HK1095519B

HK1095519B - The use of staurosporine derivatives for the manufacture of a medicament

Info

Publication number: HK1095519B
Application number: HK07100635.4A
Authority: HK
Inventors: Steven Coutre
Original assignee: Novartis Ag
Priority date: 2003-06-18
Filing date: 2004-06-17
Publication date: 2009-11-06

Description

Use of staurosporine derivatives for the preparation of a medicament

The present invention relates to the use of a staurosporine derivative in free form or in pharmaceutically acceptable salt form (hereinafter referred to as "staurosporine derivative") for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease; also relates to a method of treating warm-blooded animals, preferably humans, wherein a therapeutically effective dose of a staurosporine derivative compound is administered to a warm-blooded animal suffering from one of the diseases or conditions mentioned above.

The invention relates to the use of staurosporine derivatives of formulae (A) to (D) and, if at least one salt-forming group is present, or salts or hydrogenated derivatives thereof, for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug or food allergies, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease,

wherein R is₁And R₂Independently of one another, is 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-disubstituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono-or N, N-disubstituted aminosulfonyl; n and m are, independently of each other, a number from 0 and including 0 to 4 and including 4;

R₅is hydrogen, an aliphatic, carbocyclic or carbocyclic-aliphatic group each containing up to 29 carbon atoms, a heterocyclic or heterocyclic-aliphatic group each containing up to 20 carbon atoms and each containing up to 9 heteroatoms, or an acyl group containing up to 30 carbon atoms;

x represents 2 hydrogen atoms; 1 hydrogen atom and hydroxyl group; o; or hydrogen and lower alkoxy;

q and Q' are independently a pharmaceutically acceptable organic backbone or 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-disubstituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono-or N, N-disubstituted aminosulfonyl.

The invention particularly relates to the use of staurosporine derivatives of formulae (I) to (VI) or salts thereof (if at least one salt-forming group is present) for the preparation of a pharmaceutical composition for the treatment of FIP1L1-PDGFR alpha-induced myeloproliferative diseases,

wherein (II) is a partially hydrogenated derivative of compound (I),

wherein R is₁And R₂Independently of one another, is 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-disubstituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono-or N, N-disubstituted aminosulfonyl;

n and m are, independently of each other, a number from 0 and including 0 to 4 and including 4;

n 'and m' are independently of each other a number from 0 and including 0 to 4 and including 4;

R₃、R₄、R₈and R₁₀Independently of one another, hydrogen, -O^-Acyl having up to 30 carbon atoms, aliphatic, carbocyclic or carbocyclic-aliphatic radicals each having up to 29 carbon atoms, heterocyclic or heterocyclic-aliphatic radicals each having up to 20 carbon atoms and each having up to 9 heteroatoms, acyl having up to 30 carbon atoms, where R is₄May or may not be present;

or if R is₃Is an acyl radical having up to 30 carbon atoms, then R₄Is not acyl;

if R is₄Absent, p is 0, or if R is₃And R₄Each being present and each being one of the radicals mentioned above, p is 1;

R₇、R₆and R₉Is 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-disubstituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono-or N, N-disubstituted aminosulfonyl;

z represents hydrogen or lower alkyl; and is

The two bonds in ring a characterized by wavy lines are absent and replaced by 4 hydrogen atoms, the two wavy lines in ring B each represent a double bond together with the respective parallel bond;

alternatively, the two bonds in ring B characterized by wavy lines are absent and replaced by a total of 4 hydrogen atoms, the two wavy lines in ring a each, together with the respective parallel bond, representing a double bond;

alternatively, all 4 wavy bonds in ring a and ring B are absent and replaced by a total of 8 hydrogen atoms.

The general terms and definitions used above and below preferably have the following meanings:

the prefix "lower" indicates that the group defined preferably has up to and including 7 carbon atoms, in particular up to and including 4 carbon atoms.

Lower alkyl is especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and pentyl, hexyl or heptyl.

Unsubstituted or substituted alkyl is preferably C₁-C₂₀Alkyl, in particular lower alkyl, is generally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, which may be unsubstituted or substituted in particular by: halogen, such as fluorine, chlorine, bromine or iodine; c₆-C₁₄Aryl, such as phenyl or naphthyl; a hydroxyl group; etherified hydroxy, such as lower alkoxy, phenyl-lower alkoxy or phenoxy; esterified hydroxy, such as lower alkanoyloxy or benzoyloxy; an amino group; mono-or di-substituted amino, such as lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N-di- (phenyl-lower alkyl) amino; a cyano group; a mercapto group; substituted mercapto groups, such as lower alkylthio; a carboxyl group; esterified carboxyl groups such as lower alkoxycarbonyl groups; a carbamoyl group; n-mono-or N, N-di-substituted carbamoyl, such as N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl; a sulfo group; substituted sulfo groups, such as lower alkanesulfonyl or lower alkoxysulfonyl; aminosulfonyl or N-mono-or N, N-di-substituted aminosulfonyl, such as N-lower alkylaminosulfonyl or N, N-di-lower alkylaminosulfonyl.

Halogen is preferably fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Etherified hydroxy, especially lower alkoxy, C₆-C₁₄Aryloxy radicals, e.g. phenoxy, or C₆-C₁₄Aryl-lower alkoxy such as benzyloxy.

The esterified hydroxy group is preferably a lower alkanoyloxy group or C₆-C₁₄Arylcarbonyloxy, for example benzoyloxy.

Amino mono-or disubstituted, especially by lower alkyl, C₆-C₁₄Aryl radical, C₆-C₁₄Aryl-lower alkyl, lower alkanoyl or C₆-C₁₂Aryl radicalsCarbonyl mono-or di-substituted amino.

Substituted mercapto, especially lower alkylthio, C₆-C₁₄Arylthio group, C₆-C₁₄Aryl-lower alkylthio, lower alkanoylthio or C₆-C₁₄Aryl-lower alkanoylthio.

Esterified carboxyl, especially lower alkoxycarbonyl, C₆-C₁₄Aryl-lower alkoxycarbonyl or C₆-C₁₄An aryloxycarbonyl group.

N-mono-or N, N-di-substituted carbamoyl, especially by lower alkyl, C₆-C₁₄Aryl or C₆-C₁₄Aryl-lower alkyl N-monosubstituted or N, N-disubstituted carbamoyl.

Substituted sulphonyl radicals, in particular C₆-C₁₄Arylsulfonyl radicals such as the tosyl radical, C₆-C₁₄Aryl-lower alkanesulfonyl or lower alkanesulfonyl.

N-mono-or N, N-di-substituted aminosulfonyl especially by lower alkyl, C₆-C₁₄Aryl or C₆-C₁₄Aryl-lower alkyl N-monosubstituted or N, N-disubstituted aminosulfonyl.

C₆-C₁₄Aryl is an aryl group having from 6 to 14 carbon atoms in the ring system, for example phenyl, naphthyl, fluorenyl or indenyl, which may be unsubstituted or substituted in particular by: halogen (e.g. fluorine, chlorine, bromine or iodine), phenyl or naphthyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenoxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N-di- (phenyl-lower alkyl) amino, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N-di-lower alkylcarbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lower alkanesulfonyl, N-lower alkanoyloxy, benzoyloxy, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N-di-lower alkylcAn alkylaminosulfonyl group or an N, N-di-lower alkylaminosulfonyl group.

The indices n and m are each preferably 1, 2 or, in particular, 0. In general, particular preference is given to compounds of the formula I in which n and m are each 0.

Aliphatic hydrocarbon radicals R containing up to 29 carbon atoms₃、R₄、R₈Or R₁₀(which may be substituted by acyclic substituents, preferably having up to 18, especially up to 12, usually not more than 7 carbon atoms) may be saturated or unsaturated, and is especially straight-chain or branched lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl which is unsubstituted or substituted by acyclic substituents. Lower alkyl radicals are, 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-diene; lower alkynyl is for example propargyl or 2-butynyl. In the corresponding unsaturated groups, the double bond is in particular located in a position higher than the alpha position of the free valency. The substituents are defined as R in particular below^oAcyl of the substituent(s) of (a), preferably free or esterified carboxyl (e.g., carboxyl or lower alkoxycarbonyl), cyano or di-lower alkylamino.

Carbocyclic or carbocyclic-aliphatic radical R containing up to 29 carbon atoms₃、R₄、R₈Or R₁₀Each being in particular an aromatic, cycloaliphatic-aliphatic or aromatic-aliphatic radical, which is present in unsubstituted form or is defined as R below^oIs substituted with a substituent group. Aromatic radical (aryl) R₃Or R₄Most particularly phenyl, naphthyl, such as 1-or 2-naphthyl, biphenyl, such as particularly 4-biphenyl, anthracenyl, fluorenyl and azulenyl, and aromatic analogues thereof containing one or more saturated rings (in unsubstituted form or defined as R below)^oSubstituted with a substituent of (a). Preferred aromatic-aliphatic groups areAryl-lower alkyl and aryl-lower alkenyl, for example phenyl-lower alkyl or phenyl-lower alkenyl containing a terminal phenyl group, such as benzyl, phenethyl, 1-, 2-or 3-phenylpropyl, benzhydryl, trityl and cinnamyl and 1-or 2-naphthylmethyl. As aryl groups with acyclic radicals, for example lower alkyl, particular mention is made of o-, m-and p-tolyl radicals and xylyl radicals with the methyl radical in different positions.

Cycloaliphatic radicals R containing up to 29 carbon atoms₃、R₄、R₈Or R₁₀In particular substituted or preferably unsubstituted mono-, di-or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl. Preferably containing up to 14, especially 12, ring carbon atoms and a 3-to 8-, preferably 5-to 7-and most especially 6-membered ring, which may also bear as substituents one or more, for example two, aliphatic hydrocarbon groups (such as those defined above), especially lower alkyl or other cycloaliphatic groups. Preferred substituents are hereinafter referred to as R^oThe acyclic substituent of (1).

Cycloaliphatic-aliphatic radical R containing up to 29 carbon atoms₃、R₄、R₈Or R₁₀Are those in which the acyclic radicals and in particular those containing up to 7, preferably up to 4, carbon atoms (such as in particular methyl, ethyl and vinyl radicals) carry one or more cycloaliphatic radicals as defined above. Particular mention may be made of cycloalkyl-lower alkyl and their analogues which are unsaturated in the ring and/or chain but are not aromatic, which carry a ring at the terminal carbon atom of the chain. Preferred substituents are hereinafter referred to as R^oThe acyclic substituent of (1).

Heterocyclic radicals R each containing up to 20 carbon atoms and each containing up to 9 heteroatoms₃、R₄、R₈Or R₁₀In particular monocyclic radicals, and also bicyclic or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-or tetraaza-cyclic radicals of aromatic character, and the corresponding partially or most particularly fully saturated heterocycles of this typeThe radicals, if desired, may also carry acyclic, carbocyclic or heterocyclic radicals and/or may be mono-, di-or polysubstituted by functional groups, preferably those defined above as substituents of aliphatic hydrocarbon radicals. They are most particularly unsubstituted or substituted monocyclic radicals containing nitrogen, oxygen or sulfur atoms (e.g.2-aziridinyl) and especially aromatic radicals of this type, for example pyrrolyl, such as 2-pyrrolyl or 3-pyrrolyl, pyridyl, such as 2-, 3-or 4-pyridyl, and thienyl, such as 2-or 3-thienyl, or furyl, such as 2-furyl; similar bicyclic groups containing an oxygen, sulfur or nitrogen atom are for example indolyl and typically 2-or 3-indolyl, quinolyl and typically 2-or 4-quinolyl, isoquinolyl and typically 3-or 5-isoquinolyl, benzofuranyl and typically 2-benzofuranyl, chromenyl and typically 3-chromenyl, or benzothienyl and typically 2-or 3-benzothienyl; preferred monocyclic and bicyclic groups containing several heteroatoms are for example imidazolyl and typically 2-or 4-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, or thiazolyl and typically 2-thiazolyl, and benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, or quinazolinyl and typically 2-quinazolinyl. Suitable partially or in particular fully saturated analogous radicals are also contemplated, for example 2-tetrahydrofuryl, 2-or 3-pyrrolidinyl, 2-, 3-or 4-piperidinyl, and also 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl and N-mono-or N, N' -bis-lower-alkyl-2-piperazinyl. These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, in particular those mentioned above. Heterocyclic radical R₃Or R₄Must come from one of its carbon atoms. The heterocyclyl group may be unsubstituted or defined as R below by one or more, preferably one or two^oIs substituted with the substituent(s).

Heterocycle-aliphatic radical R₃、R₄、R₈Or R₁₀In particular lower alkyl with one, two or more heterocyclic groups, such as those defined above, in particular containing up to 7Preferably lower alkyl of up to 4 carbon atoms, such as those defined above, wherein the heterocyclic ring may be attached to the aliphatic chain via one of its nitrogen atoms. Preferred heterocyclic-aliphatic radicals R₁Examples are imidazol-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, piperazin-1-ylmethyl, 2- (morpholin-4-yl) ethyl and pyridin-3-ylmethyl. The heterocyclyl group may be unsubstituted or defined as R below by one or more, preferably one or two^oIs substituted with the substituent(s).

Heteroaliphatic radicals R each containing up to 20 carbon atoms and each containing up to 10 heteroatoms₃、R₄、R₈Or R₁₀Aliphatic radicals containing identical or different heteroatoms, such as, in particular, oxygen, sulfur and nitrogen, instead of one, two or more carbon atoms. Heteroaliphatic radical R₁A particularly preferred arrangement takes the form of oxa-alkyl radicals in which, in the alkyl radical, which is preferably straight-chain, one or more carbon atoms are replaced by oxygen atoms which are preferably separated from one another by a number, in particular 2, of carbon atoms, so that they form repeating groups, if desired multiply-repeating groups (O-CH)₂-CH₂-)_qWherein q is 1 to 7.

In addition to the acyl radical, R₃、R₄、R₈Or R₁₀Particularly preferred is lower alkyl, especially methyl or ethyl; lower alkoxycarbonyl-lower alkyl, especially methoxycarbonylmethyl or 2- (tert-butoxycarbonyl) ethyl; carboxy-lower alkyl, especially carboxymethyl or 2-carboxyethyl; or cyano-lower alkyl, especially 2-cyanoethyl.

Acyl radicals R containing up to 30 carbon atoms₃、R₄、R₆、R₇、R₈、R₉Or R₁₀Derived from carboxylic acids, if desired modified by functional groups, organic sulfonic acids or phosphoric acids, for example pyrophosphoric acid or orthophosphoric acid, if desired esterified.

Designated as Ac¹And the acyl radical derived from a carboxylic acid, optionally modified by functional groups, is in particular one of the subformulae Y-C (═ W) -, in which W is oxygen, sulphur or imino, Y isHydrogen, hydrocarbon radicals R containing up to 29 carbon atoms^oHydrocarbyloxy radicals R^o-O-, amino or substituted amino and in particular of the formula R^oHN-or R^oR^oN- (wherein R)^oThe groups may be the same as or different from each other).

Hydrocarbyl radicals R^oAre acyclic (aliphatic), carbocyclic or carbocyclic-acyclic hydrocarbon radicals which each contain up to 29 carbon atoms, in particular up to 18 carbon atoms, preferably up to 12 carbon atoms, and are saturated or unsaturated, unsubstituted or substituted. It may contain identical or different heteroatoms (such as, in particular, oxygen, sulfur and nitrogen) in the acyclic and/or cyclic moiety instead of one, two or more carbon atoms; in the latter case, it is described as a heterocyclic group or a heterocyclic-acyclic group.

Unsaturated groups are those which contain one or more, in particular conjugated and/or isolated, multiple bonds (double or triple bonds). The term cyclic group also includes aromatic and non-aromatic groups containing conjugated double bonds, such as those in which at least one 6-membered carbocyclic or 5-to 8-membered heterocyclic ring contains the largest number of non-aggregated double bonds. Carbocyclic groups in which at least one ring is present as a 6-membered aromatic ring (i.e. a benzene ring) are defined as aryl groups.

Acyclic unsubstituted hydrocarbon radicals R^oIn particular a linear or branched lower alkyl, lower alkenyl, lower alkadienyl or lower alkynyl. Lower alkyl radical R^oFor 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 alkynyl is for example propargyl or 2-butynyl. In the corresponding unsaturated groups, the double bond is in particular located in a position higher than the alpha position of the free valency.

Carbocyclic hydrocarbon group R^oIn particular mono-, bi-or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radicals or the corresponding aryl radicals. Preferably containsUp to 14, especially 12, ring carbon atoms and 3-to 8-, preferably 5-to 7-and most especially 6-membered rings, which may also carry one or more, for example two, acyclic radicals (such as those defined above), especially lower alkyl or other carbocyclic radicals. Carbocyclic-acyclic radicals are those in which acyclic radicals, in particular acyclic radicals having up to 7, preferably up to 4, carbon atoms (such as, in particular, methyl, ethyl and vinyl radicals), carry one or more carbocyclic rings (if desired aromatic radicals) as defined above. Particular mention may be made of cycloalkyl-lower alkyl and aryl-lower alkyl and 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 radical R^oMost particularly from 3 up to and including 10 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and bicyclo [2, 2 ]]Octyl, 2-bicyclo [2, 2, 1 ]]Heptyl and adamantyl, which may also be substituted with 1, 2 or more, for example, lower alkyl, especially methyl; cycloalkenyl is, for example, one of the monocyclic cycloalkyl groups already defined with a double bond in the 1-, 2-or 3-position. Cycloalkyl-lower alkyl or-lower alkenyl is for example-methyl, -1-or-2-ethyl, -1-or-2-vinyl, -1-, -2-or-3-propyl or-allyl substituted by one of the cycloalkyl groups defined above, preferably those substituted at the end of the linear chain.

Aryl radical R^oMost particularly phenyl, naphthyl, such as 1-or 2-naphthyl, biphenyl, such as particularly 4-biphenyl, and anthracenyl, fluorenyl and azulenyl, and aromatic analogs thereof containing one or more saturated rings. Preferred aryl-lower alkyl and-lower alkenyl are, for example, phenyl-lower alkyl or phenyl-lower alkenyl containing a terminal phenyl group, such as benzyl, phenethyl, 1-, 2-or 3-phenylpropyl, benzhydryl, trityl and cinnamyl and 1-or 2-naphthylmethyl. The aryl group may be unsubstituted or substituted.

Heterocyclic groups including heterocyclic-acyclic groups, in particular monocyclic groups, and also bicyclic or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza-or tetraaza-cyclic groups of aromatic character, and also the corresponding partially or most particularly fully saturated heterocyclic groups of this type; if desired, for example for the carbocyclic or aryl groups mentioned above, these groups may also carry acyclic, carbocyclic or heterocyclic groups and/or may be mono-, di-or polysubstituted by functional groups. The acyclic part of a heterocyclic-acyclic radical has, for example, the meaning indicated for the corresponding carbocyclic-acyclic radical. They are most particularly unsubstituted or substituted monocyclic radicals containing nitrogen, oxygen or sulfur atoms (e.g.2-aziridinyl) and especially aromatic radicals of this type, for example pyrrolyl, such as 2-pyrrolyl or 3-pyrrolyl, pyridyl, such as 2-, 3-or 4-pyridyl, and thienyl, such as 2-or 3-thienyl, or furyl, such as 2-furyl; similar bicyclic groups containing an oxygen, sulfur or nitrogen atom are for example indolyl and typically 2-or 3-indolyl, quinolyl and typically 2-or 4-quinolyl, isoquinolyl and typically 3-or 5-isoquinolyl, benzofuranyl and typically 2-benzofuranyl, chromenyl and typically 3-chromenyl, or benzothienyl and typically 2-or 3-benzothienyl; preferred monocyclic and bicyclic groups containing several heteroatoms are for example imidazolyl and typically 2-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, or thiazolyl and typically 2-thiazolyl, and benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, or quinazolinyl and typically 2-quinazolinyl. Suitable partially or in particular fully saturated analogous radicals are also contemplated, for example 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 2-or 3-pyrrolidinyl, 2-, 3-or 4-piperidinyl, and also 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl and N, N' -bis-lower alkyl-2-piperazinyl. These radicals may also carry one or more acyclic, carbocyclic or heterocyclic radicals, in particular those mentioned above. The heterocyclic-acyclic radicals are derived in particular from acyclic radicals containing up to 7, preferably up to 4, carbon atoms, such as those defined above, and may carry one, two or more heterocyclic radicals, such as those defined above, it being possible for the ring to be linked to the aliphatic chain via one of its nitrogen atoms.

As already mentioned, the hydrocarbon group (including heterocyclic group) may be substituted with one, two or more same or different substituents (functional groups); one or more of the following substituents may be considered: a lower alkyl group; free, etherified and esterified hydroxy groups; carboxyl and esterified carboxyl; mercapto-and lower alkylthio, optionally substituted phenylthio; halogen atoms, typically chlorine and fluorine, and also bromine and iodine; halogen-lower alkyl; oxo in the form of formyl (i.e., aldehyde) and keto (also as the corresponding acetal or ketal); an azide group; a nitro group; a cyano group; primary, secondary and preferably tertiary amino, amino-lower alkyl, mono-or disubstituted amino-lower alkyl, primary or secondary amino protected by conventional protecting groups (especially lower alkoxycarbonyl, usually tert-butoxycarbonyl), lower alkylenedioxy, and sulfo groups free or modified by functional groups and usually sulfamoyl groups or sulfo groups present in free form or as a salt. The hydrocarbon radicals may also carry free or one or two-substituted carbamoyl, ureido or guanidino groups and cyano groups. The word "group" is also used above to denote a single group.

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

Etherified hydroxy groups present as substituents in the hydrocarbon group are, for example, lower alkoxy groups, typically methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy, which may also be substituted, in particular by: (i) heterocyclyl, which may preferably have from 4 to 12 ring atoms, may be unsaturated or partially or fully saturated, may be monocyclic or bicyclic, may contain up to three heteroatoms selected from nitrogen, oxygen and sulphur, most particularly pyrrolyl such as 2-pyrrolyl or 3-pyrrolyl, pyridyl such as 2-, 3-or 4-pyridyl, and thienyl such as 2-or 3-thienyl, or furyl such as 2-furyl, indolyl and typically 2-or 3-indolyl, quinolyl and typically 2-or 4-quinolyl, isoquinolyl and typically 3-or 5-isoquinolyl, benzofuryl and typically 2-benzofuryl, chromenyl and typically 3-chromenyl, benzothienyl and typically 2-or 3-benzothienyl, imidazolyl and typically 1-or 2-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, thiazolyl and typically 2-thiazolyl, benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, quinazolinyl and typically 2-quinazolinyl, 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 2-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl or N, n' -bis-lower alkyl-2-piperazinyl; and (ii) a halogen atom, for example mono-, di-or polysubstituted, in particular in the 2-position, such as in 2, 2, 2-trichloroethoxy, 2-chloroethoxy or 2-iodoethoxy; (iii) a hydroxyl group; or (iv) lower alkoxy, each preferably mono-substituted, especially in the 2-position, as in 2-methoxyethoxy. Such etherified hydroxy groups may also be unsubstituted or substituted phenoxy and phenyl-lower alkoxy groups, such as in particular benzyloxy, benzhydryloxy and triphenylmethoxy (triphenylmethoxy) and also heterocyclyloxy, where heterocyclyl groups may preferably have 4 to 12 ring atoms, may be unsaturated or partially or fully saturated, may be mono-or bicyclic, may contain up to three heteroatoms selected from nitrogen, oxygen and sulphur, most particularly pyrrolyl, such as 2-pyrrolyl or 3-pyrrolyl, pyridyl, such as 2-, 3-or 4-pyridyl, and thienyl, such as 2-or 3-thienyl, or furyl, such as 2-furyl, indolyl, and typically 2-or 3-indolyl, quinolinyl, and typically 2-or 4-quinolinyl, isoquinolinyl, and typically 3-or 5-isoquinolinyl, benzofuranyl and typically 2-benzofuranyl, chromenyl and typically 3-chromenyl, benzothienyl and typically 2-or 3-benzothienyl, imidazolyl and typically 1-or 2-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, thiazolyl and typically 2-thiazolyl, benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, quinazolinyl and typically 2-quinazolinyl, 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 2-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl or N, N' -bis-lower alkyl-2-piperazinyl; such as in particular 2-or 4-tetrahydropyranyloxy.

Etherified hydroxy groups herein are intended to include silylated hydroxy groups, typically for example tri-lower alkylsiloxy, typically trimethylsiloxy and dimethyl-t-butylsiloxy, or phenyldi-lower alkylsiloxy and lower alkyl-diphenylsiloxy.

The esterified hydroxyl group present as a substituent in the hydrocarbon group is, for example, a lower alkanoyloxy group.

The carboxyl group present as a substituent in the hydrocarbon group is a carboxyl group in which a hydrogen atom is replaced by one of the hydrocarbon groups characterized above, preferably a lower alkyl group or a phenyl-lower alkyl group; examples of esterified carboxyl groups are lower alkoxycarbonyl and phenyl lower alkoxycarbonyl (optionally substituted in the phenyl moiety), especially methoxy, ethoxy, tert-butoxy and benzyloxycarbonyl and lactonized carboxyl groups.

Primary amino-NH as hydrocarbyl substituent₂May also be present in protected form by conventional protecting groups. The secondary amino group carries a hydrocarbon radical instead of one of the two hydrogen atoms, wherein said hydrocarbon radical is preferably unsubstituted, usually one of the hydrocarbon radicals defined above, in particular a lower alkyl radical, and may also be present in protected form.

The tertiary amino groups present as substituents in the hydrocarbon radicals carry 2 different or preferably identical hydrocarbon radicals (including heterocyclyl radicals), such as the unsubstituted hydrocarbon radicals characterized above, in particular lower alkyl radicals.

Preferred amino groups are of the formula R₁₁(R₁₂) Amino of N-, wherein R₁₁And R₁₂Each independently hydrogen, unsubstituted acyclic C₁-C₇Hydrocarbyl (e.g. especially C)₁-C₄Alkyl or C₂-C₄Alkenyl) or monocyclic aryl, aralkyl or aralkenyl, if desired by C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen and/or nitro, having up to 10 carbon atoms, where the carbon-containing groups can be connected to one another by carbon-carbon bonds or by oxygen, sulfur or nitrogen atoms, if desired substituted by hydrocarbon radicals. In this case, they may form a nitrogen-containing heterocyclic ring containing an amino nitrogen atom. The following are examples of particularly preferred disubstituted amino groups: di-lower alkylamino and usually dimethylamino or diethylamino, pyrrolidino, imidazol-1-yl, piperidino, piperazino, 4-lower alkylpiperazino, morpholino, thiomorpholino and piperazino or 4-methylpiperazino, and diphenylamino and dibenzylamino, if desired in particular in the phenyl moiety, for example by lower-alkyl, lower alkoxy, halogen and/or nitro; examples of protected groups are in particular lower alkoxycarbonylamino and usually tert-butoxycarbonylamino, phenyl-lower alkoxycarbonylamino and usually 4-methoxybenzyloxycarbonylamino and 9-fluorenylmethoxycarbonylamino.

Amino-lower alkyl is most particularly substituted at the 1-position of the lower alkyl chain by an amino group, in particular aminomethyl.

Mono-or di-substituted amino-lower alkyl is amino-lower alkyl substituted by one or two groups, wherein amino-lower alkyl is most particularly substituted by amino, particularly aminomethyl, in the 1-position of the lower alkyl chain; the amino substituents herein are preferably (if 2 substituents are present independently of each other) selected from lower alkyl and e.g. especially methyl, ethyl or n-propyl, hydroxy-lower alkyl and usually 2-hydroxyethyl, C₃-C₈Cycloalkyl and is typically cyclohexyl, amino-lower alkyl and is typically 3-aminopropyl or 4-aminobutyl, N-mono-or N, N-di (lower alkyl) -amino-lower alkyl and is 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 may also be a 5 or 6 membered saturated or unsaturated heterocyclyl group which is bonded to the lower alkyl group via a nitrogen atom (preferably in the 1-position) and which has from 0 to 2, especially 0 or 1, further heteroatoms selected from oxygen, nitrogen and sulphur, which is unsubstituted or substituted especially by one or two groups selected from lower alkyl, typically methyl, and which may also be oxo. Preferred herein are pyrrolidino (1-pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower alkylpiperazino and typically 4-methylpiperazino, imidazolio (1-imidazolyl), morpholino (4-morpholinyl) or thiomorpholino, S-oxo-thiomorpholino or S, S-dioxothiomorpholino.

Lower alkylenedioxy is especially methylenedioxy.

Carbamoyl with one or two substituents, especially aminocarbonyl (carbamoyl) substituted at the nitrogen by one or two groups; the amino substituents herein are preferably (if 2 substituents are present independently of each other) selected from lower alkyl and e.g. especially methyl, ethyl or n-propyl, hydroxy-lower alkyl and usually 2-hydroxyethyl, C₃-C₈Cycloalkyl and typically cyclohexyl, amino-lower alkyl and typically 3-aminopropyl or 4-aminobutyl, N-mono-or N, N-di (lower alkyl) -amino-lower alkyl and 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; the disubstituted amino group in carbamoyl may also be a 5-or 6-membered saturated or unsaturated heterocyclic group containing the bonded nitrogen atom and 0 to 2, especially 0 or 1, further heteroatoms selected from oxygen, nitrogen and sulphur, which is unsubstituted or substituted especially by one or two groups selected from lower alkyl, typically methyl, and which may also be oxo. Preferred herein are pyrrolidino (1-pyrrolidinyl), piperidino (1-piperidinyl), piperazino (1-piperazinyl), 4-lower alkylpiperazino and typically 4-methylpiperazino, imidazolio (1-imidazolyl), morpholino (4-morpholinyl) or thiomorpholino, S-oxo-thiomorpholino or S, S-bis-morpholinoAn oxothiomorpholino group.

Is designated as Ac²Of the formula (I) and especially of the sub-formula R^o-SO₂Acyl of (a) wherein R is^oFor hydrocarbyl groups as defined above in general and in specific terms, the latter are generally preferred herein. Particularly preferred is lower alkylphenylsulfonyl, especially 4-toluenesulfonyl.

Is designated as Ac³Acyl derived from phosphoric acid which may be esterified if desired, in particular of the sub-formula R^oO(R^oO) P (═ O) -, where the radical R^oIndependently of one another as defined in the general and specific meanings indicated above.

The simplified data given above and below for the substituents are considered to be preferred.

Preferred compounds of the invention are, for example, those in which R is^oThose having the following preferred meanings: lower alkyl and especially methyl or ethyl, amino-lower alkyl (wherein the amino group is unprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl such as tert-butoxycarbonyl) such as aminomethyl, R, S-, R-or preferably S-1-aminoethyl, tert-butoxycarbonylaminomethyl or R, S-, R-or preferably S-1- (tert-butoxycarbonylamino) ethyl, carboxy-lower alkyl and typically 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl and typically 2- (tert-butoxycarbonyl) ethyl, cyano-lower alkyl and typically 2-cyanoethyl, tetrahydropyranyl-lower alkyl and typically 4- (tetrahydropyranyl) -oxymethyl, morpholino-lower alkyl and typically 2- (morpholino) ethyl, phenyl, lower alkylphenyl and typically 4-methylphenyl, lower alkoxyphenyl and typically 4-methoxyphenyl, imidazolyl-lower alkoxyphenyl and typically 4- [2- (imidazol-1-yl) ethyl]Oxyphenyl, carboxyphenyl and usually 4-carboxyphenyl, lower alkoxycarbonylphenyl and usually 4-ethoxycarbonylphenyl or 4-methoxyphenyl, halogen-lower alkylphenyl and usually 4-chloromethylphenyl, pyrrolidinophenyl and usually 4-pyrrolidinophenylA group, imidazol-1-ylphenyl and typically 4- (imidazol-1-yl) phenyl, piperazinophenyl and typically 4-piperazinophenyl, (4-lower alkylpiperazino) phenyl and typically 4- (4-methylpiperazino) phenyl, morpholinophenyl and typically 4-morpholinophenyl, pyrrolidino-lower alkylphenyl and typically 4-pyrrolidinomethylphenyl, imidazol-1-yl-lower alkylphenyl and typically 4- (imidazolyl-1-ylmethyl) phenyl, piperazino-lower alkylphenyl and typically 4-piperazinomethylphenyl, (4-lower alkylpiperazinomethyl) -phenyl and typically 4- (4-methylpiperazinomethyl) phenyl, morpholino-lower alkylphenyl, and typically 4-morpholinomethylphenyl, piperazinocarbonylphenyl, and typically 4-piperazinocarbonylphenyl, or (4-lower alkyl-piperazino) phenyl, and typically 4- (4-methylpiperazino) phenyl.

Preferred acyl Ac¹Is of the subformula R^o-CO-characterized acyl radical of carboxylic acid, in which R^oWith the above hydrocarbon radicals R^oOne of the general and preferred meanings of (a). Radicals R which are particularly preferred here^oLower alkyl and especially methyl or ethyl, amino-lower alkyl (wherein the amino group is unprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl such as tert-butoxycarbonyl) such as aminomethyl, R, S-, R-or preferably S-1-aminoethyl, tert-butoxycarbonylaminomethyl or R, S-, R-or preferably S-1- (tert-butoxycarbonylamino) ethyl, carboxy-lower alkyl and typically 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl and typically 2- (tert-butoxycarbonyl) ethyl, tetrahydropyranyloxy-lower alkyl and typically 4- (tetrahydropyranyl) oxymethyl, phenyl, imidazolyl-lower alkoxyphenyl and typically 4- [2- (imidazol-1-yl) ethyl.]Oxyphenyl, carboxyphenyl and usually 4-carboxyphenyl, lower alkoxycarbonylphenyl and usually 4-ethoxycarbonylphenyl, halogen-lower alkylphenyl and usually 4-chloromethylphenyl, imidazol-1-ylphenyl and usually 4- (imidazolyl-1-yl) phenyl, pyrrolidino-lower alkylphenyl and usually 4-pyrrolidinomethylphenyl, piperazino-lower alkylphenyl and usually 4-ethoxycarbonylphenyl, halogen-lower alkylphenyl and usually 4-chloromethylphenyl, imidazol-1-ylphenyl and usually 4- (imidazolyl-1-yl) phenyl-piperazinomethylphenyl, (4-lower alkylpiperazinomethyl) phenyl and typically 4- (4-methyl-piperazinomethyl) phenyl, morpholino-lower alkylphenyl and typically 4-morpholinomethylphenyl, piperazinocarbonylphenyl and typically 4-piperazinocarbonylphenyl, or (4-lower alkylpiperazino) -phenyl and typically 4- (4-methylpiperazino) phenyl.

Another preferred acyl Ac¹Derived from carbonic acid monoesters and having the sub-formula R^o-O-CO-characterization. Among these derivatives, lower alkyl and especially tert-butyl are particularly preferred hydrocarbon radicals R^o。

Another preferred acyl Ac¹Derived from carbonic acid (or also thiocarbonic acid) amides and of formula R^oHN-C (═ W) -or R^oR^oN-C (═ W) -, where the radical R^oIndependently of one another, as defined above, W is sulfur and in particular oxygen. In particular, Ac is preferred among them¹Is of the formula R^oHN-C (═ W) -group compounds in which W is oxygen and R is^oHave one of the following preferred meanings: morpholino-lower alkyl and typically 2-morpholinoethyl, phenyl, lower alkoxyphenyl and typically 4-methoxyphenyl or 4-ethoxyphenyl, carboxyphenyl and typically 4-carboxyphenyl, or lower alkoxycarbonylphenyl and typically 4-ethoxycarbonylphenyl.

Preferably of the subformula R^o-SO₂Acyl of (a) Ac²Is lower alkylphenylsulfonyl, typically 4-toluenesulfonyl, wherein R^oIs a hydrocarbyl group as defined in the general and specific meanings above.

If p is 0, then R is bound₃The nitrogen atom of (a) is not charged. If p is 1, R₄Must also be present and bound with R₃And R₄The nitrogen atom (quaternary nitrogen) of (a) is positively charged.

Definitions of aliphatic, carbocyclic or carbocyclic-aliphatic radicals each containing up to 29 carbon atoms, or of heterocyclic radicals each containing up to 20 carbon atoms and each containing up to 9 heteroatomsOr heterocyclic-aliphatic radicals, or acyl radicals each containing up to 30 carbon atoms, preferably corresponding to the corresponding radical R₃And R₄The definitions given. Particularly preferred is R₅Lower alkyl, especially methyl, or most especially hydrogen.

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

If there are no two bonds represented by wavy lines in ring A, then there are no double bonds (tetrahydrogenated derivatives) but only single bonds between the carbon atoms in formula I labeled with the numbers 1, 2, 3 and 4, while ring B is aromatic (there are double bonds between the carbon atoms in formula I labeled with 8 and 9 and between the carbon atoms labeled with 10 and 11). If there are no two bonds represented by wavy lines in ring B, then there are no double bonds (tetrahydrogenated derivatives) but only single bonds between the carbon atoms marked with the numbers 8, 9, 10 and 11 in formula I, whereas ring A is aromatic (there are double bonds between the carbon atoms marked with 1 and 2 and between the carbon atoms marked with 3 and 4 in formula I). If there are not all four bonds represented by wavy lines in rings a and B and are replaced by a total of 8 hydrogen atoms, there are no double bonds (octahydrogenated derivatives) but only single bonds between the carbon atoms bearing the numbers 1, 2, 3, 4, 8, 9, 10 and 11 in formula I.

Depending on the nature of the compounds according to the invention, they may also be present in the form of pharmaceutically acceptable, i.e. physiologically acceptable salts, provided that they contain salt-forming groups. For isolation and purification, pharmaceutically unacceptable salts may also be used. For therapeutic use, only pharmaceutically acceptable salts may be used and these are preferred.

Thus, compounds of formula I having a free acid group, e.g. a free sulfo, phosphoryl or carboxyl group, may be present as a salt, preferably a physiologically acceptable salt, with a salt-forming basic component. These salts may be predominantly metal or ammonium salts, for example alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, in particular tertiary monoamines and heterocyclic bases, for example triethylamine, tris- (2-hydroxyethyl) -amine, N-ethylpiperidine or N, N' -dimethylpiperazine.

The compounds of the invention having basic properties may also be present as addition salts, in particular as acid addition salts with inorganic and organic acids, and also as quaternary salts. Thus, for example, compounds having 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, such as hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, hydroxymaleic acid, oxalic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethanedisulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, and also methionine, tryptophan, lysine or arginine and ascorbic acid.

Due to the close relationship between the free forms and their salts, including for example those salts which may be used as intermediates in the purification or identification of new compounds, and the solvate forms of the compounds, in particular the compounds of formula I, any reference to free compounds in this context may also be taken to be appropriate and advantageous as corresponding salts and solvates thereof, e.g. hydrates.

A compound of formula A, B, C, D, I, II, III, IV, V or VI, especially wherein R₅Those which are hydrogen have valuable pharmacological properties.

For the groups or compounds mentioned above and below, the general definitions may be replaced as appropriate and advantageously by the more specific definitions mentioned above and below.

Preferred are compounds of formula I, II, III, IV, V, VI or salts thereof (if at least one salt-forming group is present) as defined below: wherein the content of the first and second substances,

R₁and R₂Independently of each other, lower alkyl; lower alkyl substituted by: halogen, C₆-C₁₄Aryl, hydroxy, lower alkoxy, phenyl-lower alkoxy, phenoxy, lower alkanoyloxy, benzoyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N-di- (phenyl-lower alkyl) amino, cyano, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N-di-lower alkylcarbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lower alkylaminosulfonyl, or N, N-di-lower alkylaminosulfonyl; halogen; lower alkoxy; c₆-C₁₄An aryloxy group; c₆-C₁₄Aryl-lower alkoxy; a lower alkanoyloxy group; c₆-C₁₄An arylcarbonyloxy group; by lower alkyl, C₆-C₁₄Aryl radical, C₆-C₁₄Aryl-lower alkyl, lower alkanoyl or C₆-C₁₂Aryl carbonyl monosubstituted or disubstituted amino; a cyano group; a nitro group; a mercapto group; a lower alkylthio group; c₆-C₁₄An arylthio group; c₆-C₁₄Aryl-lower alkylthio; lower alkanoylthio; c₆-C₁₄Aryl-lower alkanoylthio; a carboxyl group; lower alkoxycarbonyl, C₆-C₁₄Aryl-lower alkoxycarbonyl; c₆-C₁₄An aryloxycarbonyl group; a carbamoyl group; by lower alkyl, C₆-C₁₄Aryl or C₆-C₁₄Aryl-lower alkyl N-mono-or N, N-di-substituted carbamoyl; a sulfo group; c₆-C₁₄An arylsulfonyl group; c₆-C₁₄Aryl-lower alkanesulfonyl; lower alkanesulfonyl; or by lower alkyl, C₆-C₁₄Aryl or C₆-C₁₄Aryl-lower alkyl N-mono-or N, N-di-substituted aminosulfonyl wherein₆-C₁₄Aryl is an aryl group containing from 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, phenoxy, lower alkanoyloxy, benzeneFormyloxy, amino, lower alkylamino, lower alkanoylamino, phenyl-lower alkylamino, N-di- (phenyl-lower alkyl) amino, cyano, mercapto, lower alkylthio, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N-di-lower alkylcarbamoyl, sulfo, lower alkanesulfonyl, lower alkoxysulfonyl, aminosulfonyl, N-lower alkylaminosulfonyl or N, N-di-lower alkylaminosulfonyl;

n and m are independently of each other 0 or 1 or 2, preferably 0;

R₃、R₄、R₈、R₁₀independently of one another, hydrogen, lower alkyl, lower alkenyl or lower alkadienyl, each of which is unsubstituted or mono-or polysubstituted, preferably mono-or disubstituted, by substituents independently selected from the group consisting of: a lower alkyl group; a hydroxyl group; lower alkoxy, which may be unsubstituted or mono-, di-or tri-substituted by: (i) heterocyclyl having 4 to 12 ring atoms which may be unsaturated, fully saturated or partially saturated, may be monocyclic or bicyclic, may contain up to three heteroatoms selected from nitrogen, oxygen and sulphur, most particularly pyrrolyl such as 2-pyrrolyl or 3-pyrrolyl, pyridyl such as 2-, 3-or 4-pyridyl, or in a broader sense also thienyl such as 2-or 3-thienyl, or furyl such as 2-furyl, indolyl and typically 2-or 3-indolyl, quinolyl and typically 2-or 4-quinolyl, isoquinolyl and typically 3-or 5-isoquinolyl, benzofuryl and typically 2-benzofuryl, chromenyl and typically 3-chromenyl, benzothienyl and typically 2-or 3-benzothienyl, imidazolyl and typically 1-or 2-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, thiazolyl and typically 2-thiazolyl, benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, quinazolinyl and typically 2-quinazolinyl, 2-tetrahydrofuranyl, 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl or N, N' -bis-lower alkyl-2-piperazinyl, (ii) halogen, (iii) hydroxy or (iv) lower alkoxy; a phenoxy group; phenyl-lower alkoxy; heterocyclyloxy, wherein heterocyclyl is pyrrolyl, such as 2-pyrrolyl or 3-pyrrolyl, pyridinyl, such as 2-, 3-or 4-pyridinyl, or in a broader sense also thiophenyl, such as 2-or 3-thiophenyl, or furanyl, such as 2-furanyl, indolyl, and typically 2-or 3-indolyl, quinolinyl, and typically 2-or 4-quinolinyl, isoquinolinyl, and typically 3-or 5-isoquinolinyl, benzofuranyl, and typically 2-benzofuranyl, chromenyl, and typically 3-chromenyl, benzothienyl, and typically 2-or 3-benzothienyl, imidazolyl, and typically 1-or 2-imidazolyl, pyrimidinyl, and typically 2-or 4-pyrimidinyl, oxazolyl, and typically 2-oxazolyl, isoxazolyl and usually 3-isoxazolyl, thiazolyl and usually 2-thiazolyl, benzimidazolyl and usually 2-benzimidazolyl, benzoxazolyl and usually 2-benzoxazolyl, quinazolinyl and usually 2-quinazolinyl, 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 2-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl or N, N' -bis-lower alkyl-2-piperazinyl, such as in particular 2-or 4-tetrahydropyranyloxy; a lower alkanoyloxy group; a carboxyl group; a lower alkoxycarbonyl group; phenyl-lower alkoxycarbonyl; a mercapto group; a lower alkylthio group; a phenylthio group; halogen; halogen-lower alkyl; oxo (except at the 1-position, as there is an acyl group in other respects); an azide group; a nitro group; a cyano group; an amino group; mono-lower alkylamino; di-lower alkylamino; a pyrrolidino group; imidazol-1-yl; piperidino; piperazino; 4-lower alkylpiperazino; a morpholino group; a thiomorpholino group; diphenylamino or dibenzylamino unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or nitro; lower alkoxycarbonylamino; phenyl-lower alkoxycarbonylamino unsubstituted or substituted in the phenyl moiety by lower alkyl or lower alkoxy; a fluorenylmethoxycarbonylamino group; amino-lower alkyl; mono-or di-substituted amino-lower alkyl, wherein aminoThe substituents being selected from lower alkyl, hydroxy-lower alkyl, C₃-C₈Cycloalkyl, amino-lower alkyl, N-mono-or N, N-di- (lower alkyl) amino-lower alkyl, amino, N-mono-or N, N-di-lower alkylamino and N-mono-or N, N-di- (hydroxy-lower alkyl) amino; pyrrolidino-lower alkyl; piperidino-lower alkyl; piperazino-lower alkyl; 4-lower alkylpiperazino-lower alkyl; imidazol-1-yl-lower alkyl; morpholino-lower alkyl; thiomorpholino-lower alkyl; s-oxo-thiomorpholino-lower alkyl; s, S-dioxothiomorpholino-lower alkyl; a lower alkylenedioxy group; a sulfamoyl group; a sulfo group; a carbamoyl group; a urea group; guanidino; a cyano group; aminocarbonyl (carbamoyl) and aminocarbonyloxy substituted on the nitrogen by one or two groups, wherein the amino substituents are independently selected from the group consisting of lower alkyl, hydroxy-lower alkyl, C₃-C₈Cycloalkyl, amino-lower alkyl, N-mono-or N, N-di- (lower alkyl) amino-lower alkyl, amino, N-mono-or N, N-di-lower alkylamino and N-mono-or N, N-di- (hydroxy-lower alkyl) amino; pyrrolidinocarbonyl; piperidinocarbonyl; piperazinocarbonyl; 4-lower alkylpiperazinocarbonyl; an imidazolocarbonyl group; morpholinocarbonyl; thiomorpholinocarbonyl; s-oxo-thiomorpholinocarbonyl; and S, S-dioxothiomorpholino;

phenyl, naphthyl, phenyl-lower alkyl or phenyl-lower alkenyl containing a terminal phenyl group, which is unsubstituted or mono-or disubstituted by radicals as defined above for the substituents of lower alkyl, lower alkenyl or lower alkadienyl;

or heterocyclyl-lower alkyl, wherein heterocyclyl is pyrrolyl, such as 2-pyrrolyl or 3-pyrrolyl, pyridinyl, such as 2-, 3-or 4-pyridinyl, or in a broader sense also thiophenyl, such as 2-or 3-thiophenyl, or furanyl, such as 2-furanyl, indolyl and typically 2-or 3-indolyl, quinolinyl and typically 2-or 4-quinolinyl, isoquinolinyl and typically 3-or 5-isoquinolinyl, benzofuranyl and typically 2-benzofuranyl, chromenyl and typically 3-chromenyl, benzothiophenyl and typically 2-or 3-benzothiophenyl, imidazolyl and typically 1-or 2-imidazolyl, pyrimidinyl and typically 2-or 4-pyrimidinyl, oxazolyl and typically 2-oxazolyl, isoxazolyl and typically 3-isoxazolyl, thiazolyl and typically 2-thiazolyl, benzimidazolyl and typically 2-benzimidazolyl, benzoxazolyl and typically 2-benzoxazolyl, quinazolinyl and typically 2-quinazolinyl, 2-tetrahydrofuryl, 4-tetrahydrofuryl, 2-or 4-tetrahydropyranyl, 1-, 2-or 3-pyrrolidinyl, 1-, 2-, 3-or 4-piperidinyl, 1-, 2-or 3-morpholinyl, 2-or 3-thiomorpholinyl, 2-piperazinyl or N, N' -bis-lower alkyl-2-piperazinyl, each of which is unsubstituted or referred to above as lower alkyl, lower alkenyl or lower alkadienyl, which is mono-or di-substituted;

or acyl of the subformula Y-C (═ W) -, where W is oxygen and Y is hydrogen, R^o、R^o-O-、R^oHN-or R^oR^oN- (wherein the radical R)^oMay be the same or different),

or of the subformula R^o-SO₂An acyl group of (a) to (b),

whereby R may also be absent for the compounds of formula II₄；

Or

Absence of R for the compound of formula II₄For compounds of formula I R₄Is hydrogen or CH₃And is and

R₃is an acyl radical of the subformula Y-C (═ W) -, where W is oxygen and Y is hydrogen, R^o、R^o-O-、R^oHN-or R^oR^oN- (wherein the radical R)^oMay be the same or different),

or is of the subformula R^o-SO₂An acyl group of (a) to (b),

wherein R in said group^oHas the following meanings: substituted or unsubstituted lower alkyl, especially methyl or ethyl, amino-lower alkyl, hydroxy-lower alkyl (wherein amino isUnprotected or protected by a conventional amino protecting group, especially by lower alkoxycarbonyl, typically tert-lower alkoxycarbonyl such as tert-butoxycarbonyl) such as aminomethyl, R, S-, R-or preferably S-1-aminoethyl, tert-butoxycarbonylaminomethyl or R, S-, R-or preferably S-1- (tert-butoxycarbonylamino) ethyl, carboxy-lower alkyl and typically 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl and typically 2- (tert-butoxycarbonyl) ethyl, cyano-lower alkyl and typically 2-cyanoethyl, tetrahydropyranyl-lower alkyl and typically 4- (tetrahydropyranyl) -oxymethyl, morpholino-lower alkyl and typically 2- (morpholino) ethyl, phenyl, lower alkylphenyl, usually 4-methylphenyl, lower alkoxyphenyl, usually 4-methoxyphenyl, imidazolyl-lower alkoxyphenyl, usually 4- [2- (imidazol-1-yl) ethyl]Oxyphenyl, carboxyphenyl and usually 4-carboxyphenyl, lower alkoxycarbonylphenyl and usually 4-ethoxycarbonylphenyl or 4-methoxyphenyl, halogen-lower alkylphenyl and usually 4-chloromethylphenyl, pyridinoalkylphenyl and usually 4-pyrrolidinophenyl, imidazol-1-ylphenyl and usually 4- (imidazolyl-1-yl) phenyl, piperazinophenyl and usually 4-piperazinophenyl, (4-lower alkylpiperazino) phenyl and usually 4- (4-methylpiperazino) phenyl, morpholinophenyl and usually 4-morpholinophenyl, pyrrolidino-lower alkylphenyl and usually 4-pyrrolidinomethylphenyl, imidazol-1-yl-lower alkylphenyl and usually 4- (imidazolyl-1- Phenylmethyl) phenyl, piperazino-lower alkylphenyl, typically 4-piperazinomethylphenyl, (4-lower alkylpiperazinomethyl) -phenyl, typically 4- (4-methylpiperazinomethyl) phenyl, morpholino-lower alkylphenyl, typically 4-morpholinomethylphenyl, piperazinocarbonylphenyl, typically 4-piperazinocarbonylphenyl, or (4-lower alkylpiperazino) phenyl, typically 4- (4-methylpiperazino) phenyl;

if R is₄Absent, p is 0, or if R is₃And R₄Are present and are each one of the abovementioned radicals, p is 1 (for compounds of the formula II);

R₅is hydrogen or lower alkyl, especially hydrogen,

x represents 2 hydrogen atoms; o; 1 hydrogen atom and hydroxyl group; or 1 hydrogen atom and lower alkoxy; z is hydrogen or especially lower alkyl, most especially methyl;

and for compounds of formula II, the two bonds in ring a characterized by wavy lines are preferably absent and replaced by 4 hydrogen atoms, the two wavy lines in ring B each represent a double bond with the respective parallel bond;

Particular preference is given to compounds of the formula I or salts thereof (if at least one salt-forming group is present) as defined below, wherein:

m and n are each 0;

R₃and R₄Independently of each other are

The presence of hydrogen in the presence of hydrogen,

lower alkyl which is unsubstituted or mono-or disubstituted, in particular monosubstituted, by radicals selected independently of one another from carboxy, lower alkoxycarbonyl and cyano;

or

R₄Is hydrogen or-CH₃And is and

R₃as defined above, or preferably R₃Is composed of

Having the sub-formula R^o-acyl of CO, wherein R^oIs lower alkyl; amino-lower alkyl, wherein the amino group is present in unprotected form or protected by a lower alkoxycarbonyl group; tetrahydropyranyloxy-lower alkyl(ii) a A phenyl group; imidazolyl-lower alkoxyphenyl; a carboxyphenyl group; lower alkoxycarbonylphenyl; halogen-lower alkyl phenyl; imidazol-1-ylphenyl; pyrrolidino-lower alkyl phenyl; piperazino-lower alkylphenyl; (4-lower alkylpiperazinomethyl) phenyl; morpholino-lower alkylphenyl; piperazinocarbonylphenyl; or (4-lower alkylpiperazino) phenyl;

or is of sub-formula R^oAcyl of-O-CO-, wherein R^oIs lower alkyl;

or is of sub-formula R^oAcyl of HN-C (═ W) -, where W is oxygen and R^oHas the following meanings: morpholino-lower alkyl, phenyl, lower alkoxyphenyl, carboxyphenyl, or lower alkoxycarbonylphenyl;

or R₃Is lower alkylphenylsulfonyl, typically 4-toluenesulfonyl;

for preferred compounds of formula II, preferred R's are also described below₃Other specific examples of the group are,

R₅is hydrogen or lower alkyl, especially hydrogen,

x represents 2 hydrogen atoms or represents O;

z is methyl or hydrogen.

Particular preference is given to compounds of the formula II or salts thereof (if at least one salt-forming group is present) as defined below, wherein:

m and n are each 0;

R₃and R₄Independently of each other are

The presence of hydrogen in the presence of hydrogen,

whereby R₄May also be absent;

or

R₄Is absent, and

R₃is of sub-formula R^o-acyl of CO, wherein R^oIs lower alkyl, especially methyl or ethyl; amino-lower alkyl (wherein the amino group is unprotected or protected by a lower alkoxycarbonyl group, typically a tert-lower alkoxycarbonyl group such as tert-butoxycarbonyl), for example aminomethyl, R, S-, R-or preferably S-1-aminoethyl, tert-butoxycarbonylaminomethyl or R, S-, R-or preferably S-1- (tert-butoxycarbonylamino) ethyl; tetrahydropyranyloxy-lower alkyl and typically 4- (tetrahydropyranyl) oxymethyl; a phenyl group; imidazolyl-lower alkoxyphenyl and typically 4- [2- (imidazol-1-yl) ethyl]An oxyphenyl group; carboxyphenyl and typically 4-carboxyphenyl; lower alkoxycarbonylphenyl and typically 4-methoxy-or 4-ethoxycarbonylphenyl; halogen-lower alkylphenyl and typically 4-chloromethylphenyl; imidazol-1-ylphenyl and typically 4- (imidazol-1-yl) -phenyl; pyrrolidino-lower alkylphenyl, and typically 4-pyrrolidinomethylphenyl; piperazino-lower alkylphenyl, and typically 4-piperazinomethylphenyl; (4-lower alkylpiperazinomethyl) phenyl and typically 4- (4-methylpiperazinomethyl) phenyl; morpholino-lower alkylphenyl and typically 4-morpholinomethylphenyl; piperazinocarbonylphenyl and typically 4-piperazinocarbonylphenyl; or (4-lower alkylpiperazino) phenyl and typically 4- (4-methylpiperazino) phenyl; or is of sub-formula R^oAcyl of-O-CO-, wherein R^oIs lower alkyl;

or is of sub-formula R^oAcyl of HN-C (═ W) -, where W is oxygen and R^oHave the following preferred meanings: morpholino-lower alkyl and typically 2-morpholinoethyl, phenyl, lower alkoxyphenyl and typically 4-methoxyphenyl or 4-ethoxyphenyl, carboxyphenyl and typically 4-carboxyphenyl, or lower alkoxycarbonylphenyl and typically 4-ethoxycarbonylphenyl;

or lower alkylphenylsulfonyl and typically 4-toluenesulfonyl;

R₅is hydrogen or lower alkyl, especially hydrogen,

x represents 2 hydrogen atoms or represents O;

z is methyl or hydrogen;

and the two bonds in ring a characterized by wavy lines are preferably absent and replaced by 4 hydrogen atoms, the two wavy lines in ring B each, together with the respective parallel bond, represent a double bond;

Most particularly preferred compounds of formula II are selected from:

8, 9, 10, 11-tetrahydrostaurosporine;

n- [4- (4-methylpiperazin-1-ylmethyl) benzoyl ] -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4-chloromethylbenzoyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4- (pyrrolidin-1-ylmethyl) benzoyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4- (morpholin-4-ylmethyl) benzoyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4- (piperazin-1-ylmethyl) benzoyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n-ethyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-tosyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-trifluoroacetyl-1, 2, 3, 4-tetrahydrostaurosporine;

n- [4- (2-imidazol-1-yl-ethoxy) benzoyl ] -1, 2, 3, 4-tetrahydrostaurosporine;

n-methoxycarbonylmethyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-carboxymethyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-terephthaloyl methyl ester-1, 2, 3, 4-tetrahydrostaurosporine;

n-terephthaloyl-1, 2, 3, 4-tetrahydrostaurosporine;

n- (4-ethylpiperazinylcarbonylbenzoyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (2-cyanoethyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n-benzoyl-1, 2, 3, 4-tetrahydrostaurosporine;

iodinated N, N-dimethyl-1, 2, 3, 4-tetrahydrostaurosporine;

N-BOC-glycyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-glycyl-1, 2, 3, 4-tetrahydrostaurosporine;

n- (3- (tert-butoxycarbonyl) propyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (3-carboxypropyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4-imidazol-1-yl) benzoyl ] -1, 2, 3, 4-tetrahydrostaurosporine;

n- [ (tetrahydro-2H-pyran-4-yloxy) acetyl ] -1, 2, 3, 4-tetrahydrostaurosporine;

N-BOC-l-alanyl-1, 2, 3, 4-tetrahydrostaurosporine;

n-l-alanyl-1, 2, 3, 4-tetrahydrostaurosporine hydrochloride;

n-methyl-1, 2, 3, 4-tetrahydro-6-methyl staurosporine;

n- (4-carboxyphenylaminocarbonyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (4-ethylphenylaminocarbonyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (N-phenylaminocarbonyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (N- [2- (1-morpholino) ethyl ] aminocarbonyl) -1, 2, 3, 4-tetrahydrostaurosporine;

n- (N- [ 4-methoxyphenyl ] aminocarbonyl) -1, 2, 3, 4-tetrahydrostaurosporine;

1, 2, 3, 4-tetrahydro-6-methyl staurosporine;

N-BOC-1, 2, 3, 4-tetrahydrostaurosporine;

N-BOC-1, 2, 3, 4-tetrahydro-6-methyl staurosporine;

N-BOC-1, 2, 3, 4-tetrahydro-6-methyl-7-oxo-staurosporine;

1, 2, 3, 4, 8, 9, 10, 11-octahydrostaurosporine;

or a pharmaceutically acceptable salt thereof (if at least one salt-forming group is present).

Most particularly preferred are compounds of formula I, designated 1, 2, 3, 4-tetrahydrostaurosporine, or (particularly pharmaceutically acceptable) salts thereof (where m and n in formula I are 0, R₃Is hydrogen, R₄Absent provided that the salt is absent (p ═ 0), or R if the salt is present (p ═ 1)₄Is hydrogen, R₅For hydrogen, two bonds represented by wavy lines in ring a are absent and replaced by a total of 4 hydrogen atoms, two bonds represented by wavy lines in ring B are each a double bond together with a parallel bond, X represents 2 hydrogen atoms, and Z is methyl).

Most particularly preferred are compounds of formula a as defined below, wherein:

A)X＝O；R₁、R₂、R₅＝H；Q＝-(CH₂)₂-O-CH(CH₂)OH-(CH₂)₂-

B)X＝O；R₁、R₂、R₅＝H；Q＝-(CH₂)₂-O-CH(CH₂N(CH₃)₂)-(CH₂)₂-

C) x ═ 2 hydrogen atoms; r₁、R₂、R₅＝H；

Most particularly preferred are compounds of formula I as defined below, wherein:

A) x ═ 2 hydrogen atoms; r₁、R₂、R₃、R₅＝H；R₄＝CH₃；Z＝CH₃(Asosporin)

B) X ═ 1 hydrogen atom and 1 hydroxyl group in the (R) or (S) isomeric forms; r₁、R₂、R₃、R₅＝H；R₄＝CH₃；Z＝CH₃(UCN-01 and UCN-02)

C) X ═ 2 hydrogen atoms; r₁、R₂、R₅＝H；R₄＝CH₃；R₃A benzoyl group; z is CH₃(CGP41251 or PKC412 or MIDOSTAURIN (MIDOSTAURIN))

D)X＝O；R₁、R₂、R₅＝H；R₃＝CH₃；R₄Ethoxycarbonyl; z is CH₃(NA 382；CAS＝143086-33-3)

E) X ═ 1 hydrogen atom and 1 hydroxyl group; r₁、R₂、R₅＝H；R₃＝CH₃；Z＝CH₃(ii) a And R is₄Is selected from- (CH)₂)₂OH；-CH₂CH(OH)CH₂OH；-CO(CH₂)₂CO₂Na；-(CH₂)₃CO₂H；-COCH₂N(CH₃)₂；

F) X ═ 2 hydrogen atoms; r₁、R₂、R₅＝H；R₃＝CH₃；Z＝CH₃(ii) a And R is₄Selected from N- [ O- (tetrahydropyran-4-yl) -D-lactyl](ii) a N- [ 2-methyl-2- (tetrahydropyran-4-yloxy) -propionyl;

n- [ O- (tetrahydropyran-4-yl) -L-lactyl ]; n- [ O- (tetrahydropyran-4-yl) -D-lactyl ];

n- [2- (tetrahydro-pyran-4-yloxy) -acetyl ]

G)X＝O；R₁、R₂、R₅＝H；R₃＝CH₃；Z＝CH₃(ii) a And R is₄Selected from N- [ O- (tetrahydropyran-4-yl) -D-lactyl](ii) a N- [2- (tetrahydro-pyran-4-yloxy) -acetyl]

H) X ═ 1 hydrogen atom and 1 hydroxyl group; r₁、R₂、R₅＝H；R₃＝CH₃；Z＝CH₃(ii) a And R is₄Selected from N- [ O- (tetrahydropyran-4-yl) -D-lactyl](ii) a N- [2- (tetrahydro-pyran-4-yloxy) -acetyl]The abbreviation "CAS" refers to chemical abstract accession number.

The most preferred compounds of formula I, for example midostaurin [ International non-proprietary name ] are included in European patent No. 0296110, published on 21.12.1988 and U.S. Pat. No. 5,093,330 and Japanese patent 2708047, published on 3.3.1992 and are described in detail. Other preferred compounds are included and described in patent applications WO 95/32974 and WO 95/32976, both published on 7.12.1995. All compounds described in these documents are incorporated herein by reference.

Most particularly preferred are compounds of formula III, as defined below, wherein:

A) x ═ 2 hydrogen atoms; r₁、R₂、R₅＝H；R₆＝CH₃；R₇Methoxycarbonyl group; Z-H (2-methyl K252a)

B) X ═ 2 hydrogen atoms; r₁、R₂、R₅、R₆＝H；R₇Methoxycarbonyl group; Z-H (K-252a)

C) X ═ 2 hydrogen atoms; r₁、R₂、R₅、R₆＝H；R₇Methoxycarbonyl group; z is CH₃(KT-5720) are most particularly preferred compounds of formula IV as defined below, wherein:

A)X＝O；R₁、R₂、R₅＝H；R₉＝CH₂-NMe₂；R₈＝CH₃；m′＝n′＝2

B)X＝O；R₁、R₂、R₅＝H；R₉＝CH₂-NH₂；R₈＝CH₃；m′＝2；n′＝1(Ro-31-8425；CAS＝151342-35-7)

most particularly preferred are compounds of formula V as defined below, wherein:

A)X＝O；R₁、R₂、R₅＝H；R₈＝CH₃；R₁₀＝-(CH₂)₃-NH₂；(Ro-31-7549；CAS＝138516-31)

B)X＝O；R₁、R₂、R₅＝H；R₈＝CH₃；R₁₀＝-(CH₂)₃-S-(C＝NH)-NH₂；(Ro-31-8220；CAS＝125314-64-9)

C)X＝O；R₁、R₂、R₅＝H；R₈＝CH₃；R₁₀＝-CH₃；

most particularly preferred are compounds of formula VI as defined below, wherein:

A) x ═ 2 hydrogen atoms; r₁、R₂、R₅＝H；R₄＝CH₃；Z＝CH₃；R₃Selected from methyl or (C)₁-C₁₀) Alkyl, arylmethyl, C₆H₂CH₂-。

Staurosporine derivatives and methods for their preparation have been described in detail in a number of prior art documents well known to those skilled in the art.

Compounds of formula A, B, C, D and methods for their preparation have been disclosed, for example, in European patent No. 0657458, published 6/14 in 1995, European patent No. 0624586, published 11/17 in 1994, European patent No. 0470490, published 2/12 in 1992, European patent No. 0328026, published 8/16 in 1989, European patent No. 0384349, published 8/29 in 1990, and in various publications such as "Barry M^＊And Weiping Tang org. Lett., 3(21), 3409-3411 ".

Compounds of formula I and their preparation have been described in detail in European patent No. 0296110, published on 21.12.1988, and U.S. Pat. No. 5,093,330 and Japanese patent No. 2708047, published on 3.3.1992. At R₄Compounds of formula I having (tetrahydropyran-4-yl) -lactyl substitution have been described in European patent No. 0624590, published 11/17 of 1994. Other compounds have been described in European patent No. 0575955, published on 29/12/1993, European patent No. 0238011 (UCN-O1), published on 23/9/1987, and International patent application EP98/04141, published on 3/7/1998 as WO 99/02532.

Compounds of formula II and their preparation have been described in detail in European patent No. 0296110, published on 21.12.1988, and U.S. Pat. No. 5,093,330 and Japanese patent No. 2708047, published on 3.3.1992.

The compounds of formula III and their preparation have been specifically described in patent applications claiming priority from US patent application US 920102 (filed 24.7.1992) (namely european patent No. 0768312 published 16.4.1997, No. 1002534 published 24.5.2000, No. 0651754 published 10.5.1995).

The compounds of formula IV and their preparation have been specifically described in patent applications claiming priority from british patent applications GB 9309602 and GB9403249 (filed 1993, 5/10 and 1994, 2/21, respectively) (i.e. european patent No. 0624586 published on 11/17 of 1994, 1002534 published on 5/24 of 2000, 0651754 published on 5/10 of 1995).

The compounds of formula V and their preparation have been specifically described in patent applications claiming priority from british patent applications GB 8803048, GB8827565, GB 8904161 and GB 8928210 (filed on days 2 and 10 1988, 11 and 25 1988, 2 and 23 1989 and 12 and 13 1989, respectively) (namely european patent No. 0328026 published on 16 1989 and No. 0384349 published on 29 1990 8).

Compounds of formula VI and methods for their preparation have been specifically described in the patent application claiming priority from U.S. patent application 07/777,395(Con) (filed 10/1991) (i.e., International patent application WO 93/07153 published at 4/15/1993).

For each case where a patent application or scientific publication is cited specifically for a staurosporine derivative compound, the subject matter of the end product, pharmaceutical preparation and claims is hereby incorporated into the present application by reference to these disclosures.

The structure of an active agent identified by a code, generic or trade name can be obtained from the current version of the standard catalog "merck index" or from a database, such as the Patents International (e.g., IMS world publication). The corresponding content of which is hereby incorporated by reference.

Preferred staurosporine derivatives of the invention are N- [ (9S, 10R, 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 ', 1 ' -lm ] pyrrolo [3, 4-j ] [1, 7] benzodiazepin-11-yl ] -N-methylbenzamide or a salt thereof (hereinafter referred to as "compound of formula VII or midostaurin").

The compound of formula VII is also known as midostaurin [ international non-proprietary name ] or PKC 412.

Midostaurin is a derivative of the naturally occurring alkaloid staurosporine and has been specifically described in european patent No. 0296110, published 12/21 in 1988, and U.S. patent No. 5,093,330 and japanese patent No. 2708047, published 3/3 in 1992.

It has now surprisingly been found that midostaurin has therapeutic properties which make it particularly useful for the treatment of allergic rhinitis, allergic dermatitis, drug or food allergies, angioneurotic edema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease. It is particularly surprising that midostaurin is also effective for the prevention or treatment of the above mentioned diseases and conditions which are resistant to imatinib or a pharmaceutically acceptable salt thereof.

Staurosporine derivatives, such as midostaurin, were originally identified as Protein Kinase C (PKC) inhibitors (Meyer T, Regenass U, Fabbro D et al: Int J Cancer 43: 851-.

The invention therefore relates to the use of staurosporine derivatives for the preparation of a medicament for the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis. The invention also relates to the use of a staurosporine derivative for the preparation of a medicament for the treatment of allergic rhinitis, allergic dermatitis, drug or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease, which is resistant to imatinib or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis, as well as all such diseases and conditions that are resistant to imatinib or a pharmaceutically acceptable salt thereof, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a staurosporine derivative, a pharmaceutically acceptable salt or prodrug thereof.

The present invention preferably provides a method for the treatment of a mammal, particularly a human, suffering from allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease, which comprises administering to a mammal, in need of such treatment, a therapeutically effective amount of N- [ (9S, 10R, 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 ', 1 ' -lm ] pyrrolo [3, 4-j ] [1, 7] benzodiazepin-11-yl ] -N-methylbenzamide or a pharmaceutically acceptable salt thereof.

The invention also relates to a method comprising: wherein a therapeutically effective amount of a compound of formula VII is administered to a mammalian subject 7 to 4 times a week, or from about 100% to about 50% of the days over a time period, for a total of one to six weeks, followed by one to three weeks without drug administration, and the cycle is repeated one to several times.

In another embodiment, the invention relates to the use of a staurosporine derivative for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease, more particularly for the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease, which are resistant to imatinib.

The in vivo activity of staurosporine derivatives, in particular compounds of formula I or II, can be demonstrated in the following administration: for example, the animals are orally administered at a dose of 0.1 to 10 or 1 to 5mg/kg body weight per day, once or up to three times daily.

In some cases allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioneurotic edema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis can be treated with the tyrosine kinase inhibitor imatinib, but will recur frequently, and it has been unexpectedly found that staurosporine derivatives and midostaurin are still active in these cases.

The exact dosage of the staurosporine derivative for the treatment of the above mentioned diseases and conditions depends on several factors, including the host, the nature and severity of the condition to be treated, the mode of administration. However, satisfactory results are generally achieved when the staurosporine derivative is administered parenterally (e.g. intraperitoneally, intravenously, intramuscularly, subcutaneously, intratumorally or rectally) or enterally (e.g. orally), preferably intravenously or preferably orally or intravenously at a daily dosage of 0.1 to 10mg/kg body weight, preferably 1 to 5mg/kg body weight. In human trials, the total dose of 225 mg/day is most likely the Maximum Tolerated Dose (MTD). A preferred intravenous daily dose is from 0.1 to 10mg/kg body weight, or for most larger primates a daily dose of 200-300 mg. Typically, the intravenous dose is 3 to 5mg/kg, 3 to 5 times a week.

The staurosporine derivative, in particular midostaurin, is most preferably administered orally in a dosage form (e.g. microemulsion, soft gel or solid dispersion) at a dose of up to about 250 mg/day, in particular 225 mg/day, once, twice or three times daily.

Typically, small doses are administered initially, and the dose is gradually increased until the optimum dose for the host being treated is determined. The upper limit of the dose is affected by side effects and can be determined by tests carried out on the host being treated.

The staurosporine derivative may be combined with one or more pharmaceutically acceptable carriers and optionally one or more other conventional pharmaceutical adjuvants and may be administered enterally (e.g. orally) in the form of tablets, capsules, caplets and the like or parenterally (e.g. intraperitoneally or intravenously) in the form of sterile injectable solutions or suspensions. Enteral and parenteral compositions may be prepared by conventional methods.

The infusion solutions of the present invention are preferably sterile. This can be easily achieved, for example, by filtration through sterile filtration membranes. Any composition that is sterile to form a liquid form, sterile filled vials, and/or combination of a pharmaceutical composition of the invention and a suitable diluent under sterile conditions is well known to the skilled person.

Staurosporine derivatives can be formulated as enteral and parenteral pharmaceutical compositions containing an amount of active agent effective in the treatment of the diseases and conditions specified above, as well as such compositions in unit dosage forms and such compositions containing a pharmaceutically acceptable carrier.

Staurosporine derivatives can be used alone or in combination with at least one other pharmaceutically active compound for these conditions. These active compounds can be combined in the same pharmaceutical preparation or in the form of a combined preparation "kit of parts", which means that the combination partners can be administered separately or by using different fixed combinations with different amounts of the combination partners, i.e. simultaneously or at different time points. The parts of the kit of parts are then, for example, administered simultaneously or chronologically staggered, i.e. at different time points and with equal or different time intervals for any part of the kit of parts. Non-limiting examples of compounds that can be used in combination with staurosporine derivatives are cytotoxic chemotherapy drugs such as cytarabine, daunorubicin, doxorubicin, cyclophosphamide, VP-16 or imatinib, and the like. Staurosporine derivatives can also be combined with other signal transduction inhibitors or other oncogene-targeted drugs in order to expect significant synergy.

Examples of useful compositions are described in european patents 0296110, 0657164, 0296110, 0733372, 0711556, 0711557.

Preferred compositions are described in European patent No. 0657164, published 6, 14, 1995. The pharmaceutical composition comprises a solution or dispersion of a compound of formula I, such as midostaurin, in saturated polyalkylene glycol glycerides which are a mixture of glyceryl and polyethylene glycol esters of one or more C8-C18 saturated fatty acids.

Two methods of preparation of these compositions are described below.

Composition A:

gelucire 44/14(82 parts) was heated to 60 ℃ to melt. To the molten material is added midostaurin powder (18 parts). The resulting mixture was homogenized and the resulting dispersion was added to hard gelatin capsules of different sizes such that some capsules contained a 25mg dose and others contained a 75mg dose of midostaurin. The resulting capsules are suitable for oral administration.

Composition B:

gelucire 44/14(86 parts) was heated to 60 ℃ to melt. To the molten material is added midostaurin powder (14 parts). The mixture was homogenized and the resulting dispersion was added to hard gelatin capsules of different sizes so that some capsules contained a 25mg dose and others contained a 75mg dose of midostaurin. The resulting capsules are suitable for oral administration.

Gelucire 44/14, commercially available from Gattefoss é, is a mixture of C8-C18 saturated fatty acid glycerides and polyethylene glycol having a molecular weight of about 1500, the weight composition specifications of the fatty acid components being 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.

The composition of a preferred example of the Gelucire formula is as follows:

Gelucire(44/14)：47g

midostaurin: 3.0g (in 60mL twist-off bottle)

Preferred examples of the softgel contain the following microemulsions:

corn oil glyceride 85.0mg

Polyethylene glycol 400128.25 mg

Cremophor RH 40 213.75mg

Midostaurin 25.0mg

DL alpha tocopherol 0.5mg

Anhydrous ethanol 33.9mg

486.4mg in total

However, it should be clearly understood that this is done for illustrative purposes only.

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

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

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

In another embodiment, the present invention relates to a composition comprising a packaging material and N- [ (9S, 10R, 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: an article of manufacture of 3 ', 2 ', 1 ' -lm ] pyrrolo [3, 4-j ] [1, 7] benzodiazepin-11-yl ] -N-methylbenzamide or a pharmaceutically acceptable salt thereof, wherein said packaging material comprises a label insert indicating: the compound of formula (VII) or the pharmaceutically acceptable salt thereof may be administered to a mammal suffering from allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mast cell disease in an amount of 50 to 500mg, preferably 100 to 300mg, preferably 125mg to 250mg, more preferably 220 to 230mg, most preferably 225mg, at a specific dose, to inhibit the development of the above-mentioned diseases and disorders.

The present invention preferably also relates to a preparation wherein a compound of formula VII is administered three times a day at a total daily dose of 220 to 230mg, preferably 225mg, preferably at a dose of 70 to 80mg, most preferably 75mg per administration, for use in the treatment of hypereosinophilic syndrome or hypereosinophilic syndrome with resistance to imatinib. A preferred embodiment relates to an article of manufacture comprising a softgel capsule containing 25mg of the compound of formula VII.

The invention also relates to a combination of a staurosporine derivative as described above and imatinib for the treatment of the above-mentioned diseases and disorders. Such combinations may be administered simultaneously (e.g. in the form of fixed, combined pharmaceutical compositions or formulations) or sequentially or chronologically staggered. It is presently preferred to administer a staurosporine derivative in a dosage form as described above and imatinib in the commercially available form (GLEEVEC in the united states)GLIVEC in Europe) And in the doses envisaged for these dosage forms.

The treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioneurotic edema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis or mastocytosis with the above combination may be a so-called first line therapy, i.e. the treatment of a newly diagnosed disease without any previous chemotherapy or the like, or it may also be a so-called second line therapy, i.e. the treatment of a disease after a first treatment with imatinib or a staurosporine derivative, depending on the severity or extent of the disease and the overall condition of the patient, etc.

The term "allergic rhinitis" as used herein means any allergic reaction of the nasal mucosa. Such allergies may occur, for example, perennially, such as vernal conjunctivitis, or seasonally, such as hay fever.

The term "allergic dermatitis" as used herein especially denotes atopic dermatitis, allergic contact dermatitis and eczematous dermatitis, also including for example seborrheic dermatitis, lichen planus, urticaria and acne. Atopic dermatitis as defined herein is a chronic inflammatory skin disorder found in individuals with a genetic predisposition having a lower skin threshold for pruritus. It is mainly characterized by extreme itching, which can cause scratching and rubbing, which in turn can lead to the typical lesions of eczema. Allergic contact dermatitis as defined herein is a form of dermatitis which is attributed to allergic sensitization to a variety of substances that produce an inflammatory response on the skin of certain persons who have had acquired allergy to allergens as they have previously been exposed to allergens.

The term "drug allergy or food allergy" as used herein relates to an allergy caused by a drug or ingested antigen, such as strawberry, milk or eggs.

The term "bronchopulmonary aspergillosis" relates to a lung infection caused by Aspergillus (Aspergillus).

The term "mast cell disease" as used herein relates to systemic mast cell diseases, such as mast cell tumors, and also to canine mast cell neoplasms. Mastocytosis is a myeloproliferative disorder with limited treatment options and generally a poor prognosis. The pathogenesis of mast cell disease has been attributed to constitutive activation of the receptor tyrosine kinase KIT. In most mast cell disease patients, abnormalities in KIT tyrosine kinase activity result from mutations within codon 816(D816V) of the protein that also produce in vitro and in vivo production of imatinib or imatinib mesylate (the latter being known as Gleevec in the United states)Or elsewhere as GlivecCommercially available).

Mast cells play an important role as the primary effector cells in the allergic disorders referred to herein. Antigen-specific IgE-mediated degranulation of mast cells can lead to the subsequent release of chemical mediators and various cytokines as well as the synthesis of leukotrienes. In addition, mast cells are involved in the pathogenesis of multiple sclerosis.

Mast cell neoplasms can occur in both humans and animals. In dogs, mast cell neoplasms are known as mast cell tumors, a disease that is very common and accounts for 7% -21% of canine tumors. A distinction must be made between human mastocytosis (usually transient or quiescent) and canine mast cell neoplasms (unpredictable in appearance and often invasive and metastatic). For example, human solitary mast cell tumors do not usually metastasize; in contrast, 50% of canine mast cell tumors appeared malignant as estimated by Hottendorf & Nielsen (1969) after investigation of 46 published reports of 938 canine tumors.

Cancer that occurs in pet populations is a spontaneous disease. Pet owners, in order to extend the quality of life of their animals, often have nationwide private recommendations for livestock hospitals and veterinary teaching hospitals to seek professional care and treatment by veterinary oncologists. Livestock cancer patients are treated in a manner similar to humans, including surgery, chemotherapy, radiation therapy, and biologic therapy. It has been estimated that there are 4.2 million dogs and about 2 million cats in the united states. Roughly estimated by cancer incidence, there are approximately 4 million dogs newly diagnosed with cancer each year, with the number of cats diagnosed being comparable to dogs.

Canine skin mast cell tumors are a common disease. Most mast cell tumors are benign and can be cured by simple resection; however, if relapsed or metastasized to the distant site, treatment options are limited. Treatment options for recurrent lesions may include external irradiation radiation therapy. For distant metastasis or disseminated disease, the use of lomustine is includedAnd vinblastine have been shown to be somewhat effective. Metastatic sites of mast cell tumors include skin, regional lymph nodes, spleen, liver and bone marrow.

Several mutations leading to constitutive activation of KIT have been detected in many mast cell lines, and this observation suggests that KIT receptors are involved in the pathogenesis of mast cell disease. For example, one point mutation in human c-KIT (which results in Val substitution in the phosphotransferase domain for Asp816 and self-activation of the receptor) occurs in the long-term human mast cell leukemia line (HMC-1) and in the corresponding codons in both rodent mast cell lines. Furthermore, this activating mutation has been identified in situ in several cases of human mastocytosis. Two other activating mutations have been found in the intracellular juxtamembrane domain of KIT, namely a Val560Gly substitution in the human HMC-1 mast cell line and a seven amino acid deletion in the rodent mast cell line called FMA3 (Thr573-His 579).

It can be shown by established test models and in particular those described herein that: staurosporine derivatives or a pharmaceutically acceptable salt of each thereof are effective in the prevention or preferably treatment of at least one of the diseases mentioned herein. The person skilled in the pertinent art is fully enabled to select relevant test models to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects. Pharmacological activity may be demonstrated, for example, in clinical studies or in experimental procedures as described essentially below.

Example 1

This example demonstrates the in vitro effect of staurosporine derivatives on SCF-dependent development of cultured human mast cell growth using the culture system described by Kinoshita T, Sawai N et al in Blood1999, 94, 496-508 from CD34⁺Cord blood cell production. More than 90% of the isolated cells were CD34 positive cells according to flow cytometric analysis.

Reagents and antibodies

Dissolving staurosporine derivative in DMSO to a concentration of 10^-2M, and storing at-80 ℃. All-trans retinoic acid (Sigma) was dissolved in ethanol to a concentration of 10^-2M, and stored in light-protected vials at-80 ℃. Purified MABs to tryptase (MAB1222) were purchased from chemicon international inc. For flow cytometric analysis, mAbs for CD34(8G12, FITC) and CD11b (Leu15, PE) were purchased from Becton Dickinson immunocytometrorysystems (Mountain View, CA), and mAbs for CD41(SZ22, FITC) were purchased from Immunotech s.a. (mosaic, france). Mabs to glycophorin a (GPA, JC159, FITC) are available from Dako (Glostrup, denmark). For Western blotting and immunoprecipitation, mAbs of c-kit (NU-c-kit) and phosphorylated tyrosine (4G10) were purchased from Nichirei and UpstateBiotechnology, Inc (Procester lake City, NY), respectively.

Suspension culture

Serum-free liquid cultureIn 24-well plates (# 3047; Becton Dickinson). 2 ten thousand CDs 34⁺Cells were cultured in each well containing 2mL of α -medium supplemented with 1% BSA, 300 μ g/mL of fully iron-saturated human transferrin (purity approximately 98%, Sigma), 16 μ g/mL of soybean lecithin (Sigma), 9.6 μ g/mL of cholesterol (Nakalai Chemicals Ltd., Japan) and 20ng/mL of SCF, 10ng/mL of GM-CSF, 2U/mL of EPO, 10ng/mL of TPO, with various concentrations of staurosporine derivatives used alone or in combination. To examine the effect of staurosporine derivatives on SCF-dependent development of mast cells, cells cultured for 10 weeks (at 20ng/mL from CD 34)⁺SCF culture of cord blood cells) as target cells. 5 to 10X 10⁴Cells cultured for 10 weeks were incubated for 2 weeks in 24-well plates containing 20ng/mL SCF (with or without varying concentrations of staurosporine derivatives). The plates were incubated at 37 ℃ under a 5% CO load₂、5％O₂And 90% N₂The mixture was incubated in a humid atmosphere. When the culture was continued for 4 weeks, half of the medium was replaced with fresh medium containing the components every 2 weeks. Viable cell numbers were detected by trypan blue exclusion assay using a hemocytometer.

Clonal cell culture

Mast cell colony analysis was performed in 35-mm Lux suspension dishes (# 171099; Nunc, IL). The culture included culturing cells (4,000 cells/mL) for 10 weeks with 10ng/mL SCF, α -medium, 0.9% methylcellulose (Shinetsu Chemical, Japan), 1% BSA, 300 μ g/mL fully iron-saturated human transferrin, 16 μ g/mL soybean lecithin, 9.6 μ g/mL cholesterol, and 100ng/mL SCF (with or without 10ng/mL SCF)^-6M staurosporine derivatives). The plates were incubated at 37 ℃ under a 5% CO fill₂、5％O₂And 90% N₂The mixture was incubated in a humid atmosphere. After 4 weeks, aggregates containing 30 or more cells were counted as mast cell colonies, while those containing 10 to 29 cells were counted as mast cell clumps. 30 individual colonies and clumps were removed and incubated with anti-tryptic egg using alkaline phosphatase anti-alkaline phosphatase (APAAP) techniqueStaining with either white enzyme mAb or murine IgG 1. Almost all of the constituent cells were positive for tryptase.

Cytochemical and immunological staining

Cultured cells were plated on slides using Cytospin II. The cytochemical reaction with Peroxidase (POX) was carried out according to a conventional method. The mAb anti-tryptase response was detected using the APAAP method (Dako APAAP kit System, Dako Corp., CA) as described by F.Ma, K.Koike et al, Br.J.Haematol.1998, 100, 427-35.

Immunoprecipitation and Western blotting

Immunoprecipitation and Western blotting were performed according to the method described by T.Kamijo, K.Koike et al, Leuk.Res.1997, 21, 1097-106.

Flow cytometric assay

For the analysis of surface markers on cultured cells, 1-2X 10 cells were assayed according to the method described by Kinoshita T, Sawai N et al in Blood1999, 94, 496-508⁵Individual cells were collected in plastic tubes and incubated with FITC-or PE-mAb diluted appropriately. The cells were washed twice and then analyzed for surface markers using a FACScan flow cytometer. The living cells are analyzed for their forward light scattering characteristics and side scattering characteristics. The proportion of positive cells was determined by comparison with cells stained with FITC-or PE-conjugated murine isotype-matched Ig.

Detection of apoptosis

Apoptosis assays were performed by flow cytometric assay using propidium iodide (PI, Sigma) following the procedure described by n.sawai, k.koike et al in Stem cells.1999, 17, 45-53. To reduce apoptotic, necrotic, or already dead cells, Percoll gradient centrifugation can be used. Cells cultured for ten weeks were layered on 27% Percoll (sigma) in alpha-medium and 54% Percoll in PBS. After centrifugation, from two differencesCells were collected at the interface of Percoll solution at concentration, washed with PBS, and washed with 1mL of Ortho PermeaFix^TMThe treatment was carried out at room temperature for 40 minutes. The cells were then incubated with RNase (Sigma) without DNase for 15 min at 37 ℃ and stained with PI for 15 min. Monitoring with flow cytometer 2X 10⁴DNA content of individual cells. Cells (2X 10) which were cultured for 10 weeks and contacted with SCF or SCF and a staurosporine derivative⁶) In 100. mu.L of hypotonic lysis buffer [10mM Tris (pH 7.5), 10mM EDTA, pH 8.0, 0.5% Triton X-100]Dissolve on ice for 10 minutes. After centrifugation at 14,000g for 10 min, the supernatant was transferred to a fresh tube and treated with 0.2mg/mL RNase A (Sigma) and 0.2mg/mL proteinase K (Sigma). The DNA was precipitated with 120. mu.L isopropanol and 20. mu.L 5M NaCl at-20 ℃ overnight. After centrifugation at 14,000g, the pellet was dried, dissolved in 20. mu.L Tris-EDTA and the sample was analyzed by gel electrophoresis in 2% agarose and ethidium bromide staining.

Analysis of Histamine, tryptase and cytokine levels

The concentration of histamine in the cell lysate (obtained by treating cultured cells with 0.5% Nonidet P-40) and in the supernatant can be determined by the histamine Radioimmunoassay (RIA) kit (Immunotech) according to the method described by Kinoshita T, Sawai N et al in Blood1999, 94, 496-508.

Statistical analysis

All experiments should be performed at least three times. To determine significant differences between two independent groups, unpaired t-tests can be used, or when data is not normally distributed, Mann-Whitney-U tests can be used.

Example 2:Method

reagent: novartis Pharma; basel, switzerland: PKC412 or midostaurin for these experiments. Before each experiment, a fresh 10mM inhibitor stock was prepared by dissolving the compound in 1ml DMSO (dimethyl sulfoxide).

Antibody: polyclonal rabbit anti-KIT antibody (c-KIT Ab-1) (c-KIT Ab-1; Oncogene, Cambridge, MA) was used at a 1: 500 dilution. An anti-phosphotyrosine antibody (PY20) (PY20 Transduction laboratories; Lockerdon, KY) diluted 1: 1000 was used. Peroxidase-conjugated goat anti-mouse antibody at a 1: 5000 dilution and goat anti-rabbit antibody (Pierce; Rockford, IL) at a 1: 10,000 dilution were used.

Cell line: BR and C2 canine mast cell tumor cell lines were obtained from George Caughey Bos (university of California, san Francisco, CA). Both cell lines were maintained with DMEM supplemented with 2% calf serum, 1mM L-glutamine, 12.5mM HEPES (pH 7.5), 0.25mg/ml histidine, 1% penicillin-streptomycin and 1% amphotericin B). BR and C2 cells were derived from canine mast Cell tumors and were initially established in long-term culture after the initial passage of immunodeficient mice (DeVinney R et al, Am J Respir Cell Mol Biol 1990; 3 (5): 413-. The BR cell line has a point mutation (T1752C) resulting in the substitution of leucine for proline at amino acid 575 (membrane proximal domain). The C2 cell line has an internal tandem repeat (ITD) of the KIT juxtamembrane domain. Translation of this ITD results in the duplication of amino acid residues at the 3' end of exon 11 (London CA et al, Exp Hematol 1999; 27 (4): 689-.

Proliferation test: cells were added to 96-well plates at a density of 40,000 cells/well using normal media and varying concentrations of SALT I). Proliferation was measured at 48-72 hours using an XTT-based assay (Roche Molecular Biochemicals; Indianapolis, IN) (HeinrichMC et al, Blood 2000; 96 (3): 925-.

Protein lysate: BR and C2 cells were washed 2 times with PBS and then left to stand in Optimem (Gibco-BRL) at 37 ℃ for about 18 hours. The cells were then incubated in the presence of different concentrations of PKC412 for 90 minutes. After incubation, the cells were pelleted and lysed with 100-. Western blot analysis was performed as described previously (Hoatlin ME et al, Blood 1998; 91 (4): 1418-.

Example 3:compound I inhibits constitutively activated KIT kinase associated with canine mast cell tumors

To test the efficacy of compound I in inhibiting kinase activity of mutant forms of canine KIT, we used two cell lines expressing two different constitutively activated KIT isoforms (BR and C2). KIT mutations in these cell lines are located in the juxtamembrane domain and correspond to mutations observed in human gastrointestinal stromal tumors (GIST) (Lux ML et al, Am J Pathol 2000; 156 (3): 791-. Lysates prepared from BR or C2 cells were probed with anti-P-Tyr antibodies and activation of KIT receptors was assessed by measuring autophosphorylation. As previously reported, autophosphorylation of KIT in these cells was observed in the absence of SLF (Ma Y et al, J Invest Dermatol 1999; 112 (2): 165-170; Ma Y et al, Journal of investive Dermatology 2000; 114 (2): 392-394). PKC412 inhibits autophosphorylation of KIT dose-dependently, complete inhibition being observed using doses of 10 and 1.0 μ M. Almost complete inhibition was observed with a dose of 0.1 μ M. A limited autophosphorylation of c-kit was observed with PKC412 at doses of 0.001-0.01. mu.M. Thus, PKC412 not only inhibits autophosphorylation of mutated c-kit receptors in these cells, but PKC412 is also a more potent inhibitor of such mutated receptors (IC) than the wild-type c-kit receptor₅₀100-200 nM). To determine whether PKC412 modulates the expression of KIT protein, membranes were stripped and re-probed with anti-c-KIT antibody. There was no change in c-kit protein expression in PKC412 treated cells. Thus, PKC412 reduces autophosphorylation of mutant canine KIT polypeptides by inhibiting the activity of KIT kinase rather than by downregulating expression of KIT proteinAnd (6) acting.

Example 4:compound I inhibits the proliferation of canine mast cell tumor cell lines

To determine the biological effects of inhibition of kinase activity of the mutant C-kit receptor, BR or C2 cells were cultured for 48-72 hours in the presence of different concentrations of PKC 412. When the inhibitor concentration is 0.1-10. mu.M, proliferation is reduced by 90-95% compared to cells treated with medium alone. Partial inhibition of proliferation was observed when PKC412 was dosed at 0.001-0.01. mu.M. Thus, PKC412 inhibits proliferation of BR and C2 cells in the same range of dose responses observed for inhibition of receptor autophosphorylation. Morphological observations of inhibitor treated cells showed changes consistent with apoptosis.

Example 5:example of prospective cases of Serial Pet dogs with measurable cutaneous mast cell tumors

The study patients were pet dogs with detectable and histologically confirmed mast cell tumors. Cases were limited to those with measurable lesions amenable to biopsy.

The qualification standard is as follows:

histologically confirmed measurable cutaneous mast cell tumors

Cases requiring serial biopsies with 2mm Keyes punch before and during treatment

-histological grading (II-medium or III-hypo-differentiation);

physical condition 0 or 1 (modified Karnofsky-Table 1)

-obtaining master consent

(a) Exclusion criteria were:

-concurrent cytotoxic chemotherapy

Prednisone and non-steroidal anti-inflammatory drugs may not be used within 30 days of the study, and if prednisone or non-steroidal anti-inflammatory drugs have been administered for more than 30 days, these drugs may continue to be administered

Abnormal serum bile acid test (liver function)

TABLE 1: physical condition (modified Karnofsky)

Pre-treatment evaluations for all cases included physical examination, complete blood count, buffy coat, serum biochemistry, urinalysis, serum bile acids (fasting and postprandial), regional lymph node size recordings, abdominal radiographs and abdominal ultrasound. The treatment regimen was 25mg/kg PO QD × 60 days of midostaurin.

All cases were treated for 60 days continuously unless disease progression was significant. For cases with partial or complete response, ongoing treatment may be considered for an additional 60 days. Cases successfully completed treatment met the conditions for re-entry into the study.

Table 2:treatment and clinical evaluation planning

Function of	Day 0	Day 7	Day 14	Day 28	q14 days
Function of	Day 0	Day 7	Day 14	Day 28	q14 days	Clinical staging	X			X	X
Physical examination	X	X	X	X	X	Clinical staging	X			X	X
Physical examination	X	X	X	X	X	Determination of tumor burden	X	X	X	X	X
25mg/kg QD for initial administration of midostaurin	X					Determination of tumor burden	X	X	X	X	X
25mg/kg QD for initial administration of midostaurin	X					Pharmacokinetics	X
Incisional biopsy	X			X		Pharmacokinetics	X
Incisional biopsy	X			X		Is staged again				X

¹Initial stages include physical examination, CBC, buffy coat, serum biochemistry, liver function tests (serum bile acids), urinalysis, abdominal X-ray pictures and abdominal ultrasound. Re-evaluation may include physical examination and tumor burden determination in separate or re-clinical stages.

²Tumor burden was determined on days 0, 7, 14, 28, and then every 14 days. Determining the response of a treatment (CR, PR, SD, PD, as defined below) against a treatable skin lesion and other lesions identified at staging

³Following the first midostaurin administration, blood was collected from the first 5 recorded cases at 0, 0.5, 1, 2, 5, 8, 12, 16 and 24 hoursAnd (4) pulping.

⁴Incisional biopsies from confirmed measurable lesions were collected from all cases on days 0 and 28. Biopsies were additionally collected at the time of Partial Response (PR) and after full objective response (CR).

Clinical endpoints were used to evaluate the efficacy of staurosporine derivatives against measurable cutaneous mast cell tumors. Biological endpoints can be obtained from a series of biopsies collected from skin tumors and blood samples obtained during treatment.

Clinical endpoints include response rates to measurable tumors, objective responses against measurable tumors, and time to measurable tumor progression. All adverse side effects were recorded.

An "objective tumor response" as defined below can be observed with staurosporine derivative treatment, indicating the efficacy of the treatment regimen.

In particular, a complete response and a partial response to treatment with staurosporine derivatives can be observed. In addition, it was observed that more treated animals exhibited stable disease, while less treated animals exhibited disease progression. Likewise, it was also observed that animals that received less treatment exhibited disease recurrence compared to untreated animals. In animals treated with staurosporine derivatives, development time, duration of remission and survival were increased.

"Complete Response (CR)" is defined as the disappearance of all clinical evidence of cancer and any symptoms associated with cancer.

"Partial Response (PR)" is defined as a 50% or greater reduction in the sum of measurements of representative lesions without any increase in the size of any lesion or the appearance of any new lesions.

"disease Stability (SD)" is defined as no response or a response lower than that defined by a partial response, or progression of the disease without any new lesions or exacerbations of clinical symptoms.

"disease Progression (PD)" is defined as any measurable lesion that clearly increases in size by at least 50% or presents as new lesion.

"recurrence (R)" is defined as the appearance of new lesions or reappearance of old lesions in dogs that have responded completely; for dogs that have only partially responded, relapse is defined as an increase of at least 50% in the sum of the measurements of representative lesions compared to the measurement obtained at the time of maximal response.

The "time to development (TTP)" is reported from day 0 of the protocol. TTP can be defined as the number of days from the start of treatment (day 0) to relapse (R).

"duration of remission" is defined as the number of days from objective response (PR or CR) to relapse.

"survival" is defined as the number of days from the start of treatment with the staurosporine derivative to death. The cause of death was noted, but may include disease progression, toxicity, and others.

Example 6

A 48 year old woman presents with fever, purpura, splenomegaly, diarrhea, and transfusion-dependent anemia and thrombocytopenia. The initial white blood cell count was 20,000/mm³(with myeloid immature and dysplastic) and 8% immature cells. Bone marrow biopsy showed 5% -10% immature cells, trilineage dysplasia and 30-50% mast cells. Peripheral blood examination showed heterozygous observations with the D816V KIT mutation and wild-type FLT-3. She was diagnosed with a systemic mastocytosis with associated mixed myelodysplastic/myeloproliferative syndrome. Two months after presentation, 30-40% of circulating mast cells appear in the disease progression. The patient is maintained by red blood cell and platelet transfusions, antihistamine blockade, and cromolyn sodium. She developed progressive liver function impairment, severe ascites and portal thrombosis. Treatment with PKC412 was initiated at a dose of 100mg twice daily orally (28 days for one cycle). At the start of the treatment, the serum histamine levels ranged from6910-7336ng/dL (normal < 100ng/dL), and serum tryptase > 200ug/L (normal < 10.9 ug/L).

At the end of 1 cycle: partial response(Valent et al, Leuk Res.2003; 27: 635-

the-Karnofsky physical condition is improved from 20% to 70%

-improved diarrhea and significantly reduced ascites; 1 portal vein thrombosis recanalization

Continuous infusion-dependent anemia and thrombocytopenia

-total/direct bilirubin is reduced from 4.8/2.8 to 2.1/1.1 mg/dL; LDH is reduced from 769 to 239IU/L

Serum histamine was reduced from 7000 to 1000 ng/dL; the serum tryptase keeps higher level more than 200ug/L

Peripheral blood: the number of mast cells is reduced from 40-50% to less than 10%; increased immaturity of myeloid development

-bone marrow: mast cell mass is free of changes caused by IPOX; after the immature cells are reduced to less than 5 percent of PKC412 and treated for 1 month, the Karnofsky physical condition of a patient is increased from 20 percent to 70 percent, the liver function and the ascites are obviously improved, and the portal vein is dredged again. Through 32 days of treatment, patients presented with normal white blood cell counts, < 5% circulating mast cells and nearly completely eliminated immature myeloid development. Bone marrow biopsy at this time indicated a reduction of immature cells to < 5% with persistent mast cells and dysplasia. Serum histamine levels were reduced to 1031 ng/dL; however, serum tryptase remained at a higher level.

At the end of 2 cycles: maintenance of partial response

Maintenance of improved clinical symptoms and Karnofsky physical performance

Transient independent platelet infusion for 2-3 weeks (platelets to 20,000 and 25,000/mm)³)

Total/direct bilirubin further improvement: from 2.1/1.1 to 1.3/0.7mg/dL

Serum histamine was kept in the range of 800-1200 ng/dL; the serum tryptase keeps higher level more than 200ug/L

-bone marrow: mast cell mass was not significantly changed; the immature cells are 10-15%

Peripheral blood: mast cell numbers remained < 10%; after 2 months of treatment with myeloid immature and immature cells increasing PKC412, the patient remained clinically stable and the need for platelet transfusion decreased.

At the end of 3 weeks: disease progression

-Karnofsky physical condition begins to decline; hepatosplenomegaly, ascites and bilirubin increase

PKC412 dose escalation to 75mg on day 91, orally, three times daily

PKC412 was discontinued on day 102 due to disease progression with worsening organ swelling

Bilirubin (14 mg/dL total), and increased peripheral blood immature cells (mast cell leukemia with associated clonal hematologic non-mast cell lineage disease may occur)

Serum histamine again starts to increase to 2525 ng/dL; the patient died on day 111

PKC412 is well tolerated without any significant adverse effects. Partial response to PKC412 in this advanced case of mast cell leukemia suggests that the compound is functional in systemic mast cell disease.

Claims

1. N- [ (9S, 10R, 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: use of 3 ', 2 ', 1 ' -lm ] pyrrolo [3, 4-j ] [1, 7] benzodiazepin-11-yl ] -N-methylbenzamide or a salt thereof for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of mast cell disease,

2. use according to claim 1, wherein said pharmaceutical composition is for the curative, palliative or prophylactic treatment of mast cell diseases resistant to imatinib.

3. Use of a compound of formula (VII) as defined in claim 1 in combination with imatinib, wherein each active ingredient is present independently of the other in free form or in the form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical composition for the treatment of mast cell diseases.