MX2008006287A - Staurosporine derivatives for use in alveolar rhabdomyosarcoma. - Google Patents

Abstract

This invention relates to staurosporine derivatives are effective when used in combination with ionizing radiation for the delay of progression or treatment of a proliferative disease, especially a disease associated with a PAX/FKHR translocation including a PAX3/FKHR translocation and a PAX7/FKHR translocation, more especially a solid tumor disease such as a Sarcoma, most especially an Alveolar Rhabdomyosarcoma.

Description

DERIVATIVES OF ESTAU ROSPORINA TO BE USED IN RABDOMIOSARCOMA ALVEOLAR This invention relates to organic compounds, in particular to pharmaceutical compositions for the purpose of being used for the delay of progress or the treatment of a proliferative disease, especially a disease associated with a translocation of PAX / FKH R, especially a sarcoma, especially alveolar rhabdomyosarcoma. We have now found that certain inhibitors of FLT-3, especially those derived from staurosporine, are effective when used in the treatment of a disease associated with translocation of PAX / FKH R, especially from a disease associated with the expression of PAX / FKH R, more especially of alveolar rhabdomyosarcoma of pediatric sarcoma ("aRMS"). In one embodiment, aRMS expresses the chimeric fusion protein PAX3 / FKH R due to a chromosomal translocation event t (2; 1 3). In another embodiment, aRMS expresses the chimeric fusion protein PAX7 / FKH R due to a chromosomal translocation event t (1; 1 3). See Mendelian Inheritance in Man ACC No. # 268220. In accordance with the foregoing, the invention provides a method for the delay of treatment or treatment of a proliferative disease, especially a disease associated with translocation of PAX / FKH R, especially a sarcoma, more especially an alveolar rhabdomyosarcoma, in a subject in need of such treatment, wherein this treatment comprises administering to the subject an effective amount of a staurosporine derivative of the formula: wherein (II) is the partially hydrogenated derivative of the compound (I), wherein Rt and R2 are, independently of each other, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, esterified carboxyl , carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl or amino-sulfonyl N-mono- or N, N-di-substituted; n and m are, independently of each other, a number from and including 0 up to and including 4; n 'and m' are, independently of each other, a number from and including 0 up to and including 4; R3- R4, Re and R10 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 radical heterocyclic or heterocyclic-aliphatic 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, where R4 may also be absent, or if R3 is acyl with up to 30 carbon atoms, R4 is not an acyl; p is 0 if R4 is absent, or is 1 if R3 and R are both present, and in each case they are one of the radicals mentioned above; R5 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; R7, R6 and R9 are acyl or - (lower alkyl) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or di-substituted amino, cyano, nitro, mercapto, substituted mercapto , carboxyl, carbonyl, carbonyl-dioxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl or amino-sulfonyl N-mono- or N, N-di -replaced; X represents 2 hydrogen atoms; 1 hydrogen atom and hydroxyl; OR; or hydrogen and lower alkoxy; Z represents hydrogen or lower alkyl; and whether the two bonds characterized by wavy lines are absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel link, means a double bond; or the two bonds characterized by dotted lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, means a double bond; or both in ring A and in ring B, all 4 wavy bonds are absent and are replaced by a total of 8 hydrogen atoms; or a salt thereof, if at least one salt-forming group is present. The general terms and definitions used hereinbefore and hereinafter, preferably have the following meanings for the staurosporine derivatives: The prefix "lower" indicates that the associated radical preferably has up to and including a maximum of 7 carbon atoms. carbon, especially up to and including a maximum of 4 carbon atoms. Lower alkyl is in particular methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, or tertiary butyl, and also pentyl, hexyl, or heptyl. Alkyl unsubstit or substit is preferably alkyl of 1 to 20 carbon atoms, especially lower alkyl, typically methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, or tertiary butyl, which is unsubstit or substit in particular by halogen, such as fluorine, chlorine, bromine, or iodine, aryl of 6 to 14 carbon atoms, such as phenyl or naphthyl, hydroxyl, etherified hydroxyl, such as lower alkoxy, phenyl-lower alkoxy or phenyloxy, esterified hydroxyl, such as lower alkanoyloxy or benzoyloxy, amino, mono- or di-substit amino, such as lower-amino-alkyl, lower-amino-alkanoyl, phenyl-alkyl lower-amino, N, N-di-lower alkyl-amino, N, N-di- (phenyl-lower alkyl) -amino, cyano, mercapto, substit mercapto, such as lower thioalkyl, carboxyl, esterified carboxyl, such as alkoxy lower carbonyl, carbamoyl, N-mono- or N, N-di-substit carbamoyl, such as N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, sulfo, substit sulfo, such as lower alkane- sulfonyl or lower alkoxyl-sulfonyl, amino-sulfonyl or amino-sulfonyl N-mono- or N, N-di-substit, such as N-lower alkyl amino-sulfonyl or N, N-di-lower alkylamino -sulfonyl. Halogen is preferably fluorine, chlorine, bromine, or iodine, especially fluorine or chlorine. Etherified hydroxyl is especially lower alkoxy, aryloxy of 6 to 14 carbon atoms, such as phenyloxy, or aryl of 6 to 14 carbon atoms-lower alkoxy, such as benzyloxy. Esterified hydroxyl is preferably lower alkanoyloxy or aryl of 6 to 14 carbon atoms-carbonyloxy, such as benzoyloxy. Mono- or di-substit amino is in particular amino mono-substit or di-substit by lower alkyl, aryl of 6 to 14 carbon atoms, aryl of 6 to 14 carbon atoms-lower alkyl, lower alkanoyl, or aryl of 6 to 12 carbon atoms-carbonyl.

Substit mercapto is in particular lower thioalkyl, thioaryl of 6 to 14 carbon atoms, aryl of 6 to 14 carbon atoms-lower thioalkyl, lower thioalkanoyl, or aryl of 6 to 14 carbon atoms-lower thioalkanoyl. Esterified carboxyl is in particular lower alkoxycarbonyl, aryl of 6 to 14 carbon atoms-lower alkoxy-carbonyl or aryloxy of 6 to 14 carbon atoms-carbonyl. Carbamoyl N-mono- or N, N-di-substit is in particular N-mono-substit carbamoyl or N, N-di-substit by lower alkyl, aryl of 6 to 14 carbon atoms, or aryl of 6 to 14 atoms of carbon-lower alkyl. Substit sulfonyl is in particular aryl of 6 to 14 carbon-sulfonyl atoms, such as toluene-sulfonyl, aryl of 6 to 14 carbon atoms-lower alkane-sulfonyl, or lower alkane-sulfonyl. N-mono- or N, N-di-substit amino-sulfonyl is in particular N-mono-substit amino-sulfonyl or N, -di-substit by lower alkyl, aryl of 6 to 14 carbon atoms, or aryl of 6 to 14 carbon atoms-lower alkyl. Aryl of 6 to 14 carbon atoms 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 in particular by halogen, such as fluorine, chlorine, bromine, or iodine, phenyl or naphthyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower-amino-alkyl, lower-amino-alkanoyl, phenyl-lower-amino-alkyl, N , N-di-alkyl lower-amino, N, N-di- (phenyl-lower alkyl) -amino, cyano, mercapto, lower thioalkyl, carboxyl, lower alkoxy-carbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N- di-lower alkyl-carbamoyl, sulfo, lower alkane-sulfonyl, lower alkoxyl-sulfonyl, amino-sulfonyl, N-lower alkyl-amino-sulfonyl, or, N-di-lower alkyl-amino-sulfonyl. The indices n and m are in each case preferably 1, 2 or especially 0. In general, compounds of the formula I are particularly preferred, where n and m are in each case 0 (zero). A radical of aliphatic carbohydrate R3, R4, R8 or R10 with up to 29 carbon atoms, which is substituted by acyclic substituents, and preferably has a maximum of 18, especially a maximum of 12, and as a rule no more than 7 carbon atoms, can be saturated or unsaturated, and is in particular a radical of lower alkyl, lower alkenyl, lower alkydlyl, or unsubstituted or straight or branched chain lower alkynyl, substituted by acyclic substituents. Lower alkyl is, for example, methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl or tertiary butyl, and also normal pentyl, isopentyl, normal hexyl, isohexyl and normal 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 alkynyl is, for example, propargyl or 2-butynyl. In the corresponding unsaturated radicals, the double bond is located especially in a position higher than the position-a in relation to the free valence.

The substituents are in particular the acyl radicals defined hereinafter as substituents of R °, preferably free or esterified carboxyl, such as carboxyl or lower alkoxycarbonyl, cyano or di-lower alkyl-amino. A carbocyclic or carbocyclic-aliphatic radical R3, R4, R8 or R0 with up to 29 carbon atoms in each case is in particular an aromatic, cycloaliphatic, cycloaliphatic-aliphatic, or aromatic-aliphatic radical, which is present in an unsubstituted form or else substituted by the radicals referred to hereinafter as substituents of R °. An aromatic radical (aryl radical) R 3 or R 4 is more especially a phenyl, also a naphthyl, such as 1 - or 2-naphthyl, a biphenylyl, such as in particular 4-biphenylyl, and also an anthryl, fluorenyl and azulenyl, as well as their aromatic analogues with one or more saturated rings, which is present in an unsubstituted form or substituted by the radicals referred to hereinafter as substituents of R °. Preferred aromatic-aliphatic radicals are the aryl-lower alkyl and aryl-lower alkenyl radicals, for example, phenyl-lower alkyl or lower phenol-lower alkenyl with a terminal phenyl radical, such as, for example, benzyl, phenethyl, 1 -, 2-, or 3-phenyl-propyl, diphenyl-methyl (benzhydyl), trityl, and cinnamyl, and also 1 - or 2-naphthyl-methyl. Of the aryl radicals bearing acyclic radicals, such as lower alkyl, special mention is made of the radicals of o-, m- and p-tolyl, and xylyl with variably located methyl radicals. A cycloaliphatic radical R3, R4, R8 or R10 with up to 29 atoms carbon is in particular a cycloalkyl, cycloalkenyl, or cycloalkadienyl radical substituted, or preferably unsubstituted, mono-, bi-, or polycyclic. The preference is for radicals with a maximum of 14, especially 12 ring carbon atoms, and rings of 3 to 8, preferably 5 to 7, and more especially of 6 members, which can also carry one or more , for example two, aliphatic hydrocarbon radicals, for example those mentioned above, especially the lower alkyl radicals, or other cycloaliphatic radicals as substituents. Preferred substituents are the acyclic substituents mentioned hereinafter for R °. A cycloaliphatic-aliphatic radical R3, R4l R8 or R10 with up to 29 carbon atoms is a radical wherein an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as in particular methyl, ethyl, and vinyl, it carries one or more cycloaliphatic radicals as defined hereinbefore. Special mention is made of the cycloalkyl-lower alkyl radicals, as well as their analogs, which are unsaturated in the ring and / or in the chain, but are non-aromatic, and which carry the ring in the terminal carbon atom of the chain. Preferred substituents are the acyclic substituents mentioned hereinafter for R °. The heterocyclic radicals R3, R4, Re or R10 with up to 20 carbon atoms each, and up to 9 heteroatoms each, one, one, are in particular monocyclic radicals, but also bi- or poly- cyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-, or tetraza-cyclic of an aromatic character, as well as the corresponding heterocyclic radicals of this type that are partially, or in a more especially saturated, possibly carrying these radicals - if necessary - other acyclic, carbocyclic, or heterocyclic radicals and / or possibly being mono-, di-, or poly-substituted by functional groups, preferably those mentioned hereinabove as substituents of the aliphatic hydrocarbon radicals. More especially they are mono-cyclic radicals unsubstituted or substituted with a nitrogen, oxygen, or sulfur atom, such as 2-aziridinyl, and in particular aromatic radicals of this type, such as pyrrhyl, for example 2-pyrryl or 3-pyrryl , 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-indole, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3-5 isoquinolyl, benzofuranyl, typically 2-benzo-furanyl, chromenyl, typically 3-chromenyl, or benzo-thienyl, typically 2- or 3-benzo-thienyl; Preferred monocyclic and bicyclic radicals with several heteroatoms are, for example, imidazolyl, typically 2- or 4-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, or thiazolyl, typically 2-thiazolyl, and benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, or quinazolyl, typically 2-quinazolinyl. Also suitable are partially or, in particular, fully saturated analog radicals, such as 2-tetrahydro-furyl, 2- or 3-pyrrolidinyl, 2-, 3-, or 4-piperidyl radicals, and also 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl and N-mono- or N, N'-bis-lower alkyl-2-piperazinyl. These radicals can also carry one or more acyclic, carbocyclic, or heterocyclic radicals, especially those mentioned hereinabove. The free valency of the heterocyclic radicals R3 or R4 must emanate from one of their carbon atoms. Heterocyclyl can be unsubstituted or substituted by one or more, preferably one or two, of the substituents mentioned hereinafter for R °. The heterocyclic-aliphatic radicals R3, R4, R8 or R10, especially the lower alkyl radicals, in particular with a maximum of 7, preferably a maximum of 4 carbon atoms, for example those mentioned hereinabove, bearing one, two, or more heterocyclic radicals, for example those mentioned 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-yl-methyl, 4-methyl-piperazin-1-l-methyl, piperazin-1-yl-methyl, 2- (morpholin-4-yl) -ethyl and also pyrid-3-yl-methyl. Heterocyclyl can be unsubstituted or substituted by one or more, preferably one or two, of the mentioned substituents later in the present for R °. A hetero-aliphatic radical R3, R4, Re or R10 with up to 20 carbon atoms each, and up to 10 heteroatoms each, one, 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. An especially preferred configuration of a hetero-aliphatic radical takes the form of the oxa-alkyl radicals, wherein one or more carbon atoms are replaced in a preferably linear alkyl, by oxygen atoms preferably separated from one another by several ( in particular 2) carbon atoms, such that they form a repeating group, if necessary, a multiple repeating group (O-CH2-CH2-) q, where q = 1 to 7. As R3, R4, R8 or R10, apart from acyl, lower alkyl, in particular methyl or ethyl, are especially preferred; lower alkoxy-carbonyl-lower alkyl, especially methoxy-carbonyl-methyl or 2- (terbutoxy-carbonyl) -ethyl; carboxy-lower alkyl, especially carboxymethyl or 2-carboxyethyl; or cyano-lower alkyl, especially 2-cyano-ethyl. An acyl radical R3, R4, R6, R7, Re, R9, or R10 with up to 30 carbon atoms is derived from a carboxylic acid, functionally modified, if necessary, an organic sulfonic acid, or a phosphoric acid, such as pyro- or ortho-phosphoric acid, esterified if necessary. An acyl designated as Ac and derived from an acid Carboxylic, optionally modified, if necessary, is in particular one of the sub-formula YC (= W) -, where W is oxygen, sulfur, or im ino and Y is hydrogen, not id rbilo rock R ° with up to 29 carbon atoms, hydrocarbyloxy R ° -0-, an amino group or a substituted amino group, especially one of the formula R ° H N- or R ° R ° N- (wherein the radicals R ° they can be identical or different from each other). The hydrocarbyl radical (hydrocarbon radical) R ° is an acyclic (aliphatic), carbocyclic, or carbocyclic-acyclic hydrocarbon radical with up to 29 carbon atoms each, especially up to 1 8, and preferably up to 12 carbon atoms , and it is saturated or unsatisfied, 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 heterocyclic-acyclic radical. The unsaturated radicals are those which contain no or more, multiple in bonds (double or triple bonds), especially conjugates and / or isolates. The term "cyclic radicals" also includes aromatic and non-aromatic radicals with conjugated double bonds, for example those in which at least one 6-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring contains the maximum number of double bonds not cumulative The carbocyclic radicals, where at least One ring is present as a 6-meter ring (that is, a benzene ring), defined as aryl radicals. A radical of an acyclic unsubstituted hydrocarbon radical is in particular a radical of lower alkyl, lower alkenyl, lower alkydlyl, or straight or branched chain lower alkynyl. Lower alkyl R ° is, for example, methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl or tertiary butyl, and also normal pentyl, isopentyl, normal hexyl, isohexyl and normal 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 alkynyl is, for example, propargyl or 2-butynyl. In the corresponding unsaturated radicals, the double bond is located especially in a position higher than the position-a in relation to the free valence. A carbocyclic hydrocarbon radical R ° is in particular a cycloalkyl, cycloalkenyl, or cycloalkadienyl radical mono-, bi-, or polycyclic, or a corresponding aryl radical. The preference is for radicals with a maximum of 14, especially 1 2 ring carbon atoms, and rings of 3 to 8, preferably 5 to 7, and more especially of 6 members, which can also carry one or more, for example two, acyclic radicals, for example those mentioned above, especially the lower alkyl radicals, or other carbocyclic radicals. The carbocyclic-acyclic radicals are those in which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, is present. carbon, such as especially methyl, ethyl and vinyl, carries one or more carbocyclic radicals, if necessary aromatics of the above definition. Special mention is made of the cycloalkyl- and aryl-lower alkyl radicals, as well as their analogs, which are unsaturated in the ring and / or in the chain, and which carry the ring in the terminal carbon atom of the ring. chain. Cycloalkyl R ° has more especially from 3 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, alkyl radicals, for example lower, especially methyl radicals; cycloalkenyl is, for example, one of the aforementioned monocyclic cycloalkyl radicals, which bears a double bond at the 1, 2, or 3 position. Cycloalkyl-lower alkyl or -lower alkenyl is, for example -methyl, -1- or -2-ethyl, -1- or -2-vinyl, -1-, -2-, or -3-propyl or -alyl substituted by one of the aforementioned cycloalkyl radicals, with those substituted at the end of the chain being preferred linear. An aryl radical R ° is more especially a phenyl, also a naphthyl, such as 1- or 2-naphthyl, a biphenylyl, such as in particular 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 -alkenyl radicals are, for example, phenyl-lower alkyl or phenyl-lower alkenyl with one radical of terminal phenyl, such as, for example, benzyl, phenethyl, 1-, 2-, or 3-phenyl-propyl, diphenyl-methyl (benzhydryl), trityl, and cinnamyl, and also 1- or 2-naphthyl-methyl. Aryl may be unsubstituted or substituted. Heterocyclic radicals, including heterocyclic-acyclic radicals, are in particular monocyclic but also bi- or polycyclic radicals, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-, or tetraza- cyclics of an aromatic character, as well as the corresponding heterocyclic radicals of this type that are partially, or more especially, fully saturated; if necessary, for example as in the case of the aforementioned carbocyclic or aryl radicals, these radicals can carry other acyclic, carbocyclic, or heterocyclic radicals and / or can be mono-, di-, or poly-substituted by functional groups . The acyclic part in the heterocyclic-acyclic radicals has, for example, the meaning indicated for the corresponding carbocyclic-acyclic radicals. More especially they are mono-cyclic radicals unsubstituted or substituted by 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, benzo -furanyl, typically 2-benzo- furanyl, chromenyl, typically 3-chromenyl, or benzo-thienyl, typically 2- or 3-benzo-thienyl; Preferred monocyclic and bi-cyclic radicals with several heteroatoms are, for example, imidazolyl, typically 2-imidazolyl, pyrimidinyl, typically 2- or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, otiazo. I i I, typically 2-thiazolyl, and benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, or quinazolyl, typically 2-quinazolinyl. Also suitable are partially partially or, in particular, fully saturated radicals, such as 2-tetrahydro-furyl, 4-tetrahydro-furyl, 2-or 3-pyrrolidyl, 2-, 3-, or 4- radicals. piperldyl, and also 2- or 3-morpholinyl, 2- or 3-tlomorpholinyl, 2-piperazinyl, and N, N'-bis-lower alkyl-2-piperazinyl. These radicals can also carry one or more acyclic, carbocyclic, or heterocyclic radicals, especially those mentioned hereinabove. Heterocyclic-acyclic radicals are derived in particular from acyclic radicals with a maximum of 7, preferably a maximum of 4 carbon atoms, for example those mentioned hereinabove, and can carry one, two, or more heterocyclic radicals , for example those mentioned hereinabove, the ring possibly linking to the aliphatic chain also by means of one of its nitrogen atoms. As already mentioned, hydrocarbyl (including a heterocyclyl) may be substituted by one, two, or more substitute identical or different groups (national groups); one or more of the following substituents may be considered: lower alkyl; hydroxyl g rou free, etherified, and this rificados; carboxyl groups and esterified carboxyl groups; mercapto and lower thioalkyl groups and, if necessary, substituted thiophenyl; halogen atoms, typically chlorine and fluorine, but also bromine and iodine; halo-lower alkyl groups; g oxo rings that are present in the formyl form (ie aldehyde form) and keto groups, also as the corresponding acetals or ketals; azido groups; nitro groups; cyano groups; g primary, secondary amino, and tertiary preference, amino-lower alkyl, mono- or di-substituted amino-lower alkyl, primary or secondary amino groups protected by conventional protective groups (especially lower alkoxycarbonyl, typically terbutoxycarbonyl), lower alkylenedioxy, and also groups sulfo free or functionally modified, typically the sulfamoyl or sulfo groups present in free form or as salts. The hydrocarbyl radical can also carry carbamoyl, ureido, or guanidino groups, which are free, or which carry one or two substituents, and cyano groups. The previous use of the word "groups" is taken to imply also an individual group. Halo-lower alkyl preferably contains from 1 to 3 halogen atoms; trifluoromethyl or chloromethyl is preferred. An etherified hydroxyl group present in the hydrocarbyl as a substituent is, for example, a lower alkoxy group, typically the methoxy group, ethoxy, propoxy, isopropoxy, butoxyl, and terbutoxyl, which may also be substituted, in particular by (i) heterocyclyl, wherein heterocyclyl may preferably have from 4 to 12 ring atoms, may be unsaturated, or partially or fully saturated, is mono- or bi-cyclic, and may contain up to three heteroatoms selected from nitrogen, oxygen, and sulfur, and is more 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-isoquinolyl, benzo-furanyl, typically 2-benzo-furanyl, chromenyl, typically 3-chromenyl, benzo-thienyl, typically 2- or 3-benzo-thienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2- or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydro-furyl, 4-tetrahydro-furyl, 2- or 4-tetrahydro-pyranyl, 1-, 2- or 3-pyrrolidyl, 1-, 2-, 3 -, or 4-piperidyl, 1-, 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or N, N'-bis-lower alkyl-2-piperazinyl; and also (ii) by halogen atoms, for example mono-, di-, or poly-substituted, especially in the 2-position, such as in the 2,2,2-trichloro-ethoxy radical, 2-chloro-ethoxy, or 2-iodo-ethoxy, or (iii) by hydroxyl, or (iv) by lower alkoxy radicals, each preferably mono-substituted, especially in the 2-position, as in the 2-radical. methoxy-ethoxy These 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 may have of 4 to 12 ring atoms, can be unsaturated, or partially or fully saturated, is mono- or bi-cyclic, and can contain up to three heteroatoms selected from nitrogen, oxygen, and sulfur, and is more especially pyrrolyl, 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-isoquinolyl, benzo-furanyl, typically 2-benzo-furanyl, chromenyl, typically 3-chromenyl, benzo-thienyl, typically 2- or 3-benzo-thienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2- or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydro-furyl, 4-tetrahydro-furyl, 2- or 4-tetrahydro-pyranyl, 1-, 2- or 3-pyrrolidyl, 1-, 2-, 3 -, or 4-piperidyl, 1-, 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or N, N'-bis-lower alkyl-2-piperazinyl; such as, in particular, 2- or 4-tetrahydro-pyranyloxy. The etherified hydroxyl groups in this context are taken to silylated hydroxyl groups, typically for example tri-lower alkyl silyloxyl, typically trimethylsiloxyl and dimethyl tertiary butyl oxy, or fenif-d i-lower alkyl-silyloxyl and lower alkyl-d ifenyl -s i I i Ii Ii. 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 characterized hereinbefore. , preferably a lower alkyl or phenyl-lower alkyl radical; an example of an esterified carboxyl group is lower alkoxy-carbonyl or phenyl-lower alkoxy-substituted carbonyl, if necessary, in the phenyl part, especially the methoxyl, ethoxy, terbutoxyl, and benzyloxycarbonyl group, as well as a group lactonized carboxyl. A primary amino group -NH2 as a 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 radical, typically one of those mentioned above, especially lower alkyl, and may also be present in a protected form. A tertiary amino group present in the hydrocarbyl as a substituent carries 2 different, or, preferably, identical hydrocarbyl radicals (including heterocyclic radicals), such such as unsubstituted hydrocarbon radicals previously characterized herein, especially lower alkyl. A preferred group is with the formula R (R i 2) -, where R and R 12 are independently, in each case, hydrogen, hydrocarbyl of 1 to 7 unsubstituted acyclic carbon atoms (such as in particular alkyl of 1 to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms), or monocyclic, aralkyl, or aralkenyl aryl, substituted, if necessary, by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, and / or nitro, and having a maximum of 10 carbon atoms, wherein the carbon-containing radicals can be intertwined through the carbon-carbon bond or an oxygen atom, a sulfur atom, or a nitrogen atom substituted, if necessary, by hydrocarbyl. In this case, they form a heterocyclic ring containing nitrogen with the nitrogen atom of the amino group. The following are examples of the especially preferred di-substituted amino groups: di-lower alkyl-amino, typically dimethylamino or diethylamino, pyrrolidino, imidazol-1-yl, piperidino, piperazino, 4-lower alkyl-piperazino, morpholino , thiomorpholino and piperazino or 4-methyl-piperazino, as well as diphenyl-amino and substituted dibenzyl-amino, if necessary, especially on the phenyl portion, for example by lower alkyl, lower alkoxy, halogen, and / or nitro; of the protected groups, especially lower alkoxy-ca rbonyl-amino, typically terbutoxy-carbonyl-amino, phenyl-lower alkoxy-carbonyl-amino, typically 4-methoxy-benzyloxy-carbonyl-amino, and 9- fluorenyl-methoxy-carbonyl-amino. Amino-lower alkyl is more especially substituted at the 1-position of the lower alkyl chain by amino, and is especially amino-methyl. Amino-mono- or di-substituted lower alkyl is amino-lower alkyl substituted by one or two radicals, wherein amino-lower alkyl is more especially substituted by amino at position 1 of the lower alkyl chain, and is especially amino -methyl; the amino substituents herein are preferably (if 2 substituents on the respective amino group are present independently of each other) from the group comprising lower alkyl, such as in particular methyl, ethyl or normal propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl, cycloalkyl of 3 to 8 carbon atoms, especially cyclohexyl, amino-lower alkyl, typically 3-amino-propyl or 4-amino-butyl, N-mono- or N, N-di- (alkyl) lower) -amino-lower alkyl, typically 3- (N, Nd-methyl-amino) -propyl, amino, N-mono- or N, N-di-lower alkyl-amino and N-mono- or N, N- di- (hydroxy-lower alkyl) -amino. Amino-disubstituted lower alkyl is also a saturated or unsaturated 5- or 6-membered heterocyclyl linked with lower alkyl by means of a nitrogen atom (preferably in position 1) and having from 0 to 2, in particular 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 herein are pyrrolidi no (1-pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower alkyl-piperazino, typically 4-methyl-piperazino, imidazolino (1-imidazolyl), morpholino (4- morpholinyl), or also thiomorpholino, S-oxo-thiomorpholino, or S, S-dioxo-thiomorpholino. Lower alkylenedioxyl is especially methylenedioxyl. A carbamoyl group bearing one or two substituents is in particular amino-carbonyl (carbamoyl), which is substituted by one or two radicals on the nitrogen atom; the amino substituents herein are preferably (if 2 substituents on the respective amino group are present independently of each other) from the group comprising lower alkyl, such as in particular methyl, ethyl or normal propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl, cycloalkyl of 3 to 8 carbon atoms, especially cyclohexyl, amino-lower alkyl, typically 3-amino-propyl or 4-amino-butyl, N-mono- or N, N-di- (alkyl) lower) -amino-lower alkyl, typically 3- (N, N-dimethylamino) -propyl, amino, N-mono- or N, N-di-lower alkyl-amino and N-mono- or N, N- di- (hydroxy-lower alkyl) -amino; amino di-substituted amino-carbamoyl is also a 5- or 6-membered heterocyclyl, saturated or unsaturated, with a linking nitrogen atom, and with 0 to 2, especially 0 or 1 different 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. Here you prefer pyrrolidino (1-pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower alkyl-piperazino, typically 4-methyl-piperazino, imidazolino (1-imidazolyl), morpholino (4-morpholinyl), or also thiomorpholino, S-oxo-thiomorpholino, or SS-dioxo-thiomorpholino. An acyl derived from an organic sulfonic acid, which is designated as Ac2, is in particular one with the sub-formula R ° -S02-, wherein R ° is a hydrocarbyl as defined above in the general and specific meanings , the latter also being preferred in general terms in the present. In particular, lower alkyl phenyl sulfonyl, in particular 4-toluene sulfonyl, is preferred. An acyl derived from a phosphoric acid, esterified, if necessary, which is designated as Ac3 is especially one with the sub-formula R ° 0 (R ° 0) P (= 0) -, where the radicals R ° are, independently of each other, as defined in the general and specific meanings indicated above. The reduced data on the substituents given hereinafter and subsequently herein are considered as preferences. Preferred compounds according to the invention are, for example, those in which R ° has the following preferred meanings: lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is deprotected or protected by a conventional amino protecting group - especially by lower alkoxycarbonyl, typically lower teralkoxycarbonyl, for example, terbutoxy-carbonyl-for example, amino-methyl, R, S-, Ro preferably S-1 -amino-ethyl, terbutoxy-carbonyl-amino-methyl or R, S-, R-, or preferably S- 1 - (terbutoxy-carbonyl-amino) -ethyl, carboxy-lower alkyl, typically 2-carboxy-ethyl, lower alkoxy-carbonyl-lower alkyl, typically 2- (terbutoxy-carbonyl) -ethyl, cyano-lower alkyl, typically -cyano-ethyl, tetrahydro-pyranyloxy-lower alkyl, typically 4- (tetrahydro-pyranyl) -oxi-methyl, morpholino-lower alkyl, typically 2- (morpholino) -ethyl, phenyl, lower alkyl-phenyl, typically 4-methyl phenyl, lower alkoxy-phenyl, typically 4-methoxy-phenyl, imidazolyl-lower alkoxy-phenyl, typically 4- [2- (imidazol-1-yl) -ethyl) -oxy-phenyl, carboxy-phenyl, typically 4- carboxy-phenyl, lower alkoxy-carbonyl-phenyl, typically 4-ethoxy-carbonyl-phenyl or 4-methoxy-phenyl, halo-lower alkyl-phenyl, typically 4-chloro-methyl-phenyl, pyrrolidino-phenyl, typically 4-pyrr olidino-phenyl, imidazol-1-phenyl, typically 4- (imidazolyl-1 -i I) -fe or p, piperazino-phenyl, typically 4-piperazino-phenyl, (4-lower alkyl-piperazino) -phenyl, typically 4- (4-methyl-piperazino) -phenyl, morpholino-phenyl, typically 4-morpholino-phenyl, pyrrolidino-lower alkyl-phenyl, typically 4-pyrrolidino-methyl-phenyl, imidazol-1-yl-lower alkyl-phenyl , typically 4- (imidazolyl-1-yl-methyl) -phenyl, piperazino-lower alkyl-phenyl, typically 4-piperazino-methyl-phenyl, (4-lower alkyl-piperazino-methyl) -phenyl, typically 4- (4 methyl-piperazino-methyl) -phenyl, morpholino-lower alkyl-phenyl, typically 4-morpholino-methyl-phenyl, piperazino-carbonyl-phenyl, typically 4-piperazino-carbonyl-phenyl, or (4-alkyl) lower p-piperazino) -phenyl, typically 4- (4-methyl-piperazin o) -fe or lo.

Preferred acyl radicals Ac1 are acyl radicals of a carboxylic acid, which are characterized by the sub-formula R ° -CO-, wherein R ° has one of the above general and preferred meanings of the hydrocarbyl radical R ° . Especially preferred radicals R ° here are lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is deprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically teralkoxy lower carbonyl, for example terbutoxycarbonyl, for example, amino-methyl, R, S-, R-, or preferably S-1-amino-ethyl, terbutoxy-carbonyl-amino-methyl or R, S-, R-, or preferably S-1 - (terbutoxi- carbonyl-amino) -ethyl, carboxy-lower alkyl, typically 2-carboxy-ethyl, lower alkoxy-carbonyl-lower alkyl, typically 2- (terbutoxy-carbonyl) -ethyl, tetrahydro-pyranyloxy-lower alkyl, typically 4- ( tetrahydro-pyranyl) -oxi-methyl, phenyl, imidazolyl-lower alkoxy-phenyl, typically 4- [2- (imidazol-1-yl) -ethyl] -oxi-phenyl, carboxy-phenyl, typically 4-carboxy-phenyl, lower alkoxy-carbonyl-phenyl, typically 4-ethoxy-carbonyl-phenyl, halo-lower alkyl-phenyl, typically 4-chloro-methyl-phenyl, imidazol-1-phenyl, typically 4- (imidazolyl-1-yl) phenyl, pyrrolidino-lower alkyl-phenyl, typically 4-pyrrolidino-methyl-phenyl, piperazino-lower alkyl-phenyl, typically 4-piperazino-methyl-phenyl, (4-lower alkyl-piperazino-methyl) -phenyl, typically 4-pyrrolidino-lower alkyl-phenyl. - (4-methyl-piperazino-methyl) -phenyl, morph olino-lower alkyl-phenyl, typically 4-morpholino-methyl-phenyl, piperazine-carbonyl-phenyl, typically 4-piperazinocarbonyl-n -yl, or (4-lower alkyl-piperazino) -phenyl, typically 4- (4-methyl-pipe-razino) -phenyl. A further preferred Acl acyl is derived from monoesters of carbonic acid, and is characterized by the sub-formula R ° -0-CO-. Lower alkyl radicals, especially tertiary butyl radicals, are especially preferred hydrocarbyl radicals R ° in these derivatives. Another preferred Acl acyl is derived from the amides of carbonic acid (or also thiocarbonic acid), and is characterized by the formula R ° H NC (= W) - or R ° R ° NC (= W) -, in where the radicals R ° are, independently of one another, as defined above, and W is sulfur and especially oxygen. In particular, compounds are preferred wherein Ac1 is a radical of the formula R ° HN-C (= W) -, wherein W is oxygen and R ° has one of the following preferred meanings: morpholino-lower alkyl, typically 2 -morpholino-ethyl, phenyl, lower alkoxy-phenyl, typically 4-methoxy-phenyl or 4-ethoxy-phenyl, carboxy-phenyl, typically 4-carboxy-phenyl, or lower alkoxy-carbonyl-phenyl, typically 4-ethoxy-carbonyl -phenyl. A preferred Ac2 acyl of the sub-formula R ° -S02-, wherein R ° is a hydrocarbyl as defined in the above general and specific meanings, is lower alkyl-phenylsulfonyl, typically 4-toluenesulfonyl. If p is 0, the nitrogen atom that binds R3 is not loaded . If p is 1, then R4 must also be present, and the nitrogen atom linking R3 and R (quaternary nitrogen) is then positively charged. The definitions for an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms each, or for a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms each, and up to 9 heteroatoms each, or acyl with up to 30 carbon atoms each, preferably according to the definitions given for the corresponding radicals R3 and R4. R5 is preferably used as lower alkyl, especially methyl, or more especially hydrogen. Z is especially lower alkyl, more especially methyl or hydrogen. If the two bonds indicated by the wavy lines in ring A are missing, then there are no double bonds (tetra-hydrogenated derivatives) present between the carbon atoms characterized in formula I by the numbers 1, 2, 3, and 4, but that there are only individual bonds, while ring B is aromatic (double bonds between carbon atoms characterized in formula I by 8 and 9, and those characterized by 1 0 and 1 1). If the two bonds indicated by the wavy lines in the ring B are missing, then there are no doubles in laces (tetrahydrogenated derivatives) present between the carbon atoms characterized in formula I by the numbers 8, 9, 1 0, and 1 1, but there are only individual links, while ring A is aromatic (double bonds between carbon atoms characterized in formula I by 1 and 2, and those characterized by 3 and 4). If the total of the four bonds indicated by the wavy lines in the rings A and B are missing, and are replaced by a total of 8 hydrogen atoms, then there are no double bonds (octa-hydrogenated derivatives) present between the carbon atoms numbered as 1, 2, 3, 4, 8, 9, 10, and 11 in the formula I, but only individual links. By their nature, the compounds of the invention may also be present in the form of pharmaceutically, ie, physiologically, acceptable salts, provided they contain salt-forming groups. For the isolation and purification, pharmaceutically unacceptable salts can also be used. For therapeutic use, only pharmaceutically acceptable salts are used, and these salts are preferred. Accordingly, the compounds of the formula I that have free acid groups, for example a sulfo, phosphoryl or free carboxyl group, can exist as a salt, preferably as a physiologically acceptable salt with a basic salt-forming component. These 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 with suitable organic amines, especially tertiary monoamines. and heterocyclic bases, for example triethylamine, tri- (2-hydroxy-ethyl) -amine, N-ethyl-piperidine or?,? '- dimethyl-piperazine.

The compounds of the invention having a basic character can also exist as addition salts, in particular as the acid addition salts with inorganic or organic acids, but also as quaternary salts. Accordingly, for example, compounds having a basic group, such as an amino group, as a substituent, can form the acid addition salts with common acids. Suitable acids are, for example, hydrohalic acids, for example, hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or perchloric acid, or the aliphatic, alicyclic, aromatic, or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxy-maleic, oxalic, pyruvic, phenyl-acetic, benzoic, p-amino-benzoic, anthranilic, p-hydroxy-benzoic acid , salicylic, p-amino-salicylic, pamoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxy ethanesulfonic acid, ethylene disulfonic acid, halobenzenesulfonic acid, toluenesulphonic acid, naphthalene sulfonic acid, or sulphanilic acid, and also methionine , tryptophan, lysine, or arginine, as well as ascorbic acid. In view of the close relationship between the compounds (especially of the formula I) in free form and in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the novel compounds, and of their solvates, any reference hereinbefore and hereinafter to the free compounds should be understood to refer also to the salts corresponding, and to the solvates thereof, for example hydrates, as appropriate and convenient. The compounds of formula A, B, C, D, I, II, III, IV, V or VI, especially those in which R5 is hydrogen, possess valuable pharmacological properties. In the case of the groups of radicals or compounds mentioned hereinbefore and hereinafter, the general definitions, to the extent appropriate and convenient, may be replaced by the more specific definitions mentioned hereinbefore and later herein. . Preference is given to a compound of the formula I, II, III, IV, V, VI wherein: Ri and R2 independently from each other, are lower alkyl, lower alkyl substituted by halogen, aryl of 6 to 14 carbon atoms, hydroxyl, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkyl-amino, lower alkanoyl-amino, phenyl-lower alkyl-amino, N, N-di-lower alkyl-amino, N, N -di- (phenyl-lower alkyl) -amino, cyano, mercapto, lower thioalkyl, carboxyl, lower alkoxy-carbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl, sulfo, lower alkane -sulfonyl, lower alkoxyl-sulfonyl, amino-sulfonyl, N-lower alkyl-amino-sulfonyl or N, N-di-lower alkyl-amino-sulfonyl; halogen; lower alkoxy; aryloxy from 6 to 14 carbon atoms; aryl of 6 to 14 carbon atoms-alkoxy lower; lower alkanoyloxy; aryl of 6 to 14 carbon atoms-carbonyloxy; amino mono-substituted or di-substituted by lower alkyl, aryl of 6 to 14 carbon atoms, aryl of 6 to 14 carbon atoms-lower alkyl, lower alkanoyl or aryl of 6 to 12 carbon atoms-carbonyl; cyano; nitro; mercapto; lower thioalkyl; thioaryl of 6 to 14 carbon atoms; aryl of 6 to 14 carbon atoms-lower thioalkyl; lower thioalkanoyl; aryl of 6 to 14 carbon atoms-lower thioalkanoyl; carboxyl; lower alkoxy-carbonyl, aryl of 6 to 14 carbon atoms-lower alkoxy-carbonyl; aryloxy from 6 to 14 carbon atoms-carbonyl; carbamoyl; carbamoyl Kimono- or N, N-di-substituted by lower alkyl, aryl of 6 to 14 carbon atoms or aryl of 6 to 14 carbon atoms-lower alkyl; sulfo; aryl of 6 to 14 carbon atoms-sulfonyl; aryl of 6 to 14 carbon atoms-lower alkane-sulfonyl; lower alkane sulfonyl; or amino-sulfonyl N-mono- or, N-di-substituted by lower alkyl, aryl of 6 to 14 carbon atoms or aryl of 6 to 14 carbon atoms-lower alkyl, wherein aryl of 6 to 14 carbon atoms is an aryl radical with 6 to 12 carbon atoms in the ring system, which may be unsubstituted or substituted by halogen, phenyl or naphthyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino , lower alkyl-amino, lower alkanoyl-amino, phenyl-lower alkyl-amino, N, N-di-lower alkyl-amino, N, N-di- (phenyl-lower alkyl) -amino, cyano, mercapto, lower thioalkyl , carboxyl, lower alkoxy-carbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,? -di-lower alkyl- carbamoyl, sulfo, lower alkane-sulfonyl, lower alkoxyl-sulfonyl, amino-sulfonyl, N-lower alkyl-amino-sulfonyl or N, N-di-lower alkylamino-sulfonyl; n and m are independently of each other 0 or 1 or 2, preferably 0; R3,, e. R10 are independently from each other hydrogen, lower alkyl, lower alkenyl or lower alkadienyl, which are each unsubstituted or mono-substituted or poly-substituted, preferably mono-substituted or di-substituted by a substituent independently selected from alkyl lower; hydroxyl; lower alkoxy, which may be unsubstituted or mono-, di-, or tri-substituted by (i) heterocyclyl with 4 to 12 ring atoms, which may be unsaturated, fully saturated, or partially saturated, is monocyclic or bicyclic, and may contain up to three heteroatoms selected from nitrogen, oxygen and sulfur, and is more especially pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 2-, 3- or 4-pyridyl, or in a sense broader 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-fold. isoquinolyl, benzofuranyl, typically 2-benzo-furanyl, chromenyl, typically 3-chromenyl, benzo-thienyl, typically 2- or 3-benzo-thienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2- or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2- thiazolyl, benzimidazole, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydro-furyl, 4-tetrahydro-furyl, 4-tetrahydro-pyranyl, 1-, 2- or 3-pyrrolidyl , 1-, 2-, 3-, or 4-piperidyl, 1-, 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or N, N'-bis-lower alkyl-2-piperazinyl, (ii) by halogen, (iii) by hydroxyl, or (iv) by lower alkoxy; phenoxy; phenyl-lower alkoxy; heterocyclyloxy, 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, benzo-furanyl, typically 2-benzo-furanyl, chromenyl, typically 3-chromenyl, benzo-thienyl, typically 2- or 3-benzo-thienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydro-furyl, 4-tetrahydro-furyl, 2- or 4-tetrahydro-pyranyl, 1-, 2- or 3-pyrrolidyl, 1-, 2-, 3 -, or 4-piperidyl, 1-, 2- or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or β, β'-bis-lower alkyl-2-piperazinyl, such as in particular 2 or 4 -tetrahydro-pyranyloxy; lower alkanoyloxy; carboxyl; lower alkoxycarbonyl; phenyl lower alkoxycarbonyl; mercapto; lower thioalkyl; thiophenyl; halogen; halo- lower alkyl; oxo (except in position 1, because otherwise it is acyl); azido; nitro; cyano; Not me; mono-lower alkyl-amino; di-lower alkyl-amino; pyrrolidino; imidazol-1-yl; piperidino; piperazine; 4-lower alkyl-piperazino; morpholino; thiomorpholino; diphenyl-amino or dibenzyl-amino unsubstituted or substituted on the phenyl portion by lower alkyl, lower alkoxy, halogen and / or nitro; lower alkylcarbonyl amino; phenyl-infenor-carbonyl-amino alkyl unsubstituted or substituted on the phenyl portion by lower alkyl or lower alkoxy; fluorenyl-methoxy-carbonyl-amino; amino-lower alkyl; amino-mono-substituted or di-substituted lower alkyl, wherein the amino substituent is selected from lower alkyl, hydroxy-lower alkyl, cycloalkyl of 3 to 8 carbon atoms, amino-lower alkyl, N-mono- or N, N-di - (- lower alkyl) -amino-lower alkyl, amino, N-mono- or N, N-di-lower alkyl-amino and N-mono- or N, N-di- (hydroxy-alkyl) Bottom) -amino; pyrrolidino-lower alkyl; piperidino-lower alkyl; piperazino-lower alkyl; 4-lower alkyl-piperazino-lower alkyl; imidazol-1-yl-lower alkyl, morpholino-lower alkyl; thiomorpholino-lower alkyl; S-oxo-thiomorpholino-lower alkyl; S, S-dioxo-thiomorpholino-lower alkyl; lower alkylenedioxyl; sulfamoyl; sulfo; carbamoyl; ureido; guanidino; cyano; aminocarbonyl (carbamoyl) and aminocarbonyloxy, which are substituted by one or two radicals on the nitrogen, wherein the amino substituents are independently selected from the group consisting of lower alkyl, hydroxy-lower alkyl, 3-cycloalkyl 8 carbon atoms, amino-lower alkyl, N-mono- or N, N-di - (- lower alkyl) -amino-lower alkyl, amino, N-mono- or N, Nd-lower alkyl-amino and N -mono- or N, N-di- (hydroxy-lower alkyl) -amino; pyrrolidinocarbonyl; piperidinocarbonyl; piperazine carbonyl; 4-lower alkyl-piperazinocarbonyl; imidazolinocarbonyl; morpholino-carbonyl; thiomorpholinocarbonyl; S-oxo-thiomorpholino-carbonyl; and S, S-dioxo-thiomorpholino; phenyl, naphthyl, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, which is unsubstituted or mono-substituted or di-substituted by the radicals mentioned above as substituents of lower alkyl, lower alkenyl or lower alkydlyl; or 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, benzo-furanyl, typically 2- benzo-furanyl, chromenyl, typically 3-chromenyl, benzo-thienyl, typically 2- or 3-benzo-thienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2- or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzimidazolyl, typically 2-benzimidazolyl, benzyl. oxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydro-furyl, 4-tetrahydro-furyl, 2- or 4-tetrahydro-pyranyl, 1-, 2- or 3-pyrrolidyl, 1-, 2- , 3-, or 4-piperidyl, 1-, 2- or 3- morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or? , β-bis-lower alkyl-2-piperazinyl, which in each case are unsubstituted or mono-substituted or di-substituted by the radicals mentioned above as substituents of lower alkyl, lower alkenyl, or lower alkydlyl; or acyl of the sub-formula u the YC (= W) -, where W is oxygen and Y is hydrogen, R °, R ° -0-, R ° HN-, or R ° R ° N- (in wherein the radicals R ° may be the same or different), or acyl of the sub-formula R ° -S02-, wherein R4 may also be absent for the compound of the formula II; or R4 is absent for the compounds of the formula II, hydrogen, or CH3 for the compounds of the formula I, and R3 is acyl of the sub-formula YC (= W) -, where W is oxygen and Y is hydrogen, R °, R ° -0-, R ° H N-, or R ° R ° N- (where the radicals R ° may be the same or different), or is acyl of the sub-formula R ° -S02-, wherein R ° in 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 deprotected or protected by an amino protecting group conventional - especially by lower alkoxy carbonyl, typically lower teralkoxycarbonyl, for example terbutoxycarbonyl-for example, amino-methyl, R, S-, R- or preferably S-1-amino-ethyl, terbutoxy-carbonyl-amino-methyl or R, S -, R-, or preferably S-1 - (terbutoxy-carbonyl-amino) -ethyl, carboxy-lower alkyl, typically 2-carboxy-ethyl, lower alkoxy-carbonyl-lower alkyl, typically 2- (terbutoxy-carbonyl) -ethyl, cyano-lower alkyl, typically 2-cyano-ethyl, tetrahydro-pyranyloxy-lower alkyl, typically 4- (tetrahydro-pyranyl) -oxi-methyl, morpholino-lower alkyl, typically 2- (morpholino) -ethyl, phenyl , lower alkyl-phenyl, typically 4-methyl-phenyl, lower alkoxy-phenyl, typically 4-methoxy-phenyl, imidazolyl-lower alkoxy-phenyl, typically 4- [2- (imidazol-1-l) -eti I) ox if eni, carboxy-phenyl, typically 4-carboxy-phenyl, lower alkoxy-carbonyl-phenyl, typically 4-ethoxy-carbonyl-phenyl or 4-methoxy-phenyl, halo-lower alkyl-phenyl, typical 4-chloro-methyl-phenyl, pyrrolidino-phenyl, typically 4-pyrrolidino-phenyl, imidazol-1-phenyl, typically 4- (imidazolyl-1 -i I) -pheni I, piperazino-phenyl, typically 4-piperazino-phenyl, (4-lower alkyl-piperazino) -phenyl, typically 4- (4-methyl-piperazino) -phenyl, morpholino-phenyl, typically 4-morpholino-phenyl, pyrrolidino-lower alkyl-phenyl, typically 4-pyrrolidino-methyl-phenyl, imidazol-1 -i I-I I or lower -phenyl, typically 4- (imidazolyl-1-methyl-methyl) -phenyl, piperazino-lower alkyl-phenyl, typically 4-piperazino-methyl-phenyl, (4-lower alkyl-piperazino-methyl) -phenyl, typically 4- (4-methyl-piperazino-methyl) -phenyl, morpholino-lower alkyl-phenyl, typically 4-morpholino-methyl-phenyl, piperazino-carbonyl-phenyl, typically 4- piperazino-ca-rbonyl-phenyl, or (4-a-lower alkyl-piperazino) -phenyl, typically 4- (4-methyl-ethyl-piperazino) -phenyl. p is 0 if R4 is absent, or is 1 if R3 and R4 are both present, and in each case are from the aforementioned radicals (for the compounds of the formula I I); R5 is hydrogen or lower alkyl, especially hydrogen, X represents 2 hydrogen atoms, O, or 1 hydrogen atom and hydroxyl; or 1 hydrogen atom and lower alkoxy; Z is hydrogen or especially lower alkyl, more especially methyl; and for the compounds of formula II, either the two bonds characterized by wavy lines are preferably absent in ring A and are replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel link, means a double bond; or also the two bonds characterized by wavy lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, means a double bond; or both in ring A and in ring B, all 4 wavy bonds are absent and are replaced by a total of 8 hydrogen atoms; or a salt thereof, if at least one salt forming group is present.

A particular preference is given to a combination of the formula I, where; m and n are each 0; R3 and R4 are independently from each other: hydrogen, unsubstituted or mono- or di-substituted, especially mono-substituted, lower alkyl radicals independently selected from carboxyl; lower alkoxycarbonyl; and cyano; or R 4 is hydrogen or -CH 3, and R 3 is as defined above or preferably R 3 is acyl of the sub-formula R ° -CO, wherein R ° is lower alkyl; amino-lower alkyl, wherein the amino group is present in an unprotected form or is protected by lower alkylcarbonyl; tetrahydro-pyranyloxy-lower alkyl; phenyl; imidazolyl-lower alkoxy-phenyl; carboxy-phenyl; lower alkoxy-carbonyl-phenyl; halo-lower alkyl-phenyl; imidazol-1-phenyl; pyrrolidino-lower alkyl-phenyl; piperazino-lower alkyl-phenyl; (4-lower alkyl-piperazino-methyl) -phenyl; morpholino-lower alkyl-phenyl; piperazinocarbonylphenyl; or (4-lower alkoyl-piperazino) -phenyl; or is acyl of the sub-formula R ° -0-CO-, wherein R ° is lower alkyl; or is acyl of the sub-formula R ° H N-C (= W) -, wherein W is oxygen and R ° has the following meanings: morpholino-lower alkyl, phenyl, lower alkoxy-phenyl, carboxy-phenyl, or alkoxy lower-carbon il-phen ilo; or R3 is lower alkyl phenyl sulfonyl, typically 4-toluene sulfonyl, where further specific examples of the preferred R3 groups for preferred compounds of formula II are described below, R5 is hydrogen or lower alkyl, especially hydrogen, X represents 2 hydrogen atoms or O; Z is methyl or hydronogen; or a salt thereof, if at least one salt forming group is present. A particular preference is given to a compound of the formula I I wherein: m and n are each 0; R3 and R4 are independently of one another: hydrogen, unsubstituted or mono- or di-substituted, especially mono-substituted, lower alkyl radicals selected independently from each other from carboxyl; lower alkoxycarbonyl; and cyano; where R4 may also be absent; or R 4 is absent, and R 3 is acyl from the sub-formula R ° -CO, wherein R ° is lower alkyl, especially methyl or ethyl; amino-lower alkyl, wherein the amino group is deprotected or protected by lower alkoxycarbonyl, typically lower teralkoxycarbonyl, e.g. terbutoxycarbonyl, e.g., amino-methyl, R, S-, R-, or preferably S-1-amino-ethyl, terbutoxy-carbonyl-amino-methyl or R, S-, R-, or preferably S-1 - (terbutoxy-carbonyl-amino) -ethyl; tetrahydro-pyranyloxy-lower alkyl, typically 4- (tetrahydro-pyranyl) -oxi-methyl; phenyl; imidazolyl-lower alkoxy-phenyl, typically 4- [2- (imidazol-1-yl) -ethyl) -oxy-phenyl; carboxy-phenyl, typically 4-carboxy-phenyl; lower alkoxy-carbonyl-phenyl, typically 4-methoxy- or 4-ethoxycarbonyl-phenyl; halo-lower alkyl-phenyl, typically 4-chloro-methyl-phenyl; Midazole-1 -i I -fe n i I o, typically 4- (im-idazolyl-1-yl) -phenyl; pyrrolidino-lower alkyl-phenyl, typically 4-pyrrolidino-methyl-phenyl; piperazino-lower alkyl-phenyl, typically 4-piperazino-methyl-phenyl; (4-lower alkyl-piperazino-methyl) -phenyl, typically 4- (4-methyl-piperazino-methyl) -phenyl; morph or flax-lower alkyl-phenyl, typically 4-morph or lino-methyl-phenyl; pipe razino-carbonyl-phenyl, typically 4-piperazino-carbonyl-phenyl; or (4-lower alkyl-piperazino) -phenyl, typically 4- (4-methyl-piperazino) -phenyl; or is acyl of the sub-formula R ° -0-CO-, wherein R ° is lower alkyl; or is acyl of the sub-formula R ° HN-C (= W) -, wherein W is oxygen and R ° has the following preferred meanings: morpholino-lower alkyl, typically 2-morpholino-ethyl, phenyl, lower alkoxy- phenyl, typically 4-methoxy-phenyl or 4-ethoxy-phenyl, carboxy-phenyl, typically 4-carboxy-phenyl, or lower alkoxy-carbonyl-phenyl, typically 4-ethoxy-carbonyl-phenyl; or is lower alkyl-phenylsulfonyl, typically 4-toluenesulfonyl; p is O if R4 is absent, or is 1 if R3 and R are both present, and in each case are from the above-mentioned radicals; R5 is hydrogen or lower alkyl, especially hydrogen, X represents 2 hydrogen atoms or O; Z is methyl or hydronogen; and whether the two bonds characterized by wavy lines are preferably absent in ring A and are replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel link, means a double bond; or also the two bonds characterized by wavy lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, means a double link; or both in ring A and in ring B, all 4 wavy bonds are absent and are replaced by a total of 8 hydrogen atoms; or a salt thereof, if at least one salt forming group is present. More especially, the preferred compounds of the formula I I are selected from; 8.9, 1 0, 1 1 -tetrahydro-staurosporine; N- [4- (4-methyl-piperazin-1-methyl-methyl) -benzoyl] -1, 2, 3,4-tetrahydro- staurosporine; N- (4-chloro-methyl-benzoyl) -, 2, 3, 4-tetrah id ro -staurosporin; N- (4- (pyrrolidin-1-methyl-methyl) -benzoyl) -1, 2,3,4-tetrahydro-staurosporine; N- (4- (morpholin-4-yl-methyl) -benzoyl) -1, 2,3,4-tetrahydro-staurosporine; N- (4- (piperazin-1-methyl-methyl) -benzoyl) -1, 2,3,4-tetrahydro-staurosporine; N-ethyl-1, 2,3,4-tetrahydro-staurosporine; N-tosyl-1, 2,3,4-tetrahydro-staurosporine; N-trifluoro-acetyl-1, 2,3,4-tetrahydro-staurosporine; N- [4- (2-imidazol-1-yl-ethoxy) -benzoyl] -1, 2,3,4-tetrahydro-staurosporine; N-methoxy-carbonyl-methyl-1, 2,3,4-tetrahydro-staurosporine; N-carboxymethyl-1, 2,3,4-tetrahydro-staurosporine; N-terephthaloyl-methyl-ester-1, 2,3,4-tetrahydro-staurosporine; N-terephthaloyl-1, 2,3,4-tetrahydro-staurosporine; N- (4-ethyl-piperazinyl-carbonyl-benzoyl) -1, 2,3,4-tetrahydro-staurosporine; N- (2-cyano-ethyl) -1, 2,3,4-tetrahydro-staurosporine; N-benzoyl-1, 2,3,4-tetrahydro-staurosporine; N, N-dimethyl-1, 2,3,4-tetrahydro-staurosporinium iodide; N-BOC-glycyl-1, 2,3,4-tetrahydro-staurosporine; N-glycyl-1, 2,3,4-tetrahydro-staurosporine; N- (3- (terbutoxy-carbonyl) -propyl) -1, 2,3,4-tetrahydro- staurosporine; N- (3-carboxy-propyl) -1, 2,3,4-tetrahydro-staurosporine; N- (4-imidazol-1-yl) -benzoyl] -1, 2,3,4-tetrahydro-staurosporine; N - [(tetrahydro-2 H -pyran-4-yloxy) -acetyl] -1,2,4,4-tetrahydro-staurosporine; N-BOC-l-alanyl-1, 2,3,4-tetrahydro-staurosporine; N-l-alanyl-1, 2,3,4-tetrahydro-staurosporine hydrochloride; N-methyl-1, 2,3,4-tetrahydro-6-methyl-staurosporine; N- (4-carboxy-phenyl-amino-carbonyl) -1, 2,3,4-tetrahydro-staurosporine; N- (4-ethyl-phenyl-amino-carbonyl) -1, 2, 3, 4-tetrahydro-staurosporine, N- (N-phenyl-amino-carbonyl) -1, 2,3,4-tetrahydro-staurosporine; N- (N- [2- (1-morpholino) -ethyl] -amino-carbonyl) -1, 2, 3, 4-tetrahydro-staurosporine; N- (N- [4-methoxy-phenyl] amino-carbonyl) -1, 2, 3, 4-tetrahydro-staurosporine; 1, 2,3,4-tetrahydro-6-methyl-staurosporine; N-BOC-1, 2, 3,4-tetrahydro-staurosporine, N-BOC-1, 2,3,4-tetrahydro-6-methyl-staurosporine; N-BOC-1, 2,3,4-tetrahydro-6-methyl-7-oxo-staurosporine; 1,2,3,4,8,9,10,11-octahydro-staurosporine; or a pharmaceutically acceptable salt thereof, if at least one salt-forming group is present. More preferably, especially the compound of the formula I designated as 1, 2,3,4-tetrahydro-staurosporine, or a salt (in particular pharmaceutically acceptable) thereof (here, m and n in formula I are 0, R3 is hydrogen, R4 is absent, with the understanding that there is no salt present (p = 0), or is hydrogen if a salt is present (p = 1), R5 is hydrogen, the two bonds represented by wavy lines are absent in ring A and are replaced by a total of 4 atoms of hydrogen, and the two bonds represented by wavy lines in ring B are in each case a double bond together with the parallel bonds, X represents 2 hydrogen atoms, and Z is methyl). More especially, the compounds of the formula A are preferred wherein: A) X = O; R1 (R2, R5 = H, Q = - (CH2) 2-0-CH (CH2) OH- (CH2) 2- B) X = O; RL R2, R5 = H; Q = - (CH2) 2-0-CH (CH2N (CH3) 2) - (CH2) 2- C) X = 2 hydrogen atoms; R1p R2, R5 = H; Q = More especially, the compounds of the formula I are preferred, wherein: A) X = 2 hydrogen atoms; Ri, R2, R3, Rs = H; R4 = CH3; Z = CH3 (staurosporine); B) X = 1 hydrogen atom and 1 hydroxyl atom in the isomeric form (R) or (S); Ri, R2, R3, R5 = H; R4 = CH3; Z = CH3 (UCN- 01 and UCN-02); C) X = 2 hydrogen atoms; Ri, R2, Rs = H; R4 = CH3; R3, = benzoyl; Z = CH3 (CGP41251 or PKC412 or MIDOSTAURIN); D) X = O; Ri, R2, R5 = H; R3, = CH3; R 4 = ethyloxycarbonyl; Z = CH3 (NA 382; CAS = 143086-33-3); E) X = 1 hydrogen atom and 1 hydroxyl atom; R (R2, R5 = H, R3 = CH3, Z = CH3, and R4 is selected from - (CH2) 2OH; -CH2CH (OH) CH2OH; -CO (CH2) 2C02Na; - (CH2) 3C02H; COCH2N (CH3) 2; - (CH2) 2OCO - / N- CH3 -CO- ^ N- CH3 -COCH- - CH3 F) X = 2 hydrogen atoms; R ,, R2, R5 = H; R3 = CH3; Z = CH3; and R 4 is selected from N- [0- (tetrahydro-pyran-4-yl) -D-lactoyl]; N- [2-methyl-2- (tetrahydro-pyran-4-yloxy) -propionyl; N- [0- (tetrahydro-pyran-4-yl) -L-lactoyl]; N- [0- (tetrahydro-pyran-4-yl) -D-lactoyl]; N- [2- (tetrahydro-pyran-4-yloxy) -acetyl)]; G) X = 0; Ri, R2, R5 = H; R3 = CH3; Z = CH3; and R 4 is selected from N- [0- (tetrahydro-pyran-4-yl) -D-lactoyl]; N- [2- (tetrahydro-pyran-4-yloxy) -acetyl)]; H) X = 1 hydrogen atom and 1 hydroxyl atom; Ri, R2, R5 = H; R3 = CH3; Z = CH3; and R 4 is selected from N- [0- (tetrahydro-pyran-4-yl) -D-lactoyl] N- [2- (tetrahydro-pyran-4-yloxy) -acetyl)]. The abbreviation "CAS" means the registration number of CHEMICAL ABSTRACTS. The most preferred compounds of formula I for example, MIDOSTAURIN [International Non-Registered Name] are covered and have been specifically described by European Patent Number 0 296 110 published on December 21, 1988, as well as in the United States Patent. of North America Number 5; 093,330 published March 3, 1992, and in Japanese Patent Number 2 708 047. Other preferred compounds are covered and described by Patent Applications Nos. WO 95/32974 and WO 95/32976, both published on December 7, 1995. All compounds described in these documents are incorporated herein by reference. More especially, the compounds of the formula are preferred III where: A) X = 2 hydrogen atoms; Ri, R2, 5 = H; R6 = CH3; R7 = methyloxycarbonyl; Z = H (2-methyl K252a), B) X = 2 hydrogen atoms; methyloxycarbonyl; Z = H (K-252a), C) X = 2 hydrogen atoms; R ,, R2, R5, R6 = H; R7 = methyloxycarbonyl; Z = CH3 (KT-5720). More especially, the compounds of the formula are preferred IV where: A) X = O; R ,, R2, R5 = H; R9 = CH2-NMe2; R8 = CH3; m '= n' = 2 B) X = O; R ,, R2, R5 = H; R9 = CH2-NH2; R8 = CH3; m '= 2; n '= 1 (Ro-31-8425; CAS = 151342-35-7).

More especially, the compounds of the formula are preferred V where: A) X = O; R1f R2, R5 = H; R8 = CH3; R10 = - (CH2) 3-NH2; (Ro-31-7549; CAS = 138516-31), B) X = O; R1f R2, R5 = H; R8 = CH3; R10 = - (CH2) 3-S- (C = NH) -NH2; (Ro-31-8220; CAS = 125314-64-9)), C) X = O; Ri, R2 R5 -CH3. More especially, the compounds of the formula are preferred VI where: A) X = 2 hydrogen atoms; Ri, R2, R5 = H; R = CH3; Z = CH3; R3 is selected from methyl or alkyl (from 1 to 10 carbon atoms), arylmethyl, C6H2CH2-. The DERIVATIVES OF STAUROSPORINE and its manufacturing process have been described in a specific manner in many previous documents, well known to the expert. The compounds of formula A, B, C, D and their manufacturing process have been described, for example, in European Patent Number 0 657 458 published on June 14, 1995, in European Patent Number 0 624 586 published on November 17, 1994, in European Patent Number 0470490 published on February 12, 1992, in European Patent Number 0 328 026 published August 16, 1989, in European Patent Number 0 384 349 published on August 29, 1990, as well as in many publications, such as Barry M. Trost * and Weiping Tang Org. Lett., 3 (21), 3409-3411.

The compounds of formula I, and their manufacturing processes have been described in a specific manner in European Patent Number 0 296 110 published on December 21, 1988, as well as in U.S. Patent Number 5; 093,330 published March 3, 1992, and in Japanese Patent Number 2 708 047. Compounds of formula I having a tetrahydro-pyran-4-yl-lactoyl substitution on R4 have been described in European Patent Number 0 624 590 published on November 17, 1994. Other compounds have been described in European Patent Number 0 575 955 published on December 29, 1993, in European Patent Number 0 238 011 published on September 23, 1987 (UCN- 01), in International Patent Application Number EP98 / 04141 published as International Publication Number WO99 / 02532 on July 3, 1998. The compounds of formula II and their manufacturing processes have been described in a specific manner in the patent. European Number 0 296 110 published on December 21, 1988, as well as in U.S. Patent Number 5; 093,330 published March 3, 1992, and in Japanese Patent Number 2708047. The compounds of formula III and their process The manufacturing processes have been described in a specific manner in the patent applications claiming the priority of U.S. Patent Application Number US 920102 filed July 24, 1992. (ie, European Patent Number 0 768 312 published on April 16, 1997, Number 1 002534 published on May 24, 2000, Number 0 651 754 published May 10, 1995). The compounds of formula IV and their manufacturing processes have been described in a specific manner in the patent applications claiming the priority of British Patent Applications Nos. GB 9309602 and GB 9403249, respectively, filed on May 10, 1993, and February 21, 1994. (ie, European Patents Number 0 624 586 published November 17, 1994, Number 1 002 534 published May 24, 2000, Number 0 651 754 published May 10, 1995) . The compounds of formula V and their manufacturing processes have been described in a specific manner in the patent applications claiming the priority of British Patent Applications Nos. GB 8803048, GB 8827565, GB 8904161 and GB 8928210, respectively, filed on February 10, 1988, the November 25, 1988, February 23, 1989 and December 13, 1989. (ie, European Patents Number 0 328 026 published on August 16, 1989, and Number 0 384 349 published on August 29, 1990). The compounds of the formula VI and their manufacturing processes have been described in a specific manner in the patent applications claiming the priority of the United States Patent Application Number 07 / 777,395 (Con), filed on 10 October 1991 (ie, International Patent Application Number WO 93/07153 published on April 15, 1993). In each case where citations of patent applications or scientific publications are given, in particular for the compounds DERIVATIVES OF STAUROSPORINE, the subject matter of the final products, the pharmaceutical preparations and the claims, are incorporated in the present application by reference to these publications. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index" or from the databases, for example, Patents International (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. The preferred ESTUROSPORINE DERIVATIVE according to the invention is N - [(9S, 1 OR, 11 R, 13f?) - 2,3, 10, 11, 12, 13-hexahydro-10-methoxy-9-methyl- 1 -oxo-9, 13-epoxy-1 -, 9 / - diindolo [1, 2,3- , 7] -benzo-diazonin-11 -yl] - / V-methyl-benzamide of the formula (VII): or a salt of it (later in the present: "The compound of the formula VII or MIDOSTAURIN ") The compound of the formula VII is also known as MIDOSTAURIN [International Unregistered Name] or PKC412. MIDOSTAURIN is a derivative of the alkaloid which naturally occurs staurosporine, and has been described in a manner specific in European Patent Number 0 296 110 published on December 21, 1988, as well as in U.S. Patent Number 5; 093,330 published March 3, 1992, and in Japanese Patent Number 2708047. In addition, the invention provides the use of a compound of the formula I (or a pharmaceutically acceptable salt or prodrug ester thereof), for the preparation of a medicament for use in the treatment of a proliferative disease In a further aspect, the invention provides the use of a compound of the formula I (or a pharmaceutically acceptable salt or prodrug ester thereof), for the treatment of a proliferative disease, in special a sarcoma, more especially aRMS. In a still further aspect, the invention provides a compound of the formula I (or a pharmaceutically acceptable salt or prodrug ester thereof), as an active ingredient for use in the treatment of a proliferative disease, especially a sarcoma, more especially aRMS. In still a further aspect, the invention provides a package, which comprises a compound of the formula I (or a salt pharmaceutically acceptable or pro-drug ester thereof), together with instructions for use for the treatment of a proliferative disease, especially a sarcoma, more especially aRMS. The term "progress delay", as used herein, means administering the composition to patients who are in an early stage of the proliferative disease to be treated. The term "solid tumor disease", as used herein, comprises but is not restricted to glioma, thyroid cancer, breast cancer, ovarian cancer, colon cancer, and in general terms of the gastrointestinal tract, cancer of cervix, lung cancer, in particular microcellular lung cancer, and non-microcellular lung cancer, head and neck cancer, bladder cancer, prostate cancer, or a sarcoma such as Kaposi's sarcoma or alveolar rhabdomyosarcoma. In a preferred embodiment of the invention, the tumor disease to be treated is alveolar rhabdomyosarcoma, glioma, prostate cancer or thyroid cancer. The present composition inhibits the growth of solid tumors, but also liquid tumors. Additionally, depending on the type of tumor and the particular composition used, a decrease in tumor volume can be obtained. The composition disclosed herein is also suitable for preventing the metastatic spread of tumors and the growth or development of micrometastases.

The nature of proliferative diseases such as solid tumor diseases is multifactorial. Under certain circumstances, drugs with different mechanisms of action can be combined. However, only considering any combination of drugs that have different modes of action does not necessarily lead to combinations with convenient effects. In one embodiment, the composition of the invention is administered in combination with radiation. "Combination" refers to the administration of an amount of a compound of the formula I in combination with the administration of an amount of ionizing radiation such that there is a synergistic effect that would not be obtained if a compound of the formula I is administered without the separate, simultaneous, or sequential administration of ionizing radiation. Where the administration of ionizing radiation can be continuous, in sequence, or sporadic. Or an effect that would not be obtained if ionizing radiation were administered without the separate, simultaneous, or sequential administration of a compound of the formula I, wherein the administration may be continuous, in sequence, or sporadic. Preferably, combination refers to the administration of an amount of a compound of formula I in combination with the administration of an amount of ionizing radiation such that there is a synergistic anti-proliferative effect and / or a clonogenic cell killing effect. that you would not get if: to. The compound of the formula I is administered without the prior, simultaneous, or subsequent administration of ionizing radiation. Where the administration can be continuous, sequential, or sporadic; b. There is administration of ionizing radiation without the prior, simultaneous, or subsequent administration of a compound of formula I. Wherein administration may be continuous, sequential, or sporadic. The term "ionizing radiation" referred to above and hereinafter, means ionizing radiation which occurs as electromagnetic rays (such as X-rays and gamma rays), or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy, and is known in this field (Hellman, Principles of Radiation Therapy, Cancer, in Principies and Practice of Oncology, 248-275 (Devita et al., Eds., 4a Edition, V1, 1993) In another combination of the invention, the compounds of the formula I, and the pharmaceutically acceptable salts and the pro-drug derivatives are preferably used in the form of pharmaceutical preparations containing the therapeutically effective amount of the active ingredient optionally together with, or in admixture with, inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for administration In a preferred embodiment, each patient receives doses of ionizing radiation during the same period and the compound of formula I. In an alternative embodiment, the ionizing radiation is given as a pre-treatment, that is, before the treatment is started with the COMPOSITION OF THE INVENTION; ionizing radiation alone is administered to the patient for a defined period of time, for example, the daily administration of ionizing radiation alone for two or three days or weeks. As mentioned above, the precise dosage of the FLT-3 inhibitor to be employed for the treatment of the diseases and conditions mentioned hereinbefore, depends on several factors, including the host, the nature and severity of the condition being is trying, and the mode of administration. However, in general, satisfactory results are achieved when the FLT-3 inhibitor is administered parenterally, for example, intraperitoneally, intravenously, intramuscularly, subcutaneously, intratumorally, or rectally, or enterally, for example, orally, preferably intravenously or, preferably orally, intravenously in a daily dosage of 0.1 to 10 milligrams / kilogram of body weight, preferably 1 to 5 milligrams / kilogram of body weight. In studies with humans, a total dose of 225 milligrams per day was more presumably the Maximum Tolerated Dose (MTD). A preferred daily intravenous dosage is 0.1 to 10 milligrams / kilogram of body weight or, for most higher primates, a daily dose of 200 to 300 milligrams. A typical intravenous dosage is 3 to 5 milligrams / kilogram, three to five times per week. Most preferably, inhibitors of FLT-3, especially MIDOSTAURIN, are administered orally, by dosage forms such as microemulsions, soft gels, or solid dispersions, in dosages up to about 250 milligrams per day, in particular 225 milligrams. per day, administered once, twice, or three times a day. Usually, a small dose is initially administered, and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper dosage limit is that imposed by side effects, and can be determined by the study for the host being treated. The FLT-3 inhibitor can be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more additional conventional pharmaceutical adjuvants, and administered enterally, for example, orally, in the form of tablets, capsules, caplets, etc. , or parenterally, for example, intraperitoneally or intravenously, in the form of sterile injectable solutions or suspensions. The enteric and parenteral compositions can be prepared by conventional means. The solutions for infusion according to the present invention are preferably sterile. This can be carried out easily, for example, by filtration through sterile filtration membranes. The aseptic formation of any composition in liquid form, the aseptic filling of flasks, and / or the combination of a pharmaceutical composition of the present invention with a suitable diluent under aseptic conditions, are well known to the skilled addressee. The FLT-3 inhibitor can be formulated in enteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for the treatment of the diseases and conditions mentioned hereinabove, these compositions being in a unit dosage form, and these compositions comprising a pharmaceutically acceptable carrier. Examples of useful compositions of inhibitors of FLT-3 are described in European Patent Nos. 0 296 110, Number 0657 164, Number 0296 110, Number 0733372, Number 0 711 556, and Number 0711 557. Preferred compositions of FLT-3 inhibitors are described in the European Patent. Number 0 657 164 published June 14, 1995. The disclosed pharmaceutical compositions comprise a solution or dispersion of the compounds of the formula I, such as MIDOSTAURIN, in a polyalkylene glycol glyceride, wherein the glycol glyceride is a mixture of esters of glyceryl and polyethylene glycol of one or more fatty acids Saturated from 8 to 18 carbon atoms. Subsequently, two manufacturing processes of these FLT-3 inhibitor compositions are described herein. Composition A: Gelucire 44/14 (82 parts) is melted by heating at 60 ° C. MIDOSTAURIN powder (18 parts) is added to the molten material. The resulting mixture is homogenized, and the dispersion obtained is filled into hard gelatin capsules of different sizes, such that some contain a dosage of 25 milligrams, and others contain a dosage of 75 milligrams of MIDOSTAURIN. The resulting capsules are suitable for oral administration. Composition B: Gelucire 44/14 (86 parts) is melted by heating at 60 ° C. MIDOSTAURIN powder (14 parts) is added to the molten material. The mixture is homogenized, and the obtained dispersion is introduced into hard gelatin capsules of different sizes, such that some contain a dosage of 25 milligrams, and the others contain a dosage of 75 milligrams of MIDOSTAURIN. The resulting capsules are suitable for oral administration. The Gelucire 44/14 commercially available in Gattefossé; is a mixture of esters of saturated fatty acids of 8 to 18 carbon atoms with glycerol and a polyethylene glycol having a molecular weight of about 1500, the specifications being for the composition of the fatty acid component, by weight, from 4 to 10 percent of caprylic acid, from 3 to 9 percent of capric acid, from 40 to 50 percent of lauric acid, from 14 to 24 percent of acid myristic, 4 to 14 percent palmitic acid, and 5 to 15 percent stearic acid. A preferred example of the Gelucire formulation consists of: Gelucire (44/14): 47 grams M IDOSTAU RIÑA: 3.0 grams filled in a 60 milliliter screw flask. A preferred example of soft gel will contain the following microemulsion: Corn oil glycerides 85.0 mg Polyethylene glycol 400 128.25 mg Cremophor RH 40 213.75 mg MIDOSTAURIN 25.0 mg DL alpha Tocopherol 0.5 mg Absolute ethanol 33.9 mg Total 486.4 mg However, it must be clearly understood that It is for illustration purposes only. In particular, a therapeutically effective amount of each combination component of the COMPOSITION OF THE INVENTION may be administered, simultaneously or in sequence and in any order, and the components may be Administer separately or as a fixed combination. For example, the method of progress delay or treatment of a proliferative disease according to the invention may comprise: (i) administration of the first combination component, and (ii) administration of the second combination component, wherein the administration of a combination component can be simultaneous or sequential in any order, in jointly effective amounts therapeutically, preferably in synergistically effective amounts, for example, in daily or weekly dosages corresponding to the amounts described herein. The individual combination components of the COMPOSITION OF THE INVENTION may be administered separately at different times during the course of therapy or in a concurrent manner. Additionally, the term "administer" also encompasses the use of a prodrug of a compound of formula I which is converted in vivo to the combination component as such. Accordingly, it should be understood that the present invention encompasses all simultaneous or alternate treatment regimens and the term "administer" should be interpreted in accordance with the foregoing. The dosage of ionizing radiation and a compound of formula I, one in relation to the other, is preferably in a proportion that is synergistic. The particular mode of administration and the dosage of a compound of formula I can be selected by the physician to attend, taking into account the patient's particular, especially age, weight, lifestyle, level of activity, etc.

The dosage of a compound of formula I may depend on different factors, such as the effectiveness and duration of action of the active ingredient, the mode of administration, the effectiveness and duration of action of ionizing radiation, and / or sex, the age, weight, and individual condition of the subject to be treated. The dosage of ionizing radiation may depend on different factors, such as the effectiveness and duration of action of the ionizing radiation, the mode of administration, the location of the administration, the effectiveness and duration of action of the compound of the formula I, and / or the sex, age, weight and individual condition of the subject to be treated. The dosage of ionizing radiation is generally defined in terms of dose of absorbed radiation, time, and fraction, and must be carefully defined by the attending physician.

In a preferred embodiment of the invention, the combination comprises A / - [(9S, 1 OR, 11R, 13fl) -2.3, 10, 11, 12,13-hexahydro-10-methoxy-9-methyl- 1-oxo-9,13-epoxy-1H, 9H-diindolo [1, 2,3-gh: 3 \ 2 ', 1' -lm] -pyrrolo- [3,4-j] [1, 7] - benzo-diazonin-11 -yl] - / V-methyl-benzamide of the formula (VII): Furthermore, the present invention relates to a method for the treatment of a warm-blooded animal having a proliferative disease., which comprises administering to the animal a composition of the invention in a manner that is jointly therapeutically effective against a proliferative disease, and wherein the combination components may also be present in the form of their pharmaceutically acceptable salts. Additionally, the present invention pertains to the use of an I NVENCTION COMPOSITION for the delay of progress or treatment of a proliferative disease, and for the preparation of a medicament for the delay of progress or the treatment of a proliferative disease. .

In one embodiment of the invention, an antidiarrheal agent is administered together with the COMPOSITION OF THE INVENTION for the purpose of preventing, controlling, or eliminating diarrhea, which is sometimes associated with the administration of a compound of formula I. , the present invention also relates to a method for preventing or controlling diarrhea associated with the administration of a compound of formula I, which comprises administering an effective amount of an anti-diarrhea agent to the patient receiving the treatment with the composition 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 methods and compositions of the invention include, but are not limited to, natural opioids, such as opium tincture, parental and synthetic codeine opioids, such as diphenoxylate, diphenoxy and loperamide, bismuth subsalicylate, octreotide (for example, available as SANDOSTATINAMR), motilin antagonists and traditional antidiarrheal remedies, such as kaolin, pectin, berberine, and muscarinic agents. The following example is intended to illustrate the invention and should not be construed as limiting the invention.

Example 1 The products of the chromosomal translocations have a crucial role both in the oncogenic process as well as objectives for therapeutic intervention. However, unlike BCR / ABL whose kinase activity can be specifically inhibited by a small molecule (Glivec), most chromosomal translocations increase the oncogenic or native chimeric oncogenic transcription factors, which are generally less susceptible to the inhibition of small molecules. Recently, we have established a genetic signature feature for alveolar rhabdomyosarcoma of pediatric sarcoma (aRMS), which expresses the chimeric fusion protein PAX3 / FKHR due to a translocalization event chromosomal t (2; 13). Based on this signature, a number of target molecules of therapeutic potential have been selected for further study, such as FGFR2. Here, we now demonstrate that PKC412, a staurosporine derivative originally developed against PKC, can efficiently inhibit cell growth of aRMS cells in vitro, and induce apoptosis due to the enhanced activity of caspase 3. Additionally, it could also be inhibited tumor growth in vivo using a mouse xenograft tumor model. Because the specific decrease in PAX3 / FKHR by either siRNA or anti-sense oligonucleotides can similarly induce apoptosis in aRMS cells, we investigated any potential effects of PKC412 on PAX3 / FKHR, by analyzing the expression of genes specific targets, such as CB1. It is interesting that the expression of CB1 was completely abolished after treatment with PKC412, suggesting that the compound regulates the activity of PAX3 / FKHR. Surprisingly, this inhibition was also observed with PAX3 / NCOA1, which, therefore, suggests that the PAX3 part of the fusion proteins is the target of the inhibitory function of PKC412. Finally, we identified several phosphorylation sites in the PAX3 region, which potentially act as regulators of their activity.

These experiments suggest that the treatment of aRMS with PKC412 leads to the induction of apoptotic cell death and the inhibition of tumor growth in vitro and in vivo, possibly mediated by inhibiting the activity of PAX3 / FKHR, a transcription factor chimeric oncogenic.

Claims (12)

1. A method for the treatment of a proliferative disease in a subject in need of such treatment, wherein the method comprises administering a compound selected from the compounds of the formulas: wherein and R2 are, independently from each other, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amino-sulfonyl or amino-sulfonyl N-mono- or N, N-di-substituted; n and m are, independently of each other, a number from and including 0 up to and including 4; n 'and m' are, independently of each other, a number from and including 1 up to and including 4; R 3 - 4, Re and R 10 are, independently of one another, hydrogen, 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. carbon in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, wherein R4 may also be absent; or R3 is acyl with up to 30 carbon atoms and R4 is not an acyl; p is 0 if R4 is absent, or is 1 if R3 and R4 are both present, and in each case they are one of the radicals mentioned above; R5 is hydronogen, 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; R7, R6 and R9 are acyl or - (lower alkyl) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxyl, etherified or esterified hydroxyl, amino, mono- or di-substituted amino, cyano, nitro, mercapto, substituted mercapto , carboxyl, carbonyl, carbonyl-dioxyl, esterified carboxyl, carbamoyl, N-mono- or N, N-di-substituted, sulfo, substituted sulfonyl, amino-sulfonyl or amino-sulfonyl N-mono- or N, N- di-substituted; X represents 2 hydrogen atoms; 1 hydrogen atom and hydroxyl; OR; or hydrogen peroxide and lower alkoxy; Z represents hydrogen or lower alkyl; and either the two bonds characterized by wavy lines are absent in ring A and are replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel link, means a double link; or the two bonds characterized by dotted lines are absent in ring B and are replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel link, means a double bond; or both in ring A and in ring B, all 4 wavy links are absent and are replaced by a total of 8 hydrogen atoms; or a salt thereof, if at least one salt forming group is present; and proliferative disease is associated with translocation of PAX / FKHR.

2. A method according to claim 1, which comprises administering a compound of the formula I: where: m and n are each 0; R3 and R4 are independently from each other, hydrogen, unsubstituted or mono- or di-substituted, especially mono-substituted, lower alkyl radicals independently selected from carboxyl; lower alkoxycarbonyl; and cyano; or R 4 is hydrogen or -CH 3, and R 3 is acyl of the sub-formula R ° -CO, where R ° is lower alkyl; amino-lower alkyl, wherein the amino group is present in an unprotected form or is protected by lower alkoxycarbonyl; tetrahydro-pyranyloxy-lower alkyl; phenyl; imidazolyl-lower alkoxy-phenyl; carboxy-phenyl; lower alkoxy-carbonyl-phenyl; halo-lower alkyl-phenyl; Midazol-1 -i l-fe n i lo; pyrrolidino-lower alkyl-phenyl; piperazino-lower alkyl-phenyl; (4-lower alkyl-piperazino-methyl) -phenyl; morpholino-lower alkyl-phenyl; piperazine-carbonyl-phenyl; or (4-lower alkyl-piperazino) -phenyl; or is acyl of the sub-formula R ° -0-CO-, wherein R ° is lower alkyl; or is acyl of the sub-formula R ° HN-C (= W) -, where W is oxygen and R ° has the following meanings: morpholino-lower alkyl, phenyl, lower alkoxy-phenyl, carboxy-phenyl, or alkoxy lower carbonyl phenyl; or R3 is lower alkyl-phenylsulfonyl, typically 4-toluenesulfonyl; R5 is hydrogen or lower alkyl, X represents 2 hydrogen atoms or O; Z is methyl or hydrogen; or a salt thereof, if at least one salt forming group is present; and proliferative disease is associated with translocation of PAX / FKHR.

3. A method according to claim 1 or 2, the which comprises administering the A / - [(9S, 10ft, 11f ?, 13ft) -2,3, 10, 11, 12,13-hexa h id ro-10-methoxy-9-methyll-oxo-9, 13-epoxy-1 / -, 9-diindolo [1, 2,3-gh: 3 ', 2', 1'-lm] -pyrrolo- [3,4-j] [1,7] -benzo- diazonin-11 -yl] - / V-methyl-benzamide. A method according to claims 1, 2 or 3, wherein the subject is a warm-blooded animal having a proliferative disease, which comprises administering to the animal a composition according to any one of claims 1, 2 or 3 , in a way that is therapeutically effective against a proliferative disease. 5. A method according to any of claims 1 to 4, which comprises administering an amount that is therapeutically effective against a proliferative disease of a compound of the formula I, and at least one pharmaceutically acceptable carrier. 6. A method according to claim 1, 2, 3, 4 or 5, for the delay of progression of a proliferative disease in a subject in need of such treatment. A method according to claim 1, 2, 3, 4 or 5, for the treatment of a proliferative disease associated with a translocation of PAX / FKHR, wherein the translocation of PAX / FKHR is selected from a translocation of PAX3 / FKHR and a translocation of PAX7 / FKHR. 8. The use of a compound of the formula I according to claim 1, 2 or 3, for the preparation of a medicament for used in the delay of progress or the treatment of a proliferative disease. 9. A method according to claims 6, 7 or 8, wherein the proliferative disease is a sarcoma. 10. A method according to claim 6, 7 or 8, wherein the proliferative disease is associated with translocation of PAX3 / FKHR. 11. A method according to claim 6, 7 or 8, wherein the proliferative disease is an alveolar rhabdomyosarcoma. 12. A package, which comprises a compound of formula I, wherein A represents O or NRN, wherein RN is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O, or a bond (or a pharmaceutically acceptable salt or pro-drug ester thereof), together with instructions for use in the treatment of a proliferative disease.