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WO2008043811A1 - Dérivés de la staurosporine et rayonnement - Google Patents

Dérivés de la staurosporine et rayonnement Download PDF

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Publication number
WO2008043811A1
WO2008043811A1 PCT/EP2007/060830 EP2007060830W WO2008043811A1 WO 2008043811 A1 WO2008043811 A1 WO 2008043811A1 EP 2007060830 W EP2007060830 W EP 2007060830W WO 2008043811 A1 WO2008043811 A1 WO 2008043811A1
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typically
lower alkyl
hydrogen
radicals
substituted
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PCT/EP2007/060830
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English (en)
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Martin Pruschy
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to organic compounds, in particular to pharmaceutical compositions for use in combination with ionizing radiation for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease.
  • FLT-3 inhibitors especially staurosporine derivatives are effective when used in combination with ionizing radiation for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease, especially a Carcinoma, especially Adenoid Cystic Carcinoma;
  • the invention provides a method for the delay of progression or treatment of a proliferative disease, , especially a solid tumor disease, especially a Carcinoma, especially Adenoid Cystic Carcinoma in a subject in need of such treatment which comprises administering to the subject an effective amount of a staurosporine derivatives of formula
  • R 1 and R 2 are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N- mono- or N,N-di-substituted aminosulfonyl;
  • n and m are, independently of one another, a number from and including 0 to and including 4;
  • n' and m' are, independently of one another, a number from and including 0 to and including 4;
  • R 3 , R 4 , Re and Ri 0 are, independently of one another, hydrogen, -O " , acyl with up to 30 carbon atoms, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, wherein R 4 may also be absent;
  • R 3 is acyl with up to 30 carbon atoms, R 4 is not an acyl
  • p is 0 if R 4 is absent, or is 1 if R 3 and R 4 are both present and in each case are one of the aforementioned radicals;
  • R 5 is hydrogen, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, or a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms;
  • R 7 , R 6 and R 9 are acyl or -(lower alkyl) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy,carbonyl, carbonyldioxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl;
  • X stands for 2 hydrogen atoms; for 1 hydrogen atom and hydroxy; for O; or for hydrogen and lower alkoxy; - A -
  • Z stands for hydrogen or lower alkyl
  • the prefix "lower” indicates that the associated radical preferably has up to and including a maximum of 7 carbon atoms, especially up to and including a maximum of 4 carbon atoms.
  • Lower alkyl is especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert- butyl, and also pentyl, hexyl, or heptyl.
  • Unsubstituted or substituted alkyl is preferably CrC 2 oalkyl, especially lower alkyl, typically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, which is unsubstituted or substituted especially by halogen, such as fluorine, chlorine, bromine, or iodine, C 6 -Ci 4 aryl, such as phenyl or naphthyl, hydroxy, etherified hydroxy, such as lower alkoxy, phenyl-lower alkoxy or phenyloxy, esterified hydroxy, such as lower alkanoyloxy or benzoyloxy, amino, mono- or disubstituted amino, such as lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N, N-di-lower alkylamino,
  • Halogen is preferably fluorine, chlorine, bromine, or iodine, especially fluorine or chlorine.
  • Etherified hydroxy is especially lower alkoxy, C 6 -Ci 4 aryloxy, such as phenyloxy, or C 6 - Ci 4 aryl-lower alkoxy, such as benzyloxy.
  • Esterified hydroxy is preferably lower alkanoyloxy or C6-Ci 4 arylcarbonyloxy, such as benzoyloxy.
  • Mono- or disubstituted amino is especially amino monosubstituted or disubstituted by lower alkyl, C 6 -Ci 4 aryl, C 6 -Ci 4 aryl-lower alkyl, lower alkanoyl, or C 6 -Ci 2 arylcarbonyl.
  • Substituted mercapto is especially lower alkylthio, C 6 -C 14 arylthio, C 6 -C 14 aryl-lower alkylthio, lower alkanoylthio, or C 6 -C 14 aryl-lower alkanoylthio.
  • Esterified carboxy is especially lower alkoxycarbonyl, C 6 -Ci 4 aryl-lower alkoxycarbonyl or C 6 - Ci 4 aryloxycarbonyl.
  • N-Mono- or N,N-disubstituted carbamoyl is especially carbamoyl N-monosubstituted or N, N- disubstituted by lower alkyl, C 6 -Ci 4 aryl or C 6 -Ci 4 aryl-lower alkyl.
  • Substituted sulfonyl is especially C 6 -Ci 4 arylsulfonyl, such as toluenesulfonyl, C 6 -Ci 4 aryl-lower alkanesulfonyl or lower alkanesulfonyl.
  • N-Mono- or N,N-disubstituted aminosulfonyl is especially aminosulfonyl N-monosubstituted or N,N-disubstituted by lower alkyl, C 6 -Ci 4 aryl or C 6 -Ci 4 aryl-lower alkyl.
  • C 6 -C 14 Aryl is an aryl radical with 6 to 14 carbon atoms in the ring system, such as phenyl, naphthyl, fluorenyl, or indenyl, which is unsubstituted or is substituted especially by halogen, such as fluorine, chlorine, bromine, or iodine, phenyl or naphthyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N, N-di-lower alkylamino, N,N-di-(phenyl-lower alkyl)amino, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N- lower alkylcarbamoyl, N
  • indices n and m are in each case preferably 1 , 2 or especially 0.
  • compounds of formula I in which n and m are in each case 0 (zero) are especially preferred.
  • Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl; lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl and 2- or 3-butenyl; lower alkadienyl is, for example, 1-penta-2,4-dienyl; lower alkinyl is, for example, propargyl or 2-butinyl.
  • the double bond is especially located in a position higher than the D-position in relation to the free valency.
  • Substituents are especially the acyl radicals defined hereinbelow as substituents of R 0 , preferably free or esterified carboxy, such as carboxy or lower alkoxycarbonyl, cyano or di-lower alkylamino.
  • a carbocyclic or carbocyclic-aliphatic radical R 3 , R 4 , R 8 or R 10 with up to 29 carbon atoms in each case is especially an aromatic, a cycloaliphatic, a cycloaliphatic-aliphatic, or an aromatic-aliphatic radical which is either present in unsubstituted form or substituted by radicals referred to hereinbelow as substituents of R 0 .
  • aromatic radical (aryl radical) R3 or R 4 is most especially a phenyl, also a naphthyl, such as 1- or 2-naphthyl, a biphenylyl, such as especially 4-biphenylyl, and also an anthryl, fluorenyl and azulenyl, as well as their aromatic analogues with one or more saturated rings, which is either present in unsubstituted form or substituted by radicals referred to hereinbelow as substituents of R 0 .
  • Preferred aromatic-aliphatic radicals are aryl-lower alkyl- and aryl-lower alkenyl radicals, e.g.
  • phenyl- lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical such as for example benzyl, phenethyl, 1-, 2-, or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl, and cinnamyl, and also 1- or 2-naphthylmethyl.
  • aryl radicals carrying acyclic radicals such as lower alkyl, special mention is made of o-, m- and p-tolyl and xylyl radicals with variously situated methyl radicals.
  • a cycloaliphatic radical R 3 , R 4 , Re or R 10 with up to 29 carbon atoms is especially a substituted or preferably unsubstituted mono-, bi-, or polycyclic cycloalkyl-, cycloalkenyl-, or cycloalkadienyl radical.
  • Preference is for radicals with a maximum of 14, especially 12, ring- carbon atoms and 3- to 8-, preferably 5- to 7-, and most especially 6-member rings which can also carry one or more, for example two, aliphatic hydrocarbon radicals, for example those named above, especially the lower alkyl radicals, or other cycloaliphatic radicals as substituents.
  • Preferred substituents are the acyclic substituents named hereinbelow for R 0 .
  • a cycloaliphatic-aliphatic radical R3, R 4 , Re or R 10 with up to 29 carbon atoms is a radical in which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as especially methyl, ethyl, and vinyl, carries one or more cycloaliphatic radicals as defined hereinabove.
  • an acyclic radical especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as especially methyl, ethyl, and vinyl
  • Preferred substituents are the acyclic substituents named herein below for R 0 .
  • Heterocyclic radicals R 3 , R 4 , R 8 or R 10 with up to 20 carbon atoms each and up to 9 heteroatoms each are especially monocyclic, but also bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-, or tetrazacyclic radicals of an aromatic character, as well as corresponding heterocyclic radicals of this type which are partly or most especially wholly saturated, these radicals - if need be - possibly carrying further acyclic, carbocyclic, or heterocyclic radicals and/or possibly mono-, di-, or polysubstituted by functional groups, preferably those named hereinabove as substituents of aliphatic hydrocarbon radicals.
  • pyrryl for example 2-pyrryl or 3-pyrryl
  • pyridyl for example 2-, 3-, or 4-pyridyl
  • thienyl for example 2- or 3-thienyl
  • furyl for example 2-furyl
  • analogous bicyclic radicals with an oxygen, sulfur, or nitrogen atom are, for example, indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2-benzofuranyl, chromenyl, typically 3-chromenyl, or benzothienyl, typically 2- or 3- benzothienyl
  • preferred monocyclic and bicyclic radicals with several heteroatoms are, for example, imidazolyl, typically 2-pyrryl or 3-pyrryl
  • pyridyl for example 2-, 3-, or 4-pyridyl
  • thienyl for example 2- or 3-thienyl
  • furyl for example 2-fury
  • radicals may also be considered, such as 2-tetrahydrofuryl, 2- or 3-pyrrolidinyl, 2-, 3-, or 4-piperidyl, and also 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl and N-mono- or N,N'-bis-lower alkyl-2-piperazinyl radicals.
  • These radicals may also carry one or more acyclic, carbocyclic, or heterocyclic radicals, especially those mentioned hereinabove.
  • the free valency of the heterocyclic radicals R3 or R 4 must emanate from one of their carbon atoms.
  • Heterocyclyl may be unsubstituted or substituted by one or more, preferably one or two, of the substituents named hereinbelow for R 0 .
  • Heterocyclic-aliphatic radicals R 3 , R 4 , R 8 or R 10 especially lower alkyl radicals, especially with a maximum of 7, preferably a maximum of 4 carbon atoms, for example those named hereinabove, which carry one, two, or more heterocyclic radicals, for example those named in the preceding paragraph, the heterocyclic ring possibly being linked to the aliphatic chain also by one of its nitrogen atoms.
  • a preferred heterocyclic-aliphatic radical Ri is, for example, imidazol-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, piperazin-1-ylmethyl, 2-(morpholin-4- yl)ethyl and also pyrid-3-ylmethyl.
  • Heterocyclyl may be unsubstituted or substituted by one or more, preferably one or two, of the substituents named hereinbelow for R 0 .
  • a heteroaliphatic radical R 3 , R 4 , R 8 or R 10 with up to 20 carbon atoms each and up to 10 heteroatoms each is an aliphatic radical which, instead of one, two, or more carbon atoms, contains identical or different heteroatoms, such as especially oxygen, sulfur, and nitrogen.
  • R 3 , R 4 , R 8 or R 10 apart from acyl, is lower alkyl, particularly methyl or ethyl; lower alkoxycarbonyl-lower alkyl, especially methoxycarbonylmethyl or 2-(tert- butoxycarbonyl)ethyl; carboxy-lower alkyl, especially carboxymethyl or 2-carboxyethyl; or cyano-lower alkyl, especially 2-cyanoethyl.
  • An acyl radical R 3 , R 4 , R 6 , R7, Re, R9, or R 10 with up to 30 carbon atoms derives from a carboxylic acid, functionally modified if need be, an organic sulfonic acid, or a phosphoric acid, such as pyro- or orthophosphoric acid, esterified if need be.
  • the hydrocarbyl (hydrocarbon radical) R 0 is an acyclic (aliphatic), carbocyclic, or carbocyclic- acyclic hydrocarbon radical, with up to 29 carbon atoms each, especially up to 18, and preferably up to 12 carbon atoms, and is saturated or unsaturated, unsubstituted or substituted. Instead of one, two, or more carbon atoms, it may contain identical or different heteroatoms, such as especially oxygen, sulfur, and nitrogen in the acyclic and/or cyclic part; in the latter case, it is described as a heterocyclic radical (heterocyclyl radical) or a hetero- cyclic-acyclic radical.
  • Unsaturated radicals are those, which contain one or more, especially conjugated and/or isolated, multiple bonds (double or triple bonds).
  • cyclic radicals includes also aromatic and non-aromatic radicals with conjugated double bonds, for example those wherein at least one 6-member carbocyclic or a 5- to 8-member heterocyclic ring contains the maximum number of non-cumulative double bonds.
  • Carbocyclic radicals, wherein at least one ring is present as a 6-member aromatic ring (i.e. a benzene ring), are defined as aryl radicals.
  • An acyclic unsubstituted hydrocarbon radical R 0 is especially a straight-chained or branched lower alkyl-, lower alkenyl-, lower alkadienyl-, or lower alkinyl radical.
  • Lower alkyl R 0 is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl;
  • lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl and 2- or 3-butenyl;
  • lower alkadienyl is, for example, 1-penta-2,4-dienyl;
  • lower alkinyl is, for example, propargyl or 2-butiny
  • a carbocyclic hydrocarbon radical R 0 is especially a mono-, bi-, or polycyclic cycloalkyl-, cycloalkenyl-, or cycloalkadienyl radical, or a corresponding aryl radical. Preference is for radicals with a maximum of 14, especially 12, ring-carbon atoms and 3- to 8-, preferably 5- to 7-, and most especially 6-member rings which can also carry one or more, for example two, acyclic radicals, for example those named above, especially the lower alkyl radicals, or other carbocyclic radicals.
  • Carbocyclic-acyclic radicals are those in which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as especially methyl, ethyl and vinyl, carries one or more carbocyclic, if need be aromatic radicals of the above definition. Special mention is made of cycloalkyl-lower and aryl-lower alkyl radicals, as well as their analogues which are unsaturated in the ring and/or chain, and which carry the ring at the terminal carbon atom of the chain.
  • Cycloalkyl R 0 has most especially from 3 up to and including 10 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, as well as bicyclo[2,2,2]octyl, 2-bicyclo[2,2,1]heptyl, and adamantyl, 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 named which carries a double bond in the 1-, 2-, or 3 position.
  • Cycloalkyl-lower alkyl or -lower alkenyl is for example a - methyl, -1- or -2-ethyl, -1- or -2-vinyl, -1-, -2-, or -3-propyl or -allyl substituted by one of the above-named cycloalkyl radicals, those substituted at the end of the linear chain being preferred.
  • An aryl radical R 0 is most especially a phenyl, also a naphthyl, such as 1- or 2-naphthyl, a biphenylyl, such as especially 4-biphenylyl, and also an anthryl, fluorenyl and azulenyl, as well as their aromatic analogues with one or more saturated rings.
  • Preferred aryl-lower alkyl and -lower alkenyl radicals are, for example, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, such as for example benzyl, phenethyl, 1-, 2-, or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl, and cinnamyl, and also 1- or 2-naphthylmethyl.
  • Aryl may be unsubstituted or substituted.
  • Heterocyclic radicals including heterocyclic-acyclic radicals, are especially monocyclic, but also bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-, or tetrazacyclic radicals of an aromatic character, as well as corresponding heterocyclic radicals of this type which are partly or most especially wholly saturated; if need be, for example as in the case of the above-mentioned carbocyclic or aryl radicals, these radicals may carry further acyclic, carbocyclic, or heterocyclic radicals and/or may be mono-, di-, or polysubstituted by functional groups.
  • heterocyclic-acyclic radicals has for example the meaning indicated for the corresponding carbocyclic-acyclic radicals.
  • they are unsubstituted or substituted monocyclic radicals with a nitrogen, oxygen, or sulfur atom, such as 2-aziridinyl, and especially aromatic radicals of this type, such as pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 2-, 3-, or 4-pyridyl, and also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl; analogous bicyclic radicals with an oxygen, sulfur, or nitrogen atom are, for example, indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2- benzofuranyl, chromenyl, typically 3-chromenyl, or benzothi
  • radicals may also be considered, such as 2-tetrahydrofuryl, 4-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 hereinabove.
  • Heterocyclic-acyclic radicals are especially derived from acyclic radicals with a maximum of 7, preferably a maximum of 4 carbon atoms, for example those named hereinabove, and may carry one, two, or more heterocyclic radicals, for example those named hereinabove, the ring possibly being linked to the aliphatic chain also by one of its nitrogen atoms.
  • a hydrocarbyl may be substituted by one, two, or more identical or different substituents (functional groups); one or more of the following substituents may be considered: lower alkyl; free, etherified and esterified hydroxyl groups; carboxy groups and esterified carboxy groups; mercapto- and lower alkylthio- and, if need be, substituted phenylthio groups; halogen atoms, typically chlorine and fluorine, but also bromine and iodine; halogen-lower alkyl groups; oxo groups which are present in the form of formyl (i.e.
  • aldehydo aldehydo
  • keto groups also as corresponding acetals or ketals; azido groups; nitro groups; cyano groups; primary, secondary and preferably tertiary amino groups, amino-lower alkyl, mono- or disubstituted amino-lower alkyl, primary or secondary amino groups protected by conventional protecting groups (especially lower alkoxycarbonyl, typically tert-butoxycarbonyl) lower alkylenedioxy, and also free or functionally modified sulfo groups, typically sulfamoyl or sulfo groups present in free form or as salts.
  • protecting groups especially lower alkoxycarbonyl, typically tert-butoxycarbonyl
  • the hydrocarbyl radical may also carry carbamoyl, ureido, or guanidino groups, which are free or which carry one or two substituents, and cyano groups.
  • groups is taken to imply also an individual group.
  • Halogen-lower alkyl contains preferably 1 to 3 halogen atoms; preferred is trifluoromethyl or chloromethyl.
  • An etherified hydroxyl group present in the hydrocarbyl as substituent is, for example, a lower alkoxy group, typically the methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, and tert- butoxy group, which may also be substituted, especially by (i) heterocyclyl, whereby heterocyclyl can have preferably 4 to 12 ring atoms, may be unsaturated, or partially or wholly saturated, is mono- or bicyclic, and may contain up to three heteroatoms selected from nitrogen, oxygen, and sulfur, and is most especially pyrrolyl, for example 2-pyrrolyl or 3- pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, and also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or
  • Such etherified hydroxyl groups are also unsubstituted or substituted phenoxy radicals and phenyl-lower alkoxy radicals, such as especially benzyloxy, benzhydryloxy, and triphenylmethoxy (trityloxy), as well as heterocyclyloxy radicals, wherein heterocyclyl can have preferably 4 to 12 ring atoms, may be unsaturated, or partially or wholly saturated, is mono- or bicyclic, and may contain up to three heteroatoms selected from nitrogen, oxygen, and sulfur, and is most especially pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, and also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, indolyl, typically 2- or 3- indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-isoquinoly
  • Etherified hydroxyl groups in this context are taken to include silylated hydroxyl groups, typically for example tri-lower alkylsilyloxy, typically trimethylsilyloxy and dimethyl-tert- butylsilyloxy, or phenyldi-lower alkylsilyloxy and lower alkyl-diphenylsilyloxy.
  • An esterified hydroxyl group present in the hydrocarbyl as a substituent is, for example, lower alkanoyloxy.
  • a carboxyl group present in the hydrocarbyl as a substituent is one in which the hydrogen atom is replaced by one of the hydrocarbyl radicals characterised hereinabove, preferably a lower alkyl- or phenyl-lower alkyl radical; an example of an esterified carboxyl group is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl substituted if need be in the phenyl part, especially the methoxy, ethoxy, tert-butoxy, and benzyloxycarbonyl group, as well as a lactonised carboxyl group.
  • a primary amino group -NH 2 as substituent of the hydrocarbyls may also be present in a form protected by a conventional protecting group.
  • a secondary amino group carries, instead of one of the two hydrogen atoms, a hydrocarbyl radical, preferably an unsubstituted one, typically one of the above-named, especially lower alkyl, and may also be present in protected form.
  • a tertiary amino group present in the hydrocarbyl as substituent carries 2 different or, preferably, identical hydrocarbyl radicals (including the heterocyclic radicals), such as the unsubstituted hydrocarbyl radicals characterised hereinabove, especially lower alkyl.
  • a preferred amino group is one with the formula R 11 (R 12 )N-, wherein R 11 and R 12 are independently in each case hydrogen, unsubstituted acyclic CrC 7 -hydrocarbyl (such as especially CrC 4 alkyl or C 2 -C 4 alkenyl) or monocyclic aryl, aralkyl, or aralkenyl, substituted if necessary by Ci-C 4 -alkyl, C- ⁇ -C 4 -alkoxy, halogen, and/or nitro, and having a maximum of 10 carbon atoms, where the carbon-containing radicals may be interlinked through a carbon- carbon bond or an oxygen atom, a sulfur atom, or a nitrogen atom substituted if necessary by hydrocarbyl.
  • R 11 and R 12 are independently in each case hydrogen, unsubstituted acyclic CrC 7 -hydrocarbyl (such as especially CrC 4 alkyl or C 2 -C 4 alkenyl) or monocyclic
  • di-lower alkylamino typically dimethylamino or diethylamino, pyrrolidino, imidazol-1-yl, piperidino, piperazino, 4-lower alkylpiperazino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, as well as diphenylamino and dibenzylamino substituted if need be, especially in the phenyl part, for example by lower- alkyl, lower-alkoxy, halogen, and/or nitro; of the protected groups, especially lower alkoxy- carbonylamino, typically tert-butoxycarbonylamino, phenyl-lower alkoxycarbonylamino, typically 4-methoxybenzyloxycarbonylamino, and 9-fluorenyl
  • Amino-lower alkyl is most especially substituted in the 1 -position of the lower alkyl chain by amino and is especially aminomethyl.
  • Mono- or disubstituted amino-lower alkyl is amino-lower alkyl substituted by one or two radicals, wherein amino-lower alkyl is most especially substituted by amino in the 1 -position of the lower alkyl chain and is especially aminomethyl; the amino substituents here are preferably (if 2 substituents are present in the respective amino group independently of one another) from the group comprising lower alkyl, such as especially methyl, ethyl or n-propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl, C 3 -C 8 cycloalkyl, especially cyclohexyl, amino- lower alkyl, typically 3-aminopropyl or 4-aminobutyl, N-mono- or N,N-di(lower alkyl)-amino- lower alkyl, typically 3-(N,N-dimethylamino)propyl, amino, N-mono- or N,N-di-lower alkyla
  • Disubstituted amino-lower alkyl is also a 5 or 6-membered, saturated or unsaturated heterocyclyl bonded to lower alkyl via a nitrogen atom (preferably in the 1 -position) and having 0 to 2, especially 0 or 1 , other heteroatoms selected from oxygen, nitrogen, and sulfur, which is unsubstituted or substituted, especially by one or two radicals from the group comprising lower alkyl, typically methyl, and also oxo.
  • Preferred here is pyrrolidino (1- pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower alkylpiperazino, typically 4-methylpiperazino, imidazolino (1-imidazolyl), morpholino (4-morpholinyl), or also thiomorpholino, S-oxo-thiomorpholino, or S,S-dioxothiomorpholino. Lower alkylenedioxy is especially methylenedioxy.
  • a carbamoyl group carrying one or two substituents is especially aminocarbonyl (carbamoyl) which is substitiuted by one or two radicals at the nitrogen; the amino substituents here are preferably (if 2 substituents are present in the respective amino group independently of one another) from the group comprising lower alkyl, such as especially methyl, ethyl or n-propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl, C 3 -C 8 cycloalkyl, especially cyclohexyl, amino- lower alkyl, typically 3-aminopropyl or 4-aminobutyl, N-mono- or N,N-di(lower alkyl)-amino- lower alkyl, typically 3-(N,N-dimethylamino)propyl, amino, N-mono- or N,N-di-lower alkylamino and N-mono- or N,N-di-(hydroxy-lower alky
  • Preferred here is pyrrolidino (1-pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower al- kylpiperazino, typically 4-methylpiperazino, imidazolino (1-imidazolyl), morpholino (4-morpho- linyl), or also thiomorpholino, S-oxo-thiomorpholino, or S,S-dioxothiomorpholino.
  • acyl derived from an organic sulfonic acid which is designated Ac 2
  • Ac 2 is especially one with the subformula R°-SO 2 -, wherein R 0 is a hydrocarbyl as defined above in the general and specific meanings, the latter also being generally preferred here.
  • R 0 is a hydrocarbyl as defined above in the general and specific meanings, the latter also being generally preferred here.
  • Especially preferred is lower alkylphenylsulfonyl, especially 4-toluenesulfonyl.
  • Preferred compounds according to the invention are, for example, those wherein R 0 has the following preferred meanings: lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is unprotected or is protected by a conventional amino protecting group - especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl - e.g.
  • Preferred acyl radicals Ac 1 are acyl radicals of a carboxylic acid which are characterised by the subformula R°-CO-, wherein R 0 has one of the above general and preferred meanings of the hydrocarbyl radical R 0 .
  • Especially preferred radicals R 0 here are lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is unprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, e.g.
  • a further preferred Acyl Ac 1 is derived from monoesters of carbonic acid and is characterised by the subformula R°-O-CO-.
  • the lower alkyl radicals, especially tert-butyl, are especially preferred hydrocarbyl radicals R 0 in these derivatives.
  • a preferred acyl Ac 2 of subformula R°-SO 2 - wherein R 0 is a hydrocarbyl as defined in the above general and specific meanings, is lower alkylphenylsulfonyl, typically 4- toluenesulfonyl. If p is 0, the nitrogen atom bonding R 3 is uncharged. If p is 1 , then R 4 must also be present, and the nitrogen atom bonding R 3 and R 4 (quaternary nitrogen) is then positively charged.
  • Z is especially lower alkyl, most especially methyl or hydrogen.
  • the compounds of the invention may also be present in the form of pharmaceutically, i.e. physiologically, acceptable salts, provided they contain salt-forming groups.
  • pharmaceutically unacceptable salts may also be used.
  • therapeutic use only pharmaceutically acceptable salts are used, and these salts are preferred.
  • compounds of formula I having free acid groups may exist as a salt, preferably as a physiologically acceptable salt with a salt-forming basic component.
  • a salt-forming basic component may be primarily metal or ammonium salts, such as alkali metal or 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 of the invention having a basic character may also exist as addition salts, especially as acid addition salts with inorganic and organic acids, but also as quaternary salts.
  • compounds which have a basic group, such as an amino group, as a substituent may form acid addition salts with common acids.
  • Suitable acids are, for example, hydrohalic acids, e.g.
  • hydrochloric and hydrobromic acid sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or 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 acid, pamoic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenedisulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid, and also methionine, tryptophan,
  • any reference hereinbefore and hereinafter to the free compounds is to be understood as referring also to the corresponding salts, and the solvates thereof, for example hydrates, as appropriate and expedient.
  • R 1 and R 2 independently of each other are lower alkyl, lower alkyl substituted by halogen, C 6 - Ci 4 aryl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N,N-di- lower alkylamino, N,N-di-(phenyl-lower alkyl)amino, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkyl- carbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lower - alkylami
  • n and m are independently of each other 0 or 1 or 2, preferably 0;
  • R3, R 4 , Re, R-io are independently of each other hydrogen, lower alkyl, lower alkenyl or lower alkadienyl, which are each unsubstituted or monosubstituted or polysubsituted, preferably monosubstituted or disubstituted by a substituent independently selected from lower alkyl; hydroxy; lower alkoxy, which may be unsubstituted or mono-, di-, or trisubstituted by (i) heterocyclyl with 4 to 12 ring atoms, which may be unsaturated, wholly saturated, or partly saturated, is monocyclic or bicyclic and may contain up to three heteroatoms selected from nitrogen, oxygen and sulfur, and is most especially pyrrolyl, for example 2-pyrrolyl or 3- pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, or in a broader sense also thienyl, for example 2- or 3-thienyl, or furyl, for example
  • phenyl, naphthyl, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical which is unsubstituted or monosubstituted or disubstituted by the radicals named above as substituents of lower alkyl, lower alkenyl or lower alkadienyl;
  • heterocyclyl-lower alkyl wherein heterocyclyl is pyrrolyl, for example 2-pyrrolyl or 3- pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, or in a broader sense also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl, indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2- benzofuranyl, chromenyl, typically 3-chromenyl, benzothienyl, typically 2- or 3-benzothienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically
  • R 4 may also be absent for the compound of formula II;
  • R 4 is absent for compounds of formula II, hydrogen or CH 3 for compounds of formula I, and
  • R 0 in the said radicals has the following meanings: substituted or unsubstituted lower alkyl, especially methyl or ethyl, amino-lower alkyl hydroxy-lower alkyl, wherein the amino group is unprotected or is protected by a conventional amino protecting group - especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl - e.g.
  • p is 0 if R 4 is absent, or is 1 if R 3 and R 4 are both present and in each case are one of the aforementioned radicals (for compounds of formula II);
  • R 5 is hydrogen or lower alkyl, especially hydrogen
  • X stands for 2 hydrogen atoms, for O, or for 1 hydrogen atom and hydroxy; or for 1 hydrogen atom and lower alkoxy; Z is hydrogen or especially lower alkyl, most especially methyl;
  • either the two bonds characterised by wavy lines are preferably absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel bond, signify a double bond;
  • n 0;
  • R 3 and R 4 are independently of each other
  • lower alkyl unsubstituted or mono- or disubstituted, especially monosubstituted, by radicals selected independently of one another from carboxy; lower alkoxycarbonyl; and cyano;;
  • R 4 is hydrogen or -CH 3 .
  • R 3 is as defined above or preferably R 3 is,
  • R 0 is lower alkyl; amino-lower alkyl, wherein the amino group is present in unprotected form or is protected by lower alkoxycarbonyl; tetrahydropyranyloxy-lower alkyl; phenyl; imidazolyl-lower alkoxyphenyl; carboxyphenyl; lower alkoxycarbonylphenyl; halogen-lower alkylphenyl; imidazol-1-ylphenyl; pyrrolidino- lower alkylphenyl; piperazino-lower alkylphenyl; (4-lower alkylpiperazinomethyl)phenyl; morpholino-lower alkylphenyl; piperazinocarbonylphenyl; or (4-lower alkylpiperazino)phenyl;
  • acyl of the subformula R°HN-C( W)-, wherein W is oxygen and R 0 has the following meanings: morpholino-lower alkyl, phenyl, lower alkoxyphenyl, carboxyphenyl, or lower alkoxycarbonylphenyl;
  • R 3 is lower alkylphenylsulfonyl, typically 4-toluenesulfonyl;
  • R 5 is hydrogen or lower alkyl, especially hydrogen
  • X stands for 2 hydrogen atoms or for O
  • Z is methyl or hydrogen; or a salt thereof, if at least one salt-forming group is present.
  • n 0;
  • R 3 and R 4 are independently of each other
  • lower alkyl unsubstituted or mono- or disubstituted, especially monosubstituted, by radicals selected independently of one another from carboxy; lower alkoxycarbonyl; and cyano; whereby R 4 may also be absent;
  • R 4 is absent
  • R 3 is acyl from the subformula R°-CO, wherein R 0 is lower alkyl, especially methyl or ethyl; amino-lower alkyl, wherein the amino group is unprotected or protected by lower alkoxy- carbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, e.g.
  • acyl of the subformula R°HN-C( W)-, wherein W is oxygen and R 0 has the following preferred meanings: morpholino-lower alkyl, typically 2-morpholinoethyl, phenyl, lower alkoxyphenyl, typically 4-methoxyphenyl or 4-ethoxyphenyl, carboxyphenyl, typically 4- carboxyphenyl, or lower alkoxycarbonylphenyl, typically 4-ethoxycarbonylphenyl;
  • alkylphenylsulfonyl typically 4-toluenesulfonyl
  • p is 0 if R 4 is absent, or is 1 if R 3 and R 4 are both present and in each case are one of the aforementioned radicals;
  • R 5 is hydrogen or lower alkyl, especially hydrogen
  • X stands for 2 hydrogen atoms or for O
  • Z is methyl or hydrogen
  • N-ethyl-1 ,2,3,4-tetrahydrostaurosporine N-tosyl-1 ,2,3,4-tetrahydrostaurosporine;
  • N-carboxymethyl-1 ,2,3,4-tetrahydrostaurosporine N-terephthaloylmethyl ester-1 ,2,3,4-tetrahydrostaurosporine; N-terephthaloyl-1 ,2,3,4-tetrahydrostaurosporine;
  • N-benzoyl-1 ,2,3,4-tetrahydrostaurosporine N,N-dimethyl -1 ,2,3,4-tetrahydrostaurosporinium iodide;
  • X 1 hydrogen and 1 hydroxy atom
  • R 1 , R 2 , R 5 H
  • R 3 CH 3
  • Z CH 3
  • R 4 is selected from -(CH 2 ) 2 OH; -CH 2 CH(OH)CH 2 OH; -CO(CH 2 ) 2 CO 2 Na; -(CH 2 ) 3 CO 2 H; - COCH 2 N(CH 3 ) 2 ;
  • R 4 is selected from N-[0-(tetrahydropyran-4-yl )-D-lactoyl]; N-[2-(tetrahydro-pyran-4-yloxy)-acetyl)]
  • CAS CHEMICAL ABSTRACTS registry number
  • the preferred STAUROSPORINE DERIVATIVE is N- [(9S, 10R, 11 R, 13R)-2,3, 10,1 1 ,12,13-hexahydro-10-methoxy-9-methyl-1 -oxo-9, 13-epoxy- 1 H,9H-diindolo[1 ,2,3-gh:3',2', 1 '-lm]pyrrolo[3,4-j][1 ,7]benzodiazonin-11 -y ⁇ ]-N- methylbenzamide of the formula (VII):
  • Compound of formula VII is also known as MIDOSTAURIN [International Nonproprietary Name] or PKC412.
  • MIDOSTAURIN is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 1 10 published on December 21 , 1988, as well as in US patent No. 5;093,330 published on March 3, 1992, and Japanese Patent No. 2 708 047.
  • the invention provides the use of a compound of formula I (or pharmaceutically acceptable salt or prodrug ester thereof) for the preparation of a medicament for use in combination with ionizing radiation in the treatment of a proliferative disease.
  • the invention provides use of a compound of formula I (or pharmaceutically acceptable salt or prodrug ester thereof) in combination with ionizing radiation for the treatment of a proliferative disease, especially a solid tumor.
  • the invention provides a compound of formula I (or pharmaceutically acceptable salt or prodrug ester thereof) as active ingredient for use in combination with ionizing radiation for the treatment of a proliferative disease, especially a solid tumor.
  • the invention provides a package comprising a compound of formula I (or pharmaceutically acceptable salt or prodrug ester thereof) together with instructions for the use in combination with ionizing radiation for the treatment of a proliferative disease, especially a solid tumor.
  • delay of progression means administration of the combination to patients being in an early phase of the proliferative disease to be treated.
  • solid tumor disease comprises, but is not restricted to glioma, thyroid cancer, breast cancer, ovarian cancer, cancer of the colon and generally the Gl tract, cervix cancer, lung cancer, in particular small-cell lung cancer, and non-small-cell lung cancer, head and neck cancer, bladder cancer, cancer of the prostate or Kaposi's sarcoma.
  • the tumor disease to be treated is glioma, cancer of the prostate or thyroid cancer.
  • the present combination inhibits the growth of solid tumors, but also liquid tumors. Furthermore, depending on the tumor type and the particular combination used, a decrease of the tumor volume can be obtained.
  • the combinations disclosed herein are also suited to prevent the metastatic spread of tumors and the growth or development of micrometastases.
  • Combination refers to administration of an amount of a compound of formula I in combination with administration of an amount of ionizing radiation such that there is a synergistic effect which would not be obtained if a compound of formula I is administered without separate, simultaneous or sequential administration of ionizing radiation.
  • administration of ionizing radiation can be continuous, sequential or sporadic.
  • an effect which would not be obtained if there is administered ionizing radiation without the separate, simultaneous or sequential administration of a compound of formula I wherein administration can be continuous, sequential or sporadic
  • combination refers to administration of an amount of a compound of formula I in combination with administration of an amount of ionizing radiation such that there is a synergistic antiproliferative effect and/ or a clonogenic cell killing effect that would not be obtained if
  • the compound of formula I is administered without prior, simultaneous or subsequent administration of ionizing radiation. Wherein administration can be continuous, sequential or sporadic;
  • ionising radiation means ionising radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionising radiation is provided in, but not limited to, radiation therapy and is known in the art (Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, 248-275 (Devita et al., ed., 4 th Ed., V1 , 1993).
  • proliferative diseases like solid tumor diseases
  • drugs with different mechanisms of action may be combined.
  • any combination of drugs having different mode of action does not necessarily lead to combinations with advantageous effects.
  • compounds of formula I and pharmaceutically acceptable salts and prodrug derivatives are preferably used in the form of pharmaceutical preparations that contain the relevant therapeutically effective amount of active ingredient optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration.
  • each patient receives doses of ionizing radiation during the same period and the compound of formula I.
  • the ionizing radiation is given as a pre-treatment, i.e. before the treatment with the COMBINATION OF THE INVENTION is started; the ionizing radiation alone is administered to the patient for a defined period of time, e.g. daily administration of the ionizing radiation alone for two or three days or weeks.
  • the precise dosage of the FLT-3 inhibitor and the HDAI to be employed for treating the diseasesand conditions mentioned hereinbefore depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration.
  • satisfactory results are achieved when the FLT- 3 inhibitor is administered parenterally, e.g., intraperitoneal ⁇ , intravenously, intramuscularly, subcutaneously, intratumorally, or rectally, or enterally, e.g., orally, preferably intravenously or, preferably orally, intravenously at a daily dosage of 0.1 to 10 mg/kg body weight, preferably 1 to 5 mg/kg body weight.
  • a preferred intravenous daily dosage is 0.1 to 10 mg/kg body weight or, for most larger primates, a daily dosage of 200-300 mg.
  • a typical intravenous dosage is 3 to 5 mg/kg, three to five times a week.
  • the FLT-3 inhibitors are administered orally, by dosage forms such as microemulsions, soft gels or solid dispersions in dosages up to about 250 mg/day, in particular 225 mg/day, administered once, twice or three times daily.
  • a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.
  • the FLT-3 inhibitors and the HDAI compounds may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g. orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intraperitoneal ⁇ or intravenously, in the form of sterile injectable solutions or suspensions.
  • enteral and parenteral compositions may be prepared by conventional means.
  • the infusion solutions according to the present invention are preferably sterile. This may be readily accomplished, e.g. by filtration through sterile filtration membranes. Aseptic formation of any composition in liquid form, the aseptic filling of vials and/or combining a pharmaceutical composition of the present invention with a suitable diluent under aseptic conditions are well known to the skilled addressee.
  • the FLT-3 inhibitors and HDAI compounds may be formulated into enteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for treating the diseases and conditions named hereinbefore, such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.
  • compositions of FLT-3 inhibitors are described in the European patents No. 0 296 110, No. 0 657 164, No. 0 296 110, No.O 733 372, No.O 711 556, No.O 711 557.
  • compositions of FLT-3 inhibitors are described in the European patent No. 0 657 164 published on June 14, 1995.
  • the described pharmaceutical compositions comprise a solution or dispersion of compounds of formula I such as MIDOSTAURIN in a saturated polyalkylene glycol glyceride, in which the glycol glyceride is a mixture of glyceryl and polyethylene glycol esters of one or more C8-C18 saturated fatty acids.
  • Composition A A:
  • Gelucire 44/14 (82 parts) is melted by heating to 60° C.
  • Powdered MIDOSTAURIN (18 parts) is added to the molten material.
  • the resulting mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the MIDOSTAURIN.
  • the resulting capsules are suitable for oral administration.
  • Composition B is a composition of Composition B:
  • Gelucire 44/14 (86 parts) is melted by heating to 60° C. Powdered MIDOSTAURIN (14 parts) is added to the molten material. The mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the MIDOSTAURIN. The resulting capsules are suitable for oral administration.
  • Gelucire 44/14 available commercially from Gattefosse is a mixture of esters of C8-C18 saturated fatty acids with glycerol and a polyethylene glycol having a molecular weight of about 1500, the specifications for the composition of the fatty acid component being, by weight, 4-10% caprylic acid, 3-9% capric acid, 40-50% lauric acid, 14-24% myristic acid, A- 14% palmitic acid and 5-15% stearic acid.
  • Gelucire formulation consists of: Gelucire (44/14): 47 g MIDOSTAURIN: 3.Og filled into a 60 mL Twist off flask
  • a preferred example of soft gel will contain the following Microemulsion:
  • a therapeutically effective amount of each combination partner of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of delay of progression or treatment of a proliferative disease according to the invention may comprise (i) administration of the first combination partner and (ii) administration of the second combination partner, wherein administration of a combination partner may be simultaneous or sequential in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily or weekly dosages corresponding to the amounts described herein.
  • the individual combination partners of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently.
  • administering also encompasses the use of a pro-drug of a compound of formula I that converts in vivo to the combination partner as such.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the dosage of ionizing radiation and a compound of formula I in relation to each other is preferably in a ratio that is synergistic.
  • the particular mode of administration and the dosage of a compound of formula I may be selected by the attending physician taking into account the particulars of the patient, especially age, weight, life style, activity level, etc.
  • the dosage of a compound of formula I may depend on various factors, such as effectiveness and duration of action of the active ingredient, mode of administration, effectiveness and duration of action of the ionizing radiation and/or sex, age, weight and individual condition of the subject to be treated.
  • the dosage of ionizing radiation may depend on various factors, such as effectiveness and duration of action of the ionizing radiation, mode of administration, location of administration, effectiveness and duration of action of the compound of formula I and/or sex, age, weight and individual condition of the subject to be treated.
  • the dosage of ionizing radiation is generally defined in terms of radiation absorbed dose, time and fraction, and must be carefully defined by the attending physician.
  • the combination comprises N- [(9S, 10R, 11 R, 13R)-2,3, 10,1 1 ,12,13-hexahydro-10-methoxy-9-methyl-1 -oxo-9, 13-epoxy- 1 H,9H-diindolo[1 ,2,3-gh:3',2', 1 '-lm]pyrrolo[3,4-j][1 ,7]benzodiazonin-11 -y ⁇ ]-N- methylbenzamide of the formula (VII):
  • the present invention relates to a method of treating a warm-blooded animal having a proliferative disease comprising administering to the animal a COMBINATION OF THE INVENTION in a way that is jointly therapeutically effective against a proliferative disease and in which the combination partners can also be present in the form of their pharmaceutically acceptable salts.
  • the present invention pertains to the use of a COMBINATION OF THE INVENTION for the delay of progression or treatment of a proliferative disease and for the preparation of a medicament for the delay of progression or treatment of a proliferative disease.
  • an antidiarrheal agent is administered together with the COMBINATION OF THE INVENTION in order to prevent, control or eliminate diarrhoea that is sometimes associated with the administration of a compound of formula I.
  • the present invention also relates to a method of preventing or controlling diarrhoea associated with administering a compound of formula I, which comprises administering an effective amount of an antidiarrhea agent to the patient receiving treatment with the COMBINATION OF THE INVENTION.
  • Antidiarrheal agents and protocols for their administration are known to those skilled in the art.
  • Antidiarrheal agents suitable for use in the inventive methods and compositions include, but are not limited to, natural opiods, such as tincture of opium, paregoric, and codeine, synthetic opioids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, octreotide (e.g. available as SAN DOSTATI NTM), motilin antagonists and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents.
  • natural opiods such as tincture of opium, paregoric, and codeine
  • synthetic opioids such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, octreotide (e.g. available as SAN DOSTATI NTM)
  • motilin antagonists e.g. available as SAN DOSTATI NTM
  • Determination of the response to treatment with fractionated doses of ionizing irradiation in solid tumor xenografts is derived from ACC3-tumor cells, using nude mice as tumor carriers.
  • nude mice are injected subcutaneously with tumor cells.
  • Measurable tumors derived from the respective tumor cells form within a tumor cell dependent time period - from 7 days (aggressive tumors) up to 3-4 weeks (slowly growing tumors).
  • Tumor volumes are determined from caliper measurements according to the formula (Lxl2/2), and tumors are allowed to expand to a minimal volume of at least 0.175cm3 +/-15% prior to any treatment.
  • the animals are treated with a single or repetitive dose of the chemical agent (applied according to the substance-dependent best mode of application) in combination with a single or multiple fractions of locoregional applied irradiation (3Gy/ fraction). Tumor volume measurements are performed on a daily basis to determine treatment response.
  • a 4x3 Gy and 4x5Gy fractionation radiation regimen is used. These tumors show a strong response to both fractionated radiation regimens, leading even to partial regression, as usually only observed with highly radiation-sensitive tumors.
  • the 4x3Gy regimen even induces a stronger response than the 4x5Gy regimen.
  • tumor regression only starts 3-4 days after the end of treatment.
  • apoptosis prone tumor cells e.g. p53- wildtype, E1A/ras transformed MEFS
  • ACC3-tumors might be highly dependent on a functional tumor vasculature, and radiation-induced damage of the tumor vasculature will only affect the tumor growth response with a certain time delay. Future in vivo experiments in combination with histological analysis will carefully investigate this highly interesting observation.
  • ACC- representative ACC-3 cell line can be regarded as a highly radioresistant tumor cell line when compared to established tumor cell lines derived from various other tumor entities.
  • most of the different antisignaling agents tested require high dosage to induce an antiproliferative effect and have only an additive antiproliferative effect when applied in combination with irradiation.
  • the only clinically relevant compound tested which shows a slight supra-additive effect in terms of proliferation and clonogenicity when combined with IR (proliferation, clonogenicity) is the protein kinase C inhibitor ⁇ /-[(9S,1 OR, 11 R, 13R)-2,3,10,1 1 ,12,13-hexahydro-10- methoxy-9-methyl-1 -oxo-9, 13-epoxy-1 /-/,9/-/-diindolo[1 ,2,3-gh:3',2', 1 '-lm]pyrrolo[3,4- j][1 ,7]benzodiazonin-11-yl]- ⁇ /-methylbenzamide.
  • tumors derived from the "in vitro-radioresistant" ACC3- cell line show a strong growth delay response even to a low-dose treatment regimen of ionizing radiation alone. These results suggest a strong involvement of the tumor microenvironment on the treatment response.

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Abstract

Cette invention concerne des dérivés de la staurosporine qui sont efficaces lorsqu'ils sont utilisés en combinaison avec un rayonnement ionisant pour le retard de la progression ou le traitement d'une maladie proliférative, notamment une maladie de tumeur solide, en particulier un carcinome, tel que le carcinome adénoïde kystique.
PCT/EP2007/060830 2006-10-12 2007-10-11 Dérivés de la staurosporine et rayonnement WO2008043811A1 (fr)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2005027910A1 (fr) * 2003-08-25 2005-03-31 Dana-Farber Cancer Institute Inc. Procede de traitement du gene de la leucemie a lignee mixte-rearrangee en leucemies lymphoblastiques aigues

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