. The reaction solution is partitioned between 20 ml of methylene chloride and 20 ml of saturated sodium carbonate solution, the organic phase is washed with a small amount of water and dried with a silicone folded filter and the solvent is removed.
  • Example 9 20 mg of N-benzoyl-7-oxo-staurosporin are dissolved in 2 ml of DMF. After the addition of 3 mg of sodium hydride (80 %), the mixture is stirred at room temperature for ten minutes. 4 mg of diethylaminoethyl chloride hydrochloride in 500 ⁇ l of DMF are then added and stirring is carried out at 60°C for 20 hours. 5 ml of 0.1 -normal HCl are added to the reaction mixture and extraction is carried out with methylene chloride. The organic phase is dried with a silicone folded filter and the solvent is removed.
  • the starting material is obtained as follows (see Chem. Abstracts 112(9):77240s and PCT Int. Appl. WO 8907105 Al):
  • an oxidising agent preferably chromium trioxide- pyridine complex (4.6 g in 50 ml of methylene chloride; Fieser & Fieser, Reagents for Organic Synthesis, Vol. 1, Wiley, 1967, page 145) is added at 0°C to 1 g of N-benzoyl- staurosporin in 10 ml of methylene chloride.
  • the reaction mixture is stirred overnight at 4°-25°C, diluted with 250 ml of methylene chloride and extracted with water.
  • the organic phases are combined and dried with a silicone folded filter, and the solvent is removed.
  • Example 10 700 mg of picolyl chloride hydrochloride are partitioned between 20 ml of methylene chloride and 5 ml of saturated sodium carbonate solution. The aqueous phase is washed with a small amount of methylene chloride, and the combined organic phases are dried with a silicone folded filter, and the solvent is removed in vacuo. 86 mg of N-benzoyl-7-oxo-staurosporin in 5 ml of methylene chloride and 7 mg of sodium hydride (80%) are added and the reaction is maintained under reflux for 6 hours.
  • reaction mixture is partitioned between ice-cold 4-normal HCl and methylene chloride, and the organic phase is washed in succession with ice-water, 5 ml of saturated sodium carbonate solution and then with a small amount of water and is dried with a silicone folded filter, and the solvent is removed.
  • Example 11 In a three-necked flask equipped with a septum, a thermometer and an argon balloon, 283 mg (0.5 mmol) of N-BOC-staurosporin are dissolved, with the exclusion of light, in 5 ml of absolute tetrahydrofuran, and 0.51 ml of a 1 -molar solution of sodium bis- (trimethylsilyl)amide in tetrahydrofuran (Fluka) is added thereto by means of a syringe. After stirring at room temperature for 15 minutes, 48 ⁇ l (0.505 mmol) of acetic anhydride are added and the reaction mixture is stirred at room temperature for 1 hour.
  • Example 13 150 mg (0.29 mmol) of 6-acetyl-staurosporin (see Example 12) are dissol ⁇ ved, with the exclusion of light, in 8 ml of chloroform (filtered before use through basic Alox [aluminium oxide]), and 56 ⁇ l (0.32 mmol) of N,N-diisopropylethylamine and 32 ⁇ l (0.34 mmol) of acetic anhydride are added thereto and the reaction mixture is stirred at room temperature for 3 hours. It is then diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation.
  • Example 17 90 ⁇ l (0.5 mmol) of N,N-diisopropylethylamine and 80 ⁇ l (0.5 mmol) of bromoacetic acid tert-butyl ester and a catalytic amount of potassium iodide are added under nitrogen and with the exclusion of light to a solution of 250 mg (0.44 mmol) of 6-benzoyl-staurosporin in 8 ml of dimethylformamide and the reaction mixture is stirred at room temperature for 20 hours. It is then concentration by evaporation and the residue is partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution.
  • Example 18 At 0° and with the exclusion of light, 200 mg (0.29 mmol) of 6-benzoyl- N-(tert-butoxycarbonyl-methyl)-staurosporin is dissolved in 10 ml of trifluoroacetic acid and the solution is stirred at 0° for 30 minutes. After a further 14 hours at room tempera ⁇ ture, the reaction solution is concentrated by evaporation, excess trifluoroacetic acid is removed by twice adding toluene and concentrating by evaporation and the residue is triturated with diethyl ether/ethyl acetate (8:2). The product is filtered off and dried under a high vacuum.
  • Example 20 43 mg (0.285 mmol) of 1 -hydroxybenzotriazole and 55 mg (0.285 mmol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) are added at 0°C under argon to a solution of 39 mg (0.219 mmol) of O-(tetrahydropyran-4-yl)-D-lactic acid in 5 ml of absolute dimethylformamide and the clear, colourless solution so obtained is stirred at 0°C for 3 hours.
  • EDC N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • the beige residue is further purified by preparative thick-layer chromatography (2 plates of Macherey-Nagel Sil-G200, UV 254) in methylene chloride/ethanol (95:5).
  • the zone containing the desired product is scraped off the plate, suspended in 100 ml of methylene chloride/methanol (9:1), stirred for 1/2 hour, filtered and concentrated by evaporation at 30°C under a high vacuum.
  • the residue crystallises from 6 ml of ethyl acetate/n-pentane (1:5).
  • Example 23 Human KB-31 (sensitive) and KB-8511 (drug-resistant, P-glycoprotein [Pgp] overexpressing) cells are incubated under a 5 % carbon dioxide atmosphere in MEM- Alpha-Medium, with the addition of ribonucleosides and deoxyribonucleosides and in the presence of 5 % foetal calf serum, 50 units/ml of the antibiotic penicillin and 50 ⁇ g/ml of the antibiotic streptomycin. The KB-8511 cells are kept as stock in the presence of 10 ng/ml of the antineoplastically active substance Colcemid (demecolcine).
  • Colcemid antineoplastically active substance
  • test substance (A: the antineoplastically active substance vin- blastine, B: the compound of formula I N,6-diacetyl-staurosporin) is added in serial dilu ⁇ tions on day 1. The plates are then incubated under the conditions mentioned above for 4 days. During that time, the control cells undergo several cell divisions.
  • the cells are fixed with 3.3 % (w/v) aqueous glutaraldehyde solution, washed with water and stained with 0.05 % (w/v) methylene blue solution. After washing, the dye is eluted with 3 % (w/v) aqueous hydrochloric acid.
  • the optical density (OD) per well which is directly proportional to the number of cells, is then measured with a photometer at 665 nm.
  • the IC 50 values are calculated by means of a computer system, using the formula
  • the IC 50 values are defined as being those concentrations of active ingredient at which the number of cells per well at the end of the incubation period amounts to only 50 % of the number of cells in the control cultures.
  • test substance [concentration] % growth of KB 851 1 cells:
  • test substance A vinblastine test substance B: N,6-diacetyl-staurosporin
  • test substance A vinblastine test substance C: N,6-di-(methoxycarbonylmethyl)-staurosporine
  • test substance A vinblastine test substance D: N-BOC-6-methoxycarbonylmethyl-staurosporin
  • the KB-8511 tumours overexpress Pgb, the product of the mdr-1 gene (S.
  • tumour regres ⁇ sion expressed in %, i.e. the decrease in tumour volume compared with the volume at the start of the treatment, was reached by adriamycin (1 x 9 mg/kg i.v.) in the case of the KB -31 tumour and amounted to 24 % on day 5 after treatment.
  • test substance D sensi ⁇ tizes the multi-drug resistant KB-8511 tumours to adriamycin and restores the activity of adriamycin against the KB-8511 tumours to an extent similar to the activity of adriamycin against the adriamycin sensitive KB-31 tumours.
  • Example 27 Tablets, each comprising 20 mg of active ingredient, for example one of the compounds of formula I described in the preceding Examples, are prepared in the usual manner with the following composition:
  • Composition active ingredient 20 mg wheat starch 60 mg lactose 50 mg colloidal silicic acid 5 mg talc 9 mg magnesium stearate 1 mg
  • Preparation The active ingredient is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid, and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath and the powder mixture is kneaded with that paste until a slightly plastic mass has been produced.
  • the plastic mass is pressed through a sieve of approximately 3 mm mesh size and dried, and the resulting dry granules are forced through a sieve once more.
  • the remainder of the wheat starch, the talc and the magnesium stearate are then added and the mixture is compressed to form tablets each weighing 145 mg and having a breaking notch.
  • Example 28 Capsules, each comprising 25 mg of active ingredient, for example one of the compounds of formula I described in the preceding Examples, are prepared as follows:
  • Composition active ingredient 25.0 mg gelucire 44/14 183.3 mg
  • a portion of the gelucire 44/14 is melted at a temperature of from 50°C to 100°C.
  • the active ingredient is mixed with the liquid gelucire 44/14 in a heated mortar to form a paste.
  • the remainder of the gelucire 44/14 is then also melted and is added to the paste.
  • the mixture is stirred at 50°C until a solution is obtained. This is introduced into the capsules while warm and is cooled.
  • the wax so obtained comprises 12 % by weight active ingredient.
  • the wax-like dispersion can also be processed in water by ultrasound treatment to form a milky liquid that can be administered orally.

Abstract

Dérivés de staurosporine de la formule (I) dans laquelle R1 représente un radical acyle contenant de 2 à 30 atomes de carbone, un radical hydrocarbure aliphatique contenant jusqu'à 29 atomes de carbone, substitué par des substituants acycliques, un radical cycloaliphatique ou cycloaliphatique-aliphatique contenant jusqu'à 29 atomes de carbone ou un radical hétérocyclique ou hétérocyclique-aliphatique ou hétéroaliphatique contenant jusqu'à 20 atomes de carbone et jusqu'à 9 hétéroatomes; R2 représente hydrogène, un radical aliphatique, carbocyclique, ou carbocyclique-aliphatique comprenant jusqu'à 29 atomes de carbone ou un radical hétérocyclique ou hétérocyclique-aliphatique contenant jusqu'à 20 atomes de carbone et jusqu'à 9 hétéroatomes, ou un radical acyle contenant jusqu'à 30 atomes de carbone; et R3 représente hydrogène, hydroxy, alcoxy inférieur ou oxo; à l'exception du composé de la formule (I) dans laquelle R1 représente méthoxycarbonylméthyle, R2 représente benzoyle et R3 représente hydrogène. Ces dérivés peuvent être utilisés pour éviter ou supprimer une résistance multiple aux agents antitumoraux.
EP95920067A 1994-06-01 1995-05-19 Derives d'indolocarbazole destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux antitumoraux Withdrawn EP0763041A1 (fr)

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CH1714/94 1994-06-01
CH171494 1994-06-01
PCT/EP1995/001910 WO1995032975A1 (fr) 1994-06-01 1995-05-19 Derives d'indolocarbazole destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux antitumoraux

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CA2245029A1 (fr) 1998-03-13 1999-09-13 University Of British Columbia Composes granulatimide en tant qu'inhibiteurs de controle g2
DE69911935T3 (de) * 1998-03-13 2008-02-07 The University Of British Columbia, Vancouver Granulatimide-derivate zur behandlung von krebs
US6127401A (en) * 1998-06-05 2000-10-03 Cephalon, Inc. Bridged indenopyrrolocarbazoles
GB9903547D0 (en) * 1999-02-16 1999-04-07 Novartis Ag Organic compounds
US6806266B1 (en) 1999-07-13 2004-10-19 Kyowa Hakko Kogyo Co., Ltd. Staurosporin derivatives
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
JO2897B1 (en) * 2004-11-05 2015-09-15 نوفارتيس ايه جي Organic compounds
JP2009504608A (ja) * 2005-08-09 2009-02-05 ヨハネス・グーテンベルク−ウニヴェルジテート・マインツ 薬剤耐性肺癌のタンパク質キナーゼ阻害剤への感作
ES2611486T3 (es) * 2014-05-30 2017-05-09 Entrechem, S.L. Actividad antitumoral de inhibidores de múltiples quinasas en el cáncer de mama triple negativo
CN108299467B (zh) * 2018-02-27 2020-04-28 中国海洋大学 具有细胞毒活性的吲哚咔唑类生物碱及制备方法、用途

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JPH10501527A (ja) 1998-02-10
AU2565895A (en) 1995-12-21

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