AU2008201869A1 - Staurosporine derivatives for hypereosinophilic syndrome - Google Patents

Description

Australian Patents Act 1990 Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Staurosporine derivatives for hypereosinophilic syndrome" The following statement is a full description of this invention, including the best method of performing it known to us:- Q \OPER\N1AL\2008\Apr0\30S31978 Novartis Div 2804 doc P \OPER\MAL 2(Xs300531l97h dl du-2nIm/211( 00 -1-

O

Staurosporine derivatives for hypereosinophilic syndrome N This is a divisional of Australian Patent Application No. 2004244747, the entire contents of which are incorporated herein by reference.

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00 The present invention relates to the use of staurosporine derivatives (hereinafter: tC1 "STAUROSPORINE DERIVATIVES") for the preparation of a drug for the treatment of 00 SFIP1L1 -PDGFRa-induced myeloproliferative diseases, especially for the curative and/or Sprophylactic treatment of hypereosinophilic syndrome and hypereosinophilic syndrome with resistance to imatinib, and to a method of treating hypereosinophilic syndrome and hypereosinophilic syndrome with resistance to Imatinib, or other diseases associated with FIPL1-PDGFRa or similar mutations that activate PDGFRa.

The invention relates In particular to the use of staurosporines derivatives of formula X NR 8 6NR, 7 5X44 7 0 4 "9 S(Ri)m B A (R) 3 or so N 2 (R B I I A 10 N 1

N

H,C

H

NN R, N I R<

R

wherein (II) Is the partially hydrogenated derivative of compound 6 NR 8

NR

X 0 (R 0m 8 X 0 4 (2) (Ri)mB A 11 J 1 00 -2-

O

O

Ne NR M

R

3 (Ri)m B A (R2) n X "s.v R R

O

O 1 o O or 00 or 00 N wherein R 1 and R 2 are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or Nmono- or N,N-di-substituted aminosulfonyl; n and m are, independently of one another, a number from and including 0 to and including 4; n' and m' are, independently of one another, a number from and including 0 to and including 4;

R

3

R

4 Re and Rio are, independently of one another, hydrogen, -0 acyl with up to carbon atoms, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and In each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, wherein R 4 may also be absent; or if R 3 is acyl with up to 30 carbon atoms, R4 is not an acyl; p is 0 if R 4 is absent, or is 1 if Ra and R 4 are both present and in each case are one of the aforementioned radicals; Rs 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 00 -3-

O

O

atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms; Ry, Re and R 9 are acyl or -(lower alkyl) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, D cyano, nitro, mercapto, substituted mercapto, carboxy,carbonyl, carbonyldloxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, N aminosulfonyl or N-mono- or N,N-di-substltuted aminosulfonyl; 00 X stands for 2 hydrogen atoms; for 1 hydrogen atom and hydroxy; for 0; or for hydrogen and lower alkoxy; Z stands for hydrogen or lower alkyl; and either the two bonds characterised 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 bond, signify a double bond; or the two bonds characterised by wavy lines are absent in ring B and replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel bond, signify a double bond; or both in ring A and in ring B all of the 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 for the preparation of a pharmaceutical composition for the treatment of FIP1L1-PDGFRa-induced myeloproliferative diseases.

The general terms and definitions used hereinbefore and hereinafter preferably have the following meanings: The prefix "lower" Indicates that the associated radical preferably has up to and including a maximum of 7 carbon atoms, especially up to and including a maximum of 4 carbon atoms.

I

00 -4- Lower alkyl is especially methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, or tert- C\ butyl, and also pentyl, hexyl, or heptyl.

Unsubstituted or substituted alkyl is preferably Cl-C 2 0 alkyl, especially lower alkyl, typically 0 methyl, ethyl, n-propyl, Isopropyl, n-butyl, Isobutyl, sec-butyl, or tert-butyl, which is 00 unsubstituted or substituted especially by halogen, such as fluorine, chlorine, bromine, or N Iodine, Ce-Ci 4 aryl, such as phenyl or naphthyl, hydroxy, etherified hydroxy, such as lower 00 alkoxy, phenyl-lower alkoxy or phenyloxy, esterifled hydroxy, such as lower alkanoyloxy or benzoyloxy, amino, mono- or dlsubstituted amino, such as lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N,N-dl-lower alkylamino, N,N-dl-(phenyl-lower alkyl)amino, cyano, mercapto, substituted mercapto, such as lower alkylthio, carboxy, esterified carboxy, such as lower alkoxycarboflyl, carbamoyl, N-mono- or N,N-disubstituted carbamnoyl, such as N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamnoyl, sulfo, substituted sulfo, such as lower alkanesulfonyl or lower alkoxysulfonyl, aminosulfonyl or Nmono- or N,N-distibstittited aminosulfoflyl, such as N-lower alkylaminosulfonyl or N,N-dilower alkylaminosulfonyl.

Halogen is preferably fluorine, chlorine, bromine, or Iodine, especially fluorine or chlorine.

Etherifled hydroxy is especially lower alkoxy, CO-Ci 4 aryloxy, such as phenyloxy, or Ce-

C

1 4 aryl-lower alkoxy, such as benzyloxy.

Esterified hydroxy Is preferably lower alkanoyloxy or C 6

-C

1 4 arylcarbonyloxy, such as benzoyloxy.

Mono- or disubstituted amino is especially amino monosubstituted or disubstituted by lower alkyl, CO-Cl 4 aryl, CS-C 1 4 aryl-lower alkyl, lower alkanoyl, or CO-C, 2 arylcarbonyl.

Substituted mercapto Is especially lower aikylthlo, C 6

-C

1 4 arylthio, 0 6 -Cl 4 aryl-lower alkylthio, lower alkanoylthlo, or CC-C 1 4 aryl-lower alkanoyithio.

Esterifled carboxy Is especially lower alkoxycarbonyl,

C

6 -Cl 4 aryi-lower alkoxycarbonyl or C 6

C

1 4 aryloxycarbonyl.

I

00 N-Mono- or N,N-disubstituted carbamoyl is especially carbamoyl N-monosubstituted or N,Ndisubstituted by lower alkyl, CO-Cl 4 aryl or C 6

-C

1 4 aryl-lower alkyl.

Substituted sulfonyl Is especially CS-C 14 arylsulfonyl, such as toluenesulfonyl,

C

6

-C

14 aryl-lower I alkanesulfonyl or lower alkanesulfonyl.

00 N-Mono- or N,N-disubstituted aminosulfonyl is especially aminosulfonyl N-monosubstituted 00 or N,N-disubstituted by-lower alkyl, C6-C 1 4 aryl or C-C 14 aryl-lower alkyl.

C6-C14Aryl is an aryl radical with 6 to 14 carbon atoms in the ring system, such as phenyl, naphthyl, fluorenyl, or indenyl, which is unsubstituted or is substituted especially by halogen, such as fluorine, chlorine, bromine, or iodine, phenyl or naphthyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N,N-di-lower alkylamino, N,N-di-(phenyl-lower alkyl)amino, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl,

N-

lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lower alkylamnosulfonyl, or N,N-di-lower alkylaminosulfonyl.

The indices n and m are in each case preferably 1, 2 or especially 0. In general, compounds of formula I in which n and m are in each case 0 (zero) are especially preferred.

An aliphatic carbohydrate radical R 3

R

4 R8 or RIo 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 not more than 7 carbon atoms, may be saturated or unsaturated and is especially an unsubstituted or a straight-chain or branched lower alkyl, lower alkenyl, lower alkadienyl, or lower alkinyl radical substituted by acyclic substituents.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl; lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl and 2- or 3-butenyl; lower alkadienyl is, for example, 1-penta-2,4-dienyl; lower alkinyl is, for example, propargyl or 2-butinyl. In corresponding unsaturated radicals, the double bond is especially located in a position higher.than the a-position in relation to the free valency. Substituents are especially the acyl 00 -o- 0

O

S radicals defined hereinbelow as substituents of R 0 preferably free or esterified carboxy, such as carboxy or lower alkoxycarbonyl, cyano or di-lower alkylamino.

A carbocyclic or carbocyclic-aliphatic radical R 3

R

4 Re or R 10 with up to 29 carbon atoms in each case is especially an aromatic, a cycloallphatic, a cycloaliphatic-aliphatic, or an 0 aromatic-aliphatic radical which is either present in unsubstituted form or substituted by radicals referred to hereinbelow as substituents of Ro. An aromatic radical (aryl radical) R 3 or N R 4 is most especially a phenyl, also a naphthyl, such as 1- or 2-naphthyl, a biphenylyl, such 00 as especially 4-biphenylyl, and also an anthryl, fluorenyl and azulenyl, as well as their aromatic analogues with one or more saturated rings, which is either present in unsubstituted form or substituted by radicals referred to hereinbelow as substituents of R°.

Preferred aromatic-aliphatic radicals are aryl-lower alkyl- and aryl-lower alkenyl radicals, e.g.

phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, such as for example benzyl, phenethyl, or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl, and cinnamyl, and also 1- or 2-naphthylmethyl. Of aryl radicals carrying acyclic radicals, such as lower alkyl, special mention is made of m- and p-tolyl and xylyl radicals with variously situated methyl radicals.

A cycloaliphatic radical Ra, R 4

R

8 or R 10 with up to 29 carbon atoms is especially a substituted or preferably unsubstltuted mono-, bi-, or polycyclic cycloalkyl-, cycloalkenyl-, or cycloalkadienyl radical. Preference is for radicals with a maximum of 14, especially 12, ringcarbon atoms and 3- to preferably 5- to and most especially 6-member rings which can also carry one or more, for example two, aliphatic hydrocarbon radicals, for example those named above, especially the lower alkyl radicals, or other cycloaliphatic radicals as substituents. Preferred substituents are the acyclic substituents named hereinbelow for R°.

A cycloaliphatic-aliphatic radical R 3

R

4 Re or R 0 oWith up to 29 carbon atoms is a radical In which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as especially methyl, ethyl, and vinyl, carries one or more cycloaliphatic radicals as defined herelnabove. Special mention is made of cycloalkyl-lower alkyl radicals, as well as their analogues which are unsaturated in the ring and/or in the chain, but are nonaromatic, and which carry the ring at the terminal carbon atom of the chain. Preferred substituents are the acyclic substituents named herein below for R°.

0

O

Heterocyclic radicals R 3

R

4 Re or Rio with up to 20 carbon atoms each and up to 9 heteroatoms each are especially monocyclic, but also bi- or polycyclic, aza-, thia-, oxa-, 0\ thlaza-, oxaza-, diaza-, triaza-, or tetrazacyclic radicals of an aromatic character, as well as N corresponding heterocyclic radicals of this type which are partly or most especially wholly saturated, these radicals if need be possibly carrying further acyclic, carbocyclic, or s heterocyclic radicals and/or possibly mono-, di-, or polysubstituted by functional groups, 00 preferably those named hereinabove as substituents of aliphatlc hydrocarbon radicals. Most N especially they are unsubstituted or substituted monocyclic radicals with a nitrogen, oxygen, 0 0 or sulfur atom, such as 2-aziridinyl, and especially aromatic radicals of this type, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 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-qulnolyl, isoqulnolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2-benzofuranyl, chromenyl, typically 3-chromenyl, or benzothienyl, typically 2- or 3benzothienyl; 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 2thiazolyl, and benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2benzoxazolyl, or qulnazolyl, typically 2-quinazolinyl. Appropriate partially or, especially, completely saturated analogous radicals may also be considered, such as 2-tetrahydrofuryl, 2- or 3-pyrrolidinyl, or 4-piperidyl, and also 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl and N-mono- or N,N'-bls-lower alkyl-2-piperazinyl radicals. These radicals may also carry one or more acyclic, carbocyclic, or heterocyclic radicals, especially those mentioned hereinabove. The free valency of the heterocyclic radicals R 3 or R 4 must emanate from one of their carbon atoms. Heterocyclyl may be unsubstituted or substituted by one or more, preferably one or two, of the substituents named hereinbelow for R°.

Heterocyclic-aliphatic radicals R 3

R

4 Re or R 1 0 especially lower alkyl radicals, especially with a maximum of 7, preferably a maximum of 4 carbon atoms, for example those named hereinabove, which carry one, two, or more heterocyclic radicals, for example those named in the preceding paragraph, the heterocycllc ring possibly being linked to the aliphatic chain also by one of its nitrogen atoms. A preferred heterocyclic-aliphatic radical R 1 is, for example, imidazol-1-ylmethyl, 4-methylplperazln-l-ylmethyl, piperazin-1-ylmethyl, 2- (morpholin-4-yl)ethyl and also pyrid-3-ylmethyl. Heterocyclyl may be unsubstituted or 00 -8- 0

O

substituted by one or more, preferably one or two, of the substituents named hereinbelow for A heteroaliphatic radical R 3

R

4 Re or R 1 0 with up to 20 carbon atoms each and up to heteroatoms each is an aliphatic radical which, instead of one, two, or more carbon atoms, contains identical or different heteroatoms, such as especially oxygen, sulfur, and nitrogen.

An especially preferred arrangement of a heteroaliphatic radical Ri takes the form of oxa- N alkyl radicals in which one or more carbon atoms are replaced in a preferably linear alkyl by oxygen atoms preferably separated from one another by several (especially 2) carbon atoms S so that they form a repeating group, if need be multi-repeating group (O-CH 2 -CH2-)q, wherein q 1 to 7.

Especially preferred as R 3

R

4 Re or Rio, apart from acyl, is lower alkyl, partlclularly methyl or ethyl; lower alkoxycarbonyl-lower alkyl, especially methoxycarbonylmethyl or 2-(tertbutoxycarbonyl)ethyl; carboxy-lower alkyl, especially carboxymethyl or 2-carboxyethyl; or cyano-lower alkyl, especially 2-cyanoethyl.

An acyl radical R 3 R4, Re, R, Re, or Rj 0 with up to 30 carbon atoms derives from a carboxylic acid, functionally modified If need be, an organic sulfonic acid, or a phosphoric acid, such as pyro- or orthophosphoric acid, esterified if need be.

An acyl designated Ac' and derived from a carboxylic acid, functionally modified if need be, is especially one of the subformula wherein W is oxygen, sulfur, or Imino and Y is hydrogen, hydrocarbyl Ro with up to 29 carbon atoms, hydrocarbyloxy an amino group or a substituted amino group, especially one of the formula ROHN- or R°R°N- (wherein the R° radicals may be identical or different from one another).

The hydrocarbyl (hydrocarbon radical) RO is an acyclic (aliphatic), carbocyclic, or carbocyclicacyclic hydrocarbon radical, with up to 29 carbon atoms each, especially up to 18, and preferably up to 12 carbon atoms, and Is saturated or unsaturated, unsubstltuted 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.

00 -9- 0

O

Unsaturated radicals are those, which contain one or more, especially conjugated and/or C0\ isolated, multiple bonds (double or triple bonds). The term cyclic radicals Includes also aromatic and non-aromatic radicals with conjugated double bonds, for example those wherein at least one 6-member carbocyclic or a 5- to 8-member heterocyclic ring contains the maximum number of non-cumulative double bonds. Carbocyclic radicals, wherein at 00 least one ring is present as a 6-member aromatic ring a benzene ring), are defined as

O

C aryl radicals.

00 0 An acyclic unsubstituted hydrocarbon radical RO is especially a straight-chained or branched lower alkyl-, lower alkenyl-, lower alkadienyl-, or lower alklnyl radical. Lower alkyl RO is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl; lower alkenyl is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl and 2- or 3-butenyl; lower alkadienyl is, for example, 1-penta-2,4-dienyl; lower alkinyl is, for example, propargyl or 2-butinyl. In corresponding unsaturated radicals, the double bond is especially located in a position higher than the aposition in relation to the free valency.

A carbocyclic hydrocarbon radical RO is especially a mono-, bi-, or polycyclic cycloalkyl-, cycloalkenyl-, or cycloalkadienyl radical, or a corresponding aryl radical. Preference is for radicals with a maximum of 14, especially 12, ring-carbon atoms and 3- to preferably to and most especially 6-member rings which can also carry one or more, for example two, acyclic radicals, for example those named above, especially the lower alkyl radicals, or other carbocyclic radicals. Carbocyclic-acyclic radicals are those in which an acyclic radical, especially one with a maximum of 7, preferably a maximum of 4 carbon atoms, such as especially methyl, ethyl and vinyl, carries one or more carbocyclic, if need be aromatic radicals of the above definition. Special mention is made of cycloalkyl-lower and aryl-lower alkyl radicals, as well as their analogues which are unsaturated in the ring and/or chain, and which carry the ring at the terminal carbon atom of the chain.

Cycloalkyl RO has most especially from 3 up to and including 10 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, as well as bicyclo[2,2,2]octyl, 2-bicyclo[2,2,1]heptyl, and adamantyl, which may also be substituted by 1, 2,.or more, for example lower, alkyl radicals, especially methyl radicals; cycloalkenyl is 00 for example one of the monocyclic cycloalkyl radicals already named which carries a double bond in the or 3 position. Cycloalkyl-lower alkyl or -lower alkenyl is for example a 0\ methyl, or -2-ethyl, or -2-vinyl, or -3-propyl or -allyl substituted by one of the above-named cycloalkyl radicals, those substituted at the end of the linear chain being preferred.

00 An aryl radical Ro is most especially a phenyl, also a naphthyl,.such as 1- or 2-naphthyl, a N biphenylyl, such as especially 4-biphenylyl, and also an anthryl, fluorenyl and azulenyl, as 0 well as their aromatic analogues with one or more saturated rings. Preferred aryl-lower alkyl and -lower alkenyl radicals are, for example, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, such as for example benzyl, phenethyl, or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl, and cinnamyl, and also 1- or 2-naphthylmethyl. Aryl may be unsubstituted or substituted.

Heterocyclic radicals, including heterocyclic-acyclic radicals, are especially monocyclic, but also bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-, or tetrazacyclic radicals of an aromatic character, as well as corresponding heterocyclic radicals of this type which are partly or most especially wholly saturated; if need be, for example as in the case of the above-mentioned carbocyclic or aryl radicals, these radicals may carry further acyclic, carbocyclic, or heterocyclic radicals and/or may be mono-, di-, or polysubstituted by functional groups. The acyclic part in heterocyclic-acyclic radicals has for example the meaning indicated for the corresponding carbocyclic-acyclic radicals. Most especially they are unsubstituted or substituted monocyclic radicals with a nitrogen, oxygen, or sulfur atom, such as 2-aziridinyl, and especially aromatic radicals of this type, such as pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example or 4-pyridyl, and also thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl; analogous bicyclic radicals with an oxygen, sulfur, or nitrogen atom are, for example, indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2benzofuranyl, chromenyl, typically 3-chromenyl, or benzothlenyl, typically 2- or 3benzothienyl; preferred monocyclic and bicyclic 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, or thlazolyl, typically 2-thiazolyl, and benzimidazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, or qulnazolyl, typically 2-qulnazollnyl. Appropriate partially or, especially, completely saturated 00 -11- Sanalogous radicals may also be considered, such as 2-tetrahydrofuryl, 4-tetrahydrofuryl, 2- S or 3-pyrrolidyl, or 4-piperidyl, and also 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2- S plperazinyl, and N,N'-bis-lower alkyl-2-plperazinyl radicals. These radicals may also carry one or more acyclic, carbocyclic, or heterocyclic radicals, especially those mentioned hereinabove. Heterocyclic-acyclic radicals are especially derived from acyclic radicals with a 0 maximum of 7, preferably a maximum of 4 carbon atoms, for example those named hereinabove, and may carry one, two, or more heterocyclic radicals, for example those N named hereinabove, the ring possibly being linked to the aliphatic chain also by one of its 00 nitrogen atoms.

As already mentioned, a hydrocarbyl (Including a heterocyclyl) may be substituted by one, two, or more identical or different substituents (functional groups); one or more of the following substituents may be considered: lower alkyl; free, etherifled and esterifled hydroxyl groups; carboxy groups and esterified carboxy groups; mercapto- and lower alkylthio- and, if need be, substituted phenylthio groups; halogen atoms, typically chlorine and fluorine, but also bromine and iodine; halogen-lower alkyl groups; oxo groups which are present in the form of formyl aldehydo) and keto groups, also as corresponding acetals or ketals; azido groups; nitro groups; cyano groups; primary, secondary and preferably tertiary amino groups, amino-lower alkyl, mono- or disubstituted amino-lower alkyl, primary or secondary amino groups protected by conventional protecting groups (especially lower alkoxycarbonyl, typically tert-butoxycarbonyl) lower alkylenedioxy, and also free or functionally modified sulfo groups, typically sulfamoyl or sulfo groups present In free form or as salts. The hydrocarbyl radical may also carry carbamoyl, ureldo, or guanidino groups, which are free or which carry one or two substituents, and cyano groups. The above use of the word "groups" is taken to imply also an individual group.

Halogen-lower alkyl contains preferably 1 to 3 halogen atoms; preferred is trifluoromethyl or chloromethyl.

An etherified hydroxyl group present in the hydrocarbyl as substituent is, for example, a lower alkoxy group, typically the methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, and tertbutoxy group, which may also be substituted, especially by heterocyclyl, whereby heterocyclyl can have preferably 4 to 12 ring atoms, may be unsaturated, or partially or wholly saturated, is mono- or blcyclic, and may contain up to three heteroatoms selected 00 -12from nitrogen, oxygen, and sulfur, and is most especially pyrrolyl, for example 2-pyrrolyl or 3pyrrolyl, pyridyl, for example 3- or 4-pyridyl, and also thienyl, for example 2- or 3-thienyl, C\ or furyl, for example 2-furyl, indolyl, typically 2- or 3-indolyl, qulnolyl, typically 2- or 4-qulnolyl, isoquinolyl, typically 3- or 5-isoquinoly, benzofuralyl, typically 2-benzofuranyl, chromenyl, typically 3-chromeflyl, benzothlenyl, typically 2- or 3-berizothienyl; imidazolyl, typically 1- or ID 2-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, 00 typically 3-isoxazolyi, thiazolyl, typically 2-thiazolyl, benzimdazolyl, typically 2-benzimidazolyi, N- benzoxazolyl, typically 2-benzoxazolyl, qulnazolyl, typically 2-quinazolinyl, 2-tetrahydrofuryl, 00 4-tetrahydrofuryl, 2- or 4-tetrahydropyralyl, 2- or 3-pyrrolidyl, or 4-piperidyl, 1-, 2-or 3-morphOinyl, 2- or 3-thlomorpholflyl, 2-piperaziflyl or N,N'-bis-lower alkyl-2-plperazlnyl; and also (11) by halogen atoms, for example mono-, di-, or polysubstituted especially In the 2position, as In the 2,2,2-trichloroethoxy, 2-chioroethoxy, or 2-lodoethoxy radical, or (ill) by hydroxy or (iv) lower alkoxy radicals, each preferably monosubstituted, especially in the. 2position, as In the 2-methoxyethoxy radical. Such etherified hydroxyl groups are also unsubstituted or substituted phenoxy radicals and phenyl-lower alkoxy radicals, such as especially benzyloxy, benzhydryloxy, and triphenylmethoxy (trltyloxy), as well as heterocyclyloxy radicals, wherein heterocyclyl can have preferably 4 to 12 ring atoms, may be unsaturated, or partially or wholly saturated, is mono- or bicyclic, and may contain up to three heteroatoms selected from nitrogen, oxygen, and sulfur, and Is most especially pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 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, qulnolyl, typically 2- or 4-qulnolyl, isoqulnolyl, typically 3- or benzofuranyl, typically 2-benzofuranyl, chromenyl, typically 3-chromenyl, benzothienyl, typically 2- or 3-benzothieflyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzlmidazolyl, typically 2-benzlmldazolyl, benzoxazolyl, typically 2benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydrofuryl, 4-tetrahydrofuryt, 2- or 4tetrahydropyranyl, 2- or 3-pyrrolldyl, or 4-piperldyl, 2-or 3-morpholinyl, 2- or 3-thiomorpholiflyl, 2-piperazinyl or N,N'-bis-lower alkyl-2-piperazirnyI; such as'especially 2- or 4-tetrahydropyralyloxy.

Etherified hydroxyl groups In this context are taken to Include sIlylated hydroxyl groups, typically for example tni-lower alkylsilyloxy, typically trimethylsilyloxy and dimethyl-tertbutylsilyloxy, or phenyldi-lower alkylsilyloxy and lower alkyl-diphelylsilyloxy.

00 -13-

O

O

An esterifled hydroxyl group present in the hydrocarbyl as a substituent Is, for example, lower alkanoyloxy.

N

A carboxyl group present in the hydrocarbyl as a substituent is one in which the hydrogen atom is replaced by one of the hydrocarbyl radicals characterised hereinabove, preferably a 00 lower alkyl- or phenyl-lower alkyl radical; an example of an esterified carboxyl group is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl substituted If need be in the phenyl part, 00 especially the methoxy, ethoxy, tert-butoxy, and benzyloxycarbonyl group, as well as a lactonlsed carboxyl group.

A primary amino group -NH 2 as substituent of the hydrocarbyls may also be present in a form protected by a conventional protecting group. A secondary amino group carries, Instead of one of the two hydrogen atoms, a hydrocarbyl radical, preferably an unsubstituted one, typically one of the above-named, especially lower alkyl, and may also be present in protected form.

A tertiary amino group present in the hydrocarbyl as substituent carries 2 different or, preferably, identical hydrocarbyl radicals (including the heterocyclic radicals), such as the unsubstituted hydrocarbyl radicals characterised hereinabove, especially lower alkyl.

A preferred amino group is one with the formula R 11 (Ri2)N-, wherein R 1 1 and R 1 2 are independently in each case hydrogen, unsubstituted acyclic C,-C 7 -hydrocarbyl (such as especially

C-C

4 alkyl or C2C 4 alkenyl) or monocyclic aryl, aralkyl, or aralkenyl, substituted If necessary by C,-C 4 -alkyl, Cl-C 4 -alkoxy, halogen, and/or nitro, and having a maximum of carbon atoms, where the carbon-containing radicals may be interlinked through a carboncarbon bond or an oxygen atom, a sulfur atom, or a nitrogen atom substituted if necessary by hydrocarbyl. In such a case, they form a nitrogen-containing heterocyclic ring with the nitrogen atom of the amino group. The following are examples of especially preferred disubstituted amino groups: di-lower alkylamino, typically dimethylamino or diethylamino, pyrrolidlno, imldazol-1-yl, piperidino, piperazino, 4-lower alkylpiperazino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, as well as diphenylamino and dibenzylamino substituted if need be, especially In the phenyl part, for example by loweralkyl, lower-alkoxy, halogen, and/or nitro; of the protected groups, especially lower alkoxy- 00 -14carbonylamino, typically tert-butoxycarbonylamino, phenyl-lower alkoxycarbonylamino, S typically 4-methoxybenzyloxycarbonylamino, and 9-fluorenylmethoxycarbonylamino.

Amino-lower alkyl is most especially substituted in the 1-position of the lower alkyl chain by amino and is especially aminomethyl.

00 Mono- or disubstituted amino-lower alkyl Is amino-lower alkyl substituted by one or two S radicals, wherein amino-lower alkyl Is most especially substituted by amino in the 1-position of the lower alkyl chain and is especially aminomethyl; the amino substituents here are preferably (If 2 substituents are present in the respective amino group independently of one another) from the group comprising lower alkyl, such as especially methyl, ethyl or n-propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl,

C

3 -Cacycloalkyl, especially cyclohexyl, aminolower alkyl, typically 3-aminopropyl.or 4-aminobutyl, N-mono- or N,N-di(lower alkyl)-aminolower alkyl, typically 3-(N,N-dimethylamino)propyl, amino, N-mono- or N,N-di-lower alkylamino and N-mono- or N,N-di-(hydroxy-lower alkyl)amino.

Disubstituted amino-lower alkyl is also a 5 or 6-membered, saturated or unsaturated heterocyclyl bonded to lower alkyl via a nitrogen atom (preferably in the 1-position) and having 0 to 2, especially 0 or 1, other heteroatoms selected from oxygen, nitrogen, and sulfur, which is unsubstituted or substituted, especially by one or two radicals from the group comprising lower alkyl, typically methyl, and also oxo. Preferred here is pyrrolidino (1pyrrolidinyl), piperidino (1 -piperidinyl), piperazino (1 -piperazinyl), 4-lower alkylpiperazino, typically 4-methylpiperazino, imidazolino (1-imidazolyl), morpholino (4-morpholinyl), or also thiomorpholino, S-oxo-thiomorpholino, or S,S-dioxothlomorpholino.

Lower alkylenedioxy is especially methylenedioxy.

A carbamoyl group carrying one or two substituents is especially aminocarbonyl (carbamoyl) which is substitiuted by one or two radicals at the nitrogen; the amino substituents here are preferably (if 2 substituents are present in the respective amino group independently of one another) from the group comprising lower alkyl, such as especially methyl, ethyl or n-propyl, hydroxy-lower alkyl, typically 2-hydroxyethyl,

C

3 -Cecycloalkyl, especially cyclohexyl, aminolower alkyl, typically 3-aminopropyl or 4-aminobutyl, N-mono- or N,N-di(lower alkyl)-aminolower alkyl, typically 3-(N,N-dimethylanmino)propyl, amino, N-mono- or N,N-di-lower 00 alkylamino and N-mono- or N,N-di-(hydroxy-lower alkyl)amino; disubstituted amino in aminocarbamoyl is also a 5 or 6-membered, saturated or unsaturated heterocyclyl with a O\ bonding nitrogen atom and 0 to 2, especially 0 or 1, other heteroatoms selected from Soxygen, nitrogen, and sulfur, which Is unsubstituted or substituted, especially by one or two radicals from the group comprising lower alkyl, typically methyl, and also oxo. Preferred here S is pyrrolidino (1-pyrrolidinyl), plperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower al- 00 kylpiperazino, typically 4-methylpiperazino, Imdazolino (1-imidazolyl), morpholino (4-morpholinyl), or also thiomorpholino, S-oxo-thiomorpholino, or S,S-dioxothlomorpholino.

00 SAn acyl derived from an organic sulfonic acid, which Is designated Ac 2 Is especially one with the subformula R 0 -S0 2 wherein R* is a hydrocarbyl as defined above in the general and specific meanings, the latter also being generally preferred here. Especially preferred is lower alkylphenylsulfonyl, especially 4-toluenesulfonyl.

An acyl derived from a phosphoric acid, esterified if necessary, which is designated AC 3 is especially one with the subformula ROO(ROO)P(=0)-, wherein the radicals RO are, independently of one another, as defined in the general and specific meanings Indicated above.

Reduced data on substituents given hereinbefore and hereinafter are considered to be preferences.

Preferred compounds according to the invention are, for example, those wherein RO has the following preferred meanings: lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group is unprotected or Is protected by a conventional amino protecting group especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl e.g. aminomethyl, R- or preferably S-1 -aminoethyl, tertbutoxycarbonylaminomethyl or or preferably S- 1-(tert-butoxycarbonylamino)ethyl, carboxy-lower alkyl, typically 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl, typically 2- (tert-butoxycarbonyl)ethyl, cyano-lower alkyl, typically 2-cyanoethyl, tetrahydropyranyloxylower alkyl, typically 4-(tetrahydropyranyl)-oxymethyl, morpholino-lower alkyl, typically 2- (morpholino)ethyl, phenyl, lower alkylphenyl, typically 4-methylphenyl, lower alkoxyphenyl, typically 4-methoxyphenyl, imidazolyl-lower alkoxyphenyl, typically 4-[2-(Imidazol-lyl)ethyl)oyxphenyl, carboxyphenyl, typically 4-carboxyphenyl, lower alkoxycarbonylphenyl, 00 -16typically 4-ethoxycarbonylphenyl or 4-methoxyphenyl, halogen-lower aikylphenyl, typically 4chioromethylpheflyl, pyrrolidinophenyl, typically 4-pyrrolidinophelyl, imidazol-1 -ylphenyl, C\ typically 4-(imidazolyl-1 -yl)phenyi, piperazinophenyl, typically 4-piperazflophelyl, (4-lower alkylpiperaziflo)phelYl, typically 4-(4-methylpiperaziflo)phelI morpholiflopheflyl, typically 4mcrpholinophenyi, pyrrolidino-lower aikyiphenyl, typically 4-pyrrolldinomethyiphell IN imidazol-1 -yi-lower alkyiphenyl, typically 4-(imidazoyl-1 -ylmethyl)phenyl, piperazino-lower 00 alkyiphenyl, typically 4-piperazinomTethylpheflyl, (4-lower alkylplperaziflomethyl)-phell N typically 4-(4-methylpiperazlflomethyl)phenyl, morpholino-lower alkylphenyl, typically 4- 00 orpholiflomethylpheflyl, piperazlnocarbonylphelyl, typically 4-piperazinocarboliPhel, or (4-lower alkyl-piperazino)phelYI typically 4-(4-methylpiperaziflo)phenyl.

Preferred acyl radicals Ac 1 are acyl radicals of a carboxylic acid which are characterised by the subformula

R

0 wherein R 0 has one of the above general and preferred meanings of the hydrocarbyl radical R 0 Especially preferred radicals R 0 here are lower alkyl, especially methyl or ethyl, amino-lower alkyl, wherein the amino group Is unprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically tert-lower alkoxycarboflyl, for example tert-butoxycarboflyl, e.g. aminomethyl, or preferably S- 1 -aminoethyl, tert-butoxycarbornyamir1omethyl or or preferably S-I -(tartbutoxycarboflylamlino)ethyl, carboxy-lower alkyl, typically 2-carboxyethyl, lower alkoxycarboflyl-lower alkyl, typically 2-(tert-butoxycarbonyl)ethyl, tetrahydropyralyloxy-lower alkyl, typically 4-(tetrahydropyranyl)oxymethyl, phenyl, imidazolyl-lower alkoxyphenyl, typically 4-[2-(imidazol-1 -yl)ethyl~oyxpheflyl, carboxyphenyl, typically 4-carboxypheflyl, lower alkoxycarbonylpheflyl, typically 4-ethoxycarbonyipheflyl, halogen-lower alkyiphenyl, typically 4-chloromethylpheflyl, lmldazot-i -ylphenyl, typically 4-(imidazolyl-1 -yl)phenyl, pyrroildinolower alkyiphenyl, typically 4-pyrroildinomfethylphenl piperazino-lower alkyiphenyl, typically 4-piperazinomethylphenyl, (4-lower alkylpiperazirlomethyl)pheflyl, typically 4-(4-methylpiperazinomethyl)phenyl, morpholino-lower alkylphenyl, typically 4-morpholiflomlethylpheflyl, piperazinocarbonylpheflyl, typically 4-piperazinocarboflylphenl, or (4-lower alkylpiperazino)mphenyl, typically 4-(4-methylpiperaziflo)pheflyl.

A further preferred Acyl Ac' is derived from monoesters of carbonic acid and Is characterised by the subformuia

R-

0 The lower alkyl. radicals, especially tert-butyl, are especially preferred hydrocarbyl radicals R* in these derivatives.

I

00 -17- Another preferred Acyl Ac' is derived from amides of carbonic acid (or also thiocarbonic acid) and Is characterised by the formula or wherein the radicals RO are, independently of one another, as defined above and W is sulfur and especially oxygen. In particular, compounds are preferred wherein Ac' is a radical of formula wherein W is oxygen and Ro has one of the following preferred meanings: morpholino-lower alkyl, typically 2-morpholinoethyl, phenyl, lower alkoxyphenyl, typically 4- 00 methoxyphenyl or 4-ethoxyphenyl, carboxyphenyl, typically 4-carboxyphenyl, or lower alkoxy- N carbonylphenyl, typically 4-ethoxycarbonylphenyl.

00 A preferred acyl Ac 2 of subformula RO-SO2, wherein RO is a hydrocarbyl as defined in the above general and specific meanings, is lower alkylphenylsulfonyl, typically 4toluenesulfonyl.

If p is 0, the nitrogen atom bonding R 3 is uncharged. If p is 1, then R 4 must also be present, and the nitrogen atom bonding R 3 and R 4 (quaternary nitrogen) is then positively charged.

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 match the definitions given for the corresponding radicals R 3 and R 4 Especially preferred is Rr lower alkyl, especially methyl, or most especially hydrogen.

Z is especially lower alkyl, most especially methyl or hydrogen.

If the two bonds indicated by wavy lines are missing in ring A, then no double bonds (tetrahydrogenated derivatives) are present between the carbon atoms characterised in formula I by the numbers 1, 2, 3, and 4, but only single bonds, whereas ring B Is aromatic (double bonds between the carbon atoms characterised in formula I by 8.and 9 and those characterised by 10 and 11). If the two bonds indicated by wavy lines are missing in ring B, then no double bonds (tetra-hydrogenated derivatives) are present between the carbon atoms characterised In formula I by the numbers 8, 9, 10, and 11, but only single bonds, whereas ring A is aromatic (double bonds between the carbon atoms characterised in formula I by 1 and 2 and those characterised by 3 and If the total of four bonds indicated by wavy lines are missing in rings A and B, and are replaced by a total of 8 hydrogen atoms, 00 -18then no double bonds (octa-hydrogenated derivatives) are present between the carbon atoms numbered 1, 2, 3, 4, 8, 9, 10, and 11 in formula I, but only single bonds.

C By their nature, the compounds of the invention may also be present in the form of pharmaceutically, i.e. physiologically, acceptable salts, provided they contain salt-forming 0 groups. For isolation and purification, pharmaceutically unacceptable salts may also be 00 used. For therapeutic use, only pharmaceutically acceptable salts are used, and these salts S are preferred.

00 Thus, compounds of formula I having free acid groups, for example a free sulfo, phosphoryl or carboxyl group, may exist as a salt, preferably as a physiologically acceptable salt with a salt-forming basic component. These may be primarily metal or ammonlum salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, especially tertiary monoamines and heterocyclic bases, for example triethylamine, tri-(2-hydroxyethyl)amine, N-ethylplperidine or N,N'-dimethylpiperazine.

Compounds of the invention having a basic character may also exist as addition salts, especially as acid addition salts with inorganic and organic acids, but also as quaternary salts. Thus, for example, compounds which have a basic group, such as an amino group, as a substituent may form acid addition salts with common acids. Suitable acids are, for example, hydrohalic acids, e.g. hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic, alicyclic, aromatic or heterocycllc carboxylic or sulfonic acids, such as formic, acetic, proplonic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzolc, salicylic, p-aminosalicylic acid, pamoic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenedisulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonlc acids or sulfanilic acid, and also methionine, tryptophan, lysine or arginine, as well as ascorbic acid.

In view of the close relationship between the compounds (especially of formula I) in free form and in the form of their salts, including those 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 is to be understood as 00 -19- S referring also to the corresponding salts, and the solvates thereof, for example hydrates, as appropriate and expedient.

(i The compounds of formula.A, B, C, D, 1, 11, 111, IV, V or VI especially those wherein R 5 Is hydrogen, possess valuable pharmacological properties.

00 In the case of the groups of radicals or compounds mentioned hereinbefore and hereinafter, N general definitions may, insofar as appropriate and expedient, be replaced by the more 00 specific definitions stated hereinbefore and hereinafter.

Preference is given to a compounds of formula 1, 11, 111, IV, V, VI wherein R, and R 2 independently of each other are lower alkyl, lower alkyl substituted by halogen, C 6

C

1 4 aryl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower aikanoylamino, phenyl-lower alkylamino, N, N-dilower alkylamino, N, N-di-(phenyl-lower alkyl)amlno, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dl-lower alkylcarbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lowe r aikylaminosulfoflYl or N, N-di-lower alkylaminosulfoflYl halogen; lower alkoxy; Ce-C, 4 aryloxy;,

C

6 -Ci 4 aryl-lower alkoxy; lower alkanoyloxy;

C

6 -Cl 4 arylcarbonyoxy; amino monosubstituted or disubstituted by lower alkyl, C 6

-C

14 aryl, CO-Cl 4 aryl-lower alkyl, lower alkanoyl or Ce-C 12 arylcarbonyl; cyano; nitro; mercapto; lower alkylthio; C 6

C

14 arylthlo; C 6

-C

14 aryl-iower alkylthio; lower alkanoylthio;

CO-C

1 4 aryilower alkanoylthio; carboxy; lower alkoxycarbonyl,

C

6 -Cj 4 aryIlower alkoxycarbonyl;

C

6

-C

1 4 aryloxycarbonyl; carbamoyl; carbamoyl N-mono- or N,Ndisubstituted by lower alkyl, C 6

-C

14 arYI or C 6 -Cl 4 aryl-lower alkyl; sulf o; CO-Cl 4 arylsulfonyl;

C

6

C

1 4 aryl-lower alkanesulfonyl; lower alkanesulfonyi; or aminosulfonyl N-mono- or N ,Ndisubstituted by lower alkyl, C 5

-C

1 4 aryl or C 6 -Cl 4 aryl-lower alkyl, wherein CrCl4aryI 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, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenyloxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamlno, lower alkanoylamino, phenyl-lower alkylamino, N,N-di-lower alkylamino, N,N-di-(phenyl-Iower alkyl)amino, cyario, mercapto, lower alkyithio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkyicarbamoyl, sulfo, lower alkanesulfoflyl, lower alkoxysulfonyl, aminosulfonyl, N-lower alkylaminosulfonyl or N, N-di-lower alkylaminosulfonl 00 n and mn are Independently of each other 0 or 1 or 2, preferably 0; C\ R 3

R

4

R

8 Rio are independently of each other hydrogen, lower alkyl, lower alkenyl or lower N alkadienyl, which are each unsubstituted or monosubstituted or polysubsituted, preferably C\ *monosubstituted or disubstituted by a substituent independently selected from lower alkyl; ID hydroxy; lower alkoxy, which may be unsubstituted or mono-, dl-, or trisubstituted by (I) 00 heterocyclyl with 4 to 12 ring atoms, which may be unsaturated, wholly saturated, or partly 0 00 nitrogen, oxygen and sulfur, and Is most especially pyrrolyl, for example 2-pyrrolyl or 3pyrrolyl, pyridyl, for example 3- or 4-pyridyl, or in a broader sense also thienyl, for example 2- or 3-thienyl, or fury], for example 2-furyl, Indolyl, typically 2- or 3-indolyl, quinolyl, typically 2- or 4-quinolyl, isoqulnolyl, typically 3- or 5-isoquinolyl, benzofuranyl, typically 2benzofuranyl, chromenyl, typically 3-chromenyl, benzothieflyl, typically 2- or 3-benzothienyl; imidazolyl, typically 1- or 2-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzlmidazoly, typically 2-benzlmldazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydrofuryl, 4-tetrahydrofuryl, 4-tetrahydropyranyl, 2- or 3-pyrrolidyl, or 4-piperidyl, 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2-piperazinyl or N,N'bis-lower alkyl-2-piperazinyl, (Ii) by halogen, (iii) by hydroxy or (iv) by lower alkoxy; phenoxy; phenyl-lower alkoxy; heterocyclyloxy, wherein heterocyclyl Is pyrrolyl, for example 2-pyrrolyl or 3-pyrrolyl, pyridyl, for example 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-isoquinolyi, benzofuranyl, typically 2benzofuranyl, chromenyl, typically 3-chromenyl, benzothienyi, typically 2- or 3-benzothlenyl; imidazolyl, typically I- or 2-ImIdazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzlmldazolyl, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydrofuryl, 4-tetrahydrofUryl, 2- or 4-tetrahydropyranyl, 2- or 3pyrrolidyl, or 4-piperidyl, 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2- *piperazinyl or N,N'-bis-lower alkyl-2-piperazinyl, such as especially 2- or 4-tetrahydropyranyloxy; lower alkanoyloxy; carboxy; lower alkoxycarbonyl; phenyl-lower alkoxycarboflyl; mercapto; lower alkylthio; phenylthio; halogen; halogen-lower alkyl; oxo (except In the I-position, because otherwise acyl); azido; nitro; cyano; amino; mono-lower alkylamino; di-lower alkylamino; pyrrolidino; imidazol-I-yl; piperidino; piperazino; 4-lower 00 -21alkylpiperazilo; morpholino; thiomorpholilno; diphenylamlflo or dlbenzylamiflo unsubsttluted or substituted In the phenyl part by lower alkyl, lower aikoxy, halogen and/or nitro; lower alkoxycarboflylamilo; phenyl-lower alkoxycarboflamlifo unsubstituted or substituted in the phenyl part by lower alkyl or lower alkoxy; fluorenyimethoxycarbofliamiflo; amino-lower alkyl; monosubstitlited or disubstituted amino-lower alkyl, wherein the amino substituent is 00 selected from lower alkyl, hydroxy-lower alkyl, C 3 -Cocycloalkyl, amino-lower alkyl, N-monoor N,N-di(-iOwer alkyl)amino-lower alkyl, amino, N-mono- or N,N-di-lower alkylamino and N- N1 mono- or N,N-dl-(hydroxy-lower alkyl)amlno; pyrrolidino-lower alkyl: piperidino-lower alkyl; 00 piperazino-lower alkyl; 4-lower alkylpiperazlno-lower alkyl; imidazol-1 -yi-iower alkyl; morpholino-lower alkyl; thiomorpholino-lower alkyl; S-oxo-thlomorpholiflo-lower alkyl; S,Sdloxothlomorpholflo-lower alkyl; lower alkylendioxy; sulfamoyl; sulfo; carbamoyl; ureido; guanidino; cyano; aminocarbonyl (carbamoyl) and amlnocarbonyloxy, which are substituted by one or two radicals on the nitrogen, wherein the amino substituents are selected independently of one another from the group comprising lower alkyl, hydroxy-lower alkyl, C 3 Cscycioalkyl, amino-lower alkyl, N-mono- or N,N-di(-lower alkyl)amino-iower alkyll, amino, Nmono- or N,N-dl-lower alkylamino and N-mono- or N,N-dl-(hydroxy-lower alkyl)amino; pyrrolidinocarbonYl; piperidinocarbonyl; piperazinocarbonyl; 4-lower alkyiperazinocarbonYl; lmidazolinocarbonyl; morpholinocarbonyl; thiomorpholilocarbofl; S-oxo-thiomorpholinocarbonyl; and S,S-dioxothlomorpholino; phenyl, naphthyl, phenyl-lower alkyl or phenyl-lower alkenyl with a terminal phenyl radical, which is unsubstituted or monosubstituted or disubstituted by the radicals named above as substituents of lower alkyl, lower alkenyl or lower alkadienyl; or heterocyclyl-lower alkyl, wherein heterocyclyl is pyrrolyl, for example 2-pyrrolyl or 3pyrrolyl, pyridyl, for example 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, qulnolyl, typically 2- or 4-quinolyl, isoquinolyl, typically 3- or 5-Isoquinolyi, benzofuralyl, typically 2benzofuranyl, chromenyl, typically 3-chromenyl, benzothienyl, typically 2- or 3-benzotllienyl; imidazolyl, typically I1- or 2-imidazolyl, pyrimidinyl, typically 2-or 4-pyrimidinyl, oxazolyl, typically 2-oxazolyl, isoxazolyl, typically 3-isoxazolyl, thiazolyl, typically 2-thiazolyl, benzimldazolyi, typically 2-benzimidazolyl, benzoxazolyl, typically 2-benzoxazolyl, quinazolyl, typically 2-quinazolinyl, 2-tetrahydrofliryl, 4-tetrahydrofuryl, 2- or 4-tetrahydropyranyl, 2or 3-pyrrolidyl, or 4-piperidyl, 2-or 3-morpholinyl, 2- or 3-thiomorpholinyl, 2- 00 -22piperazinyl or N,N'-bis-lower alkyi-2-piperazill which in each case are unsubstituted or monosubstituted or disubstituted by the radicals named above as substituents of lower alkyl, lower alkenyl, or lower alkadienyl; or acyl of the subformuia wherein W is oxygen and Y is hydrogen,

R

0

R

0 ID ROHN-, or R 0

IR

0 N- (wherein the radicals RO may be the same or different), 00 or Ni acyl of the subformula

R

0 -S0 2 00 whereby R 4 may also be absent for the compound of formula 11; or

R

4 is absent for compounds of formula 11, hydrogen or CH 3 for compounds of formula 1, and

R

3 is acyl of the subformuia wherein W is oxygen and Y is hydrogen, RO, R 0 R*HN-, or R 0 R*N- (wherein the radicals R 0 may be the same or different), or is acyl of the subformula R 0 -S0 2 wherein R 0 in the said radicals has the following meanings: substituted or unsubstituted lower alkyl, especially methyl or ethyl, amino-lower alkyl hydroxy-lower alkyl, wherein the amino group Is unprotected or Is protected by a conventional amino protecting group especially by lower alkoxycarbonyl, typically tert-lower alkoxycarboflyl, for example tertbutoxycarbonyl e.g. aminomethyl, R- or preferably S-1 -aminoethyl, tertbutoxyca rbonylamirlom ethyl or RS-, or preferably S-i -(tert-butoxycarboflamino)ethyl, carboxy-lower alkyl, typically 2-carboxyethyl, lower alkoxycarboflyl-lower alkyl, typically 2- (tort-butoxycarbonyl)ethyI, cyano-lower alkyl, typically 2-cyanoethyl, tetrahydropyralyloxylower alkyl, typically 4-(tetrahydropyranyl)oxymethyl, morpholino-lower alkyl, typically 2- (morphollno)ethyl, phenyl, lower alkyiphenyl, typically 4-methylphenyl, lower alkoxyphenyl, typically 4-methoxypherlyl, imidazolyl-lower aikoxyphenyl, typically 4-[2-(imldazo1-I yi)ethyl)oxyphenyl, carboxyphenyl, typically 4-carboxyphenyl, lower alkoxycarbonyiphelyl, typically 4-ethoxycarbonylpheflyl or 4-methoxypherlyl, halogen-lower alkylphenyl, typically 4chioromethyiphenyl, pyrrolidinophenyl, typically 4-pyrroldinopherlyl, imidazol-1 -yiphenyl, typically 4-(imidazolyl-I -yl)phenyi, piperazinophenyl, typically 4-piperazinophenyl, (4-lower alkyliperazr1o)phenyl, typically 4-(4-methylplperazino)pheflyl, morpholinophenyl, typically 4morpholinopheflyl, pyrrolidino-lower aikylphenyl, typically 4-pyrrolidinomethylphenoy, 00 -23- S imldazol-1-yl-lower alkylphenyl, typically 4-(imidazolyl-1-ylmethyl)phenyl, plperazino-lower alkylphenyl, typically 4-piperazinomethylphenyl, (4-lower alkylpiperazlnomethyl)-phenyl, typically 4-(4-methylpiperazinomethyl)phenyl, morpholino-lower alkylphenyl, typically 4morpholinomethylphenyl, piperazinocarbonylphenyl, typically 4-piperazinocarbonylphenyl, or (4-lower alkylpiperazino)phenyl, typically 4-(4-methylplperazino)phenyl.

00 p is 0 if R 4 is absent, or Is 1 if R 3 and R 4 are both present and in each case are one of the C aforementioned radicals (for compounds of formula II); 00

R

5 is hydrogen or lower alkyl, especially hydrogen, X stands for 2 hydrogen atoms, for 0, or for 1 hydrogen atom and hydroxy; or for 1 hydrogen atom and lower alkoxy; Z is hydrogen or especially lower alkyl, most especially methyl; and for compounds for formula II, either the two bonds characterised by wavy lines are preferably absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel bond, signify a double bond; or also the two bonds characterised by wavy lines are absent in ring B and replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel bond, signify a double bond; or both in ring A and in ring B all of the 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.

Particular preference Is given to a compound of formula I wherein; m and n are each 0;

R

3 and R 4 are independently of each other hydrogen,

I

00 -24lower alkyl unsubstituted or mono- or disubstituted, especially monosubsttuted, by radicals selected independently of one another from carboxy; lower alkoxycarbonyl; and cyano;; S or

R

4 is hydrogen or -CH 3 and

R

3 is as defined above or preferably

R

3 is, acyl of the subformula

R

0 -CO, wherein RO Is lower alkyl; amino-lower alkyl, wherein the 00 amino group is present in unprotected form or is protected by lower alkoxycarbonyl; S tetrahydropyranyloxy-lower alkyl; phenyl; Imidazolyl-lower alkoxyphenyl; carboxyphenyl; 00 lower alkoxycarbonylphenyl; halogen-lower alkylphenyl; imidazol-1 -ylphenyl; pyrrolidino- O lower alkylphenyl; piperazino-lower alkylphenyl; (4-lower alkylpiperazinomethyl)phenyl; morpholino-lower alkylphenyl; piperazinocarbonylphenyl; or (4-lower alkylpiperazino)phenyl; or is acyl of the subformula

R

0 wherein RO is lower alkyl; or is acyl of the subformula ROHN-C(=W)-, wherein W is oxygen and Ro has the following meanings: morpholino-lower alkyl, phenyl, lower alkoxyphenyl, carboxyphenyl, or lower alkoxycarbonylphenyl; or R3 is lower alkylphenylsulfonyl, typically 4-toluenesulfonyl; further specific examples of preferred R 3 groups are described below for the preferred compounds of formula II, is hydrogen or lower alkyl, especially hydrogen, X stands for 2 hydrogen atoms or for 0; Z is methyl or hydrogen; or a salt thereof, if at least one salt-forming group is present.

Particular preference is given to a compound of formula II wherein m and n are each 0; R and R 4 are independently of each other hydrogen, 00 lower alkyl unsubstituted or mono- or disubstituted, especially monosubstituted, by radicals selected independently of one another from carboxy; lower alkoxycarbonyl; and cyano; whereby

R

4 may also be absent; or

R

4 is absent, and

R

3 Is acyl from the subformula R*-CO, wherein R 0 Is lower alkyl, especially methyl or ethyl; 00 amino-lower alkyl, wherein the amino group is unprotected or protected by lower alkoxy- N- carbonyl, typically tert-lower alkoxycarbonyl, for example tert-butoxycarboflyl, e.g.

00 aminomethyl, or preferably 5-1-aminoethyl, tert-butoxycarbOnylamlflomethyl or or preferably S-1-(tert-butoxycarbonylamino)ethyl; tetrahydropyranyloxy-lower alkyl, typically 4-(tetrahydropyranl)oxymethyl; phenyl; imidazolyl-lower alkoxyphenyi, typically 4- [2-(imidazol-1 -yl)ethyl)oyxphenYl; carboxyphenyl, typically 4-carboxyphenyl; lower alkoxycarbonylphenyl, typically 4-methoxy- or 4-ethoxyCarbonylphelyl; halogen-lower alkylphenyl, typically 4-chloromethylpheflyl; imidazol-1 -ylphenyl, typically 4-(idazoly-1 -yl)phenyl; pyrrolidino-lower alkylphenyl, typically 4.pyrrolidinomlethylPheflyl; pipe razino-lower alkylphenyl, typically 4-piperazlnomethylphenyl; (4-lower alkylpiperazinomlethyl)phenyl, typically 4-(4-methylpiperazinomethyl)pheyl; morpholino-lower alkyiphenyl, typically 4rnorphoiinomethylphenyl; plperazlnocarbonylphenyl, typically 4-plperazinocarbonylphenyl; or (4-lower alkylpiperazino)phenyl, typically 4-(4-methylpiperazilo)phenyl; or is acyl of the subformula

R

0 wherein R' Is lower alkyl;, or is acyl of the subformula

R

0 wherein W Is oxygen and R* has the following preferred meanings: morpholino-lower alkyl, typically 2-morpholirIoethyl, phenyl, lower alkoxyphenyl, typically 4-methoxypheflyl or 4-ethoxyphenyl, carboxyphenyl, typically 4carboxyphenyl, or lower alkoxycarbonyiphenyl, typically 4-ethoxycarbonylphenyl; or is lower alkylphenylSulfoflyl, typically 4-toluenesulfolyl; p Is 0 if R 4 is absent, or is 1Iif R 3 and R 4 are both present and In each case are one of the aforementioned radicals;

R

5 is hydrogen or lower alkyl, especially hydrogen, X stands for 2 hydrogen atoms or for 0; Z is methyl or hydrogen; 00 -26and either the two bonds characterised by wavy lines are preferably absent In ring A and replaced by 4 hydrogen atoms, and the two wavy lines In ring B each, together with the respective parallel bond, signify a double bond; 00 or also the two bonds characterised by wavy lines are absent In ring B and replaced by a total of 4 hydrogen atoms, and the two wavy lines In ring A each, together with the respective N1 parallel bond, signify a double bond; 00 or both in ring A and in ring B all of the 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.

Most especially preferred compounds of formula 11 are selected from; 8,9,10,11 -Tetrahydrostaurosporine;, N-[4-(4-methylpiperaziN- I -ylmethyl)benzoyl]-l ,2,3 ,4-tetrahydrostaurosporine; N-(4-chloromethylbenzoyl)-1 ,2,3,4-tetrahydrostaurosporine; N-(4-(pyrrolidin-1 -ylmethyl)benzoyl)-I ,2,3,4-tetrahydrostaurosporine; N-(4-(morpholin-4-ylmethyl)benzoyl)l ,2,3,4-tetrahydrostaurosporine; N-(4-(piperazin-1 -ylmethyl)benzoyl)-l ,2,3,4-tetrahydrostaurosporine; N-ethyl-I 3,4-tetrahydrostaurospoflne; N-tosyl-1 ,2,3,4-tetrahydrostaurosporine; N-triflouroacetyl-1 ,2,3,4-tetrahydrotaurosporine; N-[4-(2-1imidazol-1 -yi-ethoxy)benzoyI]-l ,2,3,4-tetrahydrostaur osporine; N-methoxycarbonymethyll ,2,3,4-tetrahydrostaurosporine; N-carboxymethyl-1 ,2 ,3,4-tetrahydrostaurosporine; N-terephthaloylmethyl ester-I ,2,3,4-tetrahydrostau rosporine; N-terephthalOyl-1I,2,3,4-tetrahydrostaurosporine; N-(4-ethyipperazinylcarbonyibenzoyl)l ,2,3,4-tetrahydrostaurosporine; N-(2-cyanoethYl)-1 ,2,3,4-tetrahydrostaurosporine; N-benzoyl-1 ,2,3,4-tetrahydrostaurosporine; N, N-dimethyl -1,2,3 ,4-tetrahydrotaurospoflnium Iodide; N-BOC-glycyl-1 ,2,3 ,4-tetrahydrostaurosporine;

I

00 -27- N-glycyl-l ,2.3,4-tetrahydrostaurosporile; N-(3-(tert-butoxycarboflyl)propyl)-l 2,3 ,4-tetrahydrostaurosporile; N-(3-carboxypropyl)-I ,2,3,4-tetrahydrostaur0spoflfe; N-(4-lmidazOl-1 -yl)benzoyl]-1 ,2 ,3,4-tetrahydrostaurosporifle; N-[(tetrahydro-2h-pyrafl4-yIoxy)acety ,2,3,4-tetrahydrostaurosporifle; N-BOC-1-alanyl-1 ,2,3,4-tetrahydrostaurosporile; 00 N-l-alanyl-I ,2 ,3,4-tetrahydrOStaurosporlfle hydrochloride; Ni N-methyl-I 3,4-tetrahydro-6-methylstaurosporlfle; 00 N-(4-carboxypheflylamiflocarbonyl)l ,2,3,4-tetrahydrotaurosporile; N-(4-ethylpheflylamiflocarbonyl)l ,2,3,4-tetrahydrostaurospodnfe, N-(N-phenylamiflocarboflyl)l ,2,3,4-tetrahydrostaurosporile; morpholiflo)ethyiamiflocarbonyl l ,2 ,3 ,4-tetrahydrostaurosporile; N-(N-[4-methoxypheflyl]amnoarbonyl)l ,2,3,4-tetrahydrostaurosporile; 1,2 ,3,4-tetrahydro-6-mlethylstaurosporine; N-BOC-1 ,2,3,4-tetrahydrostaurosporle; N-BOC-I ,2,3,4-tetrahydro-6-mfethylstaurosporine; N-BQC-1 ,2,3,-erhdo mtyl7oosarsoie 1,2,3,4,8,9,10,11 -octahydrostaurospodnfe; or a pharmaceutically acceptable salt thereof, If at least one salt-forming group is present.

Most especially preferred is the compound of formula I desi gnated I ,2,3,4-tetrahydrOstaurosporine, or a (particularly pharmaceutically acceptable) salt thereof (here, mn und n in formula I are 0, R 3 is hydrogen, R4 is absent, provided no salt is present (p or is hydrogen if a salt Is present (p Rs Is hydrogen, the two bonds represented by wavy lines are absent in Ring A and are replaced by a total of 4 hydrogen atoms and the two bonds represented by wavy lines in Ring B are in each case a double bond together with the parallel bonds, X stands for 2 hydrogen atoms, and Z is methyl).

Most especially preferred are the compounds of formula A wherein; A) X= 0; R 1

R

2

R

5 H; Q= -(CH2) 2 -0-CH(CH 2 )0H(CH2)2- B) X= 0; Ri, R 2

.,R

5 H; Q= -(CH 2 2 -0-CH(CH 2

N(CH

3 2 )-(CH2)2- C) X= 2 hydrogen atoms;

R

1

RZR

5 H; Q= H "1I-C HO OCH

OH

00 -28- Most especially preferred are the compounds of formula I wherein; (i A) X= 2 hydrogen atoms; R 11

R

2

R

3

R

5 H; R4= CH- 3

Z=CH

3 (staurosporine) B) X= 1 hydrogen and 1 hydroxy atoms in or isomeric form; R 1

,R

2

R

3

,R

5

R

4

OH

3

Z=CH

3 (UCN-01 and UCN-02) C) X= 2 hydrogen atoms; R 1

,R

2

R

5

R

4

CI-

3

R

3 benzoyl; Z=CH 3 (CGP4I 251 or 00 PKC412 or MIDOSTAURIN) D) X= 0; R 1

,R

2

R

5

R

3

OH-

3

R

4 ethyloxycarbolyl;

Z=CH

3 (NA 382 CAS=143086-33- 00 3) E) X= I hydrogen and 1 hydroxy atom; R 1

R

2

R

5

R

3

OH

3

Z=CH

3 and R 4 is selected from -(CH 2 2 0H; -CH 2 CH(OH)CH2OH;

-CO(CH

2 2 C0 2 Na; -(CH 2 3 00 2 H;

COCH

2

N(CH

3 2 2 )0C-\N--CH 3 -Co- Ic-' F) X= 2 hydrogen atoms; R 1

R

2 ,Re H; R 3

CH

3

ZCH

3 and R 4 1is selected from N-[O- [0-(tetrahydropyran-4-yl )-L-lactoyi]; N-[O(tetrahydropyran-4-yi )-D-iactoylj; N-[2- (tetrahydro-pyral-4-yloxy)-acetyl)] G) X0O; Ri, R 2

R

5

R

3

OH

3 Z0CH 3 and R 4 is selected from N-[0-(tetrahydropyra1-4-yl )-D-Iactoyi]; N-2(erhdopra--ix)aey) H) X=1 hydrogen and 1 hydroxy atom R 1

R

2

R

5

R

3

CH

3

Z=CH

3 and R 4 is selected from N-[0-(tetrahydropyran-4-yi )-D-lactoyl]; N-[2-(tetrahydro-pyranlAyloxy)-acetyD)] The abbreviation "CAS" means the CHEMICAL ABSTRACTS registry number.

The most preferred compounds of formula I e.g. MIDOSTAURIN [international Nonproprietary Name] are covered and have been specifically described by the European patent No. 0 296 110 published on December 21, 1988, as well as in US patent No.

5;093,330 published on March 3, 1992, and Japanese Patent No. 2 708 047. Other preferred compounds are covered and described by the patent applications WO 95/32974 and WO 95/32976 both published on December 7, 1995. All the compounds described In these documents are incorporated into the present application by reference.

Most especially preferred are the compounds of formula Ill wherein; A) X= 2 hydrogen atoms; R 1

*R

2

R

5 H; Re= OH 3

R

7 methyloxycarbonyl; Z=H (2methyl K252a) B) X= 2 hydrogen atoms; R 1 1

R

2

R

5 Re H; R 7 rethyloxycarbolyl; Z= H (K-252a) 00 -29-

O

O

C) X= 2 hydrogen atoms; R 1

,R

2

.R

5 Re H; R 7 methyloxycarbonyl; Z= CH 3 (KT-5720) Most especially preferred are the compounds of formula IV wherein; A) X= 0; R 1

R

2 R H; R 9

CH

2 -NMa 2 R= CH 3 m'=n'=2 B) X= O; R 1

R

2

R

5 H; Re= CH 2

-NH

2 Re= CH 3 n'=1 (Ro-31-8425; CAS=151342- )0 35-7) 00 Most especially preferred are the compounds of formula V wherein; 00 A) X= O; Ri, R 2

R

5 H; R= CH; Rio= -(CH 2 3

-NH

2 (Ro-31-7549; CAS=138516-3 1 SB) X= O; Ri, R 2 R H; Re= CH 3 Rio= -(CH 2 3 -S-(C=NH)-NH2; (Ro-31-8220;

C

CAS=125314-6 4 C) X= O; R 1

R

2

R

5 H; Re= CH 3 Rio= -CH 3 Most especially preferred are the compounds of formula VI wherein; A) X= 2 hydrogen atoms; R 1

,R

2

R

5 H; R 4

CH

3

Z=CH

3 R selected from methyl or (C 1 CIo)alkyl, arylmethyl,

C

6

H

2 CHz- STAUROSPORINE DERIVATIVES and their manufacturing process have been specifically described in many prior art documents, well known by the man skilled in the art.

Compounds of formula A, B, C, D and their manufacturing process have for instance, been described in the European patents No. 0 657 458 published on June 14, 1995, in the European patents No. 0 624 586 published on November 17, 1994, in the European patents No. 0 470 490 published on February 12, 1992, in the European patents No. 0 328 026 published on August 16, 1989, in the European patents No. 0 384 349 published on August 29, 1990, as well as in many publications such as Barry M. Trost* and Welping Tang Org.

Lett., 3(21), 3409-3411.

Compounds of formula I and their manufacturing processes have specifically been described in the European patents No. 0 296 110 published on December 21, 1988, as well as in US patent No. 5;093,330 published on March 3, 1992, and Japanese Patent No. 2 708 047.

Compounds of formula I having a tetrahydropyran-4-yl )-lactoyl substitution on R 4 have been described in the European patent No. 0 624 590 published on November 17, 1994. Other compounds have been described in the European patent No. 0 575 955 published December 29, 1993, European patent No. 0 238 011 published on September 23, 1987

I

00 S (UCN-O1), International patent application EP98/04141 published as W099/02532 on July 03,1998.

Compounds of formula II and their manufacturing processes have specifically been described in the European patents No. 0 296 110 published on December 21, 1988, as well \O as in US patent No. 5;093,330 published on March 3, 1992, and Japanese Patent No. 2 708 00 047.

00 Compounds of formula III and their manufacturing processes have specifically been described In the patent applications claiming the priority of the US patent application

US

920102 filed on July 24, 1992. (L.e European patents No. 0 768 312 published on April 16, 1997, No. 1 002 534 published May 24, 2000, No. 0 651 754 published on May 10, 1995).

Compounds of formula IV and their manufacturing processes have specifically been described in the patent applications claiming the priority of the British patent applications

GB

9309602 and GB 9403249 respectively filed on May 10, 1993, and on February 21, 1994.

(i.e European patents No. 0 624 586 published on November 17, 1994, No. 1 002 534 published May 24, 2000, No. 0 651 754 published on May 10, 1995).

Compounds of formula V and their manufacturing processes have specifically been described In the patent applications claiming the priority of the British patent applications

GB

8803048, GB 8827565, GB 8904161 and GB 8928210 respectively filed on February 1988, November 25, 1988, February 23, 1989 and December 13, 1989. (I.e European patents No. 0 328 026 published on August 16,1989, and No. 0 384 349 published August 29, 1990).

Compounds of formula VI and their manufacturing processes have specifically been described in the patent applications claiming the priority of the US patent applications 07/777,395 (Con), filed on October 10, 1991 (i.e International patent application

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 STAUROSPORINE DERIVATIVE compounds, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby Incorporated into the present application by reference to these publications.

00 -31-

O

O

The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from S databases, e.g. Patents International IMS World Publications). The corresponding content thereof is hereby incorporated by reference.

The preferred STAUROSPORINE DERIVATIVE according to the invention is N- 00 [(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy- S1H,9H-diindolo[1,2,3-gh:3',2',1'-Im]pyrrolo[ 3 ,4-j][1,7]benzodiazonin-11-yl]-N- 00 methylbenzamide of the formula

(VII):

HCH

00 H,C ,OH

(VII)

or a salt thereof, (hereinafter: "Compound of formula VII or MIDOSTAURIN").

Compound of formula VII is also known as MIDOSTAURIN [International Nonproprietary Name] or PKC412.

MIDOSTAURIN is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 110 published on December 21, 1988, as well as in US patent No. 5;093,330 published on March 3, 1992, and Japanese Patent No. 2 708 047.

It has now surprisingly been found that MIDOSTAURIN possesses therapeutic properties, which render it particularly useful as an inhibitor of PDGFRa (platelet derived growth factor a, also abbreviated as PDGRA) and especially for the treatment of FlP1L1-PDGFRa-induced diseases like hypereosinophilic syndrome. FIPIL1-PDGFRa, as used hereinbefore and

I

00 -32hereinafter, Is the designation of the fusion product of the genes FIP1L1 (FIP1 like 1) with PDGFRa. Particularly surprising is that Midostaurin is effective in the prevention or treatment of imatinib-induced resistance, which is believed to occur because of the T6741 mutation in FIP1L1-PDGFRa.

STAUROSPORINE DERIVATIVES e.g. MIDOSTAURIN were originally identified as Inhibitor S of protein kinase C (PKC) (Meyer T, Regenass U, Fabbro D, et al: Int J Cancer 43: 851-856, S 1989).

00 It has now surprisingly been found that STAUROSPORINE DERIVATIVES possess therapeutic properties, which render them particularly useful as an inhibitor of FIP1L1- PDGFRa and especially in the treatment and prophylaxis of hypereosinophllic syndrome and hypereoslnophilic syndrome with resistance to Imatinib. In particular MIDOSTAURIN shows an unexpected high potency toward the FIP1L1-PDGFRaT6741 mutation.

The present invention thus concerns the use of STAUROSPORINE DERIVATIVES for the preparation of a drug for the treatment of FIP1L1I-PDGFRa-induced myeloproliferative diseases, or other diseases associated with FIPL1-PDGFRa or similar mutations that activate PDGFRa..

The term "FIP1L1-PDGFRa-induced myeloproliferatlve diseases" as used herein includes, but is not limited to, hypereosinophilic syndrome and hypereosinophilic syndrome with resistance to imatinib. This term also specifically includes diseases resulting from FIP1L1- PDGFRa mutation, particularly from the FIP1L1-PDGFRaT6741 mutation.

The present invention more particularly concerns the use of STAUROSPORINE DERIVATIVES for the preparation of a drug for the treatment of hypereosinophilic syndrome and hypereoslnophilic syndrome with resistance to imatlnib.

In another embodiment, the instant invention provides a method for treating FIP1L1- PDGFRa-induced myeloprollferative diseases comprising administering to a mammal in need of such treatment a therapeutically effective amount of STAUROSPORINE DERIVATIVES, or pharmaceutically acceptable salts or prodrugs thereof.

Preferably the instant invention provides a method for treating mammals, especially humans, suffering from FIP1L1-PDGFRa-induced myeloproliferative diseases comprising

I

00 -33-

O

S administering to a mammal in need of such treatment a FIP1L1-PDGFRa inhibiting amount Sof N-[(9S R,11R,1 3R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy- 0 1H,9H-dlndolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-][l1,7]benzodlazonin- 11-yl]-Nmethylbenzamide of the formula (VII), or a pharmaceutically acceptable salt thereof.

I The instant Invention also concerns a method wherein the therapeutically effective amount of 00 the compound of formula VII Is administered to a mammal subject 7 to 4 times a week or N about 100 to about 50% of the days In the time period, for a period of from one to six C weeks, followed by a period of one to three weeks, wherein the agent is not administered S and this cycle being repeated for from 1 to several cycles.

Preferably, this method is used for treating FIP1L1-PDGFRa-lnduced myeloproliferative diseases More preferably, this method is used for treating hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatinib.

In another embodiment, the instant invention relates to the use of STAUROSPORINE DERIVATIVES for the preparation of a pharmaceutical composition for use in treating FIP1L1-PDGFRa-induced myeloproliferative diseases, more particularly for treating hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatlnib.

STAUROSPORINE DERIVATIVES have useful pharmacological properties. In particular, MIDOSTAURIN inhibits the growth of FIPIL1-PDGFRa expressing Ba/F3 cells in concentrations in the range of 130 nM.

In vivo, the activity of the STAUROSPORINE DERIVATIVES especially compounds of formula I or II, can be demonstrated, for example, in a single or up to three oral administrations per day to animals at doses in the range of 0.1 to 10 or 1 to 5 mglkg of body weight per day.

The STAUROSPORINE DERIVATIVES are therefore very highly suitable for the treatment of diseases, which are FIP1L1 -PDGFRa-induced myeloproliferative diseases, e.g.

hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatinib.

00 -34-

O

O

FIP1L1 -PDGFRa is a cause of hypereosinophilic syndrome and a therapeutic target for the S tyrosine kinase inhibitor imatinib (International Non-proprietary Name), which is marketed N\ under the designation GLEEVEC in the US and GLIVEC in Europe.

It was surprisingly found that when a relapse occurs during the treatment of -0 hypereosinophilic syndrome with imatinlb very often a T6741 mutation in PDGFRa is diagnosed.

0 0 0 This has prompted the applicant to search for new inhibitors of the FIP1 L1-PDGFRa activity as a possible therapeutic approach in these patients, for whom current drug therapies offer little utility, and for such patients who have previously failed current available drug therapies and/or stem cell transplantation therapies.

In the present description, the term "treatment" Includes both prophylactic or preventative treatment as well as curative or disease suppressive treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as ill patients. This term further includes the treatment for the delay of progression of the disease.

The term "curative" as used herein means efficacy in treating ongoing episodes Involving FIP1L1 -PDGFRa-induced myeloprollferative diseases.

The term "prophylactic" means the prevention of the onset or recurrence of diseases involving FIP1L1-PDGFRa-induced myeloproliferative diseases.

The term "delay of progression" as used herein means administration of the active compound to patients being in a pre-stage or in an early phase of the disease to be treated, in which patients for example a pre-form of the corresponding disease is diagnosed or which patients are In a condition, e.g. during a medical treatment or a condition resulting from an accident, under which it is likely that a corresponding disease will develop.

This unforeseeable range of properties means that the use of STAUROSPORINE DERIVATIVES are of particular interest for the manufacture of a medicament for the treatment of diseases involving FIP1L1-PDGFRa-induced myeloproliferative diseases. In particular MIDOSTAURIN has a high safety margin, high affinity and selectivity.

00

O

O

This effect can especially be clinically relevant for patients with hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to Imatinib.

To demonstrate that STAUROSPORINE DERIVATIVES are particularly suitable for the treatment of FIP1L1-PDGFRa-induced myeloproliferative diseases with good therapeutic 00 margin and other advantages, clinical trials can be carried out in a manner known to the

O

C skilled person.

00 o The precise dosage of STAUROSPORINE DERIVATIVES to be employed for inhibiting inhibiting FIP1L1-PDGFRa activity or for treating FIP1 L-PDGFRa-induced myeloproliferative diseases depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration. However, in general, satisfactory inhibition of FIP1L-PDGFRa is achieved when the STAUROSPORINE DERIVATIVE is administered parenterally, intraperitoneally, intravenously, intramuscularly, subcutaneously, Intratumorally, or rectally, or enterally, orally, preferably intravenously or, preferably orally, intravenously at a daily dosage of 0.1 to mg/kg body weight, preferably 1 to 5 mg/kg body weight. In human trials a total dose of 225 mg/day was most presumably the Maximum Tolerated Dose (MTD). A preferred intravenous daily dosage is 0.1to 10 mg/kg body weight or, for most larger primates, a daily dosage of 200-300 mg. A typical Intravenous dosage is 3 to 5 mg/kg, three to five times a week.

Most preferably, the STAUROSPORINE DERIVATIVES, especially MIDOSTAURIN, are administered orally, by dosage forms such as microemulsions, soft gels or solid dispersions in dosages up to about 250 mg/day, administered once, twice or three times daily.

Usually, a small dose Is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.

The STAUROSPORINE DERIVATIVES may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g. orally, in the form of tablets, capsules, caplets, etc. or parenterally, intraperitoneally or Intravenously, in the form of 00 -36-

O

O

sterile injectable solutions or suspensions. The enteral and parenteral compositions may be prepared by conventional means.

The infusion solutions according to the present invention are preferably sterile. This may be readily accomplished, e.g. by filtration through sterile filtration membranes. Aseptic formation 0 of any composition in liquid form, the aseptic filling of vials and/or combining a pharmaceutical composition of the present invention with a suitable diluent under aseptic C conditions are well known to the skilled addressee.

00 S The STAUROSPORINE DERIVATIVES may be formulated into enteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for inhibiting FIP1L1-PDGFRa, such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.

The STAUROSPORINE DERIVATIVES can be used alone or combined with at least one other pharmaceutically active compound for use In these pathologies. These active compounds can be combined in the same pharmaceutical preparation or in the form of combined preparations "kit of parts" in the sense that the combination partners can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, simultaneously or at different time points. The parts of the kit of parts can then, be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.

Non-limiting examples of compounds which can be cited for use in combination with STAUROSPORINE DERIVATIVES are cytotoxic chemotherapy drugs, such as cytosine arabinoside, daunorublcin, doxorubicin, cyclophosphamide, VP-16, or imatinib etc. Further, STAUROSPORINE DERIVATIVES could be combined with other inhibitors of signal transduction or other oncogene-targeted drugs with the expectation that significant synergy would result.

Examples of useful compositions are described in the European patents No. 0 296 110, No.

0 657 164, No. 0 296 110, No.0 733 372, No.0 711 556, No.0 711 557.

The preferred compositions are described in the European patent No. 0 657 164 published on June 14, 1995. The described pharmaceutical compositions comprise a solution or 00 -37-

O

O

S dispersion of compounds of formula I such as MIDOSTAURIN in a saturated polyalkylene glycol glyceride, in which the glycol glyceride is a mixture of glyceryl and polyethylene glycol S esters of one or more C8-C18 saturated fatty acids.

Two manufacture processes of such compositions are described hereafter.

00 Composition

A:

S Gelucire 44/14 (82 parts) is melted by heating to 600 C. Powdered MIDOSTAURIN (18 00 0 parts) is added to the molten material. The resulting mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the MIDOSTAURIN. The resulting capsules are suitable for oral administration.

Composition

B:

Gelucire 44/14 (86 parts) is melted by heating to 600 C. Powdered MIDOSTAURIN (14 parts) is added to the molten material. The mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25mg dosage and others a 75mg dosage of the MIDOSTAURIN. The resulting capsules are suitable for oral administration.

Gelucire 44/14 available commercially from Gattefosse; is a mixture of esters of C8-C18 saturated fatty acids with glycerol and a polyethylene glycol having a molecular weight of about 1500, the specifications for the composition of the fatty acid component being, by weight, 4-10% caprylic acid, 3-9% capric acid, 40-50% lauric acid, 14-24% myristic acid, 4- 14% palmitic acid and 5-15% stearic acid.

A preferred example of Gelucire formulation consists of: Gelucire (44/14): 47 g MIDOSTAURIN: 3.0g filled Into a 60 mL Twist off flask A preferred example of soft gel will contain the following Microemulsion: Comoil glycerides 85.0 mg Polyethylenglykol 400 128.25 mg Cremophor RH 40 213.75 mg 00 -38- MIDOSTAURIN 25.0 mg DL alpha Tocopherol 0.5 mg Ethanol absolute 33.9 mg Total 486.4 mg SHowever, it should be clearly understood that it is for purposes of illustration only.

00 In a preferred embodiment this invention relates to use or method as described herein, N wherein the daily effective amount of the compound of formula VII, is 100 to 300 mg, preferably 125 mg to 250 mg most preferably 220 to 230 mg, preferably 225 mg.

Most preferably the compound of formula VII, is administered once, twice or three times a day, for a total dose of 100 to 300 mg daily.

In a very preferred embodiment the compound of formula VII, is administered three times a day, for a total dose of 220 to 230 preferably 225 mg daily, and preferably at a dose per administration of 70 to 80 mg, preferably 75 mg.

In still another embodiment, this invention relates to an article of manufacture comprising packaging material, and N-[(9S,10R,11 R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9methyl-1-oxo-9,13-epoxy-1H,9H-d[indolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-jl[1,7]benzodiazonin- 11-yl]-N-methylbenzamide of the formula (VII) or a pharmaceutically acceptable salts thereof, contained within said packaging material, wherein said packaging material comprises label directions which indicate that said compound of formula (VII), or said pharmaceutically-acceptable salt, is to be administered to mammals suffering from FIP1L1- PDGFRa-induced myeloproliferative diseases, in an amount from 50 to 500 mg, preferably 100 to 300 mg, preferably 125 mg to 250 mg, more preferably 220 to 230 mg, most preferably 225 mg following a specific dosage regimen to inhibit the development of FIP1L1- PDGFRa induced myeloproliferative diseases.

Preferably to an article of manufacture wherein the compound of formula VII, Is administered three times a day, for a total dose of 220 to 230mg, preferably 225 mg daily, and preferably a dose of 70 to 80 mg, most preferably 75 mg, per administration for the treatment of hypereosinophllic syndrome or hypereosinophilic syndrome with resistance to imatinib. A 00 -39-

O

O

S preferred embodiment relates to an article of manufacture comprising softgel capsules containing 25 mg of the compound of formula VII.

The Invention further pertains the combination of a STAUROSPORINE DERIVATIVE as described hereinbefore with imatinib for the treatment of the diseases and conditions 0O described hereinbefore. The administration of such a combination may be affected at the same time, for instance in the form of a fixed, combined pharmaceutical composition or N preparation, or sequentially or timely staggered. The administration of a STAUROSPORINE 00 DERIVATIVE in a dosage form as described hereinbefore and of imatinib in its marketed form of GLEEVEC in the US/GLIVEC@ in Europe and with the dosages envisaged for these dosage forms is currently preferred.

The treatment of FIP1L1-PDGFRa-induced myeloproliferative diseases with the above combination may be a so-called first line treatment, I.e. the treatment of a freshly diagnosed disease without any preceeding chemotherapy or the like, or it may also be a so-called second line treatment, i.e. the treatment of the disease after a preceeding treatment with imatrinib or a STAUROSPORINE DERIVATIVE, depending on the severity or stage of the disease as well as the over all condition of the patient etc..

The efficacy of STAUROSPORINE DERIVATIVES for the treatment of FIP1L1-PDGFRainduced myeloproliferative diseases is illustrated by the results of the following examples.

These examples Illustrate the invention without in any way limiting its scope: The retroviral construct MSCV-FIP1L1-PDGFRa-ires-EGFP and the corresponding T6741 mutant were described previously (Cools et al., New England Journal of Medicine Vol. 348 No. 13, p 1201-1214 2003). The N659D mutation was Introduced by PCR (polymerase chain reaction).

Cell culture and retroviral transduction 293T cells were grown in DMEM (Dulbecco's Modified Eagle Medium) supplemented with FBS (fetal bovine serum). Ba/F3 cells were grown In RPMI (Rosweli Park Memorial Institute) medium supplemented with 10 FBS and 1 ng/ml mouse IL-3. Production of retroviral vectors and transduction was described. Transformed Ba/F3 cells were grown in the absence of IL3. The kinase inhibitors Imatinib and PKC412 were stored as 10 mM stock 00

O

O

solutions in water (imatlnib) or DMSO (dimethylsulfoxide) (PKC412). These inhibitors were diluted in RPMI medium for use. For western blotting, Ba/F3 cells were incubated in the 0 presence of imatinib for 90 minutes before lysis. For dose response curves, Ba/F3 cells were Incubated for 24 hours in the presence of imatinib and the number of viable cells at the start and end point was determined by use of the Celltlter96AQueouone solution proliferation assay (Promega). Dose response curves were fitted using the OriginPro 6.1 software 00 (OriginLab, Northampton,

MA).

0 Bone marrow transplantation and treatment of the animals S Balb/c mice were purchased from Taconic (Germantown, NY). Bone marrow transplant assays (injecting 1 x 106 cells per recipient mouse) and drug treatment of the mice was performed as described previously (Schwaller et al., 1998; Kelly et al.; Weisberg et al., 2002). Imatinib (stored as powder at 4 was resuspended in a 0.5 methylcellulose

(MC)

solution in water prior to use. PKC412 w/w in Gelucire 44/14 (GC) (Gattefosse,France)) was stored at 4 °C as a waxy-solid formulation. Prior to administration, the GC/PKC412 waxy solid mixture was melted in a 44 "C water bath and diluted with sterilized deionized water. The animals were weighed at regular basis to ensure that a consistent dose (150 mg/kg/day for imatinib and 100 mg/kg/day for PKC412) of drug was administered. Dosing was performed every 12 hr for imatinib and every 24 hr for PKC412 by oral gavage of a maximum volume of 150 pl per animal using 22 gauge gavage needles (Hornbecks). Placebo animals received the same volume of a MC or GC solution. Any animals with splenomegaly (spleen boundary detectable at the dorsal medline) or that were moribund were sacrificed and analysed for signs of hematological disease.

Peripheral blood was collected from the retroorbital cavity using a heparinized glass capillary. Blood smears were stained with Wright and Giemsa. Manual and automated (ADIVA 120 Hematology system, Bayer) total and differential blood cell counts were performed. Histopathologic exam of relevant organs (spleen, liver, heart, lungs, Intestine, hindlimb bones, and kidneys) and preparation of single-cell suspensions from spleen and bone marrow for flow cytometry was performed as described. In comparing the survival time of the mice, all times are measured from the day of BMT (bone marrow transplant), and the log rank test is used to attach a significance level to the difference in the survival curve.

00 -41-

O

O

Histopatholoqy Murine tissues were fixed for at least 72 hours In 10 neutral buffered formalin (Sigma), dehydrated in alcohol, cleared in xylene, and Infiltrated with paraffin on an automated processor (Leica, Bannockburn, IL). The tissue sections (4 pm) from paraffin-embedded tissue blocks were placed on charged slides and deparaffinized in xylene, rehydrated o0 through graded alcohol solutions, and stained with hematoxylln and eosin.

0 N Immunoprecipitation and Western blotting Immunoprecipitation was performed using the anti-Myc antibody (Cell Signaling) and Protein G agarose (Roche). Each precipitation was started from 6x106 Ba/F3 cells stably expressing myc-tagged FIP1L1-PDGFRa wild type or T6741 mutant. Cells were lysed in lysis buffer (Cell Signaling) containing 1 mM Na 3

VO

4 20 pM phenylarsine oxide (Calbiochem) and complete tablets (Roche). For western blotting, Ba/F3 cells were collected by centrifugatlon and directly lysed in 1 x loading buffer containing 2 SDS (sodium dodecyl sulfate) and 40 pM DTT (dithiothreitol) (Cell Signaling), separated using 10 12 SDS-PAGE (SDS-Poly Acrylamide Gel Electrophoresis) and transferred to membranes. The antibodies used were: and anti-phospho-tyrosine (P-Tyr-100/102) (Cell Signaling), anti- PDGFRa (Upstate), anti-STAT5b (Santa-Cruz), anti-mouse-PO and anti-rabbit-PO (Amersham Pharmacia Biotech). Detection was performed using the Western Lightning system (Perkln Elmer).

The following tables illustrate the efficacy of MIDOSTAURIN (PKC412) in the treatment of FIP1 L1-PDGFRa-induced myeloproliferative diseases by way of example only: Table 1. Efficacy of imatinib for the treatment of FIP1L1-PDGFR-Induced myeloproliferative disease, and resistance to FIP1L1-PDGFRa(T6741)-lnduced disease (trial 1).

FIP1L1-PDGFRa FIP1L1-PDGFRaT6741 wild type placebo imatlnlb Imatlnib spleen welaht (a) mean 832 111 801 -42- 00

NO

00 median range n WBC (x 10 6 1M1) mean median range n 852 667 -922 8 654.4 620.2 593.8 773.0 5 106 93- 140 8 6.0 5.2 4.6-9.4 7 780 700-1,007 6 496.5 507.7 434.6 535.8 4 I Spleen weights and white blood cell counts (WBC) of mice in the different groups of trial 1, determined on time of death or at trial endpoint. n: number of mice analysed.

I

-43 00

NO

00 Table 2. Efficacy of PKC412 (MIDOSTAURIN) for the treatment of both FiPILI-PDGFRzand FiPI LI -PDGFRL(T6741 )-induced myeloproliferative disease (trial 2).

FIPI LI-PDGFR~x placebo Imatinlb PKC412 spleen weight (ci) mean median range n WBC (x 101/Ml) mean median range n 729 690 588 -922 9 101 99 82- 132 9 4.8 4.8 4.4-5.3 4 241 199 104-586 8 12.7 12.4 5.8-20.0 3 534.1 554.3 388.9 639.0 4 FIPI LI-PDGFRz T6741 placebo Imatinib PKC412 spleen weight mean median range n WBC (xI 101m1) mean median range 743 778 556 -803 7 493.2 460.6 28.7-879.8 649 645 543 -785 a 548.2 591.5 364.9 657.6 7 157 157 90 -217 9 3.8 3.1 1.9-7.2 6 Spleen weights and white blood cell counts (WBC) of mice in the different groups of trial 2, determined on time of death or at trial endpoint. n: number of mice analysed.

P lOPER7WALIXINVIO53197 dl d.2Xfl)4rbIS 00 -43A The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour 00 5 to which this specification relates.

00 Throughout this specification and the claims which follcw, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (19)

1. Use of staurosporine derivatives of formula, or (R 2 )n (R 2 N /N (H (D) S Q or or wherein R 1 and R 2 are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, amlnosulfonyl or N- mono- or N,N-di-substituted aminosulfonyl; n and m are, independently of one another, a number from and including 0 to and including 4; Rs is hydrogen, an aliphatic, carbocyclic, or carbocyclic-allphatic 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; X stands for 2 hydrogen atoms; for 1 hydrogen atom and hydroxy; for 0; or for hydrogen and lower alkoxy; 00 Q and Q' are independently a pharmaceutically acceptable organic bone or hydrogen, halogen, hydroxy, etherifled or esterified hydroxy, amino, mono- or disubstituted amino, C\ cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N- mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl; 00 or a salt thereof, if at least one salt-forming group is present, or hydrogenated derivative 0thereof, for the preparation of a pharmaceutical composition for the treatment of FIPN L1- 00 PDGFRCI-lnduced myeloproliferative diseases.

2. The use of a staurosporin derivative selected from the compounds of formula, 6 NR NR 5 X 0 x 50 7 6 5 8 4 8 (R 1 IA (RA BA A IF r 0 N N N N 2 1 0 11 1"O' H 3 C H H 3 C "H(I N- 111N I-,H 3 C IIR R 4 R 3 R 4 x 0 X e NR \4 XN 10 BR BA (R2),\B 1 00 -46- O O x a NR 0 B A (R2A R) X NR 6 (R2 2 '0 11 N N B A H'C H 0 Z"O 1 (VI) 11 1 z- (Vl) 00 N N CHi- N O R R 8 N or 1 or 00 Swherein R 1 and R 2 are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N- mono- or N,N-dl-substituted aminosulfonyl; n and m are, Independently of one another, a number from and including 0 to and including 4; n' and m' are, independently of one another, a number from and including 1 to and including 4; Ra, R 4 Re and Rio 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 heterocycllc-allphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, wherein R 4 may also be absent; or R 3 Is acyl with up to 30 carbon atoms and R 4 not an acyl; p is 0 if R 4 is absent, or is 1 if R 3 and R 4 are both present and in each case are one of the aforementioned radicals; R s 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 I 00 -47- S atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms; S RT, Re and R 9 are acyl or -(lower alkyl) -acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy,carbonyl, carbonyldioxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl; 00 X stands for 2 hydrogen atoms; for 1 hydrogen atom and hydroxy; for 0; or for hydrogen and lower alkoxy; Z stands for hydrogen or lower alkyl; and either the two bonds characterised 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 bond, signify a double bond; or the two bonds characterised by wavy lines are absent In ring B and replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel bond, signify a double bond; or both in ring A and in ring B all of the 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 for the preparation of a pharmaceutical composition for the treatment of FIP1L1-PDGFRa-induced myeloproliferative diseases.

3. The use of a staurosporin derivative of formula I, 00 -48- ONR x (RI).Ri 10 B N N A 2 (RAI~ 1 01 H 3 0C.. INN R 4 R 3 00 wherein m and n are each 0; R 3 and R 4 are Independently of each other hydrogen, lower alkyl unsubstituted or mono- or disubstituted, especially monosubstituted, by radicals selected independently of one another from carboxy; lower alkoxycarboflyl; and cyano; or R 4 is hydrogen or -CH 3 and R 3 is acyl of the subformula R 0 -GO, wherein R 0 is tower alkyl; amino-lower alkyl, wherein the amino group is present in unprotected form or is protected by lower alkoxycarbonyl; tetrahydropyralyloxy-lower alkyl; phenyl; imidazolyl-lower alkoxyphenyl; carboxyphenyl; lower alkoxycarbonylphel; halogen-lower alkylphenyl; imidazol-1 -ylphenyl; pyrrolidino- lower alkylphenyl; piperazino-lower alkylphenyl; (4-lower alkylplperaznomethyl)phel; morpholino-lower alkylphenyl; piperazinocarbonlphenyl; or (4-lower alkylpiperazilO)Phenl; or is acyl of the subformula R 0 wherein R' is lower alkyl; or is acyl of the subformula wherein W is oxygen and W~ has the following meanings: morpholino-lower alkyl, phenyl, lower alkoxyphenyl, carboxyphei'yl, or lower alkoxycarbonlphenl; or R 3 1IS lower alkylphenylsulf0Inyl, typically 4-toluenesulfonl; Rs is hydrogen or lower alkyl, X stands for 2 hydrogen atoms or for 0; Z is methyl or hydrogen; I 00 -49- O or a salt thereof, if at least one salt-forming group is present for the preparation of a pharmaceutical composition for the treatment of FIP1L1-PDGFRa-induced.myeloproliferative diseases.

4. Use according to any one of claims 1 to 3 for the treatment of FIP1L1-PDGFRa-induced I myeloproliferative diseases wherein a mutation is present in FIP1L1-PDGFRa. 00 S

5. Use according to claim 4, wherein the mutation is T6741. 00

6. Use according to any one of claims 1 to 3 for the treatment of hypereosinophilic syndrome

7. Use according to claim 6, wherein the hypereosinophilic syndrome is resistant to treatment with imatinib.

8. A method for treating mammals suffering from FIP1L1-PDGFRa-induced myeloproliferative diseases comprising administering to a mammal in need of such treatment a FIP1L1-PDGFRa inhibiting amount of staurosporine derivatives as defined in any one of claims 1 to 3

9. A method according to claim 8 for treating hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatinib.

Use of N-[(9S,1 OR,11R, 13R)-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','-lmlpyrrolo[3,4-jl[1,7]benzodiazonin-11-yl]-N- methylbenzamide of the formula (VII): 00 HC 0 00 HcC 00 00 0 CH, S(VII) or a salt thereof, for the preparation of a pharmaceutical composition for the treatment of FlP1L1 -PDGFRa-induced myeloproliferative diseases.

11. Use according to claim 10 for the treatment of hypereosinophilic syndrome or hyoereosinophilic syndrome with resistance to omatinib.

12. Pharmaceutical preparation for the treatment of FIP1L1-PDGFRa-induced myeloproliferative diseases, comprising an N-[(9S,1 OR,11R, I 3R)-2,3,10,11,12,13- hexahydro- 1 O-methoxy-9-methyl- 1 -oxo-9,13-epoxy-1 H,9H-diindolo[1 Im]pyrrolo[3,4-j][ ,7]benzodiazonin-1 1-yl]-N-methylbenzamide of the formula (VII).

13. A method for treating mammals, including man, suffering from FIP11-PDGFRa-induced myeloproliferative diseases, comprising administering to a mammal in need of such treatment a FIP1L1-PDGFRa inhibiting amount of N-[(9S,1OR,11R,13R)-2,3,10,11,12,13- hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy- H,9H-diindolo[1,2,3-gh:3',2',1'- Im]pyrrolo[3,4-j][1 ,7]benzodiazonin-1 1-yl]-N-methylbenzamide of the formula (VII) as defined in claim

14. A method according to claim 13 for treating hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatinib.

A method according to any one of claims 10 to 14, whereIn the therapeutically effective amount of the compound of formula VII Is administered to a mammal subject 7 to 4 times a 00 -51- O O M week or about 100 to about 50% of the days In the time period, for a period of from one to six weeks, followed by a period of one to three weeks, wherein the agent Is not administered and this cycle being repeated for from 1 to several cycles.

16. Use or method according to any one of claims 10 to 15, wherein the daily effective 00 amount of the compound of formula VII, is 100 to 300 mg daily preferably 220 to 230mg, most preferably 225 mg daily. 00

17. Use or method according to any one of claims 10 to 16, wherein the compound of formula VII, is administered once, two or three times a day, for a total dose of 100 to 300 mg daily preferably of 220 to 230mg, most preferably 225 mg daily.

18. Use or method according to any one of claims 10 to 17, wherein the compound of formula VII, is administered three times a day, for a total dose of 220 to 230 mg, preferably 225 mg daily, and preferably a dose of 70 to 80 mg most preferably 75 mg per administration.

19. An article of manufacture comprising packaging material, and N-[(9S,1OR,11R,13R)- 2,3,10,11,12,13-hexahydro-1 0-methoxy-9-methyl- -oxo-9,13-epoxy-1 H,9H-diindolo[1,2,3- gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzariide of the formula (VII) as defined in claim 10 or a pharmaceutically acceptable salts thereof, contained within said packaging material, wherein said packaging material comprises label directions which indicate that said compound of formula (VII), or said pharmaceutically-acceptable salt, is to be administered to mammals suffering from a FIP1L1-PDGFRa-induced myeloproliferative disease in an amount from 100 to 300 mg, preferably 220 to 230mg, most preferably 225 mg following a specific dosage regimen to inhibit FIP1L1-PDGFRa. An article of manufacture according to claim 19 wherein the compound of formula VII is administered three times a day, for a total dose of 220 to 230 mg preferably 225 mg daily, and preferably a dose of 70 to 80 mg most preferably 75 mg per administration for treating FIP1 L-PDGFRa-induced myeloproliferative diseases. S21. Use of a staurosporine derivative according to any one of claims 1 to 7 in combination with imatinib, wherein each of the active ingredients, independent of each other, may be 00 -52- 0 0 present in free form or in the form of a pharmaceutically acceptable salt, for the treatment of FIPILI-PDGFRa induced myeloproliferative diseases. 00 00 1-\