WO1995032976A1 - Derives de lactame polycyclique destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux anticancereux - Google Patents

Derives de lactame polycyclique destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux anticancereux Download PDF

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WO1995032976A1
WO1995032976A1 PCT/EP1995/001911 EP9501911W WO9532976A1 WO 1995032976 A1 WO1995032976 A1 WO 1995032976A1 EP 9501911 W EP9501911 W EP 9501911W WO 9532976 A1 WO9532976 A1 WO 9532976A1
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formula
salt
compound
radical
acid
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PCT/EP1995/001911
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Urs Regenass
Giorgio Caravatti
Oskar Wacker
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Ciba-Geigy Ag
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Priority to JP7524229A priority Critical patent/JPH10500394A/ja
Priority to AU25659/95A priority patent/AU2565995A/en
Priority to EP95920068A priority patent/EP0763042A1/fr
Publication of WO1995032976A1 publication Critical patent/WO1995032976A1/fr

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    • 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 those compounds, to the use thereof as medicaments and to processes for the preparation of the intermediates.
  • Staurosporin which forms the basis of the derivatives according to the invention, was isolated as early as 1977 from cultures of Streptomyces staurosporeus AW AY A, 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 stauro ⁇ sporin.
  • 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
  • R j is formyl, an aliphatic hydrocarbon radical having up to 29 carbon atoms that is unsubstituted or substituted by aryl, or is an aryl radical,
  • R 2 is an aliphatic, carbocyclic, carbocyclic-aliphatic, heterocyclic or heterocyclic- aliphatic radical each having up to 29 carbon atoms that is other than C j -C 5 alkyl, or is a heterocyclic or heterocyclic-aliphatic radical each having up to 20 carbon atoms and up to 9 hetero atoms, or is an acyl radical having up to 30 carbon atoms that is other than benzoyl, benzyloxycarbonyl, lower alkanoyl or ⁇ -aminoacyl having a free or protected amino group, 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.
  • organic radicals referred to as "lower” contain not more than 7, preferably not more than 4, carbon atoms.
  • An unsubstituted aliphatic hydrocarbon radical R j having up to 29 carbon atoms is an acyclic hydrocarbon radical having up to 29 carbon atoms, especially up to 18, and prefer ⁇ ably up to 12, carbon atoms, and is saturated or unsaturated. Unsaturated radicals are those containing one or more, especially conjugated and/or isolated, multiple bonds (double and/or triple bonds). An unsubstituted aliphatic hydrocarbon radical is especially a linear 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 is located especially in a position higher than the ⁇ -position with respect to the free valency.
  • An aliphatic hydrocarbon radical R j substituted by aryl is one in which an aliphatic hydro ⁇ carbon 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 aryl radicals as defined hereinbelow.
  • An aryl radical is especially a phenyl radical, but also a naphthyl radical, such as 1- or 2-naphthyl, a biphenylyl radical, such as especially 4-biphenylyl, or also an anthryl, fluorenyl or azulenyl radical, 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.
  • An aliphatic radical R 2 having up to 29 carbon atoms that is other than C j -C 5 alkyl is an unsubstituted C 6 -C 29 alkyl radical, such as especially C 7 -C 29 alkyl, preferably C 10 -C 22 alkyl, most especially C ⁇ 0 -C 18 alkyl, or is a C ⁇ -C 2 alkyl radical substituted by acyclic substituents, especially such a substituted C]-C 7 alkyl radical, or a linear or branched lower alkenyl, lower alkadienyl or lower alkynyl radical that is unsubstituted or substituted by acyclic substituents.
  • a carbocyclic radical R 2 is especially a mono-, bi- or poly-cyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical. Preference is given to 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, especially lower alkyl radicals, or further carbocyclic radicals.
  • 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.
  • An aryl radical is, for example, one of those mentioned above.
  • Carbocyclic-aliphatic radicals R 2 are those in which an aliphatic 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 aliphatic 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-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.
  • Heterocyclic radicals R 2 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.
  • 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 benzothienyl, such as 2- or 3-benzothienyl; preferred monocyclic and bicyclic radicals having a plurality of hetero atoms
  • Heterocyclic-aliphatic (heterocyclic-acyclic) radicals R 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.
  • the acyclic moiety in heterocyclic- acyclic radicals has, for example, the meanings given for the corresponding carbocyclic- aliphatic (carbocyclic-acyclic) radicals.
  • radicals may be substituted 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.
  • substituents are 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 hydrocarbon radicals, and cyano groups.
  • An etherified hydroxy group present as a substituent is, for example, a lower alkoxy group, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy group, which may also be substituted.
  • a lower alkoxy group may be substituted, for example mono-, di- or poly-substituted, by halogen atoms, especially in the 2-position, such as in the 2,2,2-trichloroethoxy, 2-chloroethoxy and 2-iodoethoxy 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 is, for example, lower alkanoyloxy.
  • An esterified carboxy group present as a substituent 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 alkoxycarbonyl 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 present as a substituent 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 carries 2 different or, preferably, identical hydrocarbyl radicals (including the heterocyclic radicals), such as the unsubsti ⁇ tuted 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 C 4 alkyl or C 2 -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 as, especially
  • 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
  • Preferred substituents are C r C 4 alkyl, C j -C 4 alkoxy, halogen, nitro, trifluoromethyl, also carboxy, C C 4 alkoxycarbonyl, methylenedioxy and/or cyano.
  • An acyl radical R 2 having up to 30 carbon atoms that is other than benzoyl, benzyloxy- carbonyl, lower alkanoyl or ⁇ -aminoacyl having a free or protected amino group is derived from such 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) hydrocarbon radical, a carbocyclic hydrocarbon radical or a carbocyclic-acyclic hydrocarbon radical other than unsubstituted benzyl, each 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.
  • heterocyclic radical heterocyclyl radical
  • heterocyclic-acyclic radical a heterocyclic radical
  • the hydrocarbyl (hydrocarbon radical) R° a is benzyl or a hydrocarbyl R° that is other than unsubstituted C r C 7 alkyl, other than the decarboxy radical of an ⁇ -amino acid having a free amino group or an amino group protected by an amino-protecting group and other than unsubstituted phenyl.
  • 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.
  • An acyclic unsubstituted hydrocarbon radical is especially a linear 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 is located
  • 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, with the exception of benzyl.
  • 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 radicals, aryl radicals, heterocyclic radicals and heterocyclic-acyclic (hetero- cyclic-aliphatic) radicals are, for example, those mentioned above.
  • a hydrocarbyl including a heterocyclyl
  • the substituents mentioned above especially come into consideration.
  • 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 1 -C 2 oalkyl, 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 j -C 2 o]alkyl the cyano group of which is preferably located in the 1- or ⁇ -position, or a carboxy- [C ] -C 2 o] alkyl the carboxy group of which is preferably located in the 1- or ⁇ -position and may, where appropriate, also be in salt form or in the form of a C r C 4 alkyl ester (C 1 -C 4 alkoxy- carbonyl) or a benzyl ester (benzyloxycarbonyl), and a C 3 -C 2 oalkenyl the free valency of which is
  • 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 ] -C 4 alkyl esters, especially methoxycarbonyl or ethoxycarbonyl.
  • 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 prefer ⁇ ably being located at one carbon atom, preferably the terminal carbon atom; but with the exception of unsubstituted benzyl.
  • 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 ] 8 alkyl, especially hydroxy-C 2 -C 14 alkyl, cyano-C r C 7 alkyl, especially cyano-C j -C alkyl, carboxy-C r C 7 alkyl, especially carboxy-C r C 4 alkyl, C C 7 - alkoxy-carbonyl-C C 7 alkyl, especially C j -C 4 alkoxy-carbonyl-C r C 4 alkyl, benzyloxy- carbonyl-C 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 C 7
  • R° is C j -C 4 alkyl, such as methyl or ethyl, hydroxy-C 2 -C 1 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 ] -C 4 alkoxycarbonyl-C 1 -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 ⁇ -position.
  • acyl derived from an organic sulfonic acid which is designated Ac 2
  • Ac 2 is especially one of the partial formula R° c -SO 2 - wherein R° c is benzyl or a hydrocarbyl R° 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° a -CO- wherein R° a has one of the above-mentioned general and preferred meanings of the hydrocarbyl radical R° a , and that are accordingly derived from a corresponding, unsubstituted or substituted acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic or heterocyclic-acyclic monocarboxylic acid.
  • a preferred hydrocarbyl in such an acyl is, for example, an unsubstituted C 8 -C 19 alkyl, especially a C n -C ]Q - or C 13 -C ]9 -alkyl, especially one that has a linear chain, or a C r C 19 alkyl, especially a C r C 7 alkyl that carries the following substituents: a carboxy group 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 group) and that is preferably located in the ⁇ -position, or one or more halogen atoms, especially fluorine or chlorine, which are preferably located vicinal to the carbonyl group.
  • acyl is a bicyclic or, especially, monocyclic aroyl that is other than unsubstituted benzoyl and that may carry one or more of the following substituents: halogen atoms, especially chlorine or fluorine, nitro groups, C r C 4 alkyl radicals, especially methyl, hydroxy groups and etherified hydroxy groups, especially C j -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 1 -C 4 alkyl ester (C r C 4 alkoxycarbonyl).
  • substituents halogen atoms, especially chlorine or fluorine, nitro groups, C r C 4 alkyl radicals, especially methyl, hydroxy groups and etherified hydroxy groups, especially C j -C 4 alkoxy, such as methoxy, phenoxy and methylenedioxy, and carboxy groups that may also be
  • the aroyl radicals carry not more than 2, and especially only one, such substituent.
  • analogous heteroaroyl radicals especially those derived from pyridine, 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.
  • C 2 _ 3 oacyl radicals R 2 that are derived from the following carboxylic acids: aliphatic monocarboxylic acids having from 8 to 20 carbon atoms, such as lauric, myristic, palmitic and stearic acid, and oleic acid, elaidic acid, linoleic acid and linolenic acid; halogenated lower alkanecarboxylic acids, such as chloroacetic acid, trifluoro- or trichloro-acetic acid, bromoacetic or ⁇ -bromoisovaleric acid; carbocyclic or carbocyclic-acyclic monocarboxylic acids, for example cyclo ⁇ propane-, cyclopentane- and cyclohexane-carboxylic acid or cyclopentane- or cyclo- hexane-ace
  • the second carboxy group may not only be free but may also be functionally modified, for example in the form of a Cj- 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 characteris ⁇ ed by the partial formula R°-O-CO-.
  • hydrocarbyl radicals R° in these derivatives there are to be mentioned, for example, the following: acyclic hydro ⁇ carbyl, especially a C j -C ⁇ o l yl, preferably a linear C j -C ⁇ oalkyl, that may be substituted by a carboxy group, preferably in a functionally modified form, such as a salt, cyano or a C C alkyl ester, that is preferably located in the ⁇ -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.
  • substituted phenyl 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° c -S0 2 -.
  • R° is a C 1 -C 7 alkyl or, especially, 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 monocyclic 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 2 is an acyl of the partial formula R°-CO- wherein R° is phenyl that is substituted by C r C 4 alkyl, C r C 4 alkoxy, halogen, such as fluorine or chlorine, nitro, trifluoromethyl, carboxy or by C j ⁇ alkoxy ⁇ carbonyl.
  • R 2 is an acyl of the partial formula R°-SO 2 - wherein R° is C r C 7 alkyl, especially C r C 4 alkyl.
  • R 2 is an acyl of the partial formula R° c -SO 2 - wherein R° c is phenyl, or also pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, 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 2 is an acyl of the partial formula R° c -SO 2 - wherein R° c is phenyl or C r C 4 alkyl- or halo-substituted phenyl or iso ⁇ quinolyl, such as 5-isoquinolyl.
  • R 2 is an acyl of the partial formula R°-O-CO- wherein R° is C r C 7 alkyl, especially C r C 4 alkyl.
  • R 2 is an acyl of the partial formula R°-O-CO- wherein R° is pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by C 1 -C 4 alkyl, C r C 4 alkoxy, halogen, nitro, trifluoromethyl, carboxy, C r C 4 alkoxy-carbonyl, methylenedioxy and/or by cyano.
  • 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 i.e. physiologically tolerable
  • salts especially pharmaceutically acceptable, i.e. physiologically tolerable, salts.
  • pharmaceutically unacceptable salts Only pharmaceutically accept ⁇ able salts are used therapeutically and these are preferred.
  • compounds of formula I having free acid groups, such as a free sulfo, phosphoryl or carboxy group may be in the form of a salt, preferably a physiologically tolerable salt, with a salt-forming basic component.
  • 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 tri- ethylamine, 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, mitozantrone 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 inhibitory action of the compounds of formula I on protein kinase C virtually no longer exists or, compared with the analogous compounds wherein R j is hydrogen, is greatly weakened.
  • pig brain protein kinase C is used, which is purified in accordance with the procedure described by T. Uchida and C.R. Filburn in J. Biol. Chem. 259, 12311-4 (1984).
  • the protein kinase C inhibitory action of the compounds of formula I was formerly determined according to the methodology of D. Fabbro et al, Arch. Bioche . Biophys. 239, 102-111 (1985).
  • 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 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 32p 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 ⁇ -[ ⁇ 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 lower alkyl, such as especially methyl, or benzyl
  • R 2 is lower alkoxycarbonyl, such as especially ethoxycarbonyl or tert- butoxycarbonyl, tetrahydropyran-4-yloxy-lower alkanoyl, such as especially 2-tetrahydro- pyran-4-yloxy-acetyl or (D)-O-tetrahydropyran-4-yl-lactoyl, or is lower alkyl substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl, or by carboxy
  • R 3 is hydroxy, lower alkoxy or preferably hydrogen or oxo, and salts of such compounds having at least one salt-forming group.
  • R j is lower alkyl, such as especially methyl, or benzyl
  • R 2 is tetrahydropyran-4-yloxy-lower alkanoyl, such as especially 2-tetrahydropyran-4-yloxy-acetyl or (D)-O-tetrahydropyran-4-yl-lactoyl, or is lower alkyl substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl, or by carboxy
  • R 3 is hydroxy, lower alkoxy or preferably hydrogen or oxo, and salts of such compounds having at least one salt-forming group.
  • R j is benzyl
  • R 2 is lower alkoxycarbonyl, such as especially ethoxycarbonyl or tert-butoxycarbonyl, tetrahydro- pyran-4-yloxy-lower alkanoyl, such as especially 2-tetrahydropyran-4-yloxy-acetyl or (D)-O-tetrahydropyran-4-yl-lactoyl, or is lower alkyl substituted by lower alkoxycarbonyl, such as especially methoxycarbonyl, or by carboxy
  • R 3 is hydroxy, lower alkoxy or preferably hydrogen or oxo, 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
  • substituents are as defined above, any functional groups present therein being, if necessary, in protected form, or a salt of such a compound having at least one salt- - 20 -
  • R j is as defined above, any functional groups present therein being, if necessary, in protected form, and Y is a leaving 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 is as defined above, any functional groups present in the radical R 2 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 , or with a salt of such a compound having at least one salt-forming group, and removing any protecting groups, and, if desired, converting a resulting compound of formula I into a different compound of formula I and/or converting a compound of formula I obtained in free form into a salt thereof and or converting a compound of formula I obtained in the form of a salt into its free form or into a different salt.
  • 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.
  • 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, benzoyl, for example benzoyl, 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-yl.
  • 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-benzyloxycarbonyl, 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 diphenylmethoxycarbon
  • 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-nitrobenzyloxycarbonyl, 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 hydrochloric acid in ethyl acetate or dioxane; unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for example, by means of hydrogenolysis, i.e.
  • unsubstituted or substituted triaryl- methylamino 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 hydro- lysis or alcoholysis.
  • a suitable hydrogenation catalyst such as a palladium catalyst
  • 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
  • an amino group protected by an organic silyl group can be freed, for example, by means of hydro- lysis or alcoholysis.
  • An amino group protected by 2-haloacetyl for example 2-chloro- acetyl
  • 2-chloro- acetyl 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 aroylmethoxycarbonyl 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 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 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-chloro- benzene-sulfonic acid).
  • a strong inorganic acid such as a hydrohalic acid (for example hydrochloric, hydrobromic or hydriodic acid)
  • an oxygen-containing mineral acid such as phosphoric acid and, especially, sulfuric acid
  • a strong organic such as aliphatic or aromatic, sulfonic acid (for example methane- and ethane- or
  • Y is a leaving group that is bonded to an aromatic carbon atom in the radical R j , for example to a phenyl radical, Y is especially a diazonium group.
  • 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).
  • 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 formyl
  • the reagent R ] 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 ITI 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 R j -OH used as acylating agent to be performed in situ in the presence of the compound of formula LI.
  • 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 alkoxyacetylene; 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'-dicyclohexylcarbodiimide;
  • N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenzo- triazole for example by the anhydride or carbodiimide method; activated N-hydroxy esters method), or silyl esters (which are obtainable, for example, by treatment of the corresponding acid with a silylating agent, for example hexamethyldisilazane, and which readily react with hydroxy groups but not with amino groups).
  • a silylating agent for example hexamethyldisilazane
  • 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-l,2-di
  • 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; imidazolide 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; imidazolide 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 II 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 acyl ⁇ ating 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'-dicyclohexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, N-hydroxy-norbornane-2,3-dicarboximide or N-hydroxybenzotriazole, where appropriate in the presence of a suitable base, for example 4-dimethylaminopyridine or tetramethyl- guanidine.
  • an N,N'-disubstituted carbodiimide for example N,N'-dicyclohexylcarbodiimide
  • an N-hydroxyamine or N-hydroxyamide for example N-hydroxysuccinimide, N-hydroxy-norbornane-2,
  • Process a) is preferably carried out by first reacting the starting material of formula IT 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 LTJ, which may also be formed in situ from the corresponding acid, at a temperature 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 II can first be reacted in a suitable solvent, such as absolute tetra ⁇ hydrofuran, with a suitable base, such as sodium bis(trimethylsilyl)amide in tetrahydro ⁇ furan, at a temperature of from 0°C to room temperature, and then a reactive acid derivative of formula HI can be added.
  • a suitable solvent such as absolute tetra ⁇ hydrofuran
  • a suitable base such as sodium bis(trimethylsilyl)amide in tetrahydro ⁇ furan
  • 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 radical X in a compound of formula V corresponds to the radical Y in the compound of formula LTJ and the reagents of formula V are analogous to the reagents of formula LLI.
  • 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 , 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-(te ⁇ t-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 cyan
  • Salt-forming groups in compounds of formulae JJ to V and salts thereof are those mentioned above for the compounds of formula I.
  • the 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 a 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
  • agents that give a basic reaction such as with inorganic hydroxides, carbonates and bicarbonates, or organic bases and ion- exchangers, such a basic fundamental form of an amine is freed.
  • 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 formula IV wherein R j is hydrogen are known or can be prepared by processes that are known per se.
  • the starting material corresponding to formula IV wherein R j 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 FERM P-3725 at the Fermentation 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.
  • the starting materials of formula V wherein R 2 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 0°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 enterally or parenterally, for example intra ⁇ peritoneally, 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 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 polyethyl ⁇ ene 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 polyethyl ⁇ ene 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 a
  • 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 excipi- ents, 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, confectioning, dissolving or lyophilising processes, and comprise approximately from 0.01 % to 90 %, and in the case of lyophilised compositions up to 100 , especially from approximately 0.1 % to approximately 50 %, most especially from 1 % to 30 %, active ingredient(s), 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 2 is BOC.
  • the nitrogen atom N-Rj, on the other hand, is designated "6", as will be apparent from the numbering given in formula I.
  • 6-methyl-staurosporin is a staurosporin derivative in which the radical R j is methyl.
  • THF tetrahydrofuran
  • Example 1 2.2 ml of a 1 -molar solution of sodium bis(trimethylsilyl)amide in tetrahydro ⁇ furan are added at room temperature under a nitrogen atmosphere to a solution of 1.13 g (0.002 mol) of N-BOC-staurosporin (described in Example 36 of EP-A-296110) in 10 ml of dry dimethylformamide and stirring is carried out for 1 hour. A solution of 0.14 ml (0.0022 mol) of methyl iodide in 2 ml of dimethylformamide is then added dropwise and stirring is continued at room temperature for 2 hours. The reaction mixture is poured onto ice and extracted with ethyl acetate.
  • the starting material is obtained as follows:
  • Example 2 are dissolved in 15 ml of methanol and, at room temperature, 0.3 ml
  • Example 4 1.65 ml of a 1-molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran are added at room temperature under a nitrogen atmosphere to a solution of 0.85 g (0.0015 mol) of N-BOC-staurosporin in 8 ml of dry dimethylformamide and stirring is carried out for one hour. 0.2 ml (0.00165 mol) and, after 3 hours, a further 0.02 ml (0.000165 mol) of benzyl bromide are added thereto and stirring is carried out at room temperature for 2 hours. The reaction mixture is poured onto ice and extracted with ethyl acetate.
  • Example 5 120 mg (0.21 mmol) of 6-benzyl-staurosporin and 31 mg (0.24 mmol) of N,N-diisopropylethylamine are introduced into 5 ml of dry dimethylformamide and, at room temperature, 28 mg (0.25 mmol) of chloroformic acid ethyl ester are added thereto.
  • the starting compound is prepared as follows:
  • Example 6 42.5 mg (0.283 mmol) of 1-hydroxybenzotriazole and 54.3 mg (0.283 mmol) of N-ethyl-N'-(3-diaminopropyl)carbodiimide hydrochloride (EDC) are added at 0°C to a solution of 35.0 mg (0.218 mmol) of 2-(tetrahydropyran-4-yloxy)-acetic acid in 2 ml of absolute N,N-dimethylformamide, and stirring is carried out at 0°C under argon for 3 hours.
  • EDC N-ethyl-N'-(3-diaminopropyl)carbodiimide hydrochloride
  • Fractions 7-1 1 are combined and concentrated by evaporation at 30° under a high vacuum. 70 mg of yellowish crystals are obtained which are subjected to a further flash-chromato ⁇ graphy at 0.3 bar on 15 g of silica gel (type Si60, Merck 9385; 0.040-0.063 mm) in methylene chloride/ethanol (98:2) (10 ml fractions). Fractions 7-12 are combined and concentrated by evaporation at 30° under a high vacuum.
  • Example 7 With stirring at room temperature under argon, 30 mg (0.75 mmol) of sodium hydride (approx. 60 %, in oil; Fluka, pract.) are added to a solution of 305 mg (0.5 mmol) of N-[2-(tetrahydropyran-4-yloxy)-acetyl]-staurosporin in 15 ml of absolute tetrahydro ⁇ furan, and the grey suspension so obtained is stirred at room temperature under argon for 3 hours.
  • the crude product (yellow crystals) is purified further by flash- chromatography at 0.4 bar on 100 g of silica gel (type Si60, Merck 9385; 0.040-0.063 mm) in ethyl acetate/petroleum ether (9:1, 25 ml fractions).
  • Fractions 61-76 and 77-92 are combined and concentrated to dryness by evaporation at 30°C under a high vacuum.
  • Beige crystals (I) are obtained from fractions 61-76 and yellow crystals (II) from fractions 77-92.
  • Example 9 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-BOC-6-methyl-staurosporin) is added in serial dilutions 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. After incubation, 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.
  • 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 B [1 ⁇ mol] + A [3.13 ng/ml] 0 test substance A: vinblastine test substance B: N-BOC-6-methyl-staurosporin
  • test substance C N-ethoxycarbonyl-6-benzyl-staurosporin
  • test substance A vinblastine test substance C: N-ethoxycarbonyl-6-benzyl-staurosporin
  • test substance D N-[2-(tetrahydropyran-4-yloxy)-acetyl]-6-methyl-staurosporin
  • test substance A vinblastine test substance D: N-[2-(tetrahydropyran-4-yloxy)-acetyl]-6-methyl-staurosporin
  • test substance B N-BOC-6-benzyl-staurosporin
  • 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 14 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.

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Abstract

Dérivés de staurosporine de la formule (I) dans laquelle R1 représente formyle, un radical hydrocarbure aliphatique contenant jusqu'à 29 atomes de carbone, éventuellement substitué par aryle, ou un radical aryle, R2 représente un radical aliphatique, carbocyclique, carbocyclique-aliphatique, hétérocyclique ou hétérocyclique-aliphatique comprenant jusqu'à 29 atomes de carbone et qui est autre qu'alkyle C1-C5, 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 qui est autre que benzoyle, benzyloxycarbone, alcanoyle inférieur ou α-aminoacyle, renfermant un groupe amino libre ou protégé, et R3 représente hydrogène, hydroxy, alcoxy inférieur ou oxo. Ces dérivés peuvent être utilisés pour éviter ou supprimer une résistance multiple aux agents antitumoraux tels que la vinblastine ou l'adriamycine.
PCT/EP1995/001911 1994-06-01 1995-05-19 Derives de lactame polycyclique destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux anticancereux WO1995032976A1 (fr)

Priority Applications (3)

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JP7524229A JPH10500394A (ja) 1994-06-01 1995-05-19 多重薬剤耐性細胞を抗腫瘍剤に対して感受性にするための多環式ラクタム誘導体
AU25659/95A AU2565995A (en) 1994-06-01 1995-05-19 Polycyclic lactam derivatives for sensitizing multidrug-resistant cells to antitumour agents
EP95920068A EP0763042A1 (fr) 1994-06-01 1995-05-19 Derives de lactame polycyclique destines a sensibiliser a des agents antitumoraux des cellules a resistance multiple aux anticancereux

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002532A2 (fr) * 1997-07-07 1999-01-21 Novartis Ag Composes polycycliques partiellement hydrogenes
WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer
US6291447B1 (en) 1998-03-13 2001-09-18 The University Of British Columbia Granulatimide compounds and uses thereof
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US6806266B1 (en) 1999-07-13 2004-10-19 Kyowa Hakko Kogyo Co., Ltd. Staurosporin derivatives
EP2305265A1 (fr) 2003-08-08 2011-04-06 Novartis AG Combinaisons contenant des staurosporines
US7973031B2 (en) 2001-10-30 2011-07-05 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0383919A1 (fr) * 1988-02-04 1990-08-29 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
WO1994006799A1 (fr) * 1992-09-21 1994-03-31 Kyowa Hakko Kogyo Co., Ltd. Remede contre la thrombopenie
WO1995000520A1 (fr) * 1993-06-17 1995-01-05 Ciba-Geigy Ag Compose d'indolocarbazole utilise comme inhibiteur de proteine-kinase c
EP0643966A1 (fr) * 1993-03-03 1995-03-22 Kyowa Hakko Kogyo Co., Ltd. Renforceur de sensibilite pour agent antineoplasique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0383919A1 (fr) * 1988-02-04 1990-08-29 Kyowa Hakko Kogyo Co., Ltd. Derives de staurosporine
WO1994006799A1 (fr) * 1992-09-21 1994-03-31 Kyowa Hakko Kogyo Co., Ltd. Remede contre la thrombopenie
EP0630898A1 (fr) * 1992-09-21 1994-12-28 Kyowa Hakko Kogyo Kabushiki Kaisha Remede contre la thrombopenie
EP0643966A1 (fr) * 1993-03-03 1995-03-22 Kyowa Hakko Kogyo Co., Ltd. Renforceur de sensibilite pour agent antineoplasique
WO1995000520A1 (fr) * 1993-06-17 1995-01-05 Ciba-Geigy Ag Compose d'indolocarbazole utilise comme inhibiteur de proteine-kinase c

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002532A2 (fr) * 1997-07-07 1999-01-21 Novartis Ag Composes polycycliques partiellement hydrogenes
WO1999002532A3 (fr) * 1997-07-07 1999-04-01 Novartis Ag Composes polycycliques partiellement hydrogenes
WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer
US6291447B1 (en) 1998-03-13 2001-09-18 The University Of British Columbia Granulatimide compounds and uses thereof
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
US7973031B2 (en) 2001-10-30 2011-07-05 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
US8222244B2 (en) 2001-10-30 2012-07-17 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
US8445479B2 (en) 2001-10-30 2013-05-21 Novartis Ag Staurosporine derivatives as inhibitors of FLT3 receptor tyrosine kinase activity
EP2305265A1 (fr) 2003-08-08 2011-04-06 Novartis AG Combinaisons contenant des staurosporines

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